JP2016056134A - Amino pyrazolone derivative having condensed ring structure - 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, W, X, Y, 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 (13).
(1) General formula (I)

[Where:
X and Z are each independently a C _{1 to} C ₃ alkylene group which may have one or two substituents independently selected from the following group A, or independently from the following group A: a substituent selected indicates one or two has good C ₂ even though -C ₃ alkenylene group,
Y represents a single bond, an oxygen atom, NR ¹ , or CR ¹ R ² ,
R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group C, and independently selected from the following group C C ₁ -C ₆ cycloalkyl group optionally having 1 to 3 substituents, and C ₁ -C ₆ optionally having 1 to 3 substituents independently selected from the following group C ₆ alkylcarbonyl group, 1 to 3 have C ₁ optionally -C ₆ alkyloxycarbonyl group a substituent selected independently from the following group C, C ₁ -C ₆ alkylsulfonyl group or toluene, Represents a sulfonyl group,
R ² represents a hydrogen atom or NR ²¹ R ²² ,
R ²¹ and R ²² are each independently a hydrogen atom, a C _{1 to} C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group C, A C _{3 to} C ₆ cycloalkyl group optionally having 1 to 3 substituents independently selected from the above, and 1 to 3 substituents independently selected from the following group C good _C 1 -C ₆ alkylcarbonyl group, a 1 to 3 may have _C 1 -C ₆ alkyloxycarbonyl group a substituent selected independently from the following group _C, C 1 -C Represents a ₆ alkylsulfonyl group, or a toluenesulfonyl group, or
In CR ¹ R ² , R ¹ and R ² together have 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring 5 A 7 to 7 membered heterocyclic ring may be formed,
The 5- to 7-membered heterocyclic ring may have 1 to 3 substituents independently selected from the following group C;
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 which may have 1 to 5 substituents independently selected from the following group D, 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 D;
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 E: 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 E below. ]
Or a pharmacologically acceptable salt thereof.
Group A: halogen atom, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ alkyl group optionally having 1 to 3 substituents independently selected from the following group B: Group B: hydroxyl group, amino _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ alkylamino group, di _C 1 -C ₆ alkylamino group C group: a halogen atom, a hydroxyl group, a phenyl _group, C 1 -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group D group: halogen atom, C ₁ -C ₆ alkyl group optionally substituted by 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy group E group: halogen atom, hydroxyl group A C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group optionally substituted by 1 to 3 halogen atoms, a C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkoxy group, _{C 1} C ₆ alkoxy _C 1 -C ₆ alkoxy group
(2) In the formula (I),
X and Z are each _{independently,} C 1 -C ₃ alkyl groups represents 1 or 2 having _C 1 optionally -C ₃ alkylene group,
Y represents an oxygen atom, NR ^1a , or CR ^1a R ^2a ,
R ^1a represents a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group F;
R ^2a represents a hydrogen atom or NR ^21a R ^22a ,
R ^21a and R ^22a are each independently a hydrogen atom or a C ₁ -C ₆ alkyl group, the compound according to (1) or a pharmacologically acceptable salt thereof.
Group F: halogen atoms, hydroxyl group, di _C 1 -C ₆ alkylamino group (3) the formula (I),
W is W ¹ or W ² below

Or a pharmacologically acceptable salt thereof according to (1) or (2).
(4) 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 (3) or a pharmacologically acceptable salt thereof.
(5) 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 or a halogen atom;
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 (1) to (4) or a pharmacologically acceptable salt thereof.
(6) General formula (IV)

[Where:
R ⁸ represents the following formula (V) or (VI)

Indicate
(Wherein R ⁸¹ represents a halogen atom,
R ⁸² represents a hydrogen atom or a halogen atom,
R ⁸³ represents an ethoxy group, an isopropoxy group, or a methoxymethoxy group,
U represents a nitrogen atom or CH)
MQT represents the following formulas (VII) to (XI)

Any one of the rings is shown.
(In the formula, R ⁹¹ represents a methylamino group or a dimethylamino group,
R ⁹² represents a hydrogen atom or a methyl group,
R ⁹³ represents a hydrogen atom, a methyl group, an ethyl group, or an isopropyl group,
R ⁹⁴ represents a hydrogen atom or a methyl group)]
Or a pharmacologically acceptable salt thereof.
(7) Any one compound or its pharmacologically acceptable salt selected from the following group.
5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide,
(+)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2- b] pyrazol-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide,
(−)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2- b] pyrazol-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole- 3-yl] amino} -4-oxobutyl) -2-ethoxypyridine-3-carboxamide,
5-Bromo-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] Pyridin-3-yl] amino} -4-oxobutyl} -2-ethoxypyridine-3-carboxamide,
(−)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3-yl] amino} -4-oxobutyl} -2-isopropoxybenzamide,
(+)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3-yl] amino} -4-oxobutyl} -2-methylbenzofuran-7-carboxamide,
(−)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3-yl] amino} -4-oxobutyl} -2-methylbenzofuran-7-carboxamide,
5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl] Amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxy-4-fluorobenzamide,
5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl] Amino} -2,2-dimethyl-4-oxobutyl) -2- (methoxymethoxy) benzamide,
(+)-5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine- 3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide,
(-)-5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine- 3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(5-methyl-2-oxo-1-phenyl-6,7-dihydro-4H-pyrazolo [1,5-a] pyrazin-3-yl ) Amino] -4-oxobutyl} -2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl] -2-ethoxybenzamide,
5-chloro-2-ethoxy-N- {4-[(6-isopropyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] Diazepin-3-yl) amino] -2,2-dimethyl-4-oxobutyl} benzamide,
5-chloro-N- {2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl} -2-ethoxy-4-fluorobenzamide,
5-chloro-N- {2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl] -2-ethoxypyridine-3-carboxamide,
5-chloro-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [ 1,4] diazepin-3-yl) amino] butyl} -2-methylbenzofuran-7-carboxamide,
5-chloro-N- [2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl] -2- (methoxymethoxy) benzamide,
5-chloro-N- {4-[(4,6-dimethyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine- 3-yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxypyridine-3-carboxamide,
5-Bromo-N- {2,2-dimethyl-4-[(4-methyl-2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [ 1,4] diazepin-3-yl) amino] -4-oxobutyl} -2-ethoxypyridine-3-carboxamide,
5-chloro-N- {2,2-dimethyl-4-[(4-methyl-2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [ 1,4] diazepin-3-yl) amino] -4-oxobutyl} -2-methylbenzofuran-7-carboxamide (8) The compound according to any one of (1) to (7) or a pharmacological agent thereof A pharmaceutical composition comprising an acceptable salt as an active ingredient.
(9) An ATPase activity inhibitor of a TIP48 / TIP49 complex, comprising as an active ingredient the compound according to any one of (1) to (7) or a pharmacologically acceptable salt thereof.
(10) An antitumor agent comprising the compound according to any one of (1) to (7) or a pharmacologically acceptable salt thereof as an active ingredient.
(11) 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 The antitumor agent according to (10), which is a bone soft tissue tumor.
(12) 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 (7) or a pharmacologically acceptable salt thereof as an active ingredient .
(13) Treatment can be carried out by inhibiting the ATPase activity of a TIP48 / TIP49 complex comprising the compound according to any one of (1) to (7) 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 alkyloxycarbonyl 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, “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 “3- to 6-membered cycloalkyl ring” is a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.

  In the present invention, “aromatic heterocycle” means a ring of an aromatic cyclic compound containing a hetero atom as a ring constituent atom. For example, furan ring, thiophene ring, pyrrole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, imidazole ring, oxadiazol ring, thiadiazol ring, triazole ring, pyrazole ring , Pyridyl ring, pyrazine ring, pyrimidine ring, or pyridazine ring.

  In the present invention, “aliphatic heterocycle” means a ring of an aliphatic cyclic compound containing a hetero atom as a ring constituent atom. For example, an oxirane ring, an aziridine ring, a thyrane ring, an oxetane ring, an azetidine ring, a thietane ring, a tetrahydrofuran ring, a pyrrolidine ring, a tetrahydrothiophene ring, a tetrahydropyran ring, a piperazine ring, a tetrahydrothiopyran ring, a morpholine ring, or a piperidine ring. Can be mentioned.

In the present invention, the “C ₁ -C ₃ alkylene group” is a divalent substituent and means a linear or branched alkylene group having 1 to 3 carbon atoms. 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 “C ₂ -C ₃ alkynylene group” is a divalent substituent and means a linear or branched alkynylene group having 2 to 3 carbon atoms. For example, an ethenylene group, a propenylene group, etc. are mentioned.

  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 the mRNA expression level and protein expression level of TIP48 gene and TIP49 gene are increased gene transcription activity, translational acceleration, protein degradation inhibition, protein 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.

X-Y-Z is preferably any of the following R ^{X1 to} R ^X22 .

More preferably, it is any one of R ^{X1 to} R ^X12 , R ^X17 , or R ^X18 .

R ³ is preferably a hydrogen atom.
R ⁴ and R ⁵ are preferably both methyl groups.
R ⁶ is preferably a phenyl group.
R ⁷ is preferably any one of the following R ^{7A to} R ^7K .

More preferably, any of R ^7C , R ^7D , R ^7E , R ^7F , R ^7G , R ^7H , or R ^7J is used.
W is preferably either W ¹ or W ² below.

More preferably a ^{W 1.}

  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 For use in 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 i) Analysis using othernal 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)

The partial structure W in the general formula (I) can be expressed as the following W ^{1 to} W ³ .

  As a main synthesis procedure, a method of constructing W between the site (B) and the site (C) represented by the general formula (1) and binding the complex and 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.

  First, the synthesis of the aminopyrazolone derivative (9) constituting the site (A) will be described. Compound (9) can be synthesized by the method of Production Method 1 or Production Method 2 shown below, but is not particularly limited thereto.

[Production Method 1]

[Wherein, R ⁶ , X, Y and Z are as defined above. R ³³ represents a protecting group for carboxylic acid, and is preferably a lower alkyl group such as a methyl group or an ethyl group. E is either a chlorine atom, a bromine atom or an iodine atom. ]

Synthesis of Compound (5) Compound (5) can be obtained by activating the carboxylic acid of compound (3) which is commercially available or appropriately synthesized and reacting in the presence of malonic acid monoester and magnesium chloride. A commercial item (3) can be obtained from Tokyo Chemical Industry Co., Ltd. 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.
Compound (5) can also be obtained by reacting a commercially available compound (4) with 2 equivalents or more of a base and then reacting with the corresponding halide or the like. A commercial item (4) can be obtained from Tokyo Chemical Industry Co., Ltd. Examples of the base used include sodium hydride or n-butyllithium, lithium diisopropylamide and the like, or a combined use thereof. Examples of the solvent to be used include tetrahydrofuran, dioxane, hexane, toluene 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.

Synthesis of Compound (6) Compound (5) can be obtained by reacting compound (5) with an appropriate hydrazine derivative in the presence or absence of a base. Suitable hydrazine derivatives can be obtained from Tokyo Chemical Industry Co., Ltd. When using a base, potassium carbonate or tert-butoxypotassium can be used. Examples of the solvent used in the reaction include ethanol, acetonitrile, N, N-dimethylformamide, toluene, 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.

Synthesis of Compound (7) The compound (6) 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. When a protecting group that is unstable under acidic conditions is contained on XYZ, the protecting group that is stable under acidic conditions can be first replaced at this point, and then nitration can be performed by this method.

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 can be optically resolved by liquid chromatography under appropriate conditions at this point, or can be resolved in subsequent steps.

Synthesis of Compound (8) Compound (6) 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.

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 acetic acid or a mixed solvent of hydrochloric acid, ethanol, and water, 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, 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 in liquid chromatography under appropriate conditions at this time, or to perform resolution in the subsequent steps. Is also possible.

[Production Method 2]

[Wherein, X, Y, Z and R ⁶ are as defined above. R ³³ represents a protecting group for carboxylic acid, and in this case, a lower alkyl group such as methyl group or ethyl group is preferred. R ³⁴ means a hydroxyl-protecting group. Examples of the hydroxyl-protecting group include a benzyl group, a tert-butoxycarbonyl group, an acetyl group, and a tert-butyldimethylsilyl group.

Synthesis of Compound (12) Compound (12) can be obtained by appropriately selecting and using the reaction conditions described in the production method of Compound (5) from Compound (3) above for Compound (10) synthesized as appropriate. .
The compound (12) can also be obtained by reacting a commercially available compound (11) available from Tokyo Chemical Industry Co., Ltd. with 2 equivalents or more of a base and then reacting with the corresponding halide. it can. Examples of the base used include sodium hydride, n-butyllithium, lithium diisopropylamide and the like. Examples of the solvent to be used include tetrahydrofuran, dioxane, hexane, toluene 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.

Synthesis of Compound (13) Compound (13) can be obtained by reacting compound (12) with an appropriate hydrazine derivative in the presence or absence of a base. Suitable hydrazine derivatives can be obtained from Tokyo Chemical Industry Co., Ltd. When using a base, potassium carbonate or tert-butoxypotassium can be used. Examples of the solvent used in the reaction include ethanol, acetonitrile, N, N-dimethylformamide, toluene, 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.

Is a leaving step of the synthesis the protecting group ^{R 34} of the compound (14).
The reaction conditions for deprotection according to the type of R ³⁴ are different. When R ³⁴ is a benzyl group or the like, the compound (13) is obtained by deprotection by adding a reducing catalyst such as palladium carbon and reacting in a hydrogen atmosphere with the compound (13) dissolved or suspended in a solvent. Can do. 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. When R ³⁴ is a tert-butoxycarbonyl group or the like, it is desirable to treat 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 ³⁴ is a tert-butyldimethylsilyl group, it is desirable to treat with hydrochloric acid or the like or treat 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.

Synthesis of Compound (15) from Compound (14) It can be obtained by reacting compound (14) with Kakuda reagent. The Kakuda reagent used includes (cyanomethylene) tri n-butylphosphorane or (cyanomethylene) trimethylphosphorane. Examples of the solvent used in the reaction include tetrahydrofuran, dimethoxyethane, benzene, 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 150 ° C. or the boiling point of the solvent, preferably in the range from around room temperature to 120 ° C.
Compound (15) can also be obtained by treating with a base after modifying the hydroxyl group of compound (14) to form a leaving group. Examples of the modifying group used include a para-toluenesulfonyl group (tosyl group) and a trifluoromethanesulfonyl group. Examples of the base used include sodium hydride and potassium carbonate. Examples of the solvent used in the reaction include tetrahydrofuran, acetonitrile, toluene 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 around room temperature to 100 ° C.
The compound (15) can also be obtained by once substituting the halogen group of the compound (14) with a halogen group and then treating with the above-mentioned base.

Synthesis of Compound (15) from Compound (16) Compound (15) can also be obtained by reacting appropriately synthesized or commercially available compound (16) with an appropriate aryl halide in the presence of a copper catalyst, a ligand and a base. You can also. 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 (9) Compound (9) is prepared by subjecting compound (15) to suitable reaction conditions from the production method from compound (6) to compound (7) or compound (8) to compound (9). It can be obtained by appropriately selecting and using.
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 in liquid chromatography under appropriate conditions at this time, or to perform resolution in the subsequent steps. Is also possible.

  Next, the synthesis of the carboxylic acid derivative (17) will be described.

First, a method for producing a compound (17a) in which W is W ¹ in the general formula (17) will be described.

[Production Method 3]

[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 (19) It can be obtained by reacting compound (18) and nitromethane in the presence of a base. 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. 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 (20) Compound (19) 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 (20) can be obtained by reducing compound (19) in a state where compound (19) is dissolved or suspended in a solvent by adding a reducing catalyst such as palladium carbon and reacting under a hydrogen atmosphere under 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 (20) requires purification, for example, a method in which the amino group is protected with an arbitrary protecting group and purified by silica gel column chromatography, followed by deprotection can be mentioned.

Synthesis of Compound (22) It can be obtained by reacting compound (20) and compound (21) in the presence of a condensing agent. As the compound (21), for example, a compound purchased from Tokyo Chemical Industry Co., Ltd. or a compound synthesized from commercially available compounds 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 (22) can also be obtained by reacting compound (20) with a compound obtained by converting the carboxyl group of compound (21) to 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 (17a).
Although the deprotection reaction conditions vary 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 (22) 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 (22) 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.

Next, a method for producing a compound (17b) in which W is represented by W ² in the general formula (17) will be described.

[Production Method 4]

[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) Compound (25) can be prepared by reacting compound (24) and compound (24) in the presence of a condensing agent, or by converting the carboxyl group of compound (24) and compound (23) to acid chloride. It can be obtained by reacting the converted compound in the presence of a base. Compound (23) may be purchased from ENAMINE or the like or may be appropriately synthesized. Compound (24) 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 production method for the compound (22).

Is a leaving step of the synthesis the protecting group ^{R 35} of Compound (17b).
Compound (17b) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (17a) for compound (25).

Synthesis of Compound (17b) from Compound (26) Compound (17b) can be obtained by reacting a commercially available product such as Compound (26) or an appropriately synthesized acid anhydride with Compound (24) 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.

Next, a method for producing the compound (17c) in which W is W ³ in the general formula (17) will be described.

[Production Method 5]

[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 (28) It can be obtained by reacting Compound (20) with Isocyanate (27). Compound (27) can be purchased from Sigma-Aldrich, Inc., or can be synthesized from a commercially available compound as appropriate. Examples of the synthesized solvent used in the reaction include tetrahydrofuran, dioxane, methylene chloride, chloroform 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 around room temperature to 100 ° C.

Is a leaving step of the synthesis the protecting group ^{R 35} of Compound (17c).
Compound (17c) can be obtained by appropriately selecting and using the reaction conditions described in the above production method of compound (17a) for compound (28).

  Next, the synthesis of the compound represented by the general formula (I) using the compound (9) and the compound (17) will be described.

[Production Method 6]

[Wherein, W, X, Y, Z, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above. ]

Synthesis of Compound (I) It can be obtained by reacting Compound (9) and Compound (17) 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.
Compound (I) is condensed with Compound (9) and Site (B) under the above conditions, and then selected with appropriate conditions from Production Method 3 to Production Method 5 as appropriate. Can also be obtained.

  When a nitrogen atom or an oxygen atom protected by a protecting group is present in Y of the compound represented by the general formula (I) synthesized by the above production method, it can be deprotected. 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 a nitrogen atom or an oxygen atom deprotected by the above-described production method exists in Y of the compound represented by the general formula (I), it can be modified by alkylation 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 2c) 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-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] Pyrazol-3-yl) amino] butyl} -2-methoxybenzamide

(Step 1) 1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-2-one Org. Chem. 1.74 g (7.32 mmol) of ethyl 6-bromo-3-oxohexanoate synthesized by the method described in 2005, 70, 3819-3825 was dissolved in 20 mL of ethanol, and 0.82 mL (8.05 mmol) of phenylhydrazine was dissolved. The mixture was heated to reflux for 4.5 hours. The temperature was returned to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the resulting residue, and the mixture was extracted with ethyl acetate. 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 was subjected to silica gel column chromatography (Shoko Scientific Co., elution solvent; hexane / 10% methanol-ethyl acetate = 70/30 to 0/100). Purification gave 0.406 g (yield 27.7%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.46-7.41 (4H, m), 7.25-7.22 (1H, m), 5.40 (1H, s), 3.38 (2H, t, J = 6.9 Hz), 2.83 (2H , t, J = 7.2 Hz), 2.41-2.35 (2H, m).

(Step 2) 3-Amino-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-2-one 1- (6-Chloro-2-pyridyl of Step 53 of Example 53 ) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one Instead of 1-phenyl-5,6-dihydro-4H-pyrrolo synthesized in Step 1 1,2-b] pyrazol-2-one was used in the same manner as in Step 53 of Example 53 to obtain the title compound as a solid.
¹ H-NMR (CD ₃ OD) δ: 7.49-7.43 (4H, m), 7.28-7.25 (1H, m), 3.14 (2H, t, J = 6.6 Hz), 2.76 (2H, t, J = 7.2 Hz), 2.38-2.33 (2H, m).
Thereafter, the following Example 1 to Example 2 were synthesized in the same manner as in Step 11 of Example 23.

Example 3 5-Chloro-N- (2,2-dimethyl-4-oxo-4-{[2'-oxo-1'-phenylspiro (1,3-dioxolane-2,5'-4, 6-Dihydropyrrolo [1,2-b] pyrazol) -3′-yl] amino} butyl) -2-ethoxybenzamide

(Step 1) 2- [2- (Chloromethyl) -1,3-dioxolan-2-yl] acetic acid 2- [2- (Chloromethyl) -1,3-dioxolane synthesized by the method described in US2000 / 6018046A1 To a solution of 8.01 g (38.4 mmol) of ethyl-2-yl] in 77 mL of ethanol, 38.0 mL (76.0 mmol) of 2N aqueous sodium hydroxide solution was added and stirred at room temperature for 100 minutes. The reaction mixture is then cooled to 0 ° C. and the pH is adjusted to about 5 by adding 66.0 mL (66.0 mmol) of 1N aqueous hydrochloric acid, twice with methylene chloride, methylene chloride / methanol (20: 1). Extracted once. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 5.31 g (yield 76.6%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.10 (4H, s), 3.73 (2H, s), 2.93 (2H, s).

(Step 2) 5-{[2- (Chloromethyl) -1,3-dioxolan-2-yl] methyl} -2-phenyl-4H-pyrazol-3-one 5-Benzyloxy of Example 4, Step 4 Using 2- [2- (chloromethyl) -1,3-dioxolan-2-yl] acetic acid synthesized in Step 1 instead of -3- [tert-butoxycarbonyl (methyl) amino] pentanoic acid, The reaction was conducted in the same manner as in Step 23 of Example 23 to obtain the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.90-7.85 (2H, m), 7.43-7.37 (2H, m), 7.22-7.16 (1H, m), 4.15-4.02 (4H, m), 3.59 (2H, s), 3.56 (2H, s), 3.04 (2H, s).
MS (ESI) m / z: 295 [(M + H) ⁺ ].

(Step 3) 1′-Phenylspiro (1,3-dioxolane-2,5′-4,6-dihydropyrrolo [1,2-b] pyrazol) -2′-one 5-{[ To a solution of 2- (chloromethyl) -1,3-dioxolan-2-yl] methyl} -2-phenyl-4H-pyrazol-3-one 3.93 g (13.3 mmol) in 70 mL of N, N-dimethylformamide, 4.40 g (31.8 mmol) of potassium carbonate and 2.62 g (15.8 mmol) of potassium iodide were added, and the mixture was stirred at 80 ° C. for 11 hours. Furthermore, 2.21 g (16.0 mmol) of potassium carbonate and 1.32 g (7.95 mmol) of potassium iodide were added, and the mixture was stirred at 80 ° C. for 6 hours. After cooling to room temperature, 120 mL of water was added, extracted twice with methylene chloride / 2-propanol (3: 1), and 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 = 88 / 12-0 / 100) to give 1.66 g of the title compound (yield 48.2%). Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.48-7.40 (4H, m), 7.26-7.20 (1H, m), 5.45 (1H, s), 4.10-3.97 (4H, m), 3.48 (2H, s) , 3.12 (2H, s).
MS (ESI) m / z: 259 [(M + H) ⁺ ].

(Step 4) 3′-amino-1′-phenylspiro (1,3-dioxolane-2,5′-4,6-dihydropyrrolo [1,2-b] pyrazol) -2′-one 2,2,2-trifluoro-N-methyl-N- (2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-5-yl of step 8 ) Instead of acetamide, 1′-phenylspiro (1,3-dioxolane-2,5′-4,6-dihydropyrrolo [1,2-b] pyrazol) -2′-one synthesized in Step 3 was used. Thereafter, the reaction was carried out in the same manner as in Step 23 of Example 23 to obtain the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.59-7.54 (2H, m), 7.45-7.38 (2H, m), 7.23-7.17 (1H, m), 4.08-3.95 (4H, m), 3.21 (2H, s), 3.03 (2H, br s), 3.02 (2H, s).
MS (ESI) m / z: 274 [(M + H) ⁺ ].
Thereafter, the following Example 3 was synthesized in the same manner as in Step 11 of Example 23.

Example 4 5-Chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole-3 -Yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide

(Step 1) 5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole-3- Yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide 5-chloro-N- (2,2-dimethyl-4-oxo-4-{[2′-] synthesized in Example 3 Oxo-1′-phenylspiro (1,3-dioxolane-2,5′-4,6-dihydropyrrolo [1,2-b] pyrazol) -3′-yl] amino} butyl) -2-ethoxybenzamide 490 mg 16 mL of 1,4-dioxane and 16 mL of 5N aqueous hydrochloric acid solution were added to (0.862 mmol) and stirred at 100 ° C. for 2.5 hours. After cooling to room temperature, 30 mL of water was added, extracted twice with methylene chloride / 2-propanol (3: 1), and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 5-chloro-N- {4-[(2,5-dioxo-1-phenyl-4,6-dihydropyrrolo [1,2-b] pyrazol-3-yl) amino] -2. , 2-dimethyl-4-oxobutyl} -2-ethoxybenzamide was obtained in an amount of 401 mg. To a solution of 386 mg of this oily substance in 3.0 mL of methanol, 0.900 mL (5.00 mmol) of dimethylamine (33% ethanol solution) and 0.660 mL (634 mg, 2.23 mmol) of tetraisopropyl orthotitanate were added in this order. For 3.5 hours. Next, 354 mg (9.36 mmol) of sodium borohydride was added, and the mixture was stirred at room temperature for 12 hours. Furthermore, methanol 3.0mL and sodium borohydride 354mg (9.36mmol) were added, and it stirred at 50 degreeC for 20 minutes. Again, 3.0 mL of methanol was added and stirred at 50 ° C. for 1 hour. Further, after adding 6.0 mL of methanol, 710 mg (18.8 mmol) of sodium borohydride was added in portions and stirred at 50 ° C. for 1 hour. After cooling the reaction mixture to 0 ° C., 10 mL of water was added and stirred, and the mixture was warmed to room temperature and stirred for 50 minutes. After adding 10 mL of methanol and stirring for 20 minutes, the reaction mixture was filtered and washed with methanol. 10 mL of water was added to the aqueous layer obtained by evaporating the organic solvent from the filtrate under reduced pressure, followed by extraction once with methylene chloride and once with methylene chloride / 2-propanol (3: 1). They were combined and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was subjected to amino silica gel column chromatography (Biotage, hexane / ethyl acetate = 50 / 50-0 / 100 → ethyl acetate / methanol = 100/0 to 90/10), and then silica gel column chromatography. Purified by chromatography (Biotage, ethyl acetate / methanol = 100/0 to 90/10 → methylene chloride / methanol = 100/0 to 90/10), 20.6 mg of the title compound (yield 4.48%) Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.90 (1H, br s), 8.35 (1H, br t, J = 6.4 Hz), 8.26 (1H, d, J = 3.1 Hz), 7.51-7.40 (4H, m ), 7.37 (1H, dd, J = 8.5, 2.4 Hz), 7.26-7.21 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 4.20 (2H, q, J = 7.1 Hz), 3.69 -3.63 (1H, m), 3.57 (1H, dd, J = 14.0, 6.7 Hz), 3.48-3.34 (3H, m), 3.07-3.01 (1H, m), 2.91 (1H, dd, J = 17.1, 5.5 Hz), 2.30 (1H, d, J = 12.2 Hz), 2.30 (6H, s), 2.25 (1H, d, J = 13.4 Hz), 1.53 (3H, t, J = 6.7 Hz), 1.09 (3H , s), 1.08 (3H, s).
MS (ESI) m / z: 554 [(M + H) ⁺ ].

Example 5 5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2 -B] pyrazol-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) N- (3-amino-2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-5-yl) -2,2,2-trifluoro -N-methylacetamide (Intermediate 5a)
Using 2-benzyloxyacetaldehyde instead of 3-benzyloxypropanal in Step 2 of Example 23, the same reaction as in Step 23 of Example 23 was carried out, and the title compound (Intermediate 5a) was obtained as an oil. Obtained as material.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.41 (4H, m), 7.24-7.21 (1H, m), 5.67-5.61 (0.6H, m), 5.15-5.09 (0.4H, m), 3.34- 3.14 (6H, m), 2.78 (0.6H, dd, J = 17.3, 3.9 Hz), 2.70 (0.4H, dd, J = 17.3, 3.9 Hz).
MS (APCI) m / z: 341 [(M + H) ⁺ ].

(Step 2) (+)-/ (-)-N- (3-amino-2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-5-yl) -2,2,2-trifluoro-N-methylacetamide N- (3-amino-2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] synthesized in Step 1 Pyrazol-5-yl) -2,2,2-trifluoro-N-methylacetamide was optically resolved with a chiral fractionator (CHIRALPAK IC, hexane / 2-propanol = 30/70), and (+)- Form (intermediate 5b) and (−)-form (intermediate 5c) were obtained as oily substances, respectively.
Intermediate 5b
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.42 (3H, m), 7.27-7.22 (2H, m), 5.69-5.62 (0.6H, m), 5.16-5.10 (0.4H, m), 3.35 3.15 (6H, m), 2.78 (0.6H, dd, J = 17.3, 3.9 Hz), 2.70 (0.4H, dd, J = 17.3, 3.9 Hz).
[α] _D ²⁰ +79.0 (c = 0.52, MeOH).
Intermediate 5c
¹ H-NMR (CDCl ₃ ) δ: 7.50-7.42 (3H, m), 7.26-7.22 (2H, m), 5.70-5.63 (0.6H, m), 5.17-5.10 (0.4H, m), 3.33- 3.13 (6H, m), 2.78 (0.6H, dd, J = 17.3, 3.9 Hz), 2.70 (0.4H, dd, J = 17.3, 3.9 Hz).
[α] _D ²⁰ -60.3 (c = 0.40, MeOH).
Thereafter, the following Examples 5 to 11 were synthesized in the same manner as in Step 11 to Step 12 of Example 23.

Example 12 5-chloro-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-4,5,6.7-tetrahydropyranzolo [1,5- a] Pyridin-3-yl) amino] butyl} -2-ethoxybenzamide

(Step 1) 3-Amino-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one 1- (6-Chloro-2) of Step 3 of Example 53 -Pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one Instead of 1-phenyl-4,5 synthesized by the method described in US2007 / 49574 Using 6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one, the reaction was carried out in the same manner as in Step 53 of Example 53 to obtain the title compound as a solid.
¹ H-NMR (CD ₃ OD) δ: 7.49-7.46 (2H, m), 7.43-7.42 (2H, m), 7.33-7.30 (1H, m), 3.04 (2H, t, J = 5.7 Hz), 2.69 (2H, t, J = 6.6 Hz), 1.97-1.93 (2H, m), 1.77-1.72 (2H, m).
Thereafter, the following Examples 12 to 18 were synthesized in the same manner as in Step 11 of Example 23.

Example 19 5-Chloro-N- (2,2-dimethyl-4-oxo-4-{[2-oxo-1- (2-pyridyl) 4,5,6,7-tetrahydropyrazolo [1 , 5-a] pyridin-3-yl] amino} butyl) -2-methoxybenzamide

(Step 1) 4,5,6,7-tetrahydro-1H-pyrazolo [1,5-a] pyridin-2-one Ethyl 7-bromo-3-oxoheptanoate synthesized by the method described in US2007 / 49574 55 g (15.0 mmol) was dissolved in 70 mL of ethanol, and 0.840 g (16.5 mmol) of hydrazine monohydrate was added under ice cooling. The reaction was stirred at room temperature for 1 hour and then heated to reflux for 2.5 hours. The temperature was returned to room temperature, the solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the resulting residue, and the mixture was extracted with ethyl acetate. 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 was subjected to silica gel column chromatography (Shoko Scientific, elution solvent; hexane / 10% methanol-ethyl acetate = 70/30 to 20/80). Purification gave 1.14 g (yield 55.1%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 5.33 (1H, s), 3.91 (2H, t, J = 6.0 Hz), 2.69 (2H, t, J = 6.3 Hz), 2.01-1.96 (2H, m), 1.82-1.77 (2H, m).
MS (ESI) m / z: 139 [(M + H) ⁺ ].

(Step 2) 1- (2-Pyridyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one 4,5,6,7-tetrahydro- synthesized in Step 1 1H-pyrazolo [1,5-a] pyridin-2-one 0.200 g (1.45 mmol) was dissolved in 4.0 mL of 1,4-dioxane, and 0.0981 mL (0.160 g, 1. 01 mmol), 0.0261 mL (0.0265 g, 0.168 mmol) of trans-N, N-dimethylcyclohexane-1,2-diamine, 0.233 g (1.69 mmol) of potassium carbonate and 0.0161 g (0. 0840 mmol) was added. The reaction solution was stirred at 100 ° C. for 17 hours under a nitrogen atmosphere, and then returned to room temperature. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (Shoko Scientific Co., elution solvent; hexane / 10% methanol-ethyl acetate = 70 / 30-0). / 100) to give 0.0859 g (yield 39.5%) of the title compound as an oily substance.
MS (ESI) m / z: 216 [(M + H) ⁺ ].

(Step 3) 3-Amino-1- (2-pyridyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one 1- (6 of Step 53 of Example 53 1- (2-pyridyl)-synthesized in Step 2 instead of -chloro-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one Using 4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one, the reaction was carried out in the same manner as in Step 4 of Example 53 to obtain the title compound as an oily substance. .
¹ H-NMR (CD ₃ OD) δ: 8.46 (1H, d, J = 4.6 Hz), 7.93 (1H, t, J = 7.2 Hz), 7.85 (1H, d, J = 8.6 Hz), 7.29 (1H , t, J = 6.0 Hz), 3.24 (2H, t, J = 5.4 Hz), 2.70 (2H, t, J = 6.3 Hz), 2.01-1.97 (2H, m), 1.78-1.73 (2H, m) .
Thereafter, the following Examples 19 to 20 were synthesized in the same manner as in Step 11 of Example 23.

Example 21 5-chloro-N- (2,2-dimethyl-4-oxo-4-{[2-oxo-1- (3-pyridyl) 4,5,6,7-tetrahydropyrazolo [1 , 5-a] pyridin-3-yl] amino} butyl) -2-methoxybenzamide

(Step 1) 3-Amino-1- (3-pyridyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one 2-bromopyridine of Step 2 of Example 19 Then, 3-bromopyridine was used in place of, and the reaction was carried out in the same manner as in Step 19 of Example 19 to obtain the title compound as an oily substance.
¹ H-NMR (CD ₃ OD) δ: 8.71 (1H, d, J = 1.7 Hz), 8.45 (1H, d, J = 4.6 Hz), 7.92 (1H, d, J = 8.0 Hz), 7.55 (1H , dd, J = 8.0, 4.6 Hz), 3.06 (2H, t, J = 5.4 Hz), 2.71 (2H, t, J = 6.6 Hz), 2.01-1.97 (2H, m), 1.79-1.74 (2H, m).
Thereafter, the following Examples 21 to 22 were synthesized in the same manner as in Step 11 of Example 23.

(Example 23 and Example 24) 5-chloro-N- [2,2-dimethyl-4-({5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1 -Phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxobutyl] -2-ethoxybenzamide (Example 23) and 5-chloro-N -(2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl Amino} -4-oxobutyl} -2-ethoxybenzamide (Example 24)

(Step 1) 3-Benzyloxypropanal A solution of 35.0 mL (52.1 g, 414 mmol) of oxalyl chloride in 500 mL of methylene chloride was cooled to −78 ° C., and 38.5 mL (42.4 g, 542 mmol) of dimethyl sulfoxide was added for 18 minutes. Over 25 minutes. Then, 43.0 mL (45.1 g, 271 mmol) of 3-benzyloxypropan-1-ol was added over 20 minutes and stirred for 70 minutes. Furthermore, 151 mL (110 g, 1090 mmol) of triethylamine was added over 5 minutes and stirred for 10 minutes, and then the temperature was raised to room temperature and stirred for 1.5 hours. Subsequently, 400 mL (200 mmol) of 0.5N hydrochloric acid aqueous solution was added and extracted with methylene chloride. The organic layer was washed twice with 0.5N aqueous hydrochloric acid and once with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 97 / 3-60 / 40) to give 39.3 g of the title compound (yield 88.2). %) As an oil.
¹ H-NMR (CDCl ₃ ) δ: 9.81 (1H, t, J = 1.8 Hz), 7.43-7.27 (5H, m), 4.54 (2H, s), 3.82 (2H, t, J = 6.1 Hz), 2.71 (2H, td, J = 6.1, 1.8 Hz).

(Step 2) Ethyl (E) -5-benzyloxypent-2-enoate 95 mL of an aqueous solution of potassium carbonate 86.9 g (629 mmol) was cooled to 0 ° C., and 63.0 mL (71. 2 g, 318 mmol) was added and stirred at 0 ° C. for 15 minutes. Next, a solution of 39.3 g (239 mmol) of 3-benzyloxypropanal synthesized in Step 1 in 110 mL of diisopropyl ether was added over 6 minutes, stirred for 5 minutes, then warmed to room temperature and stirred for 66 hours. 200 mL of water was added to the reaction mixture, and the mixture was extracted twice with diethyl ether. The organic layers were combined and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 99/1 to 75/25) to obtain 50.7 g (yield 90.3%) of the title compound. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.42-7.26 (5H, m), 6.98 (1H, dt, J = 15.8, 7.0 Hz), 5.90 (1H, d, J = 15.8 Hz), 4.52 (2H, s ), 4.19 (2H, q, J = 7.1 Hz), 3.59 (2H, t, J = 6.4 Hz), 2.56-2.48 (2H, m), 1.29 (3H, t, J = 7.0 Hz).
MS (ESI) m / z: 235 [(M + H) ⁺ ].

(Step 3) 5-Benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoic acid 46.8 g (200 mmol) of ethyl (E) -5-benzyloxypent-2-enoate synthesized in Step 2 The methanol 100 mL solution was cooled to 0 ° C., 61.0 mL (600 mmol) of methylamine (40% methanol solution) was added over 3 minutes, stirred for 10 minutes, then warmed to room temperature and stirred for 3.5 hours. The reaction mixture was concentrated under reduced pressure to obtain 51.7 g of a mixture of ethyl 5-benzyloxy-3- (methylamino) pentanoate and methyl 5-benzyloxy-3- (methylamino) pentanoate as an oily substance. After this mixture was dissolved in 500 mL of methylene chloride, the solution was cooled to 0 ° C., and 42.0 mL (30.7 g, 303 mmol) of triethylamine and a solution of 49.6 g (227 mmol) of di-tertbutyl dicarbonate in 150 mL of methylene chloride were added in this order. After stirring for 5 minutes, the mixture was warmed to room temperature and stirred for 90 hours. 400 mL of saturated aqueous sodium bicarbonate was added, and the mixture was extracted with methylene chloride. The organic layer was washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give ethyl 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoate and methyl 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoate. 73.6 g of a mixture was obtained as an oily substance. To a solution of 73.6 g of this mixture in 280 mL of tetrahydrofuran / 280 mL of ethanol was added 280 mL (560 mmol) of 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure, 220 mL of water was added to the resulting residue, and the mixture was washed twice with diethyl ether. The aqueous layer was cooled to 0 ° C., and 300 mL (600 mmol) of 2N aqueous hydrochloric acid solution was added to adjust the pH to around 1 and extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 59.3 g (yield 88.0%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.26 (5H, m), 4.54-4.42 (3H, m), 3.51-3.40 (2H, br m), 2.83-2.61 (4H, br m), 2.57- 2.43 (1H, br m), 2.00-1.75 (2H, br m), 1.44 (9H, s).

(Step 4) 7-Benzyloxy-5- [tert-butoxycarbonyl (methyl) amino] -3-oxo-heptanoic acid ethyl 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino synthesized in Step 3 ] To a solution of 56.7 g (168 mmol) of pentanoic acid in 550 mL of tetrahydrofuran, 32.8 g (202 mmol) of 1,1′-carbonyldiimidazole was added and stirred at room temperature for 90 minutes. Next, 16.0 g (168 mmol) of magnesium chloride and 42.9 g (252 mmol) of monoethyl potassium malonate were added in this order, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved by adding ethyl acetate and 1N aqueous hydrochloric acid. After separation, the organic layer was washed 4 times with saturated aqueous sodium hydrogen carbonate, once with water, once with saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 66.5 g (yield 97.1%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.27 (5H, m), 4.58-4.43 (3H, m), 4.23-4.14 (2H, m), 3.58-3.39 (4H, m), 2.93-2.67 ( 5H, m), 2.01-1.72 (2H, m), 1.49-1.38 (9H, m), 1.31-1.23 (3H, m).
MS (ESI) m / z: 308 [(M-Boc + H) ⁺ ].

(Step 5) tert-Butyl N- {3-benzyloxy-1-[(3-oxo-2-phenyl-1H-pyrazol-5-yl) methyl] propyl} -N-methyl-carbamate synthesized in Step 4 7.46 mL (9.30 g, 86.0 mmol) of phenylhydrazine was added to a solution of 33.4 g (81.9 mmol) of ethyl 7-benzyloxy-5- [tert-butoxycarbonyl (methyl) amino] -3-oxoheptanoate in 270 mL of toluene. ) And stirred at 90 ° C. for 5.5 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 97 / 3-20 / 80) to give 35.3 g (yield) of the title compound. 95.3%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.88-7.78 (2H, m), 7.43-7.27 (7H, m), 7.21-7.14 (1H, m), 4.74-4.62 (0.7H, m), 4.57-4.44 (2.3H, m), 3.86-3.77 (0.6H, m), 3.60-3.28 (3.4H, m), 2.82-2.69 (4H, m), 2.58-2.50 (1H, m), 1.96-1.78 (2H , m), 1.42-1.31 (9H, m).
MS (ESI) m / z: 452 [(M + H) ⁺ ].

(Step 6) tert-Butyl N- {3-hydroxy-1-[(3-oxo-2-phenyl-1H-pyrazol-5-yl) methyl] propyl} -N-methylcarbamate tert- synthesized in Step 5 A solution of 35.3 g (78.1 mmol) of butyl N- {3-benzyloxy-1-[(3-oxo-2-phenyl-1H-pyrazol-5-yl) methyl] propyl} -N-methylcarbamate in 500 mL of ethanol To the mixture, 8.30 g (11.8 mmol) of a 20% palladium hydroxide-carbon catalyst was added, and the mixture was stirred at 60 ° C. for 4.5 hours in a hydrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and washed with ethanol. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 90/10 to 0/100 → ethyl acetate / methanol = 100/0 to 95/5). 23.9 g (yield 84.7%) of the compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.86 (2H, d, J = 7.9 Hz), 7.42-7.36 (2H, m), 7.21-7.16 (1H, m), 4.82-4.70 (0.85H, m), 4.61-4.51 (0.15H, m), 3.72-3.35 (3.3H, m), 3.12-3.06 (0.7H, m), 2.86-2.76 (1H, m), 2.71 (3H, s), 2.63-2.55 ( 1H, m), 1.87-1.61 (2H, m), 1.44 (1.5H, s), 1.42 (7.5H, s).
MS (ESI) m / z: 362 [(M + H) ⁺ ].

(Step 7) 2,2,2-trifluoro-N-methyl-N- (2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-5 Yl) acetamide tert-butyl N- {3-hydroxy-1-[(3-oxo-2-phenyl-1H-pyrazol-5-yl) methyl] propyl} -N-methyl-carbamate synthesized in Step 6 To a 650 mL toluene solution of 9 g (66.2 mmol), 53.0 mL (48.8 g, 202 mmol) (cyanomethylene) tributylphosphorane was added and stirred at 60 ° C. for 15 hours. After cooling to room temperature and concentrating the reaction mixture under reduced pressure, the residue obtained was dissolved in 170 mL of ethanol, 170 mL (680 mmol) of 4N hydrochloric acid-1,4-dioxane solution was added, and the mixture was stirred at 50 ° C. for 40 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and 150 mL of ethyl acetate / 300 mL of diethyl ether was added to the resulting solid and stirred at room temperature. The insoluble solid was then collected by filtration, washed with ethyl acetate / diethyl ether (1: 2), and then 5- (methylamino) -1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5 -A] 22.2 g of a solid mainly containing pyridin-2-one hydrochloride was obtained. To a suspension of 22.2 g of this solid in 500 mL of methylene chloride was added 42.0 mL (31.1 g, 241 mmol) of N, N-diisopropylethylamine, and the mixture was cooled to 0 ° C. and stirred. Thereafter, 22.0 mL (33.2 g, 158 mmol) of trifluoroacetic anhydride was added, and the mixture was stirred at 0 ° C. for 30 minutes. Saturated aqueous sodium bicarbonate (250 mL) was added to the reaction mixture, liquid separation was performed, and the aqueous layer was further extracted once with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was subjected to silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate → ethyl acetate / methanol = 50 / 50-0 / 100 → 100/0 to 90/10) to obtain 9.08 g (yield 40.6%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.37 (4H, m), 7.32-7.27 (1H, m), 5.58 (0.3H, s), 5.55 (0.7H, s), 4.70-4.60 (0.7H , m), 4.19-4.10 (0.3H, m), 3.85-3.76 (1H, m), 3.16-3.12 (2.2H, m), 3.06 (0.8H, s), 3.00-2.84 (3H, m), 2.49-2.32 (1H, m), 2.08-1.98 (1H, m).
MS (ESI) m / z: 340 [(M + H) ⁺ ].

(Step 8) 2,2,2-trifluoro-N-methyl-N- (3-nitro-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] Pyridin-5-yl) acetamide 2,2,2-trifluoro-N-methyl-N- (2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, synthesized in Step 7] 5-a] pyridin-5-yl) acetamide (9.08 g, 26.8 mmol) in trifluoroacetic acid (42 mL) was cooled to 0 ° C. and concentrated nitric acid 3.90 mL (6.14 g, 67.2 mmol) was added in one portion. The mixture was stirred for 5 minutes, warmed to room temperature, and stirred for 70 minutes. To the reaction mixture, 300 mL of ice water was added and stirred at room temperature for 1.5 hours. The precipitated solid was collected by filtration, washed with water, and dried to give 10.0 g (yield 97.6%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 7.64-7.52 (3H, m), 7.48-7.41 (2H, m), 4.85-4.75 (0.7H, br m), 4.54-4.43 (0.3H, br m ), 3.88-3.30 (4H, m), 3.11-3.05 (2.2H, m), 2.97 (0.8H, s), 2.47-2.30 (1H, m), 2.12-2.03 (1H, m).
MS (ESI) m / z: 385 [(M + H) ⁺ ].

(Step 9) N- (3-amino-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-5-yl) -2,2,2- Trifluoro-N-methylacetamide 2,2,2-trifluoro-N-methyl-N- (3-nitro-2-oxo-1-phenyl-4,5,6,7-tetrahydropyra synthesized in Step 8 To a suspension of 10.0 g (26.1 mmol) of zolo [1,5-a] pyridin-5-yl) acetamide in methanol (470 mL) was added 2.78 g (2.61 mmol) of 10% palladium carbon catalyst (AD type). In addition, the mixture was stirred at 50 ° C. for 6 hours and at 55 ° C. for 1.5 hours in a hydrogen atmosphere. After cooling to room temperature, the reaction mixture was filtered and washed with ethanol, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate → ethyl acetate / methanol = 50 / 50-0 / 100 → 100 / 0-90 / 10) to give the title compound (Intermediate 23a) 8.19 g (yield 88.6%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.52-7.40 (4H, m), 7.28-7.22 (1H, m), 4.64-4.53 (0.75H, m), 4.10-4.01 (0.25H, m), 3.76- 3.68 (1H, m), 3.14 (2.2H, s), 3.12-3.03 (2.8H, m), 2.97-2.89 (1H, m), 2.88-2.65 (1H, m), 2.54-2.26 (2H, m ), 2.00-1.90 (1H, m).
MS m / z: 355 [(M + H) ⁺ ].

(Step 10) (+)-and (-)-N- (3-amino-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-5- Yl) -2,2,2-trifluoro-N-methylacetamide Intermediate 23a synthesized in Step 9 was subjected to optical resolution with a chiral fractionator (CHIRALPAK IC, hexane / ethanol = 20/80), and (+ ) -Isomer (intermediate 23b) and (-)-isomer (intermediate 23c).
Intermediate 23b
[α] _D ²⁰ +201.2 (c 0.949, MeOH).
Intermediate 23c
[α] _D ²⁰ -209.3 (c 0.943, MeOH).

(Step 11) 5-chloro-N- [2,2-dimethyl-4-({5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1-phenyl-4, 5,6,7-Tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxo-butyl] -2-ethoxybenzamide (Example 23)
Intermediate 23a 361 mg (1.02 mmol) synthesized in Step 9, Intermediate 1a 355 mg (1.13 mmol) and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethylro N, N-diisopropylethylamine 0.325 mL (241 mg, 1.86 mmol) was added to 7.4 mL of N, N-dimethylformamide in 512 mg (1.87 mmol) of nitrohexafluorophosphate (HATU), and 14 at room temperature. Stir for hours. To the reaction mixture was added saturated sodium bicarbonate water (15 mL) / water (15 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed once with saturated aqueous sodium hydrogen carbonate / water (1: 1), once with water, once with saturated brine, 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, 539 mg (yield: 81.4%) of the title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.72 (0.3H, s), 9.63 (0.7H, s), 8.39 (1H, t, J = 7.0 Hz), 8.28-8.24 (1H, m), 7.49-7.36 (5H, m), 7.31-7.22 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.71-4.60 (0.7H, m), 4.20-4.12 (0.3H, m), 4.20 (2H , q, J = 6.9 Hz), 3.96-3.79 (2H, m), 3.32-3.20 (1H, m), 3.15-2.82 (6H, m), 2.51-2.33 (2H, m), 2.21-2.13 (1H , m), 2.06-1.96 (1H, m), 1.52 (3H, t, J = 7.0 Hz), 1.10 (3H, s), 1.05 (3H, s).
MS (ESI) m / z: 650 [(M + H) ⁺ ].

(Step 12) 5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3-yl] amino} -4-oxobutyl} -2-ethoxybenzamide (Example 24)
5-chloro-N- [2,2-dimethyl-4-({5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1-phenyl-4 synthesized in Step 11 , 5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxo-butyl] -2-ethoxybenzamide 514 mg (0.791 mmol) in tetrahydrofuran 7.9 mL / methanol 1.2N mL (2.42 mmol) of 2N aqueous sodium hydroxide solution was added to the 9.5 mL solution, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added 2N aqueous hydrochloric acid solution (1.10 mL (2.20 mmol)) and water (15 mL), extracted twice with chloroform / 2-propanol (3: 1), and the organic layers were combined and dried over anhydrous sodium sulfate. . The residue obtained by removing the solvent was purified by amino silica gel column chromatography (Biotage, ethyl acetate / methanol = 100/0 to 85/15). The obtained solid was filtered and washed with ethyl acetate / diethyl ether to obtain 377 mg (yield: 86.0%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.07 (1H, s), 8.36 (1H, br t, J = 6.7 Hz), 8.22 (1H, d, J = 2.4 Hz), 7.47-7.40 (4H, m) , 7.38 (1H, dd, J = 8.9, 2.7 Hz), 7.26-7.21 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.20 (2H, q, J = 6.9 Hz), 3.66 ( 1H, dd, J = 14.0, 7.3 Hz), 3.58-3.46 (2H, m), 3.15-3.07 (1H, m), 3.05-2.99 (1H, m), 2.96-2.87 (1H, m), 2.63 ( 1H, dd, J = 14.6, 7.9 Hz), 2.46 (3H, s), 2.33-2.22 (1H, m), 2.18-2.08 (1H, m), 1.98-1.87 (1H, m), 1.52 (3H, t, J = 7.0 Hz), 1.11 (3H, s), 1.10 (3H, s).
MS (ESI) m / z: 554 [(M + H) ⁺ ].
In the same manner, the following Examples 25 to 33 were synthesized.

Example 34 5-Chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1 , 5-a] pyridin-3-yl] amino} -4-oxobutyl) -2-ethyl-1,3-benzoxazole-7-carboxamide

(Step 1) Methyl 3-amino-5-chloro-2-hydroxybenzoate 2.00 g (10.7 mmol) of methyl 5-chloro-2-hydroxybenzoate was dissolved in 6 mL of concentrated sulfuric acid and stirred at 0 ° C. To this was added 1.6 mL of concentrated sulfuric acid / concentrated nitric acid (1/1), the temperature was raised to room temperature, and the mixture was stirred for 24 hours. The reaction solution was poured into ice water, the precipitate was collected by filtration, washed with water and dried to obtain a nitro compound. This nitro compound was suspended in 15 mL of ethyl acetate and 15 mL of methanol, 0.350 g of 5% platinum sulfide carbon catalyst was added, and catalytic hydrogen reduction was performed at room temperature for 4 hours. Filtration and concentration of the filtrate gave 1.61 g (yield 74.6%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 10.84 (1H, s), 7.20 (1H, d, J = 2.4 Hz), 6.83 (1H, d, J = 2.4 Hz), 3.94 (3H, s).

(Step 2) Methyl 5-chloro-2-ethyl-1,3-benzoxazole-7-carboxylate 1.61 g (7.99 mmol) of methyl 3-amino-5-chloro-2-hydroxybenzoate synthesized in Step 3 ) Was mixed with 4.82 mL (4.22 g, 24.0 mmol) of ethyl orthopropionate, a catalytic amount of concentrated sulfuric acid was added, and the mixture was stirred at 130 ° C. for 4 hours. After returning to room temperature, water and saturated aqueous sodium hydrogen carbonate were added, 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 = 95/5 to 65/35). To obtain 1.43 g (yield 74.7%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.92 (1H, d, J = 2.0 Hz), 7.83 (1H, d, J = 2.0 Hz), 4.01 (3H, s), 3.04 (2H, q, J = 7.6 Hz), 1.48 (3H, t, J = 7.6 Hz).

(Step 3) 5-Chloro-2-ethyl-1,3-benzoxazole-7-carboxylic acid Ethyl 5-chloro-2-ethyl-1,3-benzoxazole-7-carboxylate synthesized in Step 4 43 g (5.97 mmol) was dissolved in 15 mL of methanol, 6.0 mL of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and the residue was neutralized with water and 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 1.31 g (yield 97.3%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 13.75 (1H, s), 8.09 (1H, d, J = 2.2 Hz), 7.79 (1H, d, J = 2.2 Hz), 3.02 (2H, q, J = 7.4 Hz), 1.35 (3H, t, J = 7.4 Hz).

(Step 4) Ethyl 4- (tert-butoxycarbonylamino) -3,3-dimethylbutanoate 2.50 g of ethyl 4-amino-3,3-dimethylbutanoate synthesized in Step 2 of the synthesis of intermediate 1a (12.8 mmol) was dissolved in 60 ml of tetrahydrofuran, 2.65 ml (1.93 g, 19.1 mmol) of triethylamine and 4.17 g (19.1 mmol) of di-tert-butyl dicarbonate were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (Biotage, elution solvent: ethyl acetate / hexane = 2 / 98-15 / 85) to obtain 2.30 g (yield 69.3%) of the title compound as an oily substance.
¹ H-NMR (CDCl3) δ: 4.90 (1H, br s), 4.13 (2H, q, J = 7.2 Hz), 3.04 (2H, d, J = 6.8 Hz), 2.21 (2H, s), 1.44 ( 9H, s), 1.27 (3H, t, J = 7.2 Hz), 0.99 (6H, s).

(Step 5) 4- (tert-Butoxycarbonylamino) -3,3-dimethylbutanoic acid 2.30 g of ethyl 4- (tert-butoxycarbonylamino) -3,3-dimethylbutanoate synthesized in Step 4 (8. 87 mmol) was dissolved in 80 ml of ethanol, 26.6 ml (26.6 mmol) of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 28.0 ml (28.0 mmol) of 1N hydrochloric acid was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 2.20 g of the title compound was quantitatively obtained as an oily substance.
¹ H-NMR (CDCl3) δ: 4.97 (1H, br s), 3.07 (2H, d, J = 7.1 Hz), 2.25 (2H, s), 1.46 (9H, s), 1.02 (6H, s).
MS (EI) m / z: 231 (M ⁺ ).

(Step 6) tert-butyl N- [2,2-dimethyl-4-({5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1-phenyl-4,5 , 6,7-Tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxobutyl] carbamate 4- (tert-butoxycarbonylamino) -3,3-dimethylbutane synthesized in Step 2 0.763 g (3.30 mmol) of acid was dissolved in 20 mL of N, N-dimethylformamide and O- (7-azabenzotriazol-1-yl) -N, N, N ′, N ′,-tetramethylronium 1.37 g (3.60 mmol) of hexafluorophosphate (HATU) and 0.627 mL (0.465 g, 3.60 mmol) of N, N-diisopropylethylamine were added, and nitrogen was added. The mixture was stirred at room temperature for 15 minutes under an atmosphere. To this, 1.06 g (3.00 mmol) of the intermediate 23a synthesized in Step 9 of Example 23 was added, and the mixture was stirred at room temperature for 4 hours. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering the solution, the solvent was distilled off under reduced pressure. The resulting crude product was subjected to amino silica-silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate / methylene chloride → ethyl acetate / methanol / methylene chloride = 27/63/10 to 0/90/10 → 90/0/10 to 81/9/10) to obtain 1.52 g (yield 89.3%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.51 (1H, s), 7.47-7.42 (4H, m), 7.29-7.28 (1H, m), 5.01 (1H, br s), 4.67-4.62 (1H, m ), 3.82-3.80 (1H, m), 3.33-3.29 (1H, m), 3.14 (3H, s), 3.09-2.80 (3H, m), 2.42-2.37 (1H, m), 2.29-2.27 (1H , m), 2.21-2.18 (1H, m), 2.00-1.99 (1H, m), 1.46 (9H, s), 1.01 (3H, s), 0.98 (3H, s).

(Step 7) 5-chloro-N- [2,2-dimethyl-4-({5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1-phenyl-4, 5,6,7-Tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxobutyl] -2-ethyl-1,3-benzoxazole-7-carboxamide synthesized in Step 6 tert-Butyl N- [2,2-dimethyl-4-({5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1-phenyl-4,5,6,7 -1.52 g (2.68 mmol) of tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxobutyl] carbamate was dissolved in 20 mL of ethanol, and 2.68 mL of 4N hydrochloric acid-dioxane solution was added. 6 Stir at 0 ° C. for 4 hours. The reaction solution was distilled off under reduced pressure to obtain 1.35 g of amine hydrochloride as a solid. 1.35 g (2.68 mmol) of this amine hydrochloride and 0.635 g (2.81 mmol) of 5-chloro-2-ethyl-1,3-benzoxazole-7-carboxylic acid synthesized in Step 5 were added to N, N -Dissolved in 20 mL of dimethylformamide and 1.22 g of O- (7-azabenzotriazol-1-yl) -N, N, N ', N',-tetramethylronium hexafluorophosphate (HATU) (3. 22 mmol) and 1.87 mL (1.39 g, 10.7 mmol) of N, N-diisopropylethylamine were added, and the mixture was stirred at room temperature for 4 hours under a nitrogen atmosphere. Water and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The resulting crude product was purified by amino silica-silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate → ethyl acetate / methanol = 30 / 70-0 / 100 → 100 / 0-80 / 20). Thus, 1.53 g (yield 84.6%) of the title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.89 (0.3H, s), 8.77 (0.7H, s), 8.06 (1H, s), 7.78-7.78 (1H, m), 7.59-7.52 (1H, m) , 7.46-7.45 (4H, m), 7.30-7.28 (1H, m), 4.67-4.63 (0.7H, m), 4.17 (0.3H, m), 3.87-3.82 (2H, m), 3.42-3.38 ( 1H, m), 3.13-2.87 (8H, m), 2.42-2.40 (2H, m), 2.27 (1H, d, J = 12.7 Hz), 2.02-2.00 (1H, m), 1.46 (3H, t, J = 7.6 Hz), 1.15 (3H, s), 1.11 (3H, s).
Thereafter, the following Example 34 was synthesized in the same manner as in Step 12 of Example 23.

Example 35 5-Chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine -3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide

(Step 1) 5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine- 3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide 5-chloro-N- (2,2-dimethyl-4-{[5- (Methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide 377 mg To a solution of (0.680 mmol) in 14 mL of methylene chloride, 0.520 mL (6.98 mmol) of formaldehyde (37% aqueous solution) was added and stirred at room temperature for 20 minutes. Next, 515 mg (2.43 mmol) of sodium triacetoxyborohydride and 0.136 mL (143 mg, 2.38 mmol) of acetic acid were added in this order, and the mixture was stirred at room temperature for 4 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 subjected to silica gel column chromatography (Biotage, elution solvent; methylene chloride / methanol = 100/0 to 85/15), and then amino silica gel column chromatography (Biotage, elution solvent; acetic acid). Purification was performed with ethyl / methanol = 100/0 to 85/15). The obtained solid was suspended in ethyl acetate / diethyl ether, filtered and washed to obtain 339 mg (yield 87.8%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.28 (1H, s), 8.39 (1H, br t, J = 6.4 Hz), 8.23 (1H, d, J = 3.1 Hz), 7.48-7.36 (5H, m) , 7.27-7.21 (1H, m), 6.91 (1H, d, J = 9.2 Hz), 4.20 (2H, q, J = 6.9 Hz), 3.80-3.70 (2H, m), 3.47-3.39 (1H, m ), 3.09-2.99 (1H, m), 2.91-2.82 (1H, m), 2.68-2.59 (2H, m), 2.35 (6H, s), 2.33 (1H, d, J = 15.3 Hz), 2.23 ( 1H, d, J = 12.8 Hz), 2.14-1.98 (2H, m), 1.52 (3H, t, J = 6.7 Hz), 1.12 (3H, s), 1.08 (3H, s).
MS (ESI) m / z: 568 [(M + H) ⁺ ].
Thereafter, the following Examples 36 to 42 were synthesized in the same manner.

Example 43 and Example 44 5-Chloro-N- (2,2-dimethyl-4-{[(4,5-cis) -4-methyl-5- (methylamino) -2-oxo-1 -Phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl] amino} -4-oxobutyl) -2-methylbenzofuran-7-carboxamide and 5-chloro-N -{2,2-dimethyl-4-[(4-methyl-2-oxo-1-phenyl-6,7-dihydropyrazolo [1,5-a] pyridin-3-yl) amino] -4-oxobutyl } -2-Methylbenzofuran-7-carboxamide

(Step 1) Ethyl 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] -2-methylpentanoate 5-Benzyloxy-3- [tert-butoxycarbonyl synthesized in Step 3 of Example 23 A solution of ethyl (methyl) amino] pentanoate (26.9 g, 73.6 mmol) in 300 mL of tetrahydrofuran was cooled to −78 ° C., and lithium diisopropylamide (diisopropylamine 12.5 mL (9.02 g, 89.2 mmol) in 150 mL of tetrahydrofuran). Was cooled to 0 ° C., 34.0 mL (90.1 mmol) of n-butyllithium (2.65 M hexane solution was added and stirred for 30 minutes) was added over 15 minutes, and the mixture was stirred for 60 minutes. . Next, 8.50 mL (19.9 g, 140 mmol) of iodomethane was added over 5 minutes, and the mixture was stirred at −78 ° C. for 80 minutes. Further, 4.30 mL (9.79 g, 69.0 mmol) of iodomethane was added and stirred at −78 ° C. for 40 minutes. 300 mL of saturated aqueous ammonium chloride solution was added to the reaction mixture and the temperature was raised to room temperature. The resulting reaction mixture was extracted twice with methylene chloride, and the organic layers were combined 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 = 98/2 to 50/50) to give 14.3 g of the title compound (diastereomer ratio 80:20). (Yield 55.5%) was obtained as an oily substance.
¹ H-NMR (DMSO-D ₆ , 80 ^o C) δ: 7.35-7.23 (5H, m), 4.43 (1.6H, s), 4.41 (0.4H, s), 4.12-3.93 (3H, m), 3.43-3.31 (2H, m), 2.80-2.54 (4H, m), 1.85-1.75 (2H, m), 1.39-1.33 (9H, m), 1.21-1.13 (3H, m), 1.06 (2.4H, d, J = 6.7 Hz), 0.99 (0.6H, d, J = 6.7 Hz).
MS (ESI) m / z: 380 [(M + H) ⁺ ].

(Step 2) 5-Benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] -2-methylpentanoic acid 5-Benzyloxy-3- [tert-butoxycarbonyl (methyl) amino]-synthesized in Step 1 To a solution of ethyl 2-methylpentanoate (14.3 g, 37.6 mmol) in ethanol (60 mL) / tetrahydrofuran (60 mL), 2N aqueous sodium hydroxide solution (56.0 mL, 112 mmol) was added, and the mixture was stirred at room temperature for 22 hours and at 50 ° C for 7 hours. Stir. Further, 37.0 mL (74.0 mmol) of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at 50 ° C. for 5 hours. After adding 80 mL of water to the reaction mixture and cooling to 0 ° C., the pH was adjusted to 1 to 2 with 5N aqueous hydrochloric acid solution, and extracted twice with methylene chloride / 2-propanol (3: 1). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 13.1 g (yield 99.0%) of the title compound (diastereomer ratio 70:30) as an oily substance.
¹ H-NMR (DMSO-D ₆ , 80 ^o C) δ: 11.83 (1H, br s), 7.37-7.22 (5H, m), 4.43 (1.4H, s), 4.41 (0.6H, s), 4.19 -3.92 (1H, m), 3.47-3.30 (2H, m), 2.70-2.59 (4H, m), 1.85-1.64 (2H, m), 1.42-1.33 (9H, m), 1.05 (2.1H, d , J = 6.7 Hz), 0.98 (0.9H, d, J = 7.3 Hz).
MS (ESI) m / z: 252 [(M-Boc + H) ⁺ ].

(Step 3) N- (3-amino-4-methyl-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-5-yl) -2, 2,2-trifluoro-N-methylacetamide 5-Benzyloxy- synthesized in Step 2 instead of 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoic acid in Step 4 of Example 23 Using 3- [tert-butoxycarbonyl (methyl) amino] -2-methylpentanoic acid, the same reaction as in Step 23 of Example 23 was not performed, and the title compound was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 80 ^o C) δ: 7.51-7.41 (4H, m), 7.28-7.20 (1H, m), 4.33-4.15 (1H, br m), 3.85-3.42 (3H, br m), 3.22-2.92 (5H, m), 2.42-2.23 (1H, br m), 1.95-1.85 (1H, m), 1.33 (2.4H, d, J = 6.7 Hz), 1.21 (0.6H, d, J = 6.7 Hz).
MS (ESI) m / z: 369 [(M + H) ⁺ ].

(Step 4) cis- and trans-tert-butyl N- [2,2-dimethyl-4-({4-methyl-5- [methyl (2,2,2-trifluoroacetyl) amino] -2-oxo -1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxobutyl] carbamate N- (3-amino-4 synthesized in Step 3 -Methyl-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-5-yl) -2,2,2-trifluoro-N-methylacetamide 3 .38 g (9.18 mmol), 2.58 g (11.2 mmol) of 4- (tert-butoxycarbonylamino) -3,3-dimethylbutanoic acid synthesized in Step 2 of Example 34 and O- (7-azabenzo) To a solution of 4.61 g (12.1 mmol) of triazol-1-yl) -N, N, N ′, N′-tetramethylronium hexafluorophosphate (HATU) in 60 mL of N, N-dimethylformamide, -Diisopropylethylamine 2.95mL (2.18g, 16.9mmol) was added, and it stirred at room temperature for 16 hours. To the reaction mixture was added 30 mL of saturated aqueous sodium bicarbonate / 60 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 with 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). 1.16 g (yield 21.6%) of the title compound (low polarity, cis isomer, intermediate 43a) and 3.91 g (yield 73.2%) of the title compound (high polarity, trans isomer, intermediate 43b) ) Were obtained as solids.
Intermediate 43a
¹ H-NMR (DMSO-D ₆ , 80 ^o C) δ: 8.77 (1H, br s), 7.54-7.39 (4H, m), 7.33-7.26 (1H, m), 6.42 (1H, br s), 4.39-4.25 (1H, br m), 3.76-3.68 (1H, m), 3.52-3.41 (1H, br m), 3.13 (3H, s), 2.97-2.81 (3H, m), 2.79-2.70 (1H , m), 2.15 (2H, s), 2.08-2.00 (1H, m), 1.39 (9H, s), 1.29 (3H, d, J = 6.7 Hz), 0.93 (6H, s).
MS (ESI) m / z: 582 [(M + H) ⁺ ].
Intermediate 43b
¹ H-NMR (DMSO-D ₆ , 80 ^o C) δ: 8.78 (1H, br s), 7.54-7.37 (4H, m), 7.34-7.27 (1H, m), 6.43 (1H, s), 4.42 -4.32 (0.8H, br m), 3.86-3.76 (0.2H, br m), 3.61-3.48 (1H, br m), 3.33-3.23 (1H, m), 3.22-3.13 (1H, br m), 3.11-3.05 (3H, br m), 2.97-2.91 (2H, m), 2.41-2.27 (1H, br m), 2.14 (2H, s), 2.06-1.98 (1H, m), 1.38 (9H, s ), 1.23 (3H, d, J = 6.7 Hz), 0.95 (6H, s).
MS (ESI) m / z: 582 [(M + H) ⁺ ].

(Step 5) 4-amino-3,3-dimethyl-N- {4-methyl-5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1-phenyl-4, 5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl} butanamide hydrochloride Into a solution of 1.43 g (1.99 mmol) of intermediate 43a in 4.5 mL of 1,4-dioxane, 4N hydrochloric acid-1 , 4-Dioxane solution 4.50mL (18.0mmol) was added, and it stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure to give 1.03 g of the title compound quantitatively as a solid.
¹ H-NMR (DMSO-D ₆ , 80 ^o C) δ: 9.12 (1H, br s), 7.89 (3H, br s), 7.53-7.45 (2H, m), 7.45-7.38 (2H, m), 7.34-7.27 (1H, m), 4.40-4.28 (1H, br m), 3.76-3.68 (1H, m), 3.51-3.41 (2H, m), 3.13 (3H, br s), 2.95-2.81 (3H , m), 2.40 (2H, s), 2.10-2.02 (1H, m), 1.29 (3H, d, J = 7.3 Hz), 1.07 (6H, s).
MS (ESI) m / z: 482 [(M-HCl + H) ⁺ ].

(Step 6) 5-chloro-N- [2,2-dimethyl-4-({4-methyl-5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1- Phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxobutyl] -2-methylbenzofuran-7-carboxamide In step 5 of intermediate 3a To a suspension of the synthesized 5-chloro-2-methylbenzofuran-7-carboxylic acid 350 mg (1.66 mmol) in methylene chloride 10 mL, oxalyl chloride 0.460 mL (684 mg, 5.39 mmol), N, N-dimethylformamide 0. 0200 mL (19.0 mg, 0.260 mmol) was added in this order, and the mixture was stirred at room temperature for 1 hour. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in 10 mL of methylene chloride and cooled to 0 ° C. Then, 4-amino-3,3-dimethyl-N- {4-methyl-5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1-phenyl synthesized in Step 1 -4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl} butanamide hydrochloride 487 mg (0.941 mmol) and triethylamine 0.400 mL (291 mg, 2.88 mmol) were added in this order. The mixture was stirred for 5 minutes, warmed to room temperature, and stirred for 18 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 silica gel column chromatography (Biotage, hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 90/10). 465 mg (yield 73.3%) of the compound was obtained as a solid.
¹ H-NMR (DMSO-D ₆ , 80 ^o C) δ: 8.88 (1H, br s), 8.17 (1H, t, J = 5.8 Hz), 7.70 (1H, d, J = 1.8 Hz), 7.56 ( 1H, d, J = 2.4 Hz), 7.51-7.39 (4H, m), 7.32-7.26 (1H, m), 6.63 (1H, s), 4.38-4.26 (1H, br m), 3.75-3.68 (1H , m), 3.52-3.44 (1H, br m), 3.40-3.35 (2H, m), 3.12 (3H, br s), 2.90-2.82 (1H, m), 2.79-2.65 (1H, m), 2.45 (3H, s), 2.31 (2H, s), 2.08-2.01 (1H, m), 1.29 (3H, d, J = 6.7 Hz), 1.08 (6H, s).
MS (ESI) m / z: 674 [(M + H) ⁺ ].

(Step 7) 5-chloro-N- (2,2-dimethyl-4-{[(4,5-cis) -4-methyl-5- (methylamino) -2-oxo-1-phenyl-4, 5,6,7-Tetrahydropyrazolo [1,5-a] pyridin-3-yl] amino} -4-oxobutyl) -2-methylbenzofuran-7-carboxamide (Example 43) and 5-chloro-N -{2,2-dimethyl-4-[(4-methyl-2-oxo-1-phenyl-6,7-dihydropyrazolo [1,5-a] pyridin-3-yl) amino] -4-oxobutyl } -2-Methylbenzofuran-7-carboxamide (Example 44)
5-Chloro-N- [2,2-dimethyl-4-({4-methyl-5- [methyl- (2,2,2-trifluoroacetyl) amino] -2-oxo-1 synthesized in Step 6 -Phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl} amino) -4-oxobutyl] -2-methylbenzofuran-7-carboxamide 462 mg (0.686 mmol) To a solution of 8.9 mL of methanol / 7.8 mL of tetrahydrofuran was added 1.71 mL (3.42 mmol) of 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 16 hours and at 50 ° C. for 3 hours. To the reaction mixture was added 1.20 mL (2.40 mmol) of 2N aqueous hydrochloric acid, 20 mL of saturated brine and 10 mL of water, and the mixture was extracted twice with methylene chloride / 2-propanol (3: 1). The organic layers were combined and dried. Dried with 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), 131 mg (yield 34.8%) of the title compound (Example 43) was obtained as a solid. The mixture of Example 43 and Example 44 obtained during column purification was subjected to reverse phase HPLC (Gilson, water (0.10% formic acid) / acetonitrile (0.10% formic acid)), and then amino silica gel column chromatography. (Biotage, ethyl acetate / methanol = 100/0 to 85/15). The obtained solid was filtered and washed with ethyl acetate / diethyl ether to obtain 132 mg (yield 33.3%) of the title compound (Example 44) as a solid.
Example 43
¹ H-NMR (CDCl ₃ ) δ: 8.92 (1H, br s), 7.95 (1H, d, J = 2.4 Hz), 7.89 (1H, br t, J = 6.4 Hz), 7.57 (1H, d, J = 1.8 Hz), 7.54-7.48 (2H, m), 7.47-7.40 (2H, m), 7.27-7.21 (1H, m), 6.44 (1H, s), 5.97-5.91 (1H, br m), 3.78 -3.66 (2H, br m), 3.37 (2H, t, J = 6.7 Hz), 2.63-2.54 (2H, m), 2.51 (3H, s), 2.31 (2H, s), 2.16 (3H, s) , 1.20 (6H, s).
MS (ESI) m / z: 547 [(M + H) ⁺ ].
Example 44
¹ H-NMR (CDCl ₃ ) δ: 8.67 (1H, s), 7.98 (1H, d, J = 2.4 Hz), 7.90 (1H, br t, J = 6.4 Hz), 7.57 (1H, d, J = 1.8 Hz), 7.48-7.40 (4H, m), 7.26-7.21 (1H, m), 6.44 (1H, s), 3.78-3.70 (2H, m), 3.61 (1H, dd, J = 14.0, 6.7 Hz ), 3.51-3.42 (1H, m), 2.93-2.86 (1H, m), 2.83-2.75 (1H, m), 2.51 (3H, s), 2.44 (3H, s), 2.35 (1H, d, J = 12.8 Hz), 2.31 (1H, d, J = 12.8 Hz), 2.13-2.00 (1H, m), 1.94-1.86 (1H, m), 1.32 (3H, d, J = 7.3 Hz), 1.19 (3H , s), 1.16 (3H, s).
MS (ESI) m / z: 578 [(M + H) ⁺ ].
The following Example 45 to Example 49 were synthesized in the same manner as in Step 1 of this example and Example 35.

Example 50 5-chloro-N- [4-({4-[(dimethylamino) methyl] -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5- a] pyridin-3-yl} amino) -2,2-dimethyl-4-oxobutyl] -2-ethoxybenzamide

(Step 1) 3-Iodopropoxymethylbenzene To a solution of 40.3 g (243 mmol) of 3-benzyloxy-1-propanol in 270 mL of methylene chloride was added 1.37 g (11.2 mmol) of 4-dimethylaminopyridine and 40.0 mL of triethylamine (29 2 g, 289 mmol) and 51.1 g (268 mmol) of p-toluenesulfonyl chloride were added and stirred at room temperature for 4 hours. To the reaction mixture, 170 mL of a saturated aqueous ammonium chloride solution and 170 mL of water were added, extracted twice with methylene chloride, and the organic layers were combined and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was dissolved in 480 mL of acetone, 73.1 g (487 mmol) of sodium iodide was added, and the mixture was stirred at 75 ° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with acetone. Methylene chloride was added to the residue obtained by concentrating the filtrate under reduced pressure, washed twice with water, 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 = 99/1 to 70/30) to obtain 59.3 g of the title compound (yield 88.5%). Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 4.52 (2H, s), 3.55 (2H, t, J = 5.8 Hz), 3.31 (2H, t, J = 6.7 Hz), 2.14-2.06 (2H, m).

(Step 2) Ethyl 5-benzyloxy-2-diethoxyphosphorylpentanoate To a suspension of sodium hydride (55%) 28.2 g (645 mmol) in dimethyl sulfoxide 350 mL, 2-diethoxyphosphoryl ethyl acetate 107 mL (121 g, 540 mmol) was added dropwise over 30 minutes, and the mixture was stirred at room temperature for 60 minutes. Subsequently, a solution of 59.3 g (215 mmol) of 3-iodopropoxymethylbenzene synthesized in Step 1 in 150 mL of dimethyl sulfoxide was added dropwise over 10 minutes, followed by stirring for 20 hours. To the reaction mixture, 400 mL (40.0 mmol) of 0.1N hydrochloric acid aqueous solution was added, extracted twice with diethyl ether, and the organic layers were combined 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 = 90/10 to 0/100) to obtain 50.3 g (yield 62.9%) of the title compound. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.27 (5H, m), 4.49 (2H, s), 4.25-4.09 (6H, m), 3.51-3.44 (2H, m), 2.98 (1H, ddd, J = 22.8, 10.8, 4.0 Hz), 2.11-1.92 (2H, m), 1.75-1.62 (2H, m), 1.36-1.24 (9H, m).
MS (ESI) m / z: 373 [(M + H) ⁺ ].

(Step 3) Ethyl 5-benzyloxy-2-methylenepentanoate To a solution of 48.6 g (131 mmol) of ethyl 5-benzyloxy-2-diethoxyphosphorylpentanoate synthesized in Step 2 in 280 mL of tetrahydrofuran, 54.3 g of potassium carbonate. (393 mmol) and formaldehyde (37% aqueous solution) 50.0 mL (672 mmol) were added in this order, and the mixture was stirred at room temperature for 5 hours. 600 mL of water was added to the reaction mixture, and the mixture was extracted twice with hexane. The organic layers were combined 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 = 99/1 to 67/33) to obtain 22.9 g (yield 70.6%) of the title compound. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.32 (4H, m), 7.32-7.27 (1H, m), 6.15 (1H, s), 5.53 (1H, d, J = 1.2 Hz), 4.50 (2H , s), 4.20 (2H, q, J = 7.3 Hz), 3.50 (2H, t, J = 6.4 Hz), 2.41 (2H, t, J = 7.6 Hz), 1.85-1.76 (2H, m), 1.30 (3H, t, J = 7.3 Hz).
MS (ESI) m / z: 249 [(M + H) ⁺ ].

(Step 4) 5-benzyloxy-2-{[tert-butoxycarbonyl (methyl) amino] methyl} pentanoic acid 8.31 g (33.5 mmol) of ethyl 5-benzyloxy-2-methylenepentanoate synthesized in Step 3 20.0 mL (200 mmol) of methylamine (40% methanol solution) was added to 17 mL of methanol and stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to obtain 9.17 g of a mixture containing ethyl 5-benzyloxy-2- (methylaminomethyl) pentanoate as an oily substance. A solution of 9.17 g of this oily substance in 100 mL of methylene chloride was cooled to 0 ° C., and 8.70 mL (6.36 g, 62.9 mmol) of triethylamine and 10.8 g (49.5 mmol) of di-tert-butyl dicarbonate in methylene chloride. 50 mL solution was added in this order, and the mixture was stirred for 10 minutes, then warmed to room temperature and stirred for 78 hours. 100 mL of saturated aqueous sodium hydrogen carbonate was added to the reaction mixture and the mixture was extracted with methylene chloride. The organic layer was washed with water and then saturated brine and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 14.8 g of a mixture containing ethyl 5-benzyloxy-2-{[tert-butoxycarbonyl (methyl) amino] methyl} pentanoate as an oily substance. To a solution of 14.8 g of this oily substance in 75 mL of tetrahydrofuran / 75 mL of ethanol was added 75.0 mL (150 mmol) of 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 14 hours. Subsequently, the organic solvent was distilled off under reduced pressure, 100 mL of water was added to the obtained aqueous layer, and the mixture was washed twice with diethyl ether. The aqueous layer was cooled to 0 ° C., acidified by adding 75.0 mL (150 mmol) of 2N aqueous hydrochloric acid solution, and extracted twice with methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 10.5 g (yield 89.4%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.39-7.27 (5H, m), 4.50 (2H, s), 3.55-3.37 (4H, m), 2.86 (3H, s), 2.83-2.72 (1H, br m ), 1.76-1.56 (4H, m), 1.44 (9H, s).
MS m / z: 352 [(M + H) ⁺ ].

(Step 5) N-[(3-amino-2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-4-yl) methyl] -2,2 , 2-Trifluoro-N-methylacetamide 5-Benzyloxy-2 synthesized in Step 4 instead of 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoic acid in Step 4 of Example 23 Using — {[tert-butoxycarbonyl (methyl) amino] methyl} pentanoic acid, the same reaction as in Step 23 of Example 23 was carried out to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.52-7.41 (4H, m), 7.26-7.21 (1H, m), 4.07 (1H, dd, J = 13.1, 7.6 Hz), 3.65-3.54 (2H, m) , 3.34 (1H, dd, J = 13.1, 8.8 Hz), 3.15-3.12 (3H, m), 3.05 (2H, br s), 2.46-2.37 (1H, m), 2.23-2.08 (1H, m), 1.89-1.79 (2H, m), 1.77-1.66 (1H, m).
MS (ESI) m / z: 369 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 50 to 52 were synthesized.

Example 53 5-Chloro-N- (2,2-dimethyl-4-oxo-4-{[2-oxo-1- (2-pyridyl) -5,6,7,8-tetrahydro-4H- Pyrazolo [1,5-a] azepin-3-yl] amino} butyl) -2-ethoxybenzamide

(Step 1) Ethyl 8-chloro-3-oxooctanoate 23.3 g (155 mmol) of 6-chlorohexanoic acid is dissolved in 100 mL of tetrahydrofuran, and 27.6 g (170 mmol) of 1,1′-carbonyldiimidazole is added at room temperature. For 2 hours. The reaction mixture was added to a suspension of 28.9 g (170 mmol) monoethyl potassium malonate, 16.2 g (170 mmol) magnesium chloride and 23.7 mL (17.2 g, 170 mmol) triethylamine in 200 mL tetrahydrofuran at 60 ° C. After stirring for 4 hours and returning to room temperature, 1N hydrochloric acid was added to the residue obtained by distilling off the solvent under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to quantitatively obtain 34.2 g of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.21 (2H, q, J = 7.0 Hz), 3.55-3.52 (2H, m), 3.44 (2H, s), 2.58-2.57 (2H, m), 1.79-1.78 (2H, m), 1.64-1.63 (2H, m), 1.46-1.44 (2H, m), 1.29 (3H, t, J = 7.0 Hz).

(Step 2) 1- (6-Chloro-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one 8-chloro- synthesized in Step 1 17.1 g (77.4 mmol) of ethyl 3-oxooctanoate was dissolved in 200 mL of ethanol, 11.1 g (77.4 mmol) of (6-chloro-2-pyridyl) hydrazine was added, and the mixture was stirred at room temperature for 2 hours. 16.0 g (116 mmol) of potassium carbonate was added, and the mixture was further stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, the residue was suspended in 200 mL of N, N-dimethylformamide, 16.0 g (116 mmol) of potassium carbonate was added, and the mixture was stirred at 60 ° C. for 5 hours. After returning to room temperature, water was 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 magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was purified by amino silica-silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 50/50 to 0/100) to give the title compound 8.16 g (yield 40.0%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.93 (1H, d, J = 8.1 Hz), 7.75 (1H, t, J = 8.1 Hz), 7.15 (1H, d, J = 8.1 Hz), 5.26 (1H, s), 3.78 (2H, d, J = 7.3 Hz), 2.73 (2H, d, J = 7.3 Hz), 1.85-1.76 (6H, m).

(Step 3) 1- (6-Chloro-2-pyridyl) -3-nitro-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one Synthesized in Step 2 4.16 g (15.8 mmol) of 1- (6-chloro-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one was added to 25 mL of concentrated nitric acid. Dissolved and stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the crude product obtained by concentrating the filtrate was suspended in ethyl acetate, and insolubles were collected by filtration. Drying afforded 3.78 g (77.5% yield) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, d, J = 8.3 Hz), 7.83-7.82 (1H, m), 7.29-7.28 (1H, m), 4.07-4.06 (2H, m), 3.50 -3.48 (2H, br m), 1.96-1.94 (6H, m).

(Step 4) 3-Amino-1- (2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one (hydrochloride)
1.78 g of 1- (6-chloro-2-pyridyl) -3-nitro-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one synthesized in Step 3 ( 12.2 mmol) was suspended in 30 mL of methanol / 10 mL of tetrahydrofuran / 10 mL of methylene chloride, 1.20 g of 10% palladium carbon catalyst (M type) was added, and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. The reaction mixture was filtered and the crude product obtained by concentrating the filtrate was purified by amino silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 40 / 60-0 / 100) to give the title 2.06 g (yield 60.1%) of a compound (including a part of hydrochloride) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.49-8.47 (1H, m), 8.02-8.00 (1H, m), 7.80-7.79 (1H, m), 7.13-7.12 (1H, m), 3.61-3.60 ( 2H, m), 2.81 (2H, br s), 2.74-2.71 (2H, m), 1.81-1.71 (4H, m), 1.64-1.62 (2H, m).
Thereafter, the following Examples 53 to 54 were synthesized in the same manner as in Step 11 of Example 23.

Example 55 5-Chloro-N- (2,2-dimethyl-4-{[1- (6-methyl-2-pyridyl) -2-oxo-5,6,7,8-tetrahydro-4H- Pyrazolo [1,5-a] azepin-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) 1- (6-Methyl-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one Synthesized in Step 2 of Example 51 1- (6-Chloro-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one 4.00 g (15.2 mmol) was converted to 1,4- Dissolved in 40 mL of dioxane, 6.48 mL (22.7 mmol) of trimethylboroxine (3.5 M tetrahydrofuran solution) and 6.29 g (45.5 mmol) of potassium carbonate, 4.0 mL of water, tetrakis (triphenylphosphine) palladium 75 g (1.52 mmol) was added, and the mixture was stirred at 90 ° C. for 4 hours. It returned to room temperature, water was added, and ethyl acetate extracted. 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 silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 97 The product was purified quantitatively to obtain 3.70 g of the title compound as a solid quantitatively.
¹ H-NMR (CDCl ₃ ) δ: 7.71-7.69 (2H, m), 6.99 (1H, dd, J = 6.8, 1.0 Hz), 5.27 (1H, s), 3.77-3.76 (2H, m), 2.73 -2.72 (2H, m), 2.54 (3H, s), 1.79-1.77 (6H, m).

(Step 2) 3-amino-1- (6-methyl-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one Step of Example 53 3 instead of 1- (6-chloro-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one (6-Methyl-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one is used in the same manner as in Step 53 of Example 53. Reaction was performed to give the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.81 (1H, d, J = 7.8 Hz), 7.68 (1H, t, J = 7.8 Hz), 6.98 (1H, d, J = 7.8 Hz), 3.58-3.58 ( 2H, m), 2.79 (2H, br s), 2.73-2.72 (2H, m), 2.55 (3H, s), 1.82-1.66 (6H, m).
Thereafter, the following Examples 55 to 56 were synthesized in the same manner as in Step 11 of Example 23.

Example 57 5-Chloro-N- (4-{[6- (dimethylamino) -2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a Azepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide

(Step 1) tert-butyl N-methyl-N- (7-oxooxepan-4-yl) carbamate tert-butyl N-methyl-N- (4-oxocyclohexyl) carbamate 14 synthesized according to the method described in WO2008 / 143963 0.1 g (62.2 mmol) of 200 mL of methylene chloride was cooled to 0 ° C., and 19.3 g (72.7 mmol) of 3-chloroperbenzoic acid (containing about 30% water) was divided into 3 portions over 10 minutes. The mixture was added and stirred as it was for 5 minutes, then warmed to room temperature and stirred for 20 hours. The reaction mixture was washed 3 times with 10% aqueous sodium thiosulfate solution, twice with saturated aqueous sodium hydrogen carbonate, and once with saturated brine, and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 12.9 g (yield 85.5%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 4.39-4.11 (3H, m), 2.79-2.55 (5H, m), 2.03-1.88 (3H, m), 1.86-1.70 (1H, m), 1.47 (9H, s).

(Step 2) Ethyl 4- [tert-butoxycarbonyl (methyl) amino] -6-hydroxyhexanoate 12.9 g of tert-butyl N-methyl-N- (7-oxooxepan-4-yl) carbamate synthesized in Step 1 A solution of (53.2 mmol) in 100 mL of methylene chloride / 100 mL of ethanol was cooled to 0 ° C., 7.34 g (108 mmol) of sodium ethoxide was added at once, and the mixture was stirred at 0 ° C. for 3 hours. 150 mL of water was added to the reaction mixture, extraction was performed twice with methylene chloride, and the organic layers were combined and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 13.9 g (yield 90.1%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.35-4.25 (0.75H, m), 4.23-4.13 (0.25H, m), 4.13 (2H, q, J = 7.1 Hz), 3.65-3.51 (1H, m) , 3.46-3.31 (1H, m), 2.67 (0.80H, s), 2.63 (2.2H, s), 2.36-2.22 (2H, m), 1.89-1.64 (4H, m), 1.47 (9H, s) , 1.26 (3H, t, J = 7.3 Hz).
MS (ESI) m / z: 290 [(M + H) ⁺ ].

(Step 3) Ethyl 6-benzyloxy-4- [tert-butoxycarbonyl (methyl) amino] hexanoate Ethyl 4- [tert-butoxycarbonyl (methyl) amino] -6-hydroxyhexanoate synthesized in Step 2 To a solution of 60 g (8.98 mmol) in 100 mL of methylene chloride, 5.40 mL (7.77 g, 45.4 mmol) of benzyl bromide and 3.71 g (16.0 mmol) of silver (I) oxide were added in this order. And stirred vigorously for 8.5 hours. Subsequently, 2.70 mL (3.88 g, 22.7 mmol) of benzyl bromide and 2.10 g (9.06 mmol) of silver (I) oxide were added, and the mixture was vigorously stirred at 45 ° C. for 7 hours under light shielding. After cooling to room temperature, the reaction mixture was filtered through celite and washed with methylene chloride. The residue obtained by concentrating the filtrate was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 98 / 2-60 / 40) to give 2.18 g of the title compound (yield 63.9). %) As an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.40-7.27 (5H, m), 4.71 (0.60H, d, J = 5.5 Hz), 4.53-4.41 (2H, m), 4.31-4.20 (0.40H, m) , 4.19-4.07 (2H, m), 3.48-3.38 (2H, m), 2.67 (1.8H, s), 2.63 (1.2H, s), 2.33-2.19 (2H, m), 1.86-1.69 (4H, m), 1.44 (3.6H, s), 1.42 (5.4H, s), 1.25 (3H, t, J = 7.0 Hz).
MS (ESI) m / z: 380 [(M + H) ⁺ ].

(Step 4) 6-benzyloxy-4- [tert-butoxycarbonyl (methyl) amino] hexanoic acid ethyl 6-benzyloxy-4- [tert-butoxycarbonyl (methyl) amino] hexanoic acid synthesized in Step 3 1N aqueous sodium hydroxide solution (17.0 mL, 17.0 mmol) was added to a solution of 18 g (5.74 mmol) in tetrahydrofuran (17 mL) / methanol (17 mL), and the mixture was stirred at room temperature for 65 hours. The residue obtained by distilling off the organic solvent from the reaction mixture under reduced pressure was cooled to 0 ° C., 1N hydrochloric acid (16.0 mL, 16.0 mmol) was added to adjust the pH to about 6 and then 2 with diethyl ether. Extracted once. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.74 g (yield: 86.2%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.40-7.27 (5H, m), 4.54-4.42 (2H, m), 4.35-4.11 (1H, m), 3.49-3.36 (2H, m), 2.67 (1.6H , s), 2.64 (1.4H, s), 2.36-2.27 (2H, m), 1.87-1.67 (4H, m), 1.45 (4.3H, s), 1.42 (4.7H, s).
MS (ESI) m / z: 352 [(M + H) ⁺ ].

(Step 5) N- (3-amino-2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-6-yl) -2,2, 2-Trifluoro-N-methylacetamide 6-Benzyloxy-4 synthesized in Step 4 instead of 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoic acid in Step 4 of Example 23 Using [-tert-butoxycarbonyl (methyl) amino] hexanoic acid, the reaction was carried out in the same manner as in Step 23 of Example 23 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.42 (4H, m), 7.31-7.24 (1H, m), 4.58-4.46 (0.70H, m), 3.97-3.87 (0.30H, m), 3.68- 3.59 (1H, m), 3.32-3.18 (1H, m), 3.15-3.06 (1H, m), 3.04-2.89 (5H, br m), 2.57-2.44 (1H, m), 2.04-1.61 (4H, m).
MS (ESI) m / z: 369 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 57 to 60 were synthesized.

Example 61 5-Chloro-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5- a] pyrazin-3-yl) amino] butyl} -2-ethoxybenzamide

(Step 1) Ethyl 2- (2-benzyloxyethylamino) acetate A solution of 2.00 g (12.0 mmol) of ethyl 2-bromoacetate in 20 mL of methylene chloride was cooled to 0 ° C., and 3.34 mL (2.43 g, 24.0 mmol) was added and stirred for 30 minutes. Subsequently, a 10 mL solution of methylene chloride in 3.62 g (24.0 mmol) of 2-benzyloxyethanamine was added, and the mixture was warmed to room temperature and stirred for 15.5 hours. Furthermore, 1.00 mL (0.726 g, 7.17 mmol) of triethylamine was added and stirred at 40 ° C. for 4 hours. After cooling to room temperature, water was added and extracted with methylene chloride. The organic layer was washed once with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent was purified by amino silica gel column chromatography (Yamazensha, hexane / ethyl acetate = 69/31 to 48/52) to obtain 1.28 g (yield 44.9%) of the title compound. Obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.27 (5H, m), 4.54 (2H, s), 4.19 (2H, q, J = 7.1 Hz), 3.60 (2H, t, J = 4.9 Hz), 3.44 (2H, s), 2.84 (2H, t, J = 5.2 Hz), 1.27 (3H, t, J = 7.3 Hz).
MS (ESI) m / z: 238 [(M + H) ⁺ ].

(Step 2) Ethyl 2- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] acetate 1.28 g (5.39 mmol) of ethyl 2- (2-benzyloxyethylamino) acetate synthesized in Step 1 in 55 mL of tetrahydrofuran To the solution were added 1.13 mL (0.819 g, 8.09 mmol) of triethylamine and 1.41 g (6.47 mmol) of di-tert-butyl dicarbonate, and the mixture was stirred at room temperature for 1.2 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by silica gel column chromatography (Yamazensha, hexane / ethyl acetate = 96/4 to 75/25) to give 1.79 g of the title compound (yield 98.3%). ) Was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.25 (5H, m), 4.50-4.47 (2H, m), 4.18-4.09 (2H, m), 4.08 (0.9H, s), 4.01 (1.1H, s), 3.67-3.46 (4H, m), 1.46-1.41 (9H, m), 1.24 (3H, t, J = 7.0 Hz).

(Step 3) 2- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] acetic acid 5.49 g (16. 32.5) in tetrahydrofuran (70 mL) / methanol (35 mL) was added with 1N aqueous sodium hydroxide (32.5 mL, 32.5 mmol), and the mixture was stirred at room temperature for 88 hours. Subsequently, the organic solvent was distilled off under reduced pressure, and the obtained aqueous layer was washed twice with diethyl ether. The aqueous layer was acidified with 1N aqueous hydrochloric acid and extracted three times with diethyl ether. The organic layers were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4.74 g (yield 94.2%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.28 (5H, m), 4.57-4.50 (2H, br m), 4.10 (0.7H, br s), 3.99 (1.3H, br s), 3.75-3.44 (4H, br m), 1.43 (9H, s).
MS (ESI): 210 [(M-Boc + H) ⁺ ].

(Step 4) 3-Amino-1-phenyl-5- (2,2,2-trifluoroacetyl) -6,7-dihydro-4H-pyrazolo [1,5-a] pyrazin-2-one Example 23 Instead of 5-benzyloxy-3- [tert-butoxycarbonyl (methyl) amino] pentanoic acid in Step 4 of the above, 2- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] acetic acid synthesized in Step 3 was used. Thereafter, the same reaction as in Step 23 of Example 23 was performed to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.54-7.42 (4H, m), 7.31-7.25 (1H, m), 4.66 (1.3H, s), 4.60 (0.7H, s), 4.07-4.02 (0.7H , m), 3.99-3.93 (1.3H, m), 3.39-3.21 (2H, m), 3.12-3.05 (2H, m).
MS (ESI) m / z: 327 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 61 to 65 were synthesized.

Example 66 3-({4-[(5-chloro-2-methoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-oxo-1-phenyl-4,5,7, Tertbutyl 8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate

(Step 1) Ethyl 3- (2-benzyloxyethylamino) propanoate 10.0 g (66.6 mmol) of benzyloxyacetaldehyde was dissolved in 200 mL of methylene chloride, and 12.3 g (79.9 mmol) of alanine ethyl ester hydrochloride and 13.9 mL (10.1 g, 99.9 mmol) of triethylamine was added. To this, 23.1 g (99.9 mmol) of sodium triacetoxyborohydride was added in three portions under ice cooling, and then the mixture was warmed to room temperature and stirred for 4 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with methylene chloride. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (Biotage, hexane / 10% methanol-ethyl acetate = 70 / 30 to 0/100) to obtain 9.18 g (yield 54.9%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.28 (5H, m), 4.53 (2H, s), 4.17-4.10 (3H, m), 3.59 (2H, t, J = 5.2 Hz), 2.91 (2H , t, J = 6.7 Hz), 2.83 (3H, t, J = 5.2 Hz), 2.51 (2H, t, J = 6.7 Hz), 1.25 (3H, t, J = 7.0 Hz).
MS (APCI) m / z: 252 [(M + H) ⁺ ].

(Step 2) 3- [2-Benzyloxyethyl (tert-butoxycarbonyl) amino] propanoic acid 9.18 g (36.5 mmol) of ethyl 3- (2-benzyloxyethylamino) propanoate synthesized in Step 1 was added to tetrahydrofuran. / Water 200mL / 100mL mixed solvent, lithium hydroxide monohydrate 2.30g (54.8mmol) was added, and it stirred at room temperature for 1 hour. Thereto were added 12.0 g (54.8 mmol) of di-tertbutyl carbonate and 4.60 g (54.8 mmol) of sodium bicarbonate, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was acidified with 1N hydrochloric acid and extracted with methylene chloride. 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 was purified by silica gel column chromatography to obtain 6.82 g (yield 57.7%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.34-7.28 (5H, m), 4.52 (2H, s), 3.60-3.55 (4H, m), 3.48-3.42 (2H, m), 2.69-2.61 (2H, m), 1.44 (9H, br s).
MS (APCI) m / z: 224 [(M + H-Boc) ⁺ ].

(Step 3) Ethyl 5- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] -3-oxopentanoate 3.95 g (23.2 mmol) of monoethyl potassium malonate was suspended in 150 mL of acetonitrile, and magnesium chloride was added. 2.21 g (23.2 mmol) and 3.23 mL (2.35 g, 23.2 mmol) of triethylamine were added and stirred at room temperature for 3 hours. Then, 6.82 g (21.1 mmol) of ethyl 3- (2-benzyloxyethylamino) propanoate synthesized in Step 2 was dissolved in 150 mL of acetonitrile, and 3.76 g (23.2 mmol) of N, N-carbonyldiimidazole was dissolved. And a solution prepared by stirring at room temperature for 3.2 hours was added at room temperature and stirred at 60 ° C. for 5.5 hours. After cooling to room temperature, 50 mL of 1N hydrochloric acid was added, and the organic solvent was distilled off under reduced pressure. The obtained residue was extracted with ethyl acetate, and then 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 / 5-50 / 50) to give the title compound 7.75 g (93.4% yield) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.28 (5H, m), 4.51 (2H, s), 4.18 (2H, q, J = 7.1 Hz), 3.60-3.50 (4H, m), 3.45-3.35 (4H, m), 2.88-2.81 (2H, m), 1.27 (3H, t, J = 7.1 Hz).
MS (APCI) m / z: 293 [(M + H-Boc) ⁺ ].

(Step 4) tert-Butyl N- (2-benzyloxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate 5- [5] synthesized in Step 3 7.75 g (19.7 mmol) of ethyl 2-benzyloxyethyl (tert-butoxycarbonyl) amino] -3-oxo-pentanoate was dissolved in 150 mL of toluene and 2.20 mL of phenylhydrazine (2.35 g, 21.7 mmol). And heated to reflux for 6.5 hours. By returning to room temperature and distilling off the solvent under reduced pressure, the residue obtained is purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 95 / 5-50 / 50). The title compound (7.16 g, yield 83.1%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.84 (2H, d, J = 7.9 Hz), 7.40-7.28 (7H, m), 7.19-7.15 (1H, m), 4.53 (2H, s), 3.65-3.59 (4H, m), 3.51-3.43 (3H, m), 3.32 (1H, br s), 2.73 (2H, t, J = 6.7 Hz), 1.45-1.34 (9H, m).
MS (APCI) m / z: 438 [(M + H) ⁺ ].

(Step 5) tert-Butyl N- (2-hydroxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate tert-Butyl N synthesized in Step 4 7.16 g (16.4 mmol) of-(2-benzyloxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate was dissolved in 150 mL of ethanol, 10 3.50 g of% palladium on carbon catalyst (M type) was added. The reaction mixture was stirred at 70 ° C. for 6 hours under a hydrogen atmosphere, and then returned to room temperature. After replacing the inside of the reaction system with nitrogen, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, elution solvent; hexane / 10% methanol-ethyl acetate = 70/30 to 30/70) to give 4.14 g (yield 77.6) of the title compound. %) As an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.79 (2H, d, J = 7.9 Hz), 7.39 (2H, t, J = 7.9 Hz), 7.20-7.16 (1H, m), 3.80-3.75 (2H, m ), 3.66 (1H, s), 3.59 (2H, t, J = 6.4 Hz), 3.49-3.38 (4H, m), 2.77 (2H, br s), 1.43-1.28 (9H, m).
MS (APCI) m / z: 348 [(M + H) ⁺ ].

(Step 6) 2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate tert-butyl tert synthesized in Step 5 4-butyl N- (2-hydroxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate 4.14 g (10.1 mmol) was dissolved in 90 mL of acetonitrile. , 2.02 g (10.6 mmol) of p-toluenesulfonyl chloride and 1.48 mL (1.07 g, 10.6 mmol) of triethylamine were added. After stirring at room temperature for 1 hour, 0.960 g (5.04 mmol) of p-toluenesulfonyl chloride was added, and the mixture was further stirred for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was 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 concentrating the filtrate under reduced pressure was dissolved in 90 mL of acetonitrile, 0.660 g (15.1 mmol) of sodium hydride (55%) was added, and the mixture was stirred at 60 ° C. for 1 hour. After cooling to room temperature, the reaction was stopped by adding 1N hydrochloric acid, and neutralized by adding saturated aqueous sodium hydrogen carbonate. After extraction with ethyl acetate, the organic layer was washed with 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 / 10% methanol-ethyl acetate = 50 / 50-30 / 70). Gave 1.44 g (yield 43.4%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.46 (2H, t, J = 7.9 Hz), 7.35 (2H, d, J = 7.9 Hz), 7.32-7.28 (1H, m), 5.43 (1H, s), 3.69-3.62 (4H, m), 3.55-3.53 (2H, m), 2.91 (2H, br s), 1.47 (9H, br s).
MS (APCI) m / z: 330 [(M + H) ⁺ ].

(Step 7) 3-nitro-6-nitroso-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one 2 synthesized in Step 6 1.44 g (4.37 mmol) of tert-butyl-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate in concentrated nitric acid It melt | dissolved in 10 mL and stirred at 70 degreeC for 1.2 hours. After returning to room temperature, the reaction solution was poured into ice water and neutralized by adding sodium bicarbonate. After extraction with 10% methanol-chloroform, the organic layer was washed with saturated brine. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.03 g (yield 77.7%) of the title compound as a solid.
¹ H-NMR (DMSO-D ₆ ) δ: 7.64-7.51 (3H, m), 7.45 (1H, d, J = 7.3 Hz), 7.40 (1H, d, J = 7.3 Hz), 4.74 (1H, t , J = 5.2 Hz), 4.65 (1H, t, J = 4.0 Hz), 4.16-4.10 (2H, m), 4.05-4.00 (2H, m), 3.80 (1H, t, J = 5.2 Hz), 3.58 (1H, t, J = 5.2 Hz).
MS (APCI) m / z: 304 [(M + H) ⁺ ].

(Step 8) 3-nitro-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate tertbutyl 1.44 g (3.11 mmol) of 3-nitro-6-nitroso-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one synthesized Was dissolved in methanol (10 mL), 5N hydrochloric acid (10 mL) was added, and the mixture was stirred at 100 ° C. for 4 hr. The residue obtained by returning to room temperature and concentrating under reduced pressure was dissolved in 10 mL of tetrahydrofuran and 10 mL of saturated aqueous sodium hydrogen carbonate, and 1.02 g (4.66 mmol) of di-tert-butyl carbonate and 0.870 mL (0.629 g, 0.629 g, triethylamine). 6.22 mmol) was added, and the mixture was stirred at room temperature for 13 hours. Methylene chloride was added to the reaction solution for extraction, and the organic layer was washed with 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 / 10% methanol-ethyl acetate = 70/30 to 30/70). Gave 1.20 g of the title compound quantitatively as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.54 (2H, t, J = 7.6 Hz), 7.46 (1H, t, J = 7.3 Hz), 7.29 (2H, d, J = 7.3 Hz), 3.90-3.88 ( 2H, m), 3.81-3.79 (2H, m), 3.72-3.70 (2H, m), 3.67-3.65 (2H, m), 1.48 (9H, s).
MS (APCI) m / z: 375 [(M + H) ⁺ ].

(Step 9) tertbutyl 3-amino-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate 1.20 g of tert-butyl 3-nitro-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate synthesized (3 .21 mmol) was dissolved in 20 mL of methanol, and 0.600 g of 10% palladium carbon catalyst (M type) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 4 hours, and then the reaction system was replaced with nitrogen, and insoluble materials were removed by filtration. The residue obtained by concentrating 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). 0.570 g (yield 51.6%) of the compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.46-7.41 (4H, m), 7.27-7.23 (1H, m), 3.73-3.64 (4H, m), 3.25-3.23 (2H, m), 2.98-2.95 ( 2H, br m), 2.87-2.84 (2H, br m), 1.51-1.41 (9H, br m).
MS (APCI) m / z: 345 [(M + H) ⁺ ].

(Step 10) 3-({4-[(5-Chloro-2-methoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-oxo-1-phenyl-4,5,7,8 -Tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate tertbutyl 3-amino-2-oxo-1-phenyl-4,5,7,8-tetrahydro synthesized in step 9 1.03 g (2.99 mmol) of pyrazolo [1,5-d] [1,4] diazepine-6-carboxylate 1.03 g (2.99 mmol) is dissolved in 20 mL of ethanol to obtain 0.985 g (3.29 mmol) of intermediate 1b and 4- 1.24 g (4.48 mmol) of (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholium chloride n-hydrate (DMT-MM) was added and brought to room temperature. 1 Stir for 3 hours. After evaporating the solvent from the reaction mixture under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the residue obtained by concentrating 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). The fraction containing the desired product was collected, the solvent was distilled off under reduced pressure, the resulting residue was suspended in ethyl acetate, the solid was collected by filtration and dried to give 1.45 g of the title compound (yield 74. 6%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.16 (0.6H, br s), 8.96 (0.4H, br s), 8.28 (1H, t, J = 7.0 Hz), 8.18 (1H, d, J = 2.4 Hz ), 7.47-7.38 (5H, m), 7.29-7.26 (1H, m), 6.92 (1H, d, J = 8.5 Hz), 3.97 (3H, s), 3.97 (3H, s), 3.74-3.72 ( 4H, br m), 3.57-3.53 (4H, m), 3.00-2.97 (2H, m), 2.27 (2H, s), 1.47 (9H, br s), 1.10 (6H, s).
MS (APCI) m / z: 626 [(M + H) ⁺ ].

Example 67 5-Chloro-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1, 5-d] [1,4] diazepin-3-yl) amino] butyl} -2-methoxybenzamide

(Step 1) 3-({4-[(5-Chloro-2-methoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-oxo-1- synthesized in Step 10 of Example 67 Phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylate 1.45 g (2.32 mmol) with 4N hydrochloric acid-1,4-dioxane 10 mL was added and stirred at room temperature for 2.5 hours. After evaporating the solvent from the reaction mixture under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with chloroform. The organic layer was washed with water and 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 gel column chromatography (Biotage, elution solvent; hexane / 10% methanol-ethyl acetate = 70/30 to 20/80). The fraction containing the desired product was collected, the solvent was distilled off under reduced pressure, the resulting residue was suspended in diethyl ether, the solid was collected by filtration and dried to give 1.13 g of the title compound (yield 92. 9%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.73 (1H, br s), 8.29 (1H, t, J = 6.4 Hz), 8.18 (1H, d, J = 2.4 Hz), 7.46-7.38 (5H, m) , 7.29-7.25 (1H, m), 6.92 (1H, d, J = 8.5 Hz), 3.97 (3H, s), 3.57-3.55 (4H, m), 3.14-3.12 (2H, m), 3.08-3.06 (2H, m), 2.97-2.95 (2H, m), 2.27 (2H, s), 1.11 (6H, s).
MS (APCI) m / z: 526 [(M + H) ⁺ ].

Example 68 5-chloro-N- {2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5- d] [1,4] diazepin-3-yl) amino] -4-oxobutyl} -2-methoxybenzamide

5-Chloro-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-- synthesized in Step 1 of Example 67 Pyrazolo [1,5-d] [1,4] diazepin-3-yl) amino] butyl} -2-methoxybenzamide (0.300 g, 0.570 mmol) was dissolved in methanol (6.0 mL), and acetic acid (0.0652 mL, 0.0685 g, 1.14 mmol), formaldehyde (37% aqueous solution) 0.227 mL (2.85 mmol) and sodium cyanoborohydride 0.188 g (2.85 mmol) were added, and the mixture was stirred at room temperature for 16 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the organic solvent was distilled off under reduced pressure, and the resulting residue was extracted with chloroform. The organic layer was washed with water and 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 gel column chromatography (Biotage, elution solvent; hexane / 10% methanol-ethyl acetate = 70/30 to 20/80). The fraction containing the desired product was collected, the solvent was distilled off under reduced pressure, the resulting residue was suspended in ethyl acetate, the solid was collected by filtration and dried to give 0.259 g of the title compound (yield: 84.84%). 1%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.80 (1H, br s), 8.30 (1H, t, J = 6.7 Hz), 8.18 (1H, d, J = 2.4 Hz), 7.46-7.38 (5H, m) , 7.28-7.25 (1H, m), 6.91 (1H, d, J = 9.2 Hz), 3.96 (3H, s), 3.61-3.59 (2H, m), 3.55 (2H, d, J = 6.7 Hz), 3.01-2.99 (2H, m), 2.79-2.76 (2H, m), 2.71-2.69 (2H, m), 2.42 (3H, s), 2.27 (2H, s), 1.10 (6H, s).
MS (APCI) m / z: 540 [(M + H) ⁺ ].
The following Examples 69 to 86 were synthesized in the same manner as in Examples 66 to 68.

Example 87 5-Chloro-N- (2,2-dimethyl-4-oxo-4-{[2-oxo-1-phenyl-6- (2,2,2-trifluoroethyl) -4, 5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] amino} butyl) -2-ethoxybenzamide

(Step 1) 5-chloro-N- (2,2-dimethyl-4-oxo-4-{[2-oxo-1-phenyl-6- (2,2,2-trifluoroethyl) -4,5 , 7,8-Tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] amino} butyl) -2-ethoxybenzamide 3-({4-[(5 -Chloro-2-ethoxybenzoyl) amino] -3,3-dimethylbutanoyl} amino) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1 , 4] Diazepine-6-carboxylate tert-butyl (0.499 g, 0.779 mmol) was added 4N hydrochloric acid-1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 3.5 hours. The crude amine obtained by distilling off the solvent under reduced pressure was dissolved in 10.0 mL of N, N-dimethylformamide, and 0.134 mL (0.24) of trifluoromethanesulfonic acid-2,2,2-trifluoroethyl was added. 217 g, 0.935 mmol) and 0.217 mL (0.158 g, 1.56 mmol) of triethylamine were added, and the mixture was stirred at 60 ° C. for 5 hours. The reaction solution was returned to room temperature, 0.134 mL (0.217 g, 0.935 mmol) of trifluoromethanesulfonic acid-2,2,2-trifluoroethyl and 0.217 mL (0.158 g, 1.56 mmol) of triethylamine were added, Stir at 70 ° C. for 3 hours. The reaction solution was returned to room temperature, 0.134 mL (0.217 g, 0.935 mmol) of trifluoromethanesulfonic acid-2,2,2-trifluoroethyl and 0.217 mL (0.158 g, 1.56 mmol) of triethylamine were added, Stir at 70 ° C. for 8 hours. The temperature was returned to room temperature, saturated aqueous sodium hydrogen carbonate and water were added, and the mixture was extracted with chloroform. 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 / 10% methanol-ethyl acetate = 70 / 30-0 / 100). This gave 0.302 g (yield 62.4%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.16 (1H, s), 8.38 (1H, t, J = 6.7 Hz), 8.20 (1H, d, J = 2.4 Hz), 7.46-7.36 (4H, m), 7.28-7.25 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.20 (2H, q, J = 6.9 Hz), 3.59-3.57 (4H, m), 3.19 (2H, q, J = 9.4 Hz), 3.12-3.08 (2H, m), 3.03-2.99 (4H, m), 2.27 (2H, s), 1.51 (3H, d, J = 6.9 Hz), 1.11 (6H, s).
MS (APCI) m / z: 622 [(M + H) ⁺ ].

Example 88 5-Chloro-2-ethoxy-N- (4-{[6- (2-fluoroethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1 , 5-d] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutylbenzamide

(Step 1) 5-chloro-2-ethoxy-N- (4-{[6- (2-fluoroethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1, 5-d] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutylbenzamide 5-chloro-N- {2,2-dimethyl-4-synthesized in Example 74 Oxo-[(2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [1,4] diazepin-3-yl) amino] butyl-2-ethoxy Dissolve 50.0 mg (0.0925 mmol) of benzamide in 0.5 mL / 0.5 mL of a mixed solvent of 2-propanol-1,4-dioxane, and add 24.2 mg (0.139 mmol) of 1-fluoro-2-iodoethane and carbonic acid. Caliu 14.1 mg (0.101 mmol) was added, and the mixture was stirred for 8.5 hours at 100 ° C. After returning to room temperature, 24.2 mg (0.139 mmol) of 1-fluoro-2-iodoethane was added and the mixture was stirred at 100 ° C. for 9 hours. The mixture was returned to room temperature, 24.2 mg (0.139 mmol) of 1-fluoro-2-iodoethane and 14.1 mg (0.101 mmol) of potassium carbonate were added, and the mixture was stirred for 8.5 hours at 100 ° C. The temperature was returned to room temperature. After adding water to the reaction solution and extracting with chloroform, the organic layer was dried over anhydrous sodium sulfate, and after filtration, the residue obtained by concentrating the filtrate under reduced pressure was subjected to amino silica gel column chromatography (Biotage). And the elution solvent; hexane / 10% methanol-ethyl acetate = 70/30 to 0/100). 0mg The (8.10% yield) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.02 (1H, br s), 8.36 (1H, t, J = 6.4 Hz), 8.21 (1H, d, J = 2.4 Hz), 7.46-7.36 (4H, m) , 7.27-7.22 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.63 (1H, t, J = 4.9 Hz), 4.51 (1H, t, J = 4.9 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.60-3.58 (4H, m), 3.03-3.00 (2H, m), 2.97-2.92 (3H, m), 2.90-2.85 (3H, m), 2.26 (2H, s) , 1.52 (3H, t, J = 7.0 Hz), 1.11 (6H, s).
MS (APCI) m / z: 586 [(M + H) ⁺ ].

Example 89 5-chloro-2-ethoxy-N- (4-{[6- (2-hydroxyethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1 , 5-d] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl) benzamide

(Step 1) N- {4-[(6- {2-tert-butyl (dimethyl) silyl} oxyethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5 -D] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl-5-chloro-2-ethoxybenzamide 5-chloro-N- {2, synthesized in Example 74 2-Dimethyl-4-oxo-[(2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [1,4] diazepin-3-yl) amino ] 0.343 g (0.635 mmol) of butyl-2-ethoxybenzamide was dissolved in 8.0 mL of methylene chloride, and 0.166 g (0.954 mmo) of 2- [tert-butyl (dimethyl) silyl] oxyacetaldehyde was dissolved. l) and 0.109 mL (0.115 g, 1.91 mmol) of acetic acid were added. Here, 0.425 g (1.91 mmol) of sodium triacetoxyborohydride was added and stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. (0/100 → 100/0 to 90/10) gave 0.371 g (yield 83.6%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.07 (1H, br s), 8.37 (1H, t, J = 6.7 Hz), 8.20 (1H, d, J = 2.4 Hz), 7.45-7.36 (5H, m) , 7.27-7.24 (1H, m), 6.90 (1H, d, J = 8.5 Hz), 4.19 (2H, q, J = 7.0 Hz), 3.74 (2H, t, J = 5.8 Hz), 3.58-3.54 ( 4H, m), 2.98-2.89 (6H, m), 2.72 (2H, t, J = 5.8 Hz), 2.26 (2H, s), 1.52 (3H, t, J = 7.0 Hz), 1.10 (6H, s ), 0.89 (9H, s), 0.06 (6H, s).
MS (APCI) m / z: 698 [(M + H) ⁺ ].

(Step 2) 5-chloro-2-ethoxy-N- (4-{[6- (2-hydroxyethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1, 5-d] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl) benzamide N- {4-[(6- {2-tert-butyl (synthesized in Step 1) Dimethyl) silyl} oxyethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] amino} -2,2 -0.371 g (0.531 mmol) of dimethyl-4-oxobutyl-5-chloro-2-ethoxybenzamide was dissolved in 4.0 mL of methanol, 1.0 mL of 4N hydrochloric acid-1,4-dioxane was added, and 1 at room temperature was added. Stir for 7 hours . Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic solvent was distilled off under reduced pressure, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was concentrated on silica gel column chromatography (Biotage, elution solvent; hexane / 10% methanol-ethyl acetate = 70). / 30-0 / 100). The fraction containing the desired product was collected, the solvent was distilled off under reduced pressure, the resulting residue was suspended in ethyl acetate, the solid was collected by filtration and dried to give 0.216 g of the title compound (yield 69. 6%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.15 (1H, s), 8.37 (1H, t, J = 6.7 Hz), 8.20 (1H, d, J = 2.4 Hz), 7.46-7.36 (5H, m), 7.28-7.24 (1H, m), 6.91 (1H, d, J = 9.2 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.62-3.58 (6H, m), 3.02-3.00 (2H, m) , 2.95-2.92 (2H, m), 2.86-2.84 (2H, m), 2.74-2.71 (2H, m), 2.66 (1H, t, J = 4.6 Hz), 2.26 (2H, s), 1.52 (3H , t, J = 7.0 Hz), 1.11 (6H, s).
MS (APCI) m / z: 584 [(M + H) ⁺ ].
The following Example 90 was synthesized in the same manner.

Example 91 5-Chloro-N- [4-({6- [2- (dimethylamino) ethyl] -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1, 5-d] [1,4] diazepin-3-yl} amino) -2,2-dimethyl-4-oxobutyl] -2-ethoxybenzamide

(Step 1) 5-chloro-N- (4-{[6- (2-chloroethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [ 1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl] -2-ethoxybenzamide 5-chloro-2-ethoxy-N- (4- {[6- (2-hydroxyethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl) benzamide (1.71 g, 2.93 mmol) was suspended in chloroform (40 mL), p-toluenesulfonyl chloride (0.612 g, 3.21 mmol) and triethylamine (0.529 m). L (0.384 g, 3.79 mmol) was added, and the mixture was stirred at room temperature for 80 hours, and 0.0356 g (0.291 mmol) of 4-N, N-dimethylaminopyridine was added thereto, followed by stirring at room temperature for 90 hours. To this was added 0.278 g (1.46 mmol) of p-toluenesulfonyl chloride, 0.203 mL (0.148 g, 1.46 mmol) of triethylamine and 0.0356 g (0.291 mmol) of 4-N, N-dimethylaminopyridine. The reaction mixture was added with saturated aqueous sodium bicarbonate and extracted with chloroform, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration with silica gel was subjected to silica gel column chromatography (Biotage, elution solvent: hexa / Ethyl acetate → ethyl acetate / methanol = 95 / 5~0 / 100 → 100 / 0~80 / 20) to obtain the title compound by 0.990g of (56.3% yield) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.10 (1H, br s), 8.37 (1H, t, J = 6.7 Hz), 8.21 (1H, d, J = 3.1 Hz), 7.46-7.36 (5H, m) , 7.28-7.24 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.60-3.55 (6H, m), 3.02-2.99 (2H, m ), 2.96-2.90 (4H, m), 2.88-2.86 (2H, m), 2.26 (2H, s), 1.52 (3H, t, J = 7.0 Hz), 1.11 (6H, s).
MS (APCI) m / z: 602 [(M + H) ⁺ ].

(Step 2) 5-chloro-N- [4-({6- [2- (dimethylamino) ethyl] -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5 -D] [1,4] diazepin-3-yl} amino) -2,2-dimethyl-4-oxobutyl] -2-ethoxybenzamide 5-chloro-N- (4-{[6- (2-Chloroethyl) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] amino} -2,2- Dimethyl-4-oxobutyl] -2-ethoxybenzamide (0.376 g, 0.624 mmol) was dissolved in acetonitrile (10 mL), 2.0 M dimethylamine-tetrahydrofuran solution (0.470 mL, 0.940 mmol), potassium carbonate 0.129 g (0.933 mmol) and sodium iodide 0.187 g (0.124 mmol) were added, and the mixture was stirred for 2.5 hours at 70 ° C. After returning to room temperature, water was added to the reaction mixture, and the organic solvent was removed under reduced pressure. The residue was extracted with chloroform, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain an aminosilica gel. Purification by column chromatography (Biotage, elution solvent; hexane / 10% methanol-ethyl acetate = 70 / 30-0 / 100) gave 0.195 g (yield 51.4%) of the title compound as a solid. Obtained.
¹ H-NMR (CDCl ₃ ) δ: 9.02 (1H, br s), 8.37 (1H, t, J = 6.7 Hz), 8.21 (1H, d, J = 2.4 Hz), 7.45-7.36 (5H, m) , 7.26-7.23 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.20 (2H, q, J = 7.0 Hz), 3.60-3.58 (4H, m), 3.01-2.97 (2H, m ), 2.91-2.89 (2H, m), 2.84-2.82 (2H, m), 2.66 (2H, t, J = 7.0 Hz), 2.42 (2H, t, J = 7.0 Hz), 2.26 (2H, s) , 2.24 (6H, s), 1.52 (3H, t, J = 7.0 Hz), 1.11 (6H, s).
MS (APCI) m / z: 611 [(M + H) ⁺ ].

Example 92 N- {4-[(6-acetyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-3 -Yl) amino] -2,2-dimethyl-4-oxobutyl} -5-chloro-2-ethoxybenzamide

(Step 1) N- {4-[(6-acetyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-3- Yl) amino] -2,2-dimethyl-4-oxobutyl} -5-chloro-2-ethoxybenzamide 3-({4-[(5-chloro-2-ethoxybenzoyl) amino]-synthesized in Example 73 3,3-dimethylbutanoyl} amino) -2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine-6-carboxylic acid tert- To 0.300 g (0.469 mmol) of butyl, 10 mL of 4N hydrochloric acid-1,4-dioxane was added and stirred at room temperature for 2.6 hours. The crude amine obtained by distilling off the solvent under reduced pressure was dissolved in 10 mL of tetrahydrofuran, 0.0664 mL (0.0717 g, 0.702 mmol) of acetic anhydride, 0.293 mL (0.214 g, 2.11 mmol) of triethylamine. ) And 0.0521 g (0.0426 mmol) of 4-N, N-dimethylamine were added, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the organic solvent was distilled off under reduced pressure. The residue was extracted with chloroform, and then 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 was purified by amino silica-silica gel column chromatography (Biotage, hexane / 10% methanol-ethyl acetate = 70 / 30-0 / 100). . The fraction containing the desired product was collected, the solvent was distilled off under reduced pressure, the resulting residue was suspended in ethyl acetate, the solid was collected by filtration and dried to give 0.288 g of the title compound (yield 83.8%). ) Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 9.43 (0.7H, br s), 9.29 (0.3H, br s), 8.39 (1H, t, J = 6.7 Hz), 8.20 (1H, d, J = 2.4 Hz ), 7.47-7.37 (5H, m), 7.30-7.27 (1H, m), 6.91 (1H, d, J = 9.2 Hz), 4.20 (2H, q, J = 6.9 Hz), 3.92-3.86 (2H, m), 3.83-3.81 (1.4H, m), 3.76-3.74 (0.6H, m), 3.61-3.54 (4H, m), 3.06-3.00 (2H, m), 2.28-2.27 (2.1H, m) , 2.19 (2H, s), 2.11 (0.9H, s), 1.53 (3H, t, J = 7.0 Hz), 1.12 (6H, s).
MS (APCI) m / z: 582 [(M + H) ⁺ ].

Example 93 5-Chloro-N- {2,2-dimethyl-4-oxo-[(2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5- d] [1,4] diazepin-3-yl) amino] butyl} -2- (methoxymethyl) benzofuran-7-carboxamide

(Step 1) Ethyl 3- (2-benzyloxyethylamino) propionate 71.7 mL (659 mmol) of ethyl acrylate was added dropwise to 99.6 g (659 mmol) of 2-benzyloxyethanamine under ice cooling over 15 minutes. After stirring at the same temperature for 20 minutes and then warming to room temperature, the mixture was further stirred for 18 hours to quantitatively obtain 165 g of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.27 (5H, m), 4.53 (2H, s), 4.14 (2H, q, J = 7.1 Hz), 3.59 (2H, t, J = 5.5 Hz), 2.91 (2H, t, J = 6.7 Hz), 2.83 (2H, t, J = 5.2 Hz), 2.51 (2H, t, J = 6.7 Hz), 1.25 (3H, t, J = 7.1 Hz).

(Step 2) Ethyl 3- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] propionate A solution of 165 g (656 mmol) of ethyl 3- (2-benzyloxyethylamino) propionate synthesized in Step 1 in 500 mL of methylene chloride. To the solution, 120 mL (87.1 g, 861 mmol) of triethylamine was added, and a solution of 130 g (596 mmol) of di-tertbutyl dicarbonate in 150 mL of methylene chloride was added dropwise over 30 minutes under ice cooling. After raising the temperature to room temperature, the mixture was further stirred for 18 hours. To the reaction solution was added 880 mL of 1N hydrochloric acid, and the mixture was extracted with methylene chloride. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 223 g (yield 96.7%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.38-7.27 (5H, m), 4.52 (2H, s), 4.13 (2H, q, J = 6.7 Hz), 3.63-3.52 (4H, m), 3.49-3.39 (2H, m), 2.63-2.54 (2H, m), 1.49-1.39 (9H, m), 1.25 (4H, t, J = 6.7 Hz).

(Step 3) 3- [2-Benzyloxyethyl (tert-butoxycarbonyl) amino] propionic acid Step 2 223 g (888 mmol) of ethyl 3- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] propionate synthesized 400 mL (1400 mmol) of 3.5N aqueous sodium hydroxide solution was added to 900 mL of ethanol under ice-cooling, and the mixture was returned to room temperature and stirred for 26 hours. After the reaction mixture was concentrated under reduced pressure, the residue was dissolved in 500 mL of water and washed with 500 mL of hexane and then with 500 mL of diethyl ether. Under ice cooling, the aqueous layer was acidified with concentrated hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated to obtain 188 g (yield 65.6%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.36-7.26 (5H, m), 4.52 (2H, s), 3.65-3.52 (4H, m), 3.49-3.37 (2H, m), 2.71-2.58 (2H, m), 1.44 (9H, br s).

(Step 4) Ethyl 5- [2-benzyloxyethyl (tert-butoxycarbonyl) amino] -3-oxopentanoate 3- [2-Benzyloxyethyl (tert-butoxycarbonyl) amino] propionic acid synthesized in Step 3 N, N′-carbonyldiimidazole 113 g (697 mmol) was gradually added to a solution of 188 g (582 mmol) in tetrahydrofuran 1000 mL. After stirring for 3 hours, 54.0 g (567 mmol) of magnesium chloride and 149 g (873 mmol) of monoethyl potassium malonate were added, and the mixture was further stirred for 22 hours. To the reaction mixture, 500 mL of ethyl acetate was added, and after ice cooling, 1000 mL of 1N hydrochloric acid was gradually added. After stirring for 30 minutes, 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 222 g (yield 97.1%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.25 (5H, m), 4.51 (2H, s), 4.17 (2H, q, J = 7.3 Hz), 3.62-3.49 (5H, m), 3.47-3.29 (4H, m), 2.90-2.79 (2H, m), 1.47-1.38 (9H, m), 1.26 (3H, t, J = 7.3 Hz).

(Step 5) tert-Butyl N- (2-hydroxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate 5- [2 synthesized in Step 4 -Phenylhydrazine 56.0 mL (61.1 g, 565 mmol) was added to ethanol 1000 mL solution of 222 g (565 mmol) of ethyl benzyloxyethyl (tert-butoxycarbonyl) amino] -3-oxopentanoate under ice cooling and stirred for 30 minutes. The mixture was returned to room temperature and further stirred for 7 hours. The mixture was ice-cooled again and 70.0 g (624 mmol) of potassium tert-butoxide was gradually added, and the mixture was returned to room temperature and stirred for 22 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 1200 mL of ethanol, 20 g of 20% palladium hydroxide-carbon catalyst was added, and the mixture was stirred at 50 ° C. for 13 hours in a hydrogen atmosphere. The reaction mixture was allowed to cool, insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (137 g, 69.8%) as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.79 (2H, d, J = 7.9 Hz), 7.38 (2H, t, J = 7.9 Hz), 7.21-7.14 (1H, m), 3.85-3.71 (2H, m ), 3.65 (1H, br s), 3.59 (3H, t, J = 6.4 Hz), 3.51-3.30 (4H, m), 2.80-2.72 (2H, m), 1.25-1.45 (9H, m).

(Step 6) 1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one 55.0 g (158 mmol) of tert-butyl N- (2-hydroxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazol-3-yl) ethyl] carbamate synthesized in Step 5 in tetrahydrofuran 100 g (414 mmol) of cyanomethylenetributylphosphorane (CMBP) was added to a 500 mL / toluene 500 mL solution, and the mixture was heated and stirred at 70 ° C. for 10 hours in a nitrogen atmosphere. After allowing to cool, 20 mL (349 mmol) of acetic acid and 80 mL of methanol were added to the reaction mixture, and the mixture was heated and stirred at 70 ° C. for 7 hours. The mixture was allowed to cool and then concentrated under reduced pressure. To the residue was added 250 mL of 4N hydrochloric acid-1,4-dioxane solution, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in a small amount of methanol, ethyl acetate was added, and the mixture was stirred. The precipitated solid was collected by filtration and dried. 121 mL (92.1 g, 713 mmol) of N, N-diisopropylethylamine was added to an 800 mL suspension of the resulting hydrochloride in methylene chloride and dissolved, and then 41.0 mL (59.9 g, 285 mmol) of trifluoroacetic anhydride was added under ice cooling. ) Was added dropwise and stirred at the same temperature for 3 hours. Saturated aqueous ammonium chloride solution was added and stirred for 10 minutes, followed by extraction with water and chloroform. 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; ethyl acetate / methanol = 95/5 to 90/10) to give 25.3 g of the title compound ( Yield 54.3%) was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.45-7.51 (2H, m), 7.37-7.30 (3H, m), 5.53 (1H, d, J = 8.5 Hz), 3.96-3.92 (1H, m), 3.88 -3.80 (3H, m), 3.67-3.61 (2H, m), 3.06-3.00 (2H, m).

(Step 7) 3-Nitro-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine 1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] synthesized in Step 6 25.3 g (82.9 mmol) of diazepin-2-one was dissolved in 80 mL of trifluoroacetic acid, and 11.0 mL (249 mmol) of concentrated nitric acid was added dropwise at room temperature. After stirring for 3 hours, the reaction solution was poured into ice water and stirred, and the precipitated solid was collected by filtration, washed with water and dried to obtain 30.2 g (yield 98.3%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.59-7.53 (3H, m), 7.34-7.30 (2H, m), 4.07-3.89 (6H, m), 3.80-3.72 (2H, m).

(Step 8) 3-Amino-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine 2-Nitro-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,5-d] [synthesized in Step 7 To a suspension of 1,4] diazepin-2-one 30.2 g (81.6 mmol) in tetrahydrofuran 750 mL / ethanol 750 mL was added 5% palladium carbon catalyst (PH type) 7.00 g, and at room temperature under a hydrogen atmosphere. Stir for 12 hours. The reaction solution was filtered, and the filtrate was concentrated to obtain 18.8 g (yield 67.7%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.48-7.44 (4H, m), 7.31-7.26 (3H, m), 3.98-3.95 (1H, m), 3.92-3.84 (3H, m), 3.38-3.35 ( 1H, m), 3.33-3.30 (1H, m), 3.09-2.93 (4H, m).
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 93 to 98 were synthesized.

Example 99 5-Chloro-N- (2,2-dimethyl-4-oxo-4-{[2-oxo-1- (2-pyridyl) -6- (2,2,2-trifluoroacetyl) ) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepin-3-yl] amino} butyl) -2-ethoxybenzamide

(Step 1) 3-amino-1- (2-pyridyl) -6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1 , 4] diazepin-2-one Instead of phenylhydrazine in Step 5 of Example 93, (6-chloro-2-pyridyl) hydrazine was used, and the reaction was carried out in the same manner as in Step 8 of Example 93. The title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.50-8.44 (1H, m), 8.11 (1H, t, J = 8.2 Hz), 7.86-7.79 (1H, m), 7.19-7.13 (1H, m), 4.05 -3.90 (4H, m), 3.62-3.53 (2H, m), 3.01-2.93 (2H, m), 2.97 (2H, br s).
MS (ESI) m / z: 342 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 99 to 105 were synthesized.

Example 106 5-Chloro-N- (2,2-dimethyl-4-{[1- (6-methyl-2-pyridyl) -2-oxo-5,6,7,8-tetrahydro-4H- Pyrazolo [1,5-d] [1,4] diazepin-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) 3-Amino-1- (6-methyl-2-pyridyl) -6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5- d] [1,4] diazepin-2-one Using (6-methyl-2-pyridyl) hydrazine instead of phenylhydrazine in Step 5 of Example 93, the same as in Step 93 of Example 93. The title compound was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.94-7.89 (1H, m), 7.74-7.67 (1H, m), 7.04-6.99 (1H, m), 4.07-3.90 (4H, m), 3.63-3.54 ( 2H, m), 3.02-2.91 (4H, m), 2.55 (3H, s).
MS (ESI) m / z: 356 [(M + H) ⁺ ].
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 106 to 110 were synthesized.

Example 111 5-chloro-N- (4-{[1- (6-chloro-2-pyridyl) -2-oxo-5,6,7,8-tetrahydro-4-H-pyrazolo [1, 5-d] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-methylbenzofuran-7-carboxamide

(Step 1) 5- (tert-Butoxycarbonyl- {2- [tert-butyl (diphenyl) silyl] oxyethyl} amino) -3-oxopentanoic acid instead of 2-benzyloxyethanamine in Step 1 of Example 93 Bioorg. Med. Chem. Using 2- [tert-butyl (diphenyl) silyl] oxyethanamine synthesized by the method described in 2009, 17, 2536-2543, the reaction was conducted in the same manner as in Step 93 of Example 93, and the title compound was converted into an oily product. Obtained as material.
¹ H-NMR (CDCl ₃ ) δ: 7.67-7.63 (4H, m), 7.45-7.35 (6H, m), 4.18 (2H, q, J = 7.0 Hz), 3.78-3.66 (2H, m), 3.59 -3.32 (4H, m), 2.89-2.78 (2H, m), 1.47-1.35 (9H, m), 1.27 (3H, t, J = 7.0 Hz), 1.04 (9H, s).

(Step 2) tert-butyl N- {2- [tert-butyl (diphenyl) silyl] oxyethyl} -N- {2- [1- (6-chloro-2-pyridyl) -5-oxo-4H-pyrazole- 3-yl] ethyl} carbamate 18.3 g (33.8 mmol) of ethyl 5- (tert-butoxycarbonyl- {2- [tert-butyl (diphenyl) silyl] oxyethyl} amino) -3-oxopentanoate synthesized in Step 1 ) Was added to 150 mL of ethanol, and 5.33 g (37.2 mmol) of 2-chloro-6-hydrazinylpyridine was added and stirred at room temperature for 24 hours. After cooling the reaction solution with ice, 4.18 g (37.2 mmol) of potassium tert-butoxide was gradually added, stirred for 2 hours, warmed to room temperature, and further stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with chloroform. 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 = 75/25) to give 15.3 g of the title compound (yield 73.3%). 0%) was obtained as an oil.
¹ H-NMR (CDCl ₃ ) δ: 11.30-11.24 (1H, m), 7.77 (2H, d, J = 11.0 Hz), 7.65 (7H, d, J = 16.5 Hz), 7.39 (10H, t, J = 20.8 Hz), 7.14 (1H, d, J = 20.1 Hz), 5.45 (1H, d, J = 14.6 Hz), 3.77-3.69 (3H, m), 3.61-3.55 (3H, m), 3.40-3.36 (2H, m), 2.83-2.76 (2H, m), 1.47-1.36 (9H, m), 1.05 (9H, s).

(Step 3) tert-Butyl N- {2- [2- (6-chloro-2-pyridyl) -3-oxo-1H-pyrazol-5-yl] ethyl} -N- (2-hydroxyethyl) carbamate Tert-butyl N- {2- [tert-butyl (diphenyl) silyl] oxyethyl} -N- {2- [1- (6-chloro-2-pyridyl) -5-oxo-4H-pyrazole- synthesized in Step 2 To a 200 mL tetrahydrofuran solution of 15.3 g (24.6 mmol) of 3-yl] ethyl} carbamate, 27.0 mL (27.0 mmol) of tetrabutylammonium fluoride (1M tetrahydrofuran solution) was added under ice cooling. After warming to room temperature and stirring for 15 hours, the reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 80/20) to obtain 8.89 g (yield 94.0%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 11.29 (1H, br s), 7.84-7.67 (2H, m), 7.15 (1H, d, J = 7.9 Hz), 5.49 (1H, br s), 3.86-3.72 (2H, m), 3.60-3.50 (2H, m), 3.43-3.33 (2H, m), 2.87-2.77 (2H, m), 1.35 (9H, s).

(Step 4) 1- (6-Chloro-2-pyridyl) -3-nitro-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5- d] [1,4] diazepin-2-one tert-butyl N- (2-hydroxyethyl) -N- [2- (5-oxo-1-phenyl-4H-pyrazole-3 of Example 93, step 6] Tert-Butyl N- {2- [2- [6- (2-chloro-2-pyridyl) -3-oxo-1H-pyrazol-5-yl] ethyl}-synthesized in Step 3 instead of -yl) ethyl] carbamate Using N- (2-hydroxyethyl) carbamate, the reaction was carried out in the same manner as in Step 93 of Example 93 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.91-7.85 (2H, m), 7.34-7.31 (1H, m), 4.29-4.24 (1H, m), 4.21-4.07 (4H, m), 4.06-4.00 ( 1H, m), 3.84-3.74 (2H, m).

(Step 5) 3-amino-1- (6-chloro-2-pyridyl) -6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5- d] [1,4] diazepin-2-one 1- (6-chloro-2-pyridyl) -3-nitro-6- (2,2,2-trifluoroacetyl) -4,5 synthesized in Step 4 , 7,8-Tetrahydropyrazolo [1,5-d] [1,4] diazepin-2-one 535 mg (1.32 mmol) in 10 mL of ethanol was added 80% 5% platinum sulfide carbon catalyst and hydrogenated at room temperature. Stir for 10 hours under atmosphere. The reaction solution was filtered, and the filtrate was concentrated to obtain 318 mg (yield 64.2%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.12 (1H, t, J = 8.2 Hz), 7.76 (1H, td, J = 7.9, 2.4 Hz), 7.16 (1H, dd, J = 7.9, 3.7 Hz), 4.12-3.90 (4H, m), 3.63-3.53 (2H, m), 3.04-2.89 (4H, m).
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 to synthesize Example 111 below.

Example 112 5-chloro-N- {4-[(4,6-dimethyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1 , 4] diazepin-3-yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxypyridine-3-carboxamide

(Step 1) 3-Amino-4-methyl-1-phenyl-6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1 , 4] diazepin-2-one Using ethyl methacrylate instead of ethyl acrylate in Step 1 of Example 93, the reaction was carried out in the same manner to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.49-7.43 (4H, m), 7.30-7.27 (1H, m), 4.26-4.23 (0.7H, m), 3.98-3.95 (0.7H, m), 3.84- 3.74 (1.3H, m), 3.69-3.66 (1.3H, m), 3.54-3.49 (0.3H, m), 3.34-3.28 (2.7H, m), 3.09 (1.4H, s), 3.06 (0.6H , s), 1.39 (0.9H, d, J = 7.3 Hz), 1.32 (2.1H, d, J = 7.3 Hz).
Thereafter, the reaction was carried out in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 112 to 114 were synthesized.

Example 115 5-Chloro-2-ethoxy-N- (4-{[1- (2-fluorophenyl) -6-methyl-2-oxo-4,5,7,8-tetrahydropyrazolo [1 , 5-d] [1,4] diazepin-3-yl] amino} -2,2-dimethyl-4-oxobutyl) benzamide

(Step 1) 3-amino-1- (2-fluorophenyl) -6- (2,2,2-trifluoroacetyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [ 1,4] diazepin-2-one Using 2-fluorophenylhydrazine instead of phenylhydrazine in Step 5 of Example 93, and thereafter performing the reaction in the same manner as in Step 8 of Example 93, the title compound was converted into a solid Got as.
¹ H-NMR (CDCl ₃ ) δ: 7.42-7.32 (2H, m), 7.26-7.21 (2H, m), 3.93-3.78 (4H, m), 3.38-3.28 (2H, m), 3.01-2.92 ( 2H, m), 2.60 (2H, br s).
MS (ESI) m / z: 359 [(M + H) ⁺ ].
Thereafter, the reaction was conducted in the same manner as in Step 11 to Step 12 of Example 23 and Step 1 of Example 35, and the following Examples 115 to 116 were synthesized.

Example 117 5-Chloro-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazin-3-yl) amino] butyl} -2-methoxybenzamide

(Step 1) Ethyl 4- (2-benzyloxyethoxy) -3-oxobutanoate 1.99 g (45.6 mmol) of sodium hydride (55%) was suspended in 100 mL of tetrahydrofuran, and 2-benzyloxyethanol 6 0.01 g (39.5 mmol) was added. The reaction mixture was stirred at 40 ° C. for 10 minutes, and then a solution of ethyl 4-chloro-3-oxobutanoate (5.00 g, 30.4 mmol) in 10 mL of tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 2 hours. After cooling to room temperature and further stirring for 19.5 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. After filtration, the residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Shoko Scientific, elution solvent; hexane / ethyl acetate = 90 / 10-70 / 30). The title compound (4.21 g, yield 49.4%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.37-7.33 (4H, m), 7.31-7.28 (1H, m), 4.56 (2H, s), 4.21-4.16 (4H, m), 3.72-3.70 (2H, m), 3.67-3.64 (2H, m), 3.53 (2H, s), 1.26 (3H, t, J = 7.2 Hz).

(Step 2) Ethyl 4- (2-hydroxyethoxy) -3-oxobutanoate 0.500 g (1.78 mmol) of ethyl 4- (2-benzyloxyethoxy) -3-oxobutanoate synthesized in Step 1 was added to 100 mL of methanol. After dissolution, 0.20 g of 5% palladium carbon catalyst (PH type) was added. After stirring the reaction mixture under a hydrogen atmosphere for 4.5 hours, the inside of the reaction system was replaced with nitrogen, and insoluble materials were removed by filtration. The residue obtained by concentrating the filtrate under reduced pressure was purified by silica gel column chromatography (Shoko Scientific Co., elution solvent; hexane / ethyl acetate = 70/30 to 40/60) to give the title compound 0. 277 g (81.7% yield) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.93 (1H, d, J = 1.7 Hz), 4.25-4.20 (3H, m), 3.78-3.73 (2H, m), 3.68-3.63 (1H, m), 3.55 (1H, dt, J = 11.6, 1.7 Hz), 3.46 (1H, dd, J = 11.5, 1.7 Hz), 2.66 (1H, d, J = 15.5 Hz), 2.49 (1H, d, J = 15.5 Hz) , 1.29 (3H, t, J = 7.2 Hz).

(Step 3) Ethyl 4- (2-bromoethoxy) -3-oxobutanoate 0.277 g (1.45 mmol) of ethyl 4- (2-hydroxyethoxy) -3-oxobutanoate synthesized in Step 2 was added to 15 mL of methylene chloride. After dissolution, 0.572 g (2.18 mmol) of triphenylphosphine and 0.578 g (1.75 mmol) of carbon tetrabromide were added under ice cooling. After warming to room temperature and stirring for 21.5 hours, 0.230 g (0.693 mmol) of triphenylphosphine and 0.230 g (0.784 mmol) of carbon tetrabromide were added, and the mixture was further stirred for 1 hour. The residue obtained by distilling off the solvent from the reaction solution under reduced pressure was purified by silica gel column chromatography (Shoko Scientific, elution solvent; hexane / ethyl acetate = 90 / 10-70 / 30). The title compound (0.271 g, yield 73.8%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.23-4.19 (4H, m), 3.86 (2H, t, J = 5.7 Hz), 3.55 (2H, s), 3.50 (2H, t, J = 5.7 Hz), 1.29 (3H, t, J = 7.2 Hz).

(Step 4) 1-Phenyl-6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazin-2-one 4- (2-Bromoethoxy) -3-synthesized in Step 3 0.271 g (1.07 mmol) of ethyl oxobutanoate was dissolved in 10 mL of ethanol, and 0.199 mL (0.128 g, 1.18 mmol) of phenylhydrazine was added. The reaction mixture was heated to reflux for 10 hours, then cooled to room temperature and left overnight. The reaction mixture was further heated to reflux for 6 hours, cooled to room temperature, saturated aqueous sodium hydrogen carbonate 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 purified by silica gel column chromatography (Shoko Scientific, elution solvent; hexane / 10% methanol-ethyl acetate = 50 / 50-0 / 100) to give 0.0910 g of the title compound (yield 39 0.0%) as an oil.
¹ H-NMR (CDCl ₃ ) δ: 7.46-7.41 (4H, m), 7.29-7.26 (1H, m), 5.53 (1H, s), 4.58 (2H, s), 4.06 (2H, t, J = 4.9 Hz), 3.32 (2H, t, J = 4.9 Hz).

(Step 5) 3-Amino-1-phenyl-6,7-dihydro-4H-pyrazolo [5,1-c] [1,4] oxazin-2-one 1- (6- 1-phenyl-6,7-dihydro synthesized in Step 4 instead of chloro-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one Using 4H-pyrazolo [5,1-c] [1,4] oxazin-2-one, the reaction was carried out in the same manner as in Step 53 of Example 53 to obtain the title compound as a solid.
¹ H-NMR (CD ₃ OD) δ: 7.50-7.46 (4H, m), 7.34-7.29 (1H, m), 4.60 (2H, s), 3.98 (2H, t, J = 4.6 Hz), 3.06 ( (2H, t, J = 4.6 Hz).
Thereafter, the following Examples 117 to 118 were synthesized in the same manner as in Step 11 of Example 13.

Example 119 5-Chloro-N- (2,2-dimethyl-4-oxo-4-{[2-oxo-1- (2-phenyl) -4,5,6,8-tetrahydropyrazolo [ 1,5-d] [1,4] oxyazepin-3-yl] amino} butyl) -2-ethoxybenzamide

(Step 1) Ethyl 5- (2-chloroethoxy) -3-oxopentanoate Sodium hydride (55%) (2.32 g, 53.4 mmol) was washed with a small amount of hexane and dried. This was suspended in 80 mL of tetrahydrofuran and stirred at 0 ° C., 5.88 mL (6.06 g, 46.4 mmol) of ethyl acetoacetate was added, and the mixture was stirred at 0 ° C. for 10 minutes. To the reaction solution, 19.9 mL (53.4 mmol) of n-butyllithium (2.6 M hexane solution) was added and further stirred at 0 ° C. for 10 minutes. To the reaction solution, 4.64 mL (5.94 g, 44.2 mmol) of chloroethyl chloromethyl ether was added and stirred at 0 ° C. for 15 minutes. To the reaction solution was added 100 mL of 1N hydrochloric acid, and the mixture was extracted with diethyl ether. 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 = 90 / 10-50 / 50) to give 5.64 g of the title compound ( Yield 57.3%) was obtained as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.20 (2H, q, J = 7.0 Hz), 3.78 (2H, t, J = 6.3 Hz), 3.71 (2H, t, J = 5.9 Hz), 3.60 (2H, t, J = 5.6 Hz), 3.50 (2H, s), 2.83 (2H, t, J = 6.3 Hz), 1.28 (3H, t, J = 7.0 Hz).

(Step 2) 1- (6-Chloro-2-pyridyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] oxyazepin-2-one Synthesized in Step 1 Dissolve 5.38 g (24.2 mmol) of ethyl 5- (2-chloroethoxy) -3-oxopentanoate in 20 mL of ethanol and add 3.47 g (24.2 mmol) of (6-chloro-2-pyridyl) hydrazine. And stirred at room temperature for 2 hours. To the reaction solution, 5.02 g (36.3 mmol) of potassium carbonate was added, and the mixture was further stirred at room temperature for 2 hours. The residue obtained by evaporating the solvent under reduced pressure was suspended in 20 mL of N, N-dimethylformamide, 5.02 g (36.3 mmol) of potassium carbonate was added, and the mixture was stirred at 70 ° C. for 6 hours. The reaction solution was returned to room temperature, ethyl acetate was added, and insoluble matters were removed by filtration. The crude product obtained by concentrating the filtrate was subjected to silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 90/10). To give 3.25 g (yield 50.5%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.96 (1H, d, J = 8.1 Hz), 7.76 (1H, t, J = 8.1 Hz), 7.16 (1H, d, J = 8.1 Hz), 5.34 (1H, s), 4.01-4.00 (2H, m), 3.96-3.94 (2H, m), 3.88-3.87 (2H, m), 2.99-2.98 (2H, m).

(Step 3) 3-Amino-1- (2-pyridyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] oxyazepin-2-one hydrochloride Example 53 In Step 2, instead of 1- (6-chloro-2-pyridyl) -5,6,7,8-tetrahydro-4H-pyrazolo [1,5-a] azepin-2-one 1- (6-Chloro-2-pyridyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] oxyazepin-2-one was used for the following Example 53. The reaction was carried out in the same manner as in Step 4 to obtain the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.45-8.44 (1H, m), 7.89 (1H, d, J = 8.3 Hz), 7.81 (1H, t, J = 8.3 Hz), 7.17-7.16 (1H, m ), 3.95-3.91 (4H, m), 3.85-3.84 (2H, m), 3.32-3.31 (2H, m).
Thereafter, the following Examples 119 to 120 were synthesized in the same manner as in Step 11 of Example 23.

Example 121 5-Chloro-N- (2,2-dimethyl-4-{[1- (6-methyl-2-pyridyl) -2-oxo-4,5,7,8-tetrahydropyrazolo [ 1,5-d] [1,4] oxyazepin-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide

(Step 1) 3-amino-1- (6-methyl-2-pyridyl) -4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] oxyazepin-2-one Using (6-methyl-2-pyridyl) hydrazine instead of (6-chloro-2-pyridyl) hydrazine in Step 2 of Example 119, the reaction was carried out in the same manner as in Step 3 of Example 119, and the title compound Was obtained as a solid.
¹ H-NMR (CDCl ₃ ) δ: 7.86 (1H, d, J = 7.8 Hz), 7.68 (1H, t, J = 7.8 Hz), 6.99 (1H, d, J = 7.8 Hz), 4.00-3.98 ( 4H, m), 3.58-3.57 (2H, m), 2.94-2.92 (2H, m), 2.87 (2H, br s), 2.54 (3H, s).
Thereafter, the following Examples 121 to 122 were synthesized in the same manner as in Step 11 of Example 23.

Example 123 5-Chloro-2-ethoxy-N- {3-fluoro-2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-4,5,6,7- Tetrahydropyrazolo [1,5-a] pyridin-3-yl) amino] butyl} benzamide)
Using 3-amino-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-2-one synthesized in Step 1 of Example 12, Step 11 of Example 23 In the same manner as in Example 1, the following Example 123 was synthesized.

Example 124 5-Chloro-2-ethoxy-N- [2,2,3-trimethyl-4-oxo-4-[(2-oxo-1-phenyl-4,5,6,7-tetrahydropyra) Zolo [1,5-a] pyridin-3-yl) amino] butyl] benzamide

(Step 1) Ethyl 3-cyano-2,3-dimethylbutanoate Chem. Soc. Perkin Trans. 1 A solution of ethyl 3-cyano-3-methylbutanoate 3.51 g (22.6 mmol) synthesized in accordance with the method described in 1989, 265-278 in 80 mL of tetrahydrofuran was cooled to −78 ° C., and lithium diisopropylamide (N, N— A solution of 3.80 mL (2.74 g, 27.1 mmol) of diisopropylamine in tetrahydrofuran (32 mL) was cooled to 0 ° C., 15.0 mL (24.8 mmol) of n-butyllithium (1.65 M hexane solution) was added, and 60 Was added over 3 minutes and stirred for 1.5 hours. Next, a tetrahydrofuran 10 mL solution of a mixture of 4.20 mL (9.58 g, 67.0 mmol) of iodomethane and 7.90 mL (8.13 g, 45.0 mmol) of hexamethylphosphoric triamide was added over 1 minute for 2 hours. Stir. A saturated aqueous ammonium chloride solution (120 mL) / water (30 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Extraction was performed twice with diethyl ether, the organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain a residue. The residue was obtained by silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 98 / 2 to 70/30) to give 3.24 g (yield 84.7%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 4.20 (2H, q, J = 7.1 Hz), 2.53 (1H, q, J = 7.3 Hz), 1.42 (3H, s), 1.41 (3H, s), 1.35 ( 3H, d, J = 7.3 Hz), 1.29 (3H, t, J = 7.0 Hz).

(Step 2) Ethyl 4-amino-2,3,3-trimethylbutanoate hydrochloride 3.24 g (19.1 mmol) of ethyl 3-cyano-2,3-dimethylbutanoate synthesized in Step 1 and platinum oxide (IV ) To a mixture of 0.885 g (3.90 mmol), 75 mL of ethanol and 1.50 mL (17.0 mmol) of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. Subsequently, 0.865 g (3.81 mmol) of platinum (IV) oxide and 1.50 mL (17.0 mmol) of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered and washed with ethanol and the filtrate was concentrated. The obtained residue was dissolved in 30 mL of 1,4-dioxane, 30.0 mL (120 mmol) of 4N hydrochloric acid-1,4-dioxane solution was added, and the mixture was stirred at room temperature for 10 minutes. The solid obtained by concentrating the reaction mixture under reduced pressure was filtered and washed with diethyl ether to obtain 3.70 g (yield 92.1%) of the title compound as a solid.
¹ H-NMR (CD ₃ OD) δ: 4.21-4.12 (2H, m), 3.02 (1H, d, J = 12.8 Hz), 2.87 (1H, d, J = 13.4 Hz), 2.53 (1H, q, J = 7.3 Hz), 1.27 (3H, t, J = 7.3 Hz), 1.17 (3H, d, J = 7.3 Hz), 1.08 (3H, s), 1.04 (3H, s).

(Step 3) Ethyl 4- (tert-butoxycarbonylamino) -2,3,3-trimethylbutanoate 0.905 g of ethyl 4-amino-2,3,3-trimethylbutanoate hydrochloride synthesized in Step 2 (4 .32 mmol) in 10 mL of methylene chloride was added in the order of 3.00 mL (2.19 g, 21.0 mmol) of triethylamine and 6.0 mL of methylene chloride in 1.05 g (4.81 mmol) of di-tert-butyl dicarbonate. And stirred at room temperature for 12 hours. To the reaction mixture was added 30 mL of saturated aqueous sodium bicarbonate, and the mixture was 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 silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate = 98/2 to 66/34) to give 1.12 g of the title compound (yield 94.9). %) As an oil.
¹ H-NMR (CDCl ₃ ) δ: 4.91 (1H, br s), 4.14 (2H, q, J = 7.1 Hz), 3.18 (1H, dd, J = 14.0, 7.9 Hz), 2.87 (1H, dd, J = 14.0, 5.5 Hz), 2.40 (1H, q, J = 7.1 Hz), 1.44 (9H, s), 1.27 (3H, t, J = 7.3 Hz), 1.11 (3H, d, J = 7.3 Hz) , 0.95 (3H, s), 0.91 (3H, s).

(Step 4) 4- (tert-Butoxycarbonylamino) -2,3,3-trimethylbutanoic acid Ethyl 4- (tert-butoxycarbonylamino) -2,3,3-trimethylbutanoate synthesized in Step 3 To a solution of 12 g (4.10 mmol) in 11 mL of ethanol was added 6.14 mL (12.3 mmol) of a 2N aqueous sodium hydroxide solution, and the mixture was stirred at room temperature for 24 hours. Ethanol was distilled off from the reaction mixture under reduced pressure, 20 mL of water was added to the resulting residue, and the mixture was washed twice with diethyl ether. The aqueous layer was cooled to 0 ° C., 13.0 mL (13.0 mmol) of 1N hydrochloric acid aqueous solution was added to adjust pH to 1-2, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.755 g (yield 75.1%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 4.95 (1H, br t, J = 6.4 Hz), 3.19 (1H, dd, J = 14.6, 6.7 Hz), 2.98 (1H, dd, J = 14.3, 7.0 Hz) , 2.43 (1H, q, J = 6.9 Hz), 1.46 (9H, s), 1.13 (3H, d, J = 7.3 Hz), 0.96 (3H, s), 0.92 (3H, s).

(Step 5) tert-butyl N- {2,2,3-trimethyl-4-oxo-4-[(2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5- a] Pyridin-3-yl) amino] butyl} carbamate 3-amino-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine-synthesized in Step 1 of Example 12 282 mg (1.23 mmol) of 2-one, 250 mg (1.02 mmol) of 4- (tert-butoxycarbonylamino) -2,3,3-trimethylbutanoic acid synthesized in Step 4 and 4- (4,6-dimethoxy- To a mixture of 486 mg (1.65 mmol) of 1,3,5-triazin-2-yl) -4-methylmorpholinium chloride n hydrate (DMT-MM), 3.0 mL of ethanol and N , N-diisopropylethylamine 0.270 mL (200 mg, 1.55 mmol) was added, and the mixture was stirred at room temperature for 10 minutes and at 60 ° C. for 9 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate 8.0 mL / 8.0 mL water was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue obtained was silica gel column chromatography (Biotage, elution solvent; hexane / ethyl acetate → ethyl acetate / methanol = 70 / 30-0 / 100 → 100/0 to 92/8) to obtain 53.3 mg (yield 11.4%) of the title compound as an oily substance.
¹ H-NMR (CDCl ₃ ) δ: 7.69 (1H, br s), 7.47-7.38 (4H, m), 7.30-7.22 (1H, m), 5.28-5.18 (1H, br m), 3.32-3.19 ( 3H, m), 3.08-2.98 (1H, m), 2.86-2.70 (2H, m), 2.37 (1H, q, J = 7.3 Hz), 2.03-1.95 (2H, m), 1.86-1.78 (2H, m), 1.44 (9H, s), 1.18 (3H, d, J = 6.7 Hz), 0.99 (3H, s), 0.96 (3H, s).
MS (ESI) m / z: 457 [(M + H) ⁺ ]

(Step 6) 5-chloro-2-ethoxy-N-[{2,2,3-trimethyl-4-oxo-4-[(2-oxo-1-phenyl-4,5,6,7-tetrahydropyra Zolo [1,5-a] pyridin-3-yl) amino] butyl} benzamide tert-butyl N- {2,2,3-trimethyl-4-oxo-4-[(2-oxo-) synthesized in Step 5 1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl) amino] butyl} carbamate 53.3 mg (0.117 mmol) of 1,4-dioxane 0.33 mL / To a 0.66 mL solution of ethanol, 0.330 mL (1.32 mmol) of 4N hydrochloric acid-1,4-dioxane solution was added and stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure to give 4-amino-2,3,3-trimethyl-N- (2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a]. 66.2 mg of an oily substance mainly containing pyridin-3-yl) butanamide hydrochloride was obtained. 66.2 mg of this oily substance, 26.1 mg (0.130 mmol) of 5-chloro-2-ethoxybenzoic acid synthesized in Step 4 of Intermediate 1a, and O- (7-azabenzotriazol-1-yl) -N, N, N′-N′-tetramethylronium hexafluorophosphate (HATU) 56.1 mg (0.148 mmol) in N, N-dimethylformamide 1.0 mL solution, N, N-diisopropylethylamine 0.0530 mL ( 39.3 mg, 0.304 mmol) was added, and the mixture was stirred at room temperature for 83 hours. 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 silica gel column chromatography (Biotage, elution solvent: hexane / ethyl acetate → ethyl acetate / methanol = 50/50 to 0/100 → 100/0 to 90/10). did. The resulting residue was triturated with 0.10 mL of ethyl acetate / 3.0 mL of diethyl ether to produce a solid. The solid was collected by filtration and washed with diethyl ether to obtain 39.5 mg (yield 62.6%) of the title compound as a solid.
¹ H-NMR (CDCl ₃ ) δ: 8.95 (1H, br s), 8.35 (1H, br t, J = 6.4 Hz), 8.24 (1H, d, J = 2.4 Hz), 7.47-7.35 (5H, m ), 7.26-7.20 (1H, m), 6.91 (1H, d, J = 8.5 Hz), 4.20 (2H, q, J = 6.9 Hz), 4.18-4.12 (1H, m), 3.38-3.31 (1H, m), 3.20-3.13 (1H, m), 3.09 (1H, dd, J = 14.0, 5.5 Hz), 2.75 (2H, t, J = 6.4 Hz), 2.49 (1H, q, J = 6.9 Hz), 2.04-1.93 (2H, m), 1.90-1.69 (2H, m), 1.53 (3H, t, J = 7.0 Hz), 1.15 (3H, d, J = 7.3 Hz), 1.04 (3H, s), 1.00 (3H, s).
MS (ESI) m / z: 539 [(M + H) ⁺ ].

[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 Tables 31-1 to 31-4.

[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 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 31.
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 a 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. It was shown in 32-1-2.

[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. Each of the compounds of Examples shown in Table 57 was suspended in 0.5% solvent MC, and 200, 150, 100, or 75 mg / kg was administered twice a day (BID) and orally administered for 4 consecutive days. It was measured.
Also in the above test, the tumor growth inhibition rate was calculated by the following formula and shown in the table.
Table 33 shows the results of tumor growth inhibition rate (%) (= 100− (average value of tumor volume in test compound administration group) / (average 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 (13)

Formula (I)

[Where:
X and Z are each independently a C _{1 to} C ₃ alkylene group which may have one or two substituents independently selected from the following group A, or independently from the following group A: a substituent selected indicates one or two has good C ₂ even though -C ₃ alkenylene group,
Y represents a single bond, an oxygen atom, NR ¹ , or CR ¹ R ² ,
R ¹ is a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group C, and independently selected from the following group C C ₁ -C ₆ cycloalkyl group optionally having 1 to 3 substituents, and C ₁ -C ₆ optionally having 1 to 3 substituents independently selected from the following group C ₆ alkylcarbonyl group, 1 to 3 have C ₁ optionally -C ₆ alkyloxycarbonyl group a substituent selected independently from the following group C, C ₁ -C ₆ alkylsulfonyl group or toluene, Represents a sulfonyl group,
R ² represents a hydrogen atom or NR ²¹ R ²² ,
R ²¹ and R ²² are each independently a hydrogen atom, a C _{1 to} C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group C, A C _{3 to} C ₆ cycloalkyl group optionally having 1 to 3 substituents independently selected from the above, and 1 to 3 substituents independently selected from the following group C good _C 1 -C ₆ alkylcarbonyl group, a 1 to 3 may have _C 1 -C ₆ alkyloxycarbonyl group a substituent selected independently from the following group _C, C 1 -C Represents a ₆ alkylsulfonyl group, or a toluenesulfonyl group, or
In CR ¹ R ² , R ¹ and R ² together have 1 to 3 heteroatoms independently selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom in the ring 5 A 7 to 7 membered heterocyclic ring may be formed,
The 5- to 7-membered heterocyclic ring may have 1 to 3 substituents independently selected from the following group C;
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 which may have 1 to 5 substituents independently selected from the following group D, 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 D;
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 E: 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 E below. ]
Or a pharmacologically acceptable salt thereof.
Group A: halogen atom, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ alkyl group optionally having 1 to 3 substituents independently selected from the following group B: Group B: hydroxyl group, amino _group, C 1 -C ₆ alkoxy _group, C 1 -C ₆ alkylamino group, di _C 1 -C ₆ alkylamino group C group: a halogen atom, a hydroxyl group, a phenyl _group, C 1 -C ₆ alkylamino group, di C ₁ -C ₆ alkylamino group D group: halogen atom, C ₁ -C ₆ alkyl group optionally substituted by 1 to 3 halogen atoms, C ₁ -C ₆ alkoxy group E group: halogen atom, hydroxyl group A C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group optionally substituted by 1 to 3 halogen atoms, a C ₁ -C ₆ alkoxy C ₁ -C ₆ alkyl group, a C ₃ -C ₆ cycloalkoxy group, _{C 1} C ₆ alkoxy _C 1 -C ₆ alkoxy group In the formula (I),
X and Z are each _{independently,} C 1 -C ₃ alkyl groups represents 1 or 2 having _C 1 optionally -C ₃ alkylene group,
Y represents an oxygen atom, NR ^1a , or CR ^1a R ^2a ,
R ^1a represents a hydrogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 substituents independently selected from the following group F;
R ^2a represents a hydrogen atom or NR ^21a R ^22a ,
The compound according to claim 1 or a pharmacologically acceptable salt thereof, wherein R ^21a and R ^22a each independently represent a hydrogen atom or a C ₁ -C ₆ alkyl group.
Group F: halogen atom, hydroxyl group, di-C ₁ -C ₆ alkylamino group In the formula (I),
W is W ¹ or W ² below

The compound according to claim 1 or 2 or a pharmacologically acceptable salt thereof. 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 3, 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 or a halogen atom;
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 4, or a pharmacologically acceptable salt thereof. Formula (IV)

[Where:
R ⁸ represents the following formula (V) or (VI)

Indicate
(Wherein R ⁸¹ represents a halogen atom,
R ⁸² represents a hydrogen atom or a halogen atom,
R ⁸³ represents an ethoxy group, an isopropoxy group, or a methoxymethoxy group,
U represents a nitrogen atom or CH)
MQT represents the following formulas (VII) to (XI)

Any one of the rings is shown.
(In the formula, R ⁹¹ represents a methylamino group or a dimethylamino group,
R ⁹² represents a hydrogen atom or a methyl group,
R ⁹³ represents a hydrogen atom, a methyl group, an ethyl group, or an isopropyl group,
R ⁹⁴ represents a hydrogen atom or a methyl group)]
Or a pharmacologically acceptable salt thereof. Any one compound chosen from the following group, or its pharmacologically acceptable salt.
5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazol-3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide,
(+)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2- b] pyrazol-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide,
(−)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2- b] pyrazol-3-yl] amino} -4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-5,6-dihydro-4H-pyrrolo [1,2-b] pyrazole- 3-yl] amino} -4-oxobutyl) -2-ethoxypyridine-3-carboxamide,
5-Bromo-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] Pyridin-3-yl] amino} -4-oxobutyl} -2-ethoxypyridine-3-carboxamide,
(−)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3-yl] amino} -4-oxobutyl} -2-isopropoxybenzamide,
(+)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3-yl] amino} -4-oxobutyl} -2-methylbenzofuran-7-carboxamide,
(−)-5-chloro-N- (2,2-dimethyl-4-{[5- (methylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1, 5-a] pyridin-3-yl] amino} -4-oxobutyl} -2-methylbenzofuran-7-carboxamide,
5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl] Amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxy-4-fluorobenzamide,
5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridin-3-yl] Amino} -2,2-dimethyl-4-oxobutyl) -2- (methoxymethoxy) benzamide,
(+)-5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine- 3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide,
(-)-5-chloro-N- (4-{[5- (dimethylamino) -2-oxo-1-phenyl-4,5,6,7-tetrahydropyrazolo [1,5-a] pyridine- 3-yl] amino} -2,2-dimethyl-4-oxobutyl) -2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(5-methyl-2-oxo-1-phenyl-6,7-dihydro-4H-pyrazolo [1,5-a] pyrazin-3-yl ) Amino] -4-oxobutyl} -2-ethoxybenzamide,
5-chloro-N- {2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl] -2-ethoxybenzamide,
5-chloro-2-ethoxy-N- {4-[(6-isopropyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] Diazepin-3-yl) amino] -2,2-dimethyl-4-oxobutyl} benzamide,
5-chloro-N- {2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl} -2-ethoxy-4-fluorobenzamide,
5-chloro-N- {2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl] -2-ethoxypyridine-3-carboxamide,
5-chloro-N- {2,2-dimethyl-4-oxo-4-[(2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [ 1,4] diazepin-3-yl) amino] butyl} -2-methylbenzofuran-7-carboxamide,
5-chloro-N- [2,2-dimethyl-4-[(6-methyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1, 4] diazepin-3-yl) amino] -4-oxobutyl] -2- (methoxymethoxy) benzamide,
5-chloro-N- {4-[(4,6-dimethyl-2-oxo-1-phenyl-4,5,7,8-tetrahydropyrazolo [1,5-d] [1,4] diazepine- 3-yl) amino] -2,2-dimethyl-4-oxobutyl} -2-ethoxypyridine-3-carboxamide,
5-Bromo-N- {2,2-dimethyl-4-[(4-methyl-2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [ 1,4] diazepin-3-yl) amino] -4-oxobutyl} -2-ethoxypyridine-3-carboxamide,
5-chloro-N- {2,2-dimethyl-4-[(4-methyl-2-oxo-1-phenyl-5,6,7,8-tetrahydro-4H-pyrazolo [1,5-d] [ 1,4] diazepin-3-yl) amino] -4-oxobutyl} -2-methylbenzofuran-7-carboxamide A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 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 7 or a pharmacologically acceptable salt thereof as an active ingredient. An antitumor agent comprising the compound according to any one of claims 1 to 7 or a pharmacologically acceptable salt thereof 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 according to claim 10, which is a soft tissue tumor. The therapeutic agent of the tumor in which the expression level of TIP48 / TIP49 complex is increased, comprising the compound according to any one of claims 1 to 7 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 7, or its pharmacologically acceptable salt as an active ingredient. .