RU2805922C2 - Urea compound that is antagonist of lpa1 receptor - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to an urea compound having an LPA1 receptor antagonist effect represented by formula [I], or a pharmaceutically acceptable salt or hydrate thereof. The meanings of the radicals in formula [I] are defined in the claims. Also the following is proposed: a medicinal product for the prevention or treatment of a disease caused by LPA1, containing a compound of formula [I], in particular for the prevention or treatment of systemic scleroderma.

EFFECT: compound represented by formula [I] has an antagonistic effect on the LPA1 receptor and can be used to prepare a drug effective for the prevention or treatment of diseases associated with fibrosis such as systemic scleroderma.

15 cl, 210 tbl, 632 ex

Description

TECHNICAL FIELD

The present invention relates to a medicament containing an LPA1 receptor antagonist as an active ingredient. More specifically, the present invention relates to a medicament containing a urea compound that is an LPA1 receptor antagonist as an active ingredient.

BACKGROUND OF THE ART

Lysophosphatidic acids (they may also be referred to herein as "LPAs") are physiologically active phospholipids in which a fatty acid is linked to the first position or second position of the glycerol backbone and a phosphate group is linked to the third position, and examples include 1-acyl-LPA, 1-alkyl-LPA and 2-acyl-LPA. They also show diversity in terms of the type of fatty acid bound, and there are many subtypes of LPA that exhibit different chemical and physiological properties depending on the length of the carbon chain and the degree of unsaturation of the fatty acid.

LPAs are produced in vivo by various LPA-producing enzymes and are known to bind to G protein-coupled receptors on the cell surface, thereby transducing signals into the cell and exhibiting a variety of physiological actions. Regarding the LPA receptor, six subtypes are known, receptors LPA1 - LPA6. Three types of receptors, LPA1 receptor, LPA2 receptor and LPA3 receptor, belong to the EDG (endothelial differentiation gene) family, and are designated EDG2, EDG4 and EDG7, respectively. The LPA4 - LPA6 receptors do not belong to the EDG family and have low homology with the EDG family mentioned above. LPA receptor subtypes are distributed throughout the living organism, but their localization varies depending on the subtype, and the subtypes are thought to contribute to the physiological function of the tissues in which they exist.

LPAs have been shown to be involved in various fibrotic diseases, and the receptor family of EDG receptors in particular has been suggested to be involved. With regard to pulmonary fibrosis, it has been reported that LPA concentration is increased in alveolar lavage fluid from patients with idiopathic pulmonary fibrosis and in a mouse model of bleomycin-induced pulmonary fibrosis, and that in the same mouse model, progression of fibrosis is markedly suppressed in Lpar1-deficient mice and in mice administered an LPA1 receptor antagonist drug (see NPL 1). Likewise, serum LPA concentrations are also increased in patients with systemic scleroderma, and LPA1 receptor antagonist drugs and LPA1/3 antagonist drugs have been reported to have an inhibitory effect on fibrosis in a mouse model of bleomycin-induced skin fibrosis (see NPL 2-4). In renal fibrosis, LPA production is accelerated in a unilateral ureteral ligation mouse model, and fibrosis formation has been reported to be inhibited in Lpar1-deficient mice and by LPA1 receptor antagonist drugs (see NPLs 4 and 5). In addition, with regard to liver fibrosis, the blood concentration of LPA has been reported to be increased in patients with chronic hepatitis C, and its extent has been reported to correlate with the histological stage of fibrosis (see NPL 6). In addition, it has been shown that the expression of autotaxin, which is the enzyme that produces LPA, is accelerated in the blood of patients with non-alcoholic fatty liver disease (NAFLD), and that autotaxin inhibitors exhibit inhibitory effects in various mouse models of liver disease (see NPL 7 and 8). In addition, it has been reported that the accumulation of LPA at high concentrations in atherosclerotic plaques leads to accelerated inflammation and apoptosis-inducing effects, but damage in a mouse model is reduced by administration of LPA1/3 antagonist drugs, suggesting the involvement of LPA also in diseases of the circulatory system ( see NPL 9).

LPAs are also known to induce migration and proliferation of cancer cells, and increased concentrations of LPA and increased expression of LPA1 receptors have been observed in tissues of patients with various types of cancer (see NPL 10-12).

In addition, LPAs have been reported to contract bladder smooth muscle cells, promote prostate cell proliferation, and participate in the regulation of urethral internal pressure in vivo, suggesting their involvement in lower urinary tract diseases (see PTL 1 and NPL 13 and 14).

In addition, LPAs have been reported to contract bladder smooth muscle cells, promote prostate cell proliferation, and participate in the regulation of urethral internal pressure in vivo, suggesting their involvement in lower urinary tract diseases (see PTL 1 and NPL 13 and 14).

In addition, LPA and LPA receptors are expressed in the nervous system, and LPAs have been shown to induce the expression of neuropathic pain through the LPA1 receptor. Lpar1 knockout mice have been reported to exhibit no pain symptoms in a nerve ligation mouse model of pain (see NPL 15).

Also reported as a substance that antagonizes the LPA1 receptor are, for example, alkanoic acid compounds having (PTL 2-4), cyclohexylcarboxylic acid compounds having a triazole ring (PTL 5), and carboxylic acid compounds having an amide structure (PTL 6 -7), but there is no description of the urea compounds of the present invention.

LIST OF QUOTES

PATENT LITERATURE

PTL 1: WO 02/062389

PTL 2: WO03/099765

PTL 3: WO2004/031118

PTL 4: WO2005/058790

PTL 5: WO2017/223016

PTL 6: WO2015/025164

PTL 7: WO2017/177004

NON-PATENT LITERATURE

NPL 1: Nat Med. 2008 Jan; 14(1): 45-54.

NPL 2: Int J Med Sci. 2009 Jun 5; 6(4): 168-76.

NPL 3: Exp Dermatol. 2015 Sep; 24(9): 698-702.

NPL 4: Pharmacol Exp Ther. Mar 2011; 336(3): 693-700.

NPL 5: J Am Soc Nephrol. 2007 Dec; 18(12): 3110-8.

NPL 6: J Clin Gastroenterol. July 2007; 41(6): 616-23.

NPL 7: Obesity (Silver Spring). May 2015; 23(5): 965-972.

NPL 8: J Pharmacol Exp Ther. 2017 Jan; 360(1): 1-13.

NPL 9: Sci Rep. 2016 Nov 24; 6: 37585.

NPL 10: JAMA. 1998 Aug 26; 280(8): 719-23.

NPL 11: Endocrinology. 2006 Oct; 147(10): 4883-92.

NPL 12: Proc Natl Acad Sci U S A. 2006 Jun 20; 103(25): 9643-8.

NPL 13: J Urol. 1999 Nov; 162(5): 1779-84.

NPL 14: J Urol. Mar 2000; 163(3): 1027-32.

NPL 15: Nat Med. July 2004; 10(7): 712-8.

SUMMARY OF THE INVENTION

TECHNICAL PROBLEM

The object of the present invention is to obtain a new compound that is an antagonist of the LPA1 receptor.

SOLUTION

As a result of careful studies aimed at solving the problems described above, the present inventors have discovered that the compound represented by the following formula [I] (hereinafter may also be referred to as compound [I]) has an antagonistic effect on the LPA1 receptor.

Next, the present invention will be described in detail.

That is, aspects of the present invention are as follows.

(1) One aspect of the present invention is to prepare the compound represented by formula [I]:

[Chemical formula 1]

,

or a pharmaceutically acceptable salt or hydrate thereof,

where X represents carboxy, C _1-4 alkoxycarbonyl, carbamoyl, tetrazolyl, or a group selected from the group of formulas [II]:

[Chemical formula 2]

;

W represents a linear C _1-3 alkanediyl or a structure selected from the group of formulas [III]:

[Chemical formula 3]

,

Where

linear C _1-3 alkanediyl is optionally substituted by one group selected from the group consisting of C _1-6 alkyl (C _1-6 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and carboxy), halo-C _1-6 alkyl, C _3-8 cycloalkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and

if a linear C _1-3 alkanediyl is substituted with one methyl, it is optionally further substituted with one methyl,

ring A ¹ , ring A ² and ring A ³ are each a C _3-8 cycloalkane, a partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle containing a sulfur atom 4-8- membered saturated heterocycle, or 4-8 membered saturated heterocycle containing a nitrogen atom,

Where

the sulfur atom in the 4-8-membered saturated heterocycle containing a sulfur atom is optionally replaced by one or two oxo,

the nitrogen atom in the nitrogen atom-containing 4-8 membered saturated heterocycle is optionally substituted by one group selected from the group consisting of C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl, and

R ^A11 , R ^A21 and R ^A31 each independently represent a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl, or a nitrogen-containing 4-6 membered saturated heterocyclyl (nitrogen containing 4-6 membered saturated heterocyclyl optionally substituted with one C _1-3 alkyl), and

R ^A12 , R ^A22 and R ^A32 each independently represent a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally together form an oxo, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally form a C _3-6 cycloalkane together with carbon atoms in the adjacent ring;

R ¹ represents a hydrogen atom or methyl;

R ² represents C _6-10 alkyl, C _6-10 alkenyl, C _6-10 alkynyl, or a group represented by formula [IV-1] or [IV-2]:

[Chemical formula 4]

,

Where

ring B ¹ is a C _3-8 cycloalkyl, nitrogen-containing 4-8-membered saturated heterocyclyl, phenyl or nitrogen-containing 5-6-membered heteroaryl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy,

L ¹ represents C _3-8 alkanediyl (C _3-8 alkanediyl is optionally substituted with 1-5 fluorine atoms), the structure represented by the formula [V-6]: -CH ₂ CH ₂ CH=C(CH ₃ )- or the structure, represented by formula [V-1]:

[Chemical formula 5]

,

Where

n11 represents an integer from 0 to 3,

n12 represents an integer from 0 to 5,

n13 is an integer from 0 to 3, and

one carbon atom in the C _3-8 alkanediyl, which is two or more atoms away from the nitrogen atom to which R ² is attached, is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L11 )- and in addition ,

two consecutive carbon atoms in a C _3-8 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L12 )-,

R ^L11 represents a hydrogen atom or C _1-3 alkyl, and

R ^L12 represents a hydrogen atom or C _1-3 alkyl,

ring B ² is a partially saturated 9-10 membered fused ring aryl or a nitrogen-containing 9-10 membered fused ring heteroaryl,

R ^B21 and R ^B22 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy,

L ² is C _1-2 alkanediyl (C _1-2 alkanediyl optionally substituted with 1-4 fluorine atoms), C _3-6 alkanediyl (C _3-6 alkanediyl optionally substituted with 1-5 fluorine atoms) or the structure represented by the formula [V -2]:

[Chemical formula 6]

,

Where

n21 represents an integer from 0 to 3,

n22 represents an integer from 0 to 5,

n23 is an integer from 0 to 3, and

one carbon atom in the C _3-6 alkanediyl, which is two or more atoms from the nitrogen atom to which R ² is attached, is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L21 )-, and in addition Togo,

two consecutive carbon atoms in a C _3-6 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L22 )-,

R ^L21 represents a hydrogen atom or C _1-3 alkyl, and

R ^L22 represents a hydrogen atom or C _1-3 alkyl;

R ³ represents a hydrogen atom or C _1-3 alkyl (C _1-3 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and methoxy); And

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 7]

,

Where

ring C is a phenyl containing a nitrogen atom, a 6-membered heteroaryl or a 9-10-membered fused ring heteroaryl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of of hydroxy and _C1-6 alkoxy), halo- _C1-6 alkyl (halogen- _C1-6 alkyl is optionally substituted with one hydroxy), _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl (C _3-8 cycloalkyl is optionally substituted with one hydroxy), C _1-6 alkoxy, halogen-C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono- _C1-6 alkylamino, di- _C1-6 alkylamino, C1-6 alkylcarbonyl, halo- _C1-6 alkylcarbonyl, _C1-6 alkoxycarbonyl, mono- _C1-6 alkylaminocarbonyl _and di- _C1-6 alkylaminocarbonyl,

the nitrogen-containing 6-membered heteroaryl is replaced by one C _1-6 alkoxy, and in addition,

the nitrogen atom-containing 6-membered heteroaryl is optionally substituted with one to two groups, the same or different, selected from the group consisting of cyano, C _1-6 alkyl, C _1-6 alkoxy and oxo, and

The 9-10 membered fused ring heteroaryl is optionally substituted with one to four groups, identical or different, selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and oxo; or

R ³ and R ⁴ , together with their adjacent carbon atom, optionally form a partially substituted 9-10 membered fused hydrocarbon aromatic ring or a partially substituted oxygen atom-containing 9-10 membered fused heteroaromatic ring,

Where

the partially saturated 9-10 membered fused hydrocarbon aromatic ring is optionally substituted with one to two halogen atoms, and

the partially saturated oxygen atom containing 9-10 membered fused heteroaromatic ring is optionally substituted with one to two halogen atoms.

(2) Another aspect of the present invention is to provide the compound of (1) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the formula of group [III] for W,

R ^A11 , R ^A21 and R ^A31 each independently represent a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy or nitrogen-containing 4-6 membered saturated heterocyclyl (nitrogen-containing 4- The 6-membered saturated heterocyclyl is optionally substituted with one C _1-3 alkyl), and

R ^A12 , R ^A22 and R ^A32 each independently represent a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally together form an oxo, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally form a C _3-6 cycloalkane together with carbon atoms in the adjacent ring, and

where, in formula [IV-1] for R ² ,

L ¹ is C _3-8 alkanediyl (C _3-8 alkanediyl is optionally substituted with 1-5 fluorine atoms) or the structure represented by the formula [V-1],

Where

one carbon atom in the C _3-8 alkanediyl, which is two or more atoms away from the nitrogen atom to which R ² is attached, is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L11 )- and in addition ,

two consecutive carbon atoms in a C _3-8 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L12 )-,

R ^L11 represents a hydrogen atom or C _1-3 alkyl, and

R ^L12 represents a hydrogen atom or C _1-3 alkyl.

(3) Another aspect of the present invention is to provide the compound of (1) or (2) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

W represents a linear C _1-3 alkanediyl or a structure selected from the group of formulas [III]:

[Chemical formula 8]

,

Where

linear C _1-3 alkanediyl is optionally substituted by one group selected from the group consisting of C _1-6 alkyl (C _1-6 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and carboxy), halo-C _1-6 alkyl, C _3-8 cycloalkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and

if a linear C _1-3 alkanediyl is substituted with one methyl, it is optionally further substituted with one methyl,

ring A ¹ is a C _3-8 cycloalkane, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, azetidine, pyrrolidine or piperidine,

ring A ² is a C _3-8 cycloalkane or tetrahydropyran, and

ring A ³ is a C _3-8 cycloalkane, dihydroindene or tetrahydropyran,

Where

the sulfur atom in the tetrahydrothiopyran is optionally replaced by one to two oxos, and

the nitrogen atom in each of azetidine, pyrrolidine and piperidine is optionally replaced by one C _1-4 alkylcarbonyl, and

R ^A11 represents a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl or nitrogen-containing 4-6-membered saturated heterocyclyl (containing a 4-6-nitrogen atom the saturated heterocyclyl member is optionally substituted with one C _1-3 alkyl), and

R ^A12 represents a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 optionally together form oxo,

R ^A21 and R ^A22 both represent hydrogen atoms,

R ^A31 and R ^A32 both represent hydrogen atoms, and in addition,

R ^A11 and R ^A12 optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent ring;

R ² represents a C _6-10 alkyl or a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 9]

,

Where

ring B ¹ is C _3-8 cycloalkyl, piperidinyl, phenyl, pyrazolyl or pyridyl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy, and

L ¹ is any of the structures represented by formulas [V-3] - [V-12] and [V-14] - [V-19]:

[Chemical formula 10]

,

Where

n4 represents an integer from 3 to 5,

n12' represents an integer from 0 to 3,

n12'' is an integer from 0 to 3, and

ring B ² is dihydroindenyl, indolyl or isoindolinyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 11]

,

Where

n5 is an integer from 1 to 2; And

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 12]

,

Where

ring C is phenyl, pyridyl, pyrimidinyl, dihydropyridinyl, dihydrobenzofuranyl, benzodioxanyl, indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, indolinyl or dihydroquinazolinyl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of of hydroxy and C _1-6 alkoxy), halo-C _1-6 alkyl (halo-C _1-6 alkyl is optionally substituted with one hydroxy), C _2-6 alkenyl, C _3-8 cycloalkyl (C _3-8 cycloalkyl is optionally substituted single hydroxy), C _1-6 alkoxy, halogen-C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl and mono-C _1-6 alkylaminocarbonyl,

pyridyl is substituted with one C _1-6 alkoxy and in addition,

pyridyl is optionally substituted with one group selected from the group consisting of cyano and C _1-6 alkoxy,

pyrimidinyl is substituted with one C _1-6 alkoxy and in addition,

pyrimidinyl is optionally substituted with one C _1-6 alkoxy,

dihydropyridinyl is substituted with one C _1-6 alkoxy, and in addition,

The dihydropyridinyl is optionally substituted with one to two groups, the same or different, selected from the group consisting of C _1-6 alkyl and oxo,

dihydrobenzofuranyl and benzodioxanyl are optionally substituted with one C ₁ - ₆ alkoxy,

indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl and indolinyl are optionally substituted with one or two groups, the same or different, selected from the group consisting of C _1-6 alkyl and C _1-6 alkoxy, and

dihydroquinazolinyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and oxo; or

the fused ring formed by R ³ and R ⁴ together with their adjacent carbon atom is dihydroindene or dihydrobenzofuran, and

The dihydroindene and dihydrobenzofuran are optionally substituted with one or two halogen atoms.

(4) Another aspect of the present invention is to provide a compound of (1) or (2) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

X represents carboxy, C _1-4 alkoxycarbonyl or tetrazolyl;

R ¹ represents a hydrogen atom; And

R ² represents the group represented by the above formula [IV-1] or [IV-2]:

[Chemical formula 13]

.

(5) Another aspect of the present invention is to provide a compound of any one of (1), (2), and (4) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

W represents methandiyl or the structure represented by formula [III-1]:

[Chemical formula 14]

,

Where

methanediyl is optionally substituted with one group selected from the group consisting of C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of hydroxy and carboxy), halo-C _1-6 alkyl, C _{3- 8} cycloalkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and

if methandiyl is substituted with one methyl, it is optionally further substituted with one methyl, and

where, in the structure represented by formula [III-1],

ring A ¹ is a C _3-8 cycloalkane, a partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle, containing a sulfur atom 4-8 membered saturated heterocycle or containing a nitrogen atom 4- 8-membered saturated heterocycle,

Where

the sulfur atom in the sulfur atom-containing 4-8-membered saturated heterocycle is optionally replaced by one to two oxos, and

the nitrogen atom in the nitrogen atom-containing 4-8 membered saturated heterocycle is optionally substituted by one group selected from the group consisting of C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl, and

R ^A11 represents a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy or a nitrogen-containing 4-6-membered saturated heterocyclyl (a nitrogen-containing 4-6-membered saturated heterocyclyl is optionally substituted with one C _1-3 alkyl), and

R ^A12 represents a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 optionally together form oxo and furthermore

R ^A11 and R ^A12 optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent ring.

(6) Another aspect of the present invention is to provide a compound of any of (1), (2), (4), and (5) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 15]

,

Where

ring C is phenyl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of of hydroxy and _C1-6 alkoxy), halo- _C1-6 alkyl (halogen- _C1-6 alkyl is optionally substituted with one hydroxy), _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl (C _3-8 cycloalkyl is optionally substituted with one hydroxy), C _1-6 alkoxy, halogen-C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono- C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, mono-C _1-6 alkylaminocarbonyl and di-C _1-6 alkylaminocarbonyl.

(7) Another aspect of the present invention is to provide a compound of any one of (1), (2), and (4) to (6) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 16]

,

Where

ring B ¹ represents phenyl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy, and

L ¹ is any of the structures represented by formulas [V-3] - [V-5], [V-7] - [V-8], [V-11] - [V-12] and [V-14] - [V-16]:

[Chemical formula 17]

,

Where

n4 represents an integer from 3 to 5, and

ring B ² is dihydroindenyl, indolyl or isoindolinyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is a structure represented by the formula [V-20]:

[Chemical formula 18]

,

Where

n5 represents an integer between 1 and 2.

(8) Another aspect of the present invention is to provide a compound according to any one of (4) to (7) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

X represents carboxy;

W is any of the structures represented by formulas [III-4] - [III-17]:

[Chemical formula 19]

;

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 20]

,

Where

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by the formula [V-3], [V-8], [V-12], [V-14] or [V-15]:

[Chemical formula 21]

,

Where

n4 is an integer between 3 and 4, and

ring B ² is dihydroindenyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 22]

,

Where

n5 is 2;

R ³ represents methyl having the spatial configuration represented by formula [VII]:

[Chemical formula 23]

; And

R ⁴ represents a group represented by any of the formulas [VI-1] - [VI-21]:

[Chemical formula 24]

[Chemical formula 25]

[Chemical formula 26]

.

(9) Another aspect of the present invention is to provide a compound according to any one of (4) to (7) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

X represents carboxy;

W is a structure represented by any of the formulas [III-4] - [III-11], [III-13] - [III-14] and [III-18] - [III-19]:

[Chemical formula 27]

;

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 28]

,

Where

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by formula [V-3], [V-8] or [V-14]:

[Chemical formula 29]

,

Where

n4 is equal to, and

ring B ² is dihydroindenyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 30]

,

Where

n5 is 2;

R ³ represents methyl having the spatial configuration represented by formula [VII]:

[Chemical formula 31]

; And

R ⁴ represents a group represented by the formula [VI-2], [VI-3], [VI-8], [VI-10] - [VI-12], [VI-16], [VI-19] or [VI-21]:

[Chemical formula 32]

[Chemical formula 33]

.

(10) Another aspect of the present invention is to provide a compound according to any one of (4) to (7) or a pharmaceutically acceptable salt or hydrate thereof,

where, in the above formula [I],

X represents carboxy or tetrazolyl;

W is a structure represented by the formula [III-5], [III-8] - [III-11] or [III-13]:

[Chemical formula 34]

;

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 35]

,

Where

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by formula [V-3], [V-12] or [V-14]:

[Chemical formula 36]

,

Where

n4 represents an integer from 4, and

ring B ² is dihydroindenyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 37]

,

Where

n5 is 2;

R ³ represents methyl having the spatial configuration represented by formula [VII]:

[Chemical formula 38]

; And

R ⁴ represents a group represented by the formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11] or [VI-12]:

[Chemical formula 39]

.

(11) Another aspect of the present invention is to provide the compound of (1), which is any of the following:

[Chemical formula 40]

[Chemical formula 41]

[Chemical formula 42]

[Chemical formula 43]

[Chemical formula 44]

or a pharmaceutically acceptable salt or hydrate thereof.

(12) Another aspect of the present invention is to provide the compound of (1), which is any of the following:

[Chemical formula 45]

[Chemical formula 46]

[Chemical formula 47]

or a pharmaceutically acceptable salt or hydrate thereof.

(13) Another aspect of the present invention is to provide a medicament containing a compound according to any one of (1) to (12) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

(14) Another aspect of the present invention is to provide an LPA1 receptor antagonist containing the compound of any one of (1) to (12) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

(15) Another aspect of the present invention is to provide a medicament for the prevention or treatment of systemic scleroderma containing a compound according to any of (1) to (12) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

(16) Another aspect of the present invention is to provide an LPA1 receptor antagonist containing as an active ingredient a compound represented by formula [Ia]:

[Chemical formula 48]

,

or a pharmaceutically acceptable salt or hydrate thereof,

Where

X represents carboxy, C _1-4 alkoxycarbonyl, carbamoyl, tetrazolyl or a structure selected from the group of formulas [IIa]:

[Chemical formula 49]

;

W represents a linear C _1-3 alkanediyl or a structure selected from the group of formulas [IIIa]:

[Chemical formula 50]

,

Where

linear C _1-3 alkanediyl is optionally substituted by one group selected from the group consisting of C _1-6 alkyl (C _1-6 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and carboxy), halo-C _1-6 alkyl, C _3-8 cycloalkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and

if a linear C _1-3 alkanediyl is substituted with one methyl, it is optionally further substituted with one methyl,

ring A ¹ , ring A ² and ring A ³ are each a C _3-8 cycloalkane, partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle, partially substituted containing a 9- oxygen atom 10-membered fused saturated heterocycle containing a sulfur atom 4-8-membered saturated heterocycle, partially substituted containing a nitrogen atom 9-10-membered fused saturated heterocycle containing a nitrogen atom 4-8-membered saturated heterocycle or partially substituted containing a sulfur atom 9- 10-membered fused heterocycle,

Where

the sulfur atom in each of the sulfur-containing 4-8-membered saturated heterocycles and the partially saturated sulfur-containing 9-10-membered saturated heterocycles is optionally substituted by one to two oxo, and

the nitrogen atom in each of the nitrogen atom containing 4-8 membered saturated heterocycles and the partially saturated nitrogen atom containing 9-10 membered saturated heterocycles is optionally replaced by one group selected from the group consisting of C _1-4 alkylcarbonyl and C _{1- 4} alkoxycarbonyls,

R ^A11 , R ^A21 and R ^A31 each independently represent a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl or a nitrogen-containing 4-6 membered saturated heterocyclyl (the nitrogen containing 4-6 membered saturated heterocyclyl is optionally substituted with one C _1-3 alkyl), and

R ^A12 , R ^A22 and R ^A32 each independently represent a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally together form an oxo, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent A ring;

R ¹ represents a hydrogen atom or methyl;

R ² represents C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl or a group represented by the formula [IVa]:

[Chemical formula 51]

,

Where

ring B is _C3-8 cycloalkyl, 4-8 membered saturated heterocyclyl, phenyl, 9-10 membered fused aryl, 5-6 membered heteroaryl or 9-10 membered fused heteroaryl,

R ^B1 and R ^B2 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy, and

L is C _1-2 alkanediyl (C _1-2 alkanediyl optionally substituted with 1-4 fluorine atoms), C _3-8 alkanediyl (C _3-8 alkanediyl optionally substituted with 1-5 fluorine atoms), the structure represented by the formula [V- 6]: -CH ₂ CH ₂ CH=C(CH ₃ )- or the structure represented by the formula [V-1a]:

[Chemical formula 52]

,

Where

n1 is an integer from 0 to 3,

n2 represents an integer from 0 to 5,

n3 is an integer from 0 to 3, and

one carbon atom in the C _3-8 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L1 )- and in addition ,

two consecutive carbon atoms in a C _3-8 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L2 )-,

R ^L1 represents a hydrogen atom or C _1-3 alkyl, and

R ^L2 represents a hydrogen atom or C _1-3 alkyl;

R ³ represents a hydrogen atom or C _1-3 alkyl (C _1-3 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and methoxy); And

R ⁴ represents a group represented by the formula [VIa]:

[Chemical formula 53]

,

Where

ring C is phenyl, 9-10 membered fused aryl, 5-6 membered heteroaryl or 9-10 membered fused heteroaryl,

phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of of hydroxy and C _1-6 alkoxy), halo-C _1-6 alkyl (halo-C _1-6 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and C _1-6 alkoxy), C _2-6 alkenyl , C _2-6 alkynyl, C _3-8 cycloalkyl (C _3-8 cycloalkyl is optionally substituted with one group selected from the group consisting of hydroxy and C _1-6 alkoxy), C _1-6 alkoxy, halogen-C _1-6 alkoxy (C _1-6 alkoxy and halo-C _1-6 alkoxy are optionally substituted with one group selected from the group consisting of hydroxy and C _1-6 alkoxy), C _3-8 cycloalkoxy (C _3-8 cycloalkoxy is optionally substituted with one group , selected from the group consisting of hydroxy and C _1-6 alkoxy), C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl (C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl and C _1-6 alkylsulfonyl is optionally substituted with one group selected from the group consisting of hydroxy and C _1-6 alkoxy), mono-C _1-6 alkylamino, di-C _1-6 alkylamino (mono-C _1-6 alkylamino and di-C _{1- 6} alkylamino is optionally substituted with one group selected from the group consisting of hydroxy and C _1-6 alkoxy), C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, mono-C _1-6 alkylaminocarbonyl and di-C _1-6 alkylaminocarbonyl (C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, mono-C _1-6 alkylaminocarbonyl and di-C _1-6 alkylaminocarbonyl are optionally substituted with one group selected from group consisting of hydroxy and C _1-6 alkoxy),

The 9-10 membered fused aryl is optionally substituted with one to three groups, identical or different, selected from the group consisting of a halogen atom, C _1-6 alkyl and C _1-6 alkoxy,

The 5-6 membered heteroaryl is optionally substituted with one to three groups, identical or different, selected from the group consisting of halogen, cyano, C _1-6 alkyl, C _1-6 alkoxy and oxo, and

The 9-10 membered fused heteroaryl is optionally substituted with one to four groups, identical or different, selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and oxo; or

R ³ and R ⁴ , together with their adjacent carbon atom, optionally form a partially substituted 9-10 membered fused hydrocarbon aromatic ring or a partially substituted 9-10 membered fused heteroaromatic ring,

Where

the partially saturated 9-10 membered fused hydrocarbon aromatic ring is optionally substituted with one to two halogen atoms, and

the partially saturated 9-10 membered fused heteroaromatic ring is optionally substituted with one to two halogen atoms.

(17) Another aspect of the present invention is to provide an LPA1 receptor antagonist according to (16),

where, in the formula of group [IIIa] for W,

R ^A11 , R ^A21 and R ^A31 each independently represent a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy or nitrogen-containing 4-6 membered saturated heterocyclyl (nitrogen-containing 4- The 6-membered saturated heterocyclyl is optionally substituted with one C _1-3 alkyl), and

R ^A12 , R ^A22 and R ^A32 each independently represent a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally together form an oxo, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent A ring, and

where, in formula [IVa] for R ² ,

L is C _1-2 alkanediyl (C _1-2 alkanediyl optionally substituted with 1-4 fluorine atoms), C _3-8 alkanediyl (C _3-8 alkanediyl optionally substituted with 1-5 fluorine atoms) or the structure represented by the formula [V- 1a], where

one carbon atom in the C _3-8 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L1 )- and in addition ,

two consecutive carbon atoms in a C _3-8 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L2 )-,

R ^L1 represents a hydrogen atom or C _1-3 alkyl, and

R ^L2 represents a hydrogen atom or C _1-3 alkyl.

(18) Another aspect of the present invention is to provide a medicament for the prevention or treatment of systemic scleroderma containing the compound represented by formula [Ia] of (16) or (17) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

(19) Another aspect of the present invention is to provide a method of preventing or treating systemic scleroderma, comprising administering to a patient in need thereof a therapeutically effective amount of a compound represented by formula [Ia] according to (16) or (17) or a pharmaceutically acceptable salt or hydrate thereof .

(20) Another aspect of the present invention is to provide a medicament containing a compound represented by formula [Ia] of (16) or (17) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient.

USEFUL EFFECT OF THE INVENTION

The compound of the present invention (hereinafter may also be referred to as “the compound of the present invention”) has an antagonistic effect on the LPA1 receptor.

DESCRIPTION OF IMPLEMENTATION OPTIONS

The present invention relates to a compound represented by the above formula [I] having an LPA1 receptor antagonistic effect, or a pharmaceutically acceptable salt or hydrate thereof.

The compound of the present invention will be described in more detail below, but the present invention is not limited to the examples presented.

The term "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term "C _1-3 alkyl" refers to a linear or branched alkyl having from 1 to 3 carbon atoms. Examples thereof include methyl, ethyl, n-propyl and isopropyl.

The term "C _1-4 alkyl" refers to a linear or branched alkyl having from 1 to 4 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The term "C _1-6 alkyl" refers to a linear or branched alkyl having from 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and n-hexyl.

The term "C _1-10 alkyl" refers to a linear or branched alkyl having from 1 to 10 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl , isoheptyl and isooctyl.

The term "C _6-10 alkyl" refers to a linear or branched alkyl having from 6 to 10 carbon atoms. Examples thereof include n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, isoheptyl and isooctyl.

The term "C _5-9 alkyl" refers to a linear or branched alkyl having from 5 to 9 carbon atoms. Examples thereof include n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, isoheptyl and isooctyl.

The term "halogen-C _1-6 alkyl" refers to a linear or branched alkyl having from 1 to 6 carbon atoms, substituted with a halogen atom. The number of substitutions with halogen atoms is preferably from 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof include monofluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 3,3,3-trifluoropropyl , 4,4,4-trifluorobutyl, 5,5,5-trifluoropentyl and 6,6,6-trifluorohexyl.

The term "hydroxy-C _1-6 alkyl" refers to a linear or branched alkyl having from 1 to 6 carbon atoms substituted with a hydroxyl group. The number of hydroxyl group substitutions is preferably 1. Examples thereof include monohydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl.

The term "C _2-3 alkenyl" refers to a linear or branched alkenyl having from 2 to 3 carbon atoms. Examples thereof include ethenyl, (E)-prop-1-en-1-yl, (Z)-prop-1-en-1-yl, prop-1-en-2-yl and prop-2-en-1 -il.

The term "C _2-6 alkenyl" refers to linear or branched alkenyl having from 2 to 6 carbon atoms. Examples thereof include ethenyl, (E)-prop-1-en-1-yl, (Z)-prop-1-en-1-yl, prop-2-en-1-yl, but-3-en-1 -yl, pent-4-en-1-yl, hex-5-en-1-yl, 1-methylethenyl.

The term "C _2-10 alkenyl" refers to linear or branched alkenyl having from 2 to 10 carbon atoms. Examples thereof include ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl and n-decenyl.

The term "C _5-9 alkenyl" refers to linear or branched alkenyl having from 5 to 9 carbon atoms. Examples thereof include n-pentenyl, n-hexenyl, n-heptenyl, n-octenyl and n-nonenyl.

The term "C _6-10 alkenyl" refers to linear or branched alkenyl having from 6 to 10 carbon atoms. Examples thereof include n-hexenyl, n-heptenyl, n-octenyl, n-nonenyl and n-decenyl.

The term "C _2-6 alkynyl" refers to a linear or branched alkynyl having from 2 to 6 carbon atoms. Examples thereof include ethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, but-3-yn-1-yl, pent-4-yn-1-yl and hex-5-yne -1-il.

The term "C _2-10 alkynyl" refers to a linear or branched alkynyl having from 2 to 10 carbon atoms. Examples thereof include ethynyl, n-propynyl, n-butynyl, n-pentynyl, n-hexynyl, n-heptynyl, n-octynyl, n-noninyl and n-decynyl.

The term "C _5-9 alkynyl" refers to a linear or branched alkynyl having from 5 to 9 carbon atoms. Examples thereof include n-pentynyl, n-hexynyl, n-heptynyl, n-octynyl and n-noninyl.

The term "C _6-10 alkynyl" refers to a linear or branched alkynyl having from 6 to 10 carbon atoms. Examples thereof include n-hexynyl, n-heptynyl, n-octinyl, n-nonynyl and n-decynyl.

The term "C _3-6 cycloalkane" refers to a hydrocarbon ring containing from 3 to 6 carbon atoms. Examples thereof include cyclopropane, cyclobutane, cyclopentane and cyclohexane.

The term "C _3-8 cycloalkane" refers to a hydrocarbon ring containing from 3 to 8 carbon atoms. Examples thereof include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.

The term "C _3-8 cycloalkyl" refers to a cyclic alkyl containing from 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The term "9-10 membered fused aryl" refers to a 9-10 membered fused polycyclic hydrocarbon aromatic ring group having 9 to 10 carbon atoms. Its examples include naphthyl.

Also, in a 9-10 membered fused aryl, partially saturated groups are also included in the "9-10 membered fused aryl". Examples thereof include dihydroindenyl, dihydronaphthyl and tetrahydronaphthyl.

The term "partially saturated 9-10 membered fused hydrocarbon aromatic ring" refers to a partially substituted 9-10 membered fused polycyclic hydrocarbon aromatic ring containing 9-10 carbon atoms. Examples thereof include dihydroindene, dihydronaphthalene and tetrahydronaphthalene.

The term "partially saturated 9-10 membered fused aryl" refers to a partially substituted 9-10 membered fused polycyclic hydrocarbon aromatic ring having 9-10 carbon atoms. Examples thereof include dihydroindenyl, dihydronaphthyl and tetrahydronaphthyl.

The term "4-8 membered saturated heterocyclyl" refers to a 4-8 membered monocyclic saturated heterocyclyl group consisting of 1 atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, and 3-7 carbon atoms, where it optionally further contains 1 atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned oxygen atom, sulfur atom or nitrogen atom. Examples thereof include oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, azetidinyl, pyrrolidinyl, piperidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

The term "oxygen-containing 4-8 membered saturated heterocycle" refers to a 4-8 membered monocyclic saturated heterocycle consisting of 1 oxygen atom and 3-7 carbon atoms. Examples thereof include oxetane, tetrahydrofuran and tetrahydropyran.

The term “sulfur-containing 4-8 membered saturated heterocycle” refers to a 4-8 membered monocyclic saturated heterocycle consisting of 1 sulfur atom and 3-7 carbon atoms. Examples thereof include thietane, tetrahydrothiophene and tetrahydrothiopyran.

The term “nitrogen atom-containing 4-8 membered saturated heterocycle” refers to a 4-8 membered monocyclic saturated heterocycle consisting of 1 nitrogen atom and 3-7 carbon atoms, where it optionally further contains 1 atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned nitrogen atom. Examples include azetidine, pyrrolidine, piperidine, azepane, morpholine, thiomorpholine and piperazine.

The term “nitrogen atom-containing 4-6 membered saturated heterocyclyl” refers to a 4-6 membered monocyclic saturated heterocyclyl group consisting of 1 nitrogen atom and 3-5 carbon atoms, where it optionally further contains 1 atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the nitrogen atom mentioned above. Examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

The term “nitrogen atom-containing 4-8 membered saturated heterocyclyl” refers to a 4-8 membered monocyclic saturated heterocyclyl group consisting of 1 nitrogen atom and 3-7 carbon atoms, where it optionally further contains 1 atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the nitrogen atom mentioned above. Examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, azepanil, morpholinyl, thiomorpholinyl and piperazinyl.

The term "5-6 membered heteroaryl" refers to a 5-6 membered monocyclic aromatic heterocyclic group consisting of 1 or more identical or different atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, and from 1 to 5 carbon atoms. Examples thereof include furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

In addition, in 5-6 membered heteroaryl, partially saturated groups are also included in "5-6 membered heteroaryl". Examples thereof include dihydrothiazolyl, dihydropyridinyl and tetrahydropyridinyl.

The term “nitrogen atom-containing 5-6 membered heteroaryl” refers to a 5-6 membered monocyclic aromatic heterocyclic group consisting of 1-4 nitrogen atoms and 1-5 carbon atoms, where it optionally additionally contains 1 atom selected from the group, consisting of an oxygen atom and a sulfur atom, in addition to the aforementioned nitrogen atoms. Examples thereof include pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

In addition, in the nitrogen atom-containing 5-6 membered heteroaryl, partially saturated groups are also included in the “nitrogen atom-containing 5-6 membered heteroaryl”. Examples thereof include dihydrothiazolyl, dihydropyridinyl and tetrahydropyridinyl.

The term “nitrogen-containing 6-membered heteroaryl” refers to a 6-membered monocyclic aromatic heterocyclic group consisting of 1-3 nitrogen atoms and 3-5 carbon atoms. Examples thereof include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.

In addition, in the nitrogen-containing 6-membered heteroaryl, partially saturated groups are also included in the “nitrogen-containing 6-membered heteroaryl.” Examples thereof include dihydropyridinyl and tetrahydropyridinyl.

The term "9-10 membered fused heteroaryl" refers to a 9-10 membered fused polycyclic aromatic heterocyclic group consisting of 1 atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom and from 5 to 9 carbon atoms, wherein it optionally further contains from 1 to 3 identical or different atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned oxygen atom, sulfur atom or nitrogen atom. Examples thereof include benzofuranyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl and pyrazolopyridinyl.

In addition, in the 9-10 membered fused heteroaryl, partially saturated groups are also included in the "9-10 membered fused heteroaryl". Examples thereof include dihydrobenzofuranyl, dihydrobenzothiophenyl, indolinyl, dihydrobenzodioxynyl, dihydroquinazolinyl and isoindolinyl.

The term "partially saturated 9-10 membered united heteroaromatic ring" refers to a partially substituted 9-10 membered fused polycyclic aromatic heterocycle consisting of 1 atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, and from 5 up to 9 carbon atoms, where it optionally further contains from 1 to 3 identical or different atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned oxygen atom, sulfur atom or nitrogen atom. Examples thereof include dihydrobenzofuran, dihydrobenzothiophene, indoline, dihydrobenzodioxine and dihydroquinazoline.

The term “nitrogen-containing 9-10 membered fused heteroaryl” refers to a 9-10 membered fused polycyclic aromatic heterocyclic group consisting of 1 nitrogen atom and 5-9 carbon atoms, where it optionally additionally contains from 1 to 3 identical or different an atom selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned nitrogen atom. Examples thereof include indolyl, indazolyl, benzimidazolyl and pyrazolopyridinyl.

In addition, in the nitrogen atom-containing 9-10 membered fused heteroaryl, partially saturated groups are also included in the “nitrogen atom-containing 9-10 membered fused heteroaryl”. Examples thereof include indolinyl and dihydroquinazolinyl.

The term "partially saturated oxygen-containing 9-10 membered fused heterocycle" refers to a partially substituted 9-10 membered fused polycyclic aromatic heterocycle consisting of 1 oxygen atom and 5-9 carbon atoms, where it optionally further contains from 1 to 3 the same or different atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned oxygen atom. Examples thereof include dihydrobenzofuran.

The term "partially saturated sulfur-containing 9-10 membered fused heterocycle" refers to a partially substituted 9-10 membered fused polycyclic aromatic heterocycle consisting of 1 sulfur atom and 5-9 carbon atoms, where it optionally further contains from 1 to 3 the same or different atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned sulfur atom. Examples thereof include dihydrobenzothiophene.

The term "partially saturated nitrogen atom containing 9-10 membered fused heterocycle" refers to a partially substituted 9-10 membered fused polycyclic aromatic heterocycle consisting of 1 nitrogen atom and 5-9 carbon atoms, where it optionally further contains from 1 to 3 the same or different atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom, in addition to the above-mentioned nitrogen atom. Examples of these include indoline.

The term "phenyl-C _1-3 alkyl" refers to the above-mentioned "C _1-3 alkyl" having one phenyl as a substituent. Examples thereof include benzyl, phenethyl and 3-phenylpropyl.

The term "pyridyl-C _1-3 alkyl" refers to the above-mentioned "C _1-3 alkyl" having one pyridyl as a substituent. Examples thereof include (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, 2-(pyridin-2-yl)ethyl and 3-(pyridin-2-yl) drank

The term "C _1-4 alkoxy" refers to linear or branched alkoxy having from 1 to 4 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy.

The term "C _1-6 alkoxy" refers to linear or branched alkoxy having from 1 to 6 carbon atoms. Examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy and n-hexyloxy.

The term "halogen-C _1-6 alkoxy" refers to a linear or branched alkoxy having from 1 to 6 carbon atoms, substituted with a halogen atom. The number of substitutions with halogen atoms is preferably from 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof include monofluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 1,1-difluoroethoxy, 2-fluoroethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2,2-pentafluoroethoxy, 3,3,3-trifluoropropoxy , 4,4,4-trifluorobutoxy, 5,5,5-trifluoropentyloxy and 6,6,6-trifluorohexyloxy.

The term "C _3-8 cycloalkoxy" refers to a cyclic alkoxy having from 3 to 8 carbon atoms. Examples thereof include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and cyclooctyloxy.

The term "C _1-6 alkylsulfanyl" refers to the group formed by combining the above-mentioned "C _1-6 alkyl" and sulfanyl. Examples thereof include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl, sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl and n-hexylsulfanyl.

The term "C _1-6 alkylsulfinyl" refers to the group formed by linking the above-mentioned "C _1-6 alkyl" and sulfinyl. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, n-pentylsulfinyl and n-hexylsulfinyl.

The term "C _1-6 alkylsulfonyl" refers to the group formed by combining the above-mentioned "C _1-6 alkyl" and sulfonyl. Examples thereof include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl and n-hexylsulfonyl.

The term "C _1-4 alkylsulfonyloxy" refers to the group formed by linking the above-mentioned "C _1-4 alkyl" and sulfonyloxy. Examples thereof include methylsulfonyloxy, ethylsulfonyloxy, n-propylsulfonyloxy, isopropylsulfonyloxy, n-butylsulfonyloxy, isobutylsulfonyloxy, sec-butylsulfonyloxy and tert-butylsulfonyloxy.

The term "mono-C _1-6 alkylamino" refers to an amino having one of the above-mentioned "C _1-6 alkyls" as a substituent. Examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino, t-butylamino, n-pentylamino and n-hexylamino.

The term "di-C _1-6 alkylamino" refers to an amino group having two of the above "C _1-6 alkyls", which are the same or different, as substituents. Examples thereof include dimethylamino, diethylamino, di(n-propyl)amino, di(isopropyl)amino, ethylmethylamino and methyl(n-propyl)amino.

The term "C _1-4 alkylcarbonyl" refers to the group formed by combining the above-mentioned "C _1-4 alkyl" and carbonyl. Examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl and tert-butylcarbonyl.

The term "C _1-6 alkylcarbonyl" refers to the group formed by linking the above-mentioned "C _1-6 alkyl" and carbonyl. Examples thereof include methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl and n-hexylcarbonyl.

The term "halo-C _1-6 alkylcarbonyl" refers to the group formed by combining the above-mentioned "halo-C _1-6 alkyl" and carbonyl. The number of substitutions with halogen atoms is preferably from 1 to 5, and the preferred halogen atom is a fluorine atom. Examples thereof include monofluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl, 1-fluoroethylcarbonyl, 1,1-difluoroethylcarbonyl, 2-fluoroethylcarbonyl, 2,2,2-trifluoroethylcarbonyl, 1,1,2,2,2-pentafluoroethylcarbonyl, 3,3,3-trifluoropropylcarbonyl , 4,4,4-trifluorobutylcarbonyl, 5,5,5-trifluoropentylcarbonyl and 6,6,6-trifluorohexylcarbonyl.

The term "C _1-4 alkoxycarbonyl" refers to the group formed by combining the above-mentioned "C _1-4 alkoxy" and carbonyl. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl and t-butoxycarbonyl.

The term "C _1-6 alkoxycarbonyl" refers to the group formed by combining the above-mentioned "C _1-6 alkoxy" and carbonyl. Examples thereof include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, t-butoxycarbonyl, n-pentyloxycarbonyl and n-hexyloxycarbonyl.

The term "mono-C _1-6 alkylaminocarbonyl" refers to the group formed by combining the above-mentioned "mono-C _1-6 alkylamino" and carbonyl. Examples thereof include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, n-butylaminocarbonyl, isobutylaminocarbonyl, sec-butylaminocarbonyl, t-butylaminocarbonyl, n-pentylaminocarbonyl and n-hexylaminocarbonyl.

The term "di-C _1-6 alkylaminocarbonyl" refers to the group formed by combining the above-mentioned "di-C _1-6 alkylamino" and carbonyl. Examples thereof include dimethylaminocarbonyl, diethylaminocarbonyl, di(n-propyl)aminocarbonyl, di(isopropyl)aminocarbonyl, ethylmethylaminocarbonyl and methyl(n-propyl)aminocarbonyl.

The term "oxo" refers to a substituent (=O) in which the substitution of an oxygen atom occurs through a double bond. Accordingly, in the case when a carbon atom is replaced by oxo, it forms a carbonyl together with this carbon atom, in the case when one sulfur atom is replaced by one oxo, it forms sulfinyl together with this sulfur atom, and in the case when one sulfur atom is replaced by two oxo, they together with this sulfur atom form a sulfonyl.

Examples of saturated heterocyclyl substituted with oxo include, for example, 2-oxopyrrolidinyl, 2-oxopiperidinyl, 2-oxopiperazinyl, 1,1-dioxidotetrahydrothiophenyl, 1-oxidotetrahydro-2H-thiopyranyl, 1,1-dioxidotetrahydro-2H-thiopyranyl, 1,1 -dioxidoisothiazolidinyl, 2-oxo-1,3-oxazolidinyl and 2-oxo-1,3-oxazinanyl.

Also examples of partially saturated heteroaryl substituted with oxo include, for example, 6-oxo-1,6-dihydropyridinyl, 6-oxo-1,1-dihydropyridazinyl, 2-oxo-1,2-dihydroquinolyl, 2-oxo-1,2 -dihydroquinazolyl and 1-oxo-1,2,3,4-tetrahydroisoquinolyl.

The term "linear C _1-3 alkanediyl" refers to a divalent linear hydrocarbon group formed by the removal of one hydrogen atom from an alkyl having 1 to 3 carbon atoms. Examples thereof include methandiyl, ethane-1,2-diyl and propane-1,3-diyl.

The term "C _1-2 alkanediyl" refers to a divalent linear hydrocarbon group formed by the removal of one hydrogen atom from an alkyl having 1 to 2 carbon atoms. Examples thereof include methandiyl, ethane-1,1-diyl and ethane-1,2-diyl.

The term "C _1-8 alkanediyl" refers to a divalent hydrocarbon group formed by the removal of one hydrogen atom from an alkyl group having from 1 to 8 carbon atoms. Examples thereof include methandiyl, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4 -diyl, pentane-1,4-diyl, pentane-1,5-diyl, pentane-2,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octan-1,8-diyl , 2-methylbutan-1,4-diyl, 2-methylpentan-2,5-diyl and 4-methylpentan-1,4-diyl.

The term "C _2-7 alkanediyl" refers to a divalent hydrocarbon group formed by the removal of one hydrogen atom from an alkyl having 2 to 7 carbon atoms. Examples thereof include ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl , pentane-1,4-diyl, pentane-1,5-diyl, pentane-2,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, 2-methylbutan-1,4-diyl , 2-methylpentan-2,5-diyl and 4-methylpentan-1,4-diyl. The term "C _3-6 alkanediyl" refers to a divalent hydrocarbon group formed by the removal of one hydrogen atom from an alkyl having from 3 to 6 carbon atoms. Examples thereof include propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,4-diyl, pentane-1,5-diyl , pentane-2,5-diyl, hexane-1,6-diyl, 2-methylbutan-1,4-diyl, 2-methylpentan-2,5-diyl and 4-methylpentan-1,4-diyl.

The term "C _3-8 alkanediyl" refers to a divalent hydrocarbon group formed by the removal of one hydrogen atom from an alkyl having from 3 to 8 carbon atoms. Examples thereof include propane-1,1-diyl, propane-1,3-diyl, propane-2,2-diyl, butane-1,4-diyl, pentane-1,4-diyl, pentane-1,5-diyl , pentane-2,5-diyl, hexane-1,6-diyl, heptane-1,7-diyl, octan-1,8-diyl, 2-methylbutan-1,4-diyl, 2-methylpentane-2,5 -diyl and 4-methylpentane-1,4-diyl.

The term "C ₄ alkanediyl" refers to a divalent hydrocarbon group formed by the removal of one hydrogen atom from an alkyl having 4 carbon atoms. Examples thereof include butane-1,4-diyl.

One preferred aspect of the compound of the present invention is aspect (A) below.

Aspect (A):

In the compound represented by the above formula [I]:

[Chemical formula 54]

,

or a pharmaceutically acceptable salt thereof;

X represents carboxy, C _1-4 alkoxycarbonyl, tetrazolyl, or a group represented by the formula [II-2] - [II-5]:

[Chemical formula 55]

.

in the present aspect, W is a linear C _1-3 alkanediyl or a structure selected from the group of formulas [III]:

[Chemical formula 56]

,

Where

linear C _1-3 alkanediyl is optionally substituted with one group selected from the group consisting of C _1-6 alkyl, halo-C _1-6 alkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and

if a linear C _1-3 alkanediyl is substituted with one methyl, it is optionally further substituted with one methyl,

ring A ¹ , ring A ² and ring A ³ are each a C _3-8 cycloalkane, a partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle containing a sulfur atom 4-8- membered saturated heterocycle or 4-8 membered saturated heterocycle containing a nitrogen atom,

Where

the sulfur atom in the 4-8-membered saturated heterocycle containing a sulfur atom is optionally replaced by one or two oxo,

the nitrogen atom in the nitrogen atom-containing 4-8 membered saturated heterocycle is optionally replaced by one C _1-4 alkylcarbonyl, and

R ^A11 , R ^A21 and R ^A31 each independently represent a hydrogen atom, hydroxy, a halogen atom, C _1-6 alkyl, C _1-6 alkoxy or a nitrogen-containing 4-6 membered saturated heterocyclyl, and

R ^A12 , R ^A22 and R ^A32 each independently represent a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally together form an oxo, or

R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent ring.

More preferably, W is a linear C _1-3 alkanediyl or a structure selected from the group of formulas [III]:

[Chemical formula 57]

,

Where

linear C _1-3 alkanediyl is optionally substituted with one group selected from the group consisting of C _1-4 alkyl, halo-C ₂ alkyl, phenyl-C _1-2 alkyl and pyridyl-C ₁ alkyl, and

if a linear C _1-3 alkanediyl is substituted with one methyl, it is optionally further substituted with one methyl,

ring A ¹ is a C _3-7 cycloalkane, a partially substituted 9-membered fused hydrocarbon aromatic ring containing an oxygen atom 4-6-membered saturated heterocycle, containing a sulfur atom 6-membered saturated heterocycle or containing a nitrogen atom 4-6-membered saturated heterocycle,

Where

the sulfur atom in the sulfur atom-containing 6-membered saturated heterocycle is optionally replaced by one to two oxos, and

the nitrogen atom in the nitrogen atom-containing 4-6 membered saturated heterocycle is optionally replaced by one C ₁ alkylcarbonyl, and

R ^A11 represents a hydrogen atom, hydroxy, a halogen atom, C ₁ alkyl, C _1-3 alkoxy or a nitrogen-containing 6-membered saturated heterocyclyl, and

R ^A12 represents a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 optionally together form oxo, or

R ^A11 and R ^A12 optionally form a C ₄ cycloalkane together with the carbon atoms in the adjacent ring,

ring A ² is a C ₃ cycloalkane or a 6-membered saturated heterocycle containing an oxygen atom,

Where

R ^A21 represents a hydrogen atom, and

R ^A22 represents a hydrogen atom, and

ring A ³ is a C _3-5 cycloalkane, a partially substituted 9-membered fused hydrocarbon aromatic ring or an oxygen-containing 6-membered saturated heterocycle,

Where

R ^A31 represents a hydrogen atom, and

R ^A32 represents a hydrogen atom.

Another preferred W is methandiyl, propane-1,3-diyl, or the structure represented by the formula [III-1] to [III-3]:

[Chemical formula 58]

,

Where

methanediyl is optionally substituted with one group selected from the group consisting of methyl, n-butyl, haloethyl, benzyl, phenethyl and pyridylmethyl, and

if methandiyl is substituted with one methyl, it is optionally further substituted with one methyl,

ring A ¹ is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, azetidine, pyrrolidine or piperidine,

Where

the sulfur atom in the tetrahydrothiopyran is optionally replaced by two oxos, and

the nitrogen atom in azetidine, pyrrolidine and piperidine is optionally replaced by one methyl carbonyl, and

R ^A11 represents a hydrogen atom, hydroxy, a fluorine atom, methyl, methoxy, ethoxy, isopropoxy or morpholinyl, and

R ^A12 represents a hydrogen atom, a fluorine or methyl atom, or

R ^A11 and R ^A12 optionally together form oxo, or

R ^A11 and R ^A12 optionally form a cyclobutane together with a hydrogen atom in the adjacent ring,

ring A ² is cyclopropane or tetrahydropyran,

Where

R ^A21 represents a hydrogen atom, and

R ^A22 represents a hydrogen atom, and

ring A ³ is cyclopropane, cyclobutane, cyclopentane, dihydroindene or tetrahydropyran,

Where

R ^A31 represents a hydrogen atom, and

R ^A32 represents a hydrogen atom.

R ¹ represents a hydrogen atom.

R ² represents a C _6-10 alkyl or a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 59]

,

Where

ring B ¹ represents C _3-8 cycloalkyl, phenyl or nitrogen-containing 5-6-membered heteroaryl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy, and

L ¹ represents C _3-8 alkanediyl (C _3-8 alkanediyl is optionally substituted with 1-5 fluorine atoms), the structure represented by the formula [V-6]: -CH ₂ CH ₂ CH=C(CH ₃ )- or the structure, represented by formula [V-1]:

[Chemical formula 60]

,

Where

n11 represents an integer from 0 to 3,

n12 represents an integer from 0 to 5,

n13 is an integer from 0 to 3, and

one carbon atom in the C _3-8 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-, the formula -S-, or the formula -N(R ^L11 )-, and

R ^L1 is C _1-3 alkyl, and

ring B ² is a partially saturated 9-10 membered fused aryl or a partially saturated nitrogen containing 9-10 membered fused heteroaryl,

R ^B1 and R ^B2 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy, and

L ² is C _1-2 alkanediyl (C _1-2 alkanediyl is optionally substituted with 1-4 fluorine atoms).

More preferred R ² is C _7-8 alkyl or a group represented by formula [IV-1] or [IV-2]:

[Chemical formula 61]

,

Where

ring B ¹ is a C ₆ cycloalkyl, phenyl or nitrogen-containing 6-membered heteroaryl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C ₁ alkyl or a C ₁ alkoxy, and

L ¹ represents a C _3-5 alkanediyl (C _3-5 alkanediyl optionally substituted with 1-2 fluorine atoms), the structure represented by the formula [V-6]: -CH ₂ CH ₂ CH=C(CH ₃ )- or the structure, represented by formula [V-1]:

[Chemical formula 62]

,

Where

n1 is an integer from 0 to 1,

n2 equals 1,

n3 is an integer between 0 and 1, and

one carbon atom in the C _3-5 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-, the formula -S-, or the formula -N(R ^L1 )-, and

R ^L1 is C ₁ alkyl, and

ring B ² is a partially saturated 9-membered fused aryl or a partially saturated nitrogen-containing 9-membered fused heteroaryl,

R ^B1 and R ^B2 both represent hydrogen atoms, and

L ² represents C ₂ alkanediyl.

Another preferred R ² is isoheptyl, isooctyl, or a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 63]

,

Where

ring B ¹ is cyclohexyl, phenyl or pyridyl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a fluorine atom, methyl or methoxy and L ¹ is any of the structures represented by formulas [V-3] - [V-12] and [V-14] - [V-19 ]:

[Chemical formula 64]

[Chemical formula 65]

,

Where

n4 represents an integer from 3 to 5,

n12' is 1, and

n12'' is 1, and

ring B ² is dihydroindenyl or isoindolinyl,

R ^B1 and R ^B2 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 66]

,

Where

n5 is 2.

R ³ represents a hydrogen atom or C _1-3 alkyl (C _1-3 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and methoxy),

more preferably, R ³ represents a hydrogen atom or a C _1-2 alkyl (C _1-2 alkyl is optionally substituted with one group selected from the group consisting of hydroxy and methoxy), and

another preferred R ³ is hydrogen, methyl (methyl optionally substituted with one group selected from the group consisting of hydroxy and methoxy) or ethyl.

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 67]

,

Where

ring C is phenyl containing a nitrogen atom, 6-membered heteroaryl or 9-10-membered fused heteroaryl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of hydroxy and C _1-6 alkoxy), halo-C _1-6 alkyl (halo-C _1-6 alkyl is optionally substituted with one hydroxy), C _2-6 alkenyl, C _3-8 cycloalkyl (C _3-8 cycloalkyl is optionally substituted with one hydroxy ), C _1-6 alkoxy, halogen-C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl and mono-C _1-6 alkylaminocarbonyl,

the nitrogen-containing 6-membered heteroaryl is replaced by one C _1-6 alkoxy, and in addition,

the nitrogen-containing 6-membered heteroaryl is optionally substituted with one group selected from the group consisting of cyano and C _1-6 alkoxy, and

The 9-10 membered fused heteroaryl is optionally substituted with one to two groups, the same or different, selected from the group consisting of C _1-6 alkyl or C _1-6 alkoxy.

More preferably, R ⁴ is a group represented by formula [VI]:

[Chemical formula 68]

,

Where

ring C is phenyl containing a nitrogen atom, 6-membered heteroaryl or 9-10-membered fused heteroaryl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-3 alkoxy and C _1-2 alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to three groups, the same or different, selected from the group consisting of hydroxy, carbamoyl, cyano, halogen atom, C _1-3 alkyl (C _1-3 alkyl is optionally substituted with one group selected from the group consisting of hydroxy and C ₁ alkoxy), halogen-C ₂ alkyl (halogen-C ₂ alkyl is optionally substituted with one hydroxy), C _2-3 alkenyl, C ₃ cycloalkyl (C ₃ cycloalkyl is optionally substituted with one hydroxy), C _1-3 alkoxy, halogen- C ₂ alkoxy, C ₃ cycloalkoxy, C ₁ alkylsulfinyl, C ₁ alkylsulfonyl, mono-C ₂ alkylamino, di-C _1-2 alkylamino, C _1-2 alkylcarbonyl, halo-C ₁ alkylcarbonyl, C ₁ alkoxycarbonyl and mono-C ₁ alkylaminocarbonyl,

the 6-membered heteroaryl containing a nitrogen atom is replaced by one C _1-2 alkoxy, and in addition,

the nitrogen atom-containing 6-membered heteroaryl is optionally substituted with one group selected from the group consisting of cyano and C _1-2 alkoxy, and

The 9-10 membered fused heteroaryl is optionally substituted with one to two groups, the same or different, selected from the group consisting of C _2-3 alkyl or C ₂ alkoxy.

Another preferred R ⁴ is a group represented by formula [VI]:

[Chemical Formula 69]

,

Where

ring C is phenyl, pyridyl, pyrimidinyl, indolyl, indazolyl, benzimidazolyl, pyrazolopyridyl, dihydrobenzofuranyl or dihydroindolyl,

phenyl is substituted by one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylcarbonyl and ethylcarbonyl and in addition,

phenyl is optionally substituted with one to four groups, identical or different, selected from the group consisting of hydroxy, carbamoyl, cyano, fluorine atom, chlorine atom, bromine atom, methyl, ethyl, n-propyl, isopropyl, (methyl, ethyl, n- propyl and isopropyl are optionally substituted by one group selected from the group consisting of hydroxy and methoxy), haloethyl (halogenethyl is optionally substituted by one hydroxy), ethenyl, isopropenyl, cyclopropyl (cyclopropyl is optionally substituted by one hydroxy), methoxy, ethoxy, n-propoxy, isopropoxy , haloethoxy, cyclopropoxy, methylsulfinyl, methylsulfonyl, ethylamino, ethylmethylamino, diethylamino, methylcarbonyl, ethylcarbonyl, halomethylcarbonyl, methoxycarbonyl and methylaminocarbonyl,

pyridyl and pyrimidinyl are replaced by one methoxy or ethoxy, and in addition,

they are optionally substituted by one group selected from the group consisting of cyano and ethoxy,

the pyrimidinyl is substituted with one methoxy and further, it is optionally substituted with one methoxy, and

indolyl, indazolyl, benzimidazolyl, pyrazolopyridyl, dihydrobenzofuranyl or dihydroindolyl is optionally substituted with one to two groups, the same or different, selected from the group consisting of ethyl, n-propyl or ethoxy.

Alternatively, if ^R3 and ^R4 , together with their neighboring carbon atom, form a fused ring,

the preferred fused ring is a partially substituted 9-10 membered fused hydrocarbon aromatic ring (the partially saturated 9-10 membered fused hydrocarbon aromatic ring is optionally substituted with one to two halogen atoms) or a partially substituted oxygen containing 9-10 membered fused heteroaromatic ring (a partially saturated oxygen atom containing 9-10 membered fused heteroaromatic ring is optionally substituted with one to two halogen atoms)

a more preferred fused ring is a partially substituted 9-membered fused hydrocarbon aromatic ring (a partially saturated 9-membered fused hydrocarbon aromatic ring optionally substituted with one to two halogen atoms) or a partially substituted oxygen-containing 9-membered fused heteroaromatic ring (partially saturated atom-containing oxygen, the 9-membered fused heteroaromatic ring is optionally substituted with one or two halogen atoms), and

another preferred fused ring is dihydroindene (dihydroindene optionally substituted with one to two halogen atoms) or dihydrobenzofuran (dihydrobenzofuran optionally substituted with one to two halogen atoms).

Another preferred aspect of the compound of the present invention is aspect (B) below.

Aspect (B):

In the compound represented by the above formula [I] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I] is the compound represented by formula [I-1]:

[Chemical formula 70]

,

Where

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 71]

.

In this aspect,

X represents carboxy, C _1-4 alkoxycarbonyl or tetrazolyl,

one more preferred X is carboxy or tetrazolyl,

in this case, one other preferred X is carboxy, and

in this case, another preferred X is tetrazolyl, and

another more preferred X is C _1-4 alkoxycarbonyl,

in this case, one other preferred X is C ₁ alkoxycarbonyl,

in this case, another preferred X is C ₂ alkoxycarbonyl, and

in this case, another preferred X is C ₄ alkoxycarbonyl.

W represents methandiyl or the structure represented by formula [III-1]:

[Chemical formula 72]

,

Where

methanediyl is optionally substituted with one group selected from the group consisting of C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of hydroxy and carboxy), halo-C _1-6 alkyl, C _{3- 8} cycloalkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and

if methandiyl is substituted with one methyl, it is optionally further substituted with one methyl, and

in the structure represented by formula [III-1],

preferred ring A ¹ is a C _3-8 cycloalkane, a partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle containing a sulfur atom 4-8 membered saturated heterocycle or containing a nitrogen atom 4 -8-membered saturated heterocycle,

Where

the sulfur atom in the sulfur atom-containing 4-8-membered saturated heterocycle is optionally replaced by one to two oxos, and

the nitrogen atom in the nitrogen atom-containing 4-8 membered saturated heterocycle is optionally substituted by one group selected from the group consisting of C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl,

preferred R ^A11 is a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy or nitrogen-containing 4-6 membered saturated heterocyclyl (nitrogen-containing 4-6 member saturated heterocyclyl is optionally substituted one C _1-3 alkyl), and

preferred R ^A12 is a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 optionally together form oxo, or

R ^A11 and R ^A12 optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent ring.

More preferably, W is methandiyl or the structure represented by formula [III-1]:

[Chemical formula 73]

,

Where

methanediyl is optionally substituted by one group selected from the group consisting of C _1-4 alkyl (C _1-4 alkyl is optionally substituted by one group selected from the group consisting of hydroxy and carboxy), halo-C ₂ alkyl, phenyl-C _{1- 2} alkyl and pyridyl-C ₁ alkyl, and

if methandiyl is substituted with one methyl, it is optionally further substituted with one methyl, and

in the structure represented by formula [III-1],

the preferred ring A ¹ is a C _3-7 cycloalkane, a partially substituted 9-membered fused hydrocarbon aromatic ring containing an oxygen atom 4-6 membered saturated heterocycle, a sulfur atom containing 6-membered saturated heterocycle or a nitrogen atom containing 4-6 membered saturated heterocycle,

Where

the sulfur atom in the sulfur atom-containing 6-membered saturated heterocycle is optionally substituted with one to two oxos, and

the nitrogen atom in the nitrogen atom-containing 4-6 membered saturated heterocycle is optionally substituted by one group selected from the group consisting of C ₁ alkylcarbonyl,

preferred R ^A11 is

a hydrogen atom, hydroxy, carboxy, a halogen atom, C ₁ alkyl, C _1-3 alkoxy or a nitrogen-containing 5-6 membered saturated heterocyclyl (the nitrogen-containing 5-6 member saturated heterocyclyl is optionally substituted with one C ₁ alkyl), and

preferred R ^A12 is a hydrogen atom, a halogen or methyl atom, or

R ^A11 and R ^A12 optionally together form oxo, or

R ^A11 and R ^A12 optionally form a C ₄ cycloalkane together with the carbon atoms in the adjacent ring.

Another preferred W is methandiyl or the structure represented by formula [III-1]:

[Chemical formula 74]

,

Where

methandiyl is optionally substituted by one group selected from the group consisting of methyl (methyl is optionally substituted by one group selected from the group consisting of hydroxy and carboxy), ethyl, n-butyl, isobutyl, haloethyl, benzyl, phenethyl and pyridylmethyl, and

if methandiyl is substituted with one methyl, it is optionally further substituted with one methyl, and

in the structure represented by formula [III-1],

preferred ring A ¹ is cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, azetidine, pyrrolidine or piperidine,

Where

the sulfur atom in tetrahydrothiopyran is optionally replaced by two oxos, and

the nitrogen atom in azetidine, pyrrolidine and piperidine is optionally replaced by one methyl carbonyl,

preferred R ^A11 is

a hydrogen atom, hydroxy, carboxy, fluorine atom, methyl, methoxy, ethoxy, isopropoxy, pyrrolidinyl, morpholinyl or piperazinyl (piperazinyl is optionally substituted with one methyl), and

preferred R ^A12 is a hydrogen atom, a fluorine or methyl atom, or

R ^A11 and R ^A12 optionally together form oxo, or

R ^A11 and R ^A12 optionally form a cyclobutane together with a hydrogen atom in the adjacent ring.

Ring B ¹ represents phenyl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy,

L ¹ is C _3-8 alkanediyl (C _3-8 alkanediyl is optionally substituted with one to five fluorine atoms), and

the one carbon atom in the C _3-8 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-.

Ring B ² is a partially saturated 9-10 membered fused aryl or a nitrogen atom containing 9-10 membered fused heteroaryl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is C _1-2 alkanediyl (C _1-2 alkanediyl is optionally substituted with 1-4 fluorine atoms).

A more preferred ring B ¹ is phenyl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C ₁ alkyl or a C ₁ alkoxy,

L ¹ is C _3-6 alkanediyl (C _3-6 alkanediyl is optionally substituted with one to two fluorine atoms), and

the one carbon atom in the C _3-6 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-.

A more preferred ring B ² is a partially saturated 9-membered fused aryl or a nitrogen-containing 9-membered fused heteroaryl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² represents C _1-2 alkanediyl.

Another preferred ring B ¹ is phenyl,

R ^B11 and R ^B12 each independently represent a hydrogen atom, a fluorine atom, methyl or methoxy, and

L ¹ is any of the structures represented by formulas [V-3] - [V-5], [V-7] - [V-8], [V-11] - [V-12] and [V-14] - [V-16]:

[Chemical formula 75]

[Chemical formula 76]

,

Where

n4 represents an integer between 3 and 5.

Another preferred ring B ² is dihydroindenyl, indolyl or isoindolinyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 77]

,

Where

n5 represents an integer between 1 and 2.

R ³ represents C _1-3 alkyl (C _1-3 alkyl is optionally substituted with one group selected from the group consisting of hydroxy and methoxy),

more preferably R ³ is methyl (methyl optionally substituted with one group selected from the group consisting of hydroxy and methoxy) or ethyl,

another preferred R ³ is methyl, and

A particularly preferred R ³ is methyl having the spatial configuration represented by formula [VII]:

[Chemical formula 78]

.

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 79]

,

Where

ring C is phenyl,

Where

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one group selected from the group consisting of of hydroxy and _C1-6 alkoxy), halo- _C1-6 alkyl (halogen- _C1-6 alkyl is optionally substituted with one hydroxy), _C2-6 alkenyl, _C2-6 alkynyl, _C3-8 cycloalkyl (C _3-8 cycloalkyl is optionally substituted with one hydroxy), C _1-6 alkoxy, halogen-C _1-6 alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono- C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, mono-C _1-6 alkylaminocarbonyl and di-C _1-6 alkylaminocarbonyl.

More preferably, R ⁴ is a group represented by formula [VI]:

[Chemical Formula 80]

,

Where

ring C is phenyl,

Where

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-3 alkoxy and C _1-2 alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-3 alkyl (C _1-3 alkyl is optionally substituted with one group selected from the group consisting of of hydroxy and C ₁ alkoxy), halo-C _1-2 alkyl (halo-C _1-2 alkyl is optionally substituted with one hydroxy), C _2-3 alkenyl, C ₃ cycloalkyl (C ₃ cycloalkyl is optionally substituted with one hydroxy), C _{1 -3} alkoxy, halo- _C2 alkoxy, _C3 cycloalkoxy, C1 alkylsulfinyl, _C1 alkylsulfonyl, _mono - _C2 alkylamino, di- _C2 alkylamino, _C1-2 alkylcarbonyl, halo- _C1 alkylcarbonyl, _C1 alkoxycarbonyl and mono-C ₁ alkylaminocarbonyl.

Another preferred R ⁴ is a group represented by formula [VI]:

[Chemical formula 81]

,

Where

ring C is phenyl,

Where

phenyl is substituted by one group selected from the group consisting of a fluorine atom, a chlorine atom, a bromine atom, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylcarbonyl and ethylcarbonyl, and further,

phenyl is optionally substituted with one to four groups, identical or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, fluorine atom, chlorine atom, bromine atom, methyl (methyl is optionally substituted by one group selected from the group consisting of hydroxy and methoxy), ethyl, n-propyl, isopropyl (ethyl, n-propyl and isopropyl optionally substituted with one hydroxy), halomethyl, haloethyl (halogenethyl optionally substituted with one hydroxy), ethenyl, isopropenyl, cyclopropyl (cyclopropyl optionally substituted with one hydroxy), methoxy , ethoxy, n-propoxy, isopropoxy, haloethoxy, cyclopropoxy, methylsulfinyl, methylsulfonyl, monoethylamino, diethylamino, methylcarbonyl, ethylcarbonyl, halomethylcarbonyl, methoxycarbonyl and methylaminocarbonyl.

Another preferred aspect of the compound of the present invention is aspect (C) below.

Aspect (C):

in the present aspect (C), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-2]:

[Chemical formula 82]

,

Where

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 83]

;

Where

W, ring ^B1 , ^RB11 , ^RB12 , ^L1 , ring ^B2 , ^RB21 , ^RB22 , ^L2 and ^R4 are as described above.

In the present aspect (C), the following aspect is more preferred.

In the above formula [I-2],

W represents methandiyl or the structure represented by formula [III-1]:

[Chemical formula 84]

,

Where

methandiyl is optionally substituted with one methyl, and

The methandiyl is optionally further substituted with one methyl, and

in the structure represented by formula [III-1],

ring A ¹ is a C _3-4 cycloalkane or a 4-5 membered saturated heterocycle containing an oxygen atom,

R ^A11 represents a hydrogen atom, hydroxy, halogen atom, C ₁ alkyl or C _1-2 alkoxy,

R ^A12 represents a hydrogen atom, a halogen atom or a methyl atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ represents C _3-5 alkanediyl (C _3-5 alkanediyl is optionally substituted with one to two fluorine atoms),

Where

one carbon atom in the C _3-5 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached, optionally substituted by the formula -O-,

ring B ² is a partially saturated 9-membered fused aryl,

R ^B21 and R ^B22 both represent hydrogen atoms;

L ² represents C ₂ alkanediyl; And

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 85]

,

Where

ring C is phenyl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-2 alkoxy and C ₁ alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, identical or different, selected from the group consisting of cyano, halogen, C _1-3 alkyl (C _1-3 alkyl is optionally substituted with one hydroxy), C ₂ alkenyl, C ₃ cycloalkyl, C _{1 -2} alkoxy, mono-C ₂ alkylamino and C ₁ alkylcarbonyl.

In the present aspect (C), another preferred aspect is as follows.

In the above formula [I-2],

W is any of the structures represented by formulas [III-4] - [III-17]:

[Chemical formula 86]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by the formula [V-3], [V-8], [V-12], [V-14] or [V-15]:

[Chemical formula 87]

,

Where

n4 represents an integer between 3 and 4, and

ring B ² is dihydroindenyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 88]

,

Where

n5 is 2; And

R ⁴ represents any of the groups represented by the formula [VI-1] - [VI-21]:

[Chemical formula 89]

[Chemical formula 90]

[Chemical formula 91]

.

Another preferred aspect of the compound of the present invention is aspect (D) below.

Aspect (D):

in the present aspect (D), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-3]:

[Chemical formula 92]

,

Where

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 93]

;

Where

W, ring ^B1 , ^RB11 , ^RB12 , ^L1 , ring ^B2 , ^RB21 , ^RB22 , ^L2 and ^R4 are as described above.

In the present aspect (D), the more preferred aspect is as follows.

In the above formula [I-3],

W represents methandiyl or the structure represented by formula [III-1]:

[Chemical formula 94]

,

Where

methandiyl is optionally substituted with one methyl, and

The methandiyl is optionally further substituted with one methyl, and

in the structure represented by formula [III-1],

ring A ¹ is a C _3-4 cycloalkane,

R ^A11 represents a hydrogen atom, a halogen atom, C ₁ alkyl or C _1-2 alkoxy, and

R ^A12 represents a hydrogen atom, a halogen atom or a methyl atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ is C _4-5 alkanediyl (C _4-5 alkanediyl is optionally substituted with two fluorine atoms), and

one carbon atom in the C _4-5 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached, optionally substituted by the formula -O-,

ring B ² is a partially saturated 9-membered fused aryl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² represents C ₂ alkanediyl; And

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 95]

,

Where

ring C is phenyl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-2 alkoxy and C ₁ alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to four groups, identical or different, selected from the group consisting of a halogen atom, C _1-3 alkyl (C _1-3 alkyl is optionally substituted with one hydroxy), C _1-2 alkoxy, mono-C ₂ alkylamino and C ₁ alkylcarbonyl.

In the present aspect (D), another preferred aspect is as follows.

In the above formula [I-3],

W is a structure represented by any of the formulas [III-4] - [III-11], [III-13] - [III-14] and [III-18] - [III-19]:

[Chemical formula 96]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by formula [V-3], [V-8] or [V-14]:

[Chemical formula 97]

,

Where

n4 is 4, and

ring B ² is dihydroindenyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 98]

,

Where

n5 is 2; And

R ⁴ represents any of the groups represented by the formula [VI-2], [VI-3], [VI-8], [VI-10] - [VI-12], [VI-16], [VI-19 ] and [VI-21]:

[Chemical formula 99]

[Chemical formula 100]

.

Another preferred aspect of the compound of the present invention is aspect (E) below.

Aspect (E):

in the present aspect (E), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-4]:

[Chemical formula 101]

,

Where

R ⁴ is a group represented by the formula [VI-22]:

[Chemical formula 102]

,

the group represented by formula [VI-22] is substituted with one to two C _1-6 alkoxy; And

preferred W, ring B ¹ , RB ¹¹ , RB ¹² and L ¹ are as described above.

In the present aspect (E), the following aspect is more preferred.

In the above formula [I-4],

W is the structure represented by formula [III-1]:

[Chemical formula 103]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ is a C ₄ cycloalkane,

R ^A11 is C _1-2 alkoxy, and

R ^A12 represents a hydrogen atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ is C ₅ alkanediyl, and

one carbon atom in the C ₅ alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-; And

R ⁴ represents the group represented by the above formula [VI-22]:

[Chemical formula 104]

,

Where

the group represented by the formula [VI-22] is substituted with two C ₂ alkoxy.

In the present aspect (E), another preferred aspect is as follows.

In the above formula [I-4],

W is any of the structures represented by formulas [III-8] - [III-11]:

[Chemical formula 105]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is the structure represented by the formula [V-14]:

[Chemical formula 106]

;

R ⁴ is a group represented by the formula [VI-6]:

[Chemical formula 107]

.

Then, in the present aspect (E), one particularly preferred aspect is the following.

In case the compound represented by the above formula [I-4] is one of the following:

[Chemical formula 108]

.

Also in the present aspect (E), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-4] is as follows:

[Chemical formula 109]

.

Also in the present aspect (E), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-4] is as follows:

[Chemical formula 110]

.

Also in the present aspect (E), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-4] is as follows:

[Chemical formula 111]

.

Also in the present aspect (E), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-4] is as follows:

[Chemical formula 112]

.

Another preferred aspect of the compound of the present invention is aspect (F) below.

Aspect (F):

in the present aspect (F), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-5]:

[Chemical formula 113]

,

Where

W, L ² and R ⁴ are as described above.

In the present aspect (F), the following aspect is more preferred.

In the above formula [I-5],

W is the structure represented by formula [III-1]:

[Chemical formula 114]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ is a C ₄ cycloalkane,

R ^A11 is C ₁ alkoxy, and

R ^A12 represents a hydrogen atom;

L ² represents C ₂ alkanediyl; And

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 115]

,

Where

ring C is phenyl,

phenyl is substituted with three groups, identical or different, selected from the group consisting of C ₂ alkoxy and C ₁ alkylcarbonyl, and in addition,

phenyl is optionally substituted with one C ₁ alkyl.

In the present aspect (F), another preferred aspect is as follows.

In the above formula [I-5],

W is a structure represented by formula [III-8] or [III-9]:

[Chemical formula 116]

;

L ² is the structure represented by the formula [V-20]:

[Chemical formula 117]

,

Where

n5 is 2; And

R ⁴ represents a group represented by the formula [VI-10] or [VI-12]:

[Chemical formula 118]

.

Then, in the present aspect (F), one particularly preferred aspect is the following.

In case the compound represented by the above formula [I-5] is one of the following:

[Chemical formula 119]

.

Also in the present aspect (F), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-5] is as follows:

[Chemical formula 120]

.

Also in the present aspect (F), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-5] is as follows:

[Chemical formula 121]

.

Also in the present aspect (F), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-5] is as follows:

[Chemical formula 122]

.

Also in the present aspect (F), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-5] is as follows:

[Chemical formula 123]

.

Another preferred aspect of the compound of the present invention is aspect (F-2) below.

Aspect (F-2):

in the present aspect (F-2), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by the formula [I-1] is the compound represented by the formula [I-5-2]:

[Chemical formula 124]

,

Where

R ⁴ is a group represented by the formula [VI-26]:

[Chemical formula 125]

,

the group represented by the formula [VI-26] is replaced by one group selected from the group consisting of C _1-6 alkyl, C _3-8 cycloalkyl and C _1-6 alkylcarbonyl, and further,

it is optionally substituted by one group selected from the group consisting of a halogen atom and a C _1-6 alkyl; And

W is as described above.

In the present aspect (F-2), the following aspect is more preferred.

In the above formula [I-5-2],

W is the structure represented by formula [III-1]:

[Chemical formula 126]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ is a C ₄ cycloalkane,

R ^A11 is C _1-2 alkoxy, and

R ^A12 represents a hydrogen atom;

R ⁴ represents the group represented by the above formula [VI-26]:

[Chemical formula 127]

,

Where

the group represented by the formula [VI-26] is replaced by one group selected from the group consisting of C ₁ alkyl, C ₃ cycloalkyl and C ₁ alkylcarbonyl, and further,

it is optionally substituted by one group selected from the group consisting of a halogen atom and a C ₁ alkyl atom.

In the present aspect (F-2), another preferred aspect is as follows.

In the above formula [I-5-2],

W is a structure represented by formula [III-8] or [III-10]:

[Chemical formula 128]

; And

R ⁴ represents a group represented by the formula [VI-2], [VI-6], [VI-10] - [VI-12], [VI-27] or [VI-28]:

[Chemical formula 129]

.

Then, in the present aspect (F-2), the following aspect is especially preferred.

In case the compound represented by the above formula [I-5-2] is as follows:

[Chemical formula 130]

.

Another preferred aspect of the compound of the present invention is aspect (G) below.

Aspect (G):

in the present aspect (G), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-6]:

[Chemical formula 131]

,

Where

R ⁴ is a group represented by the formula [VI-23]:

[Chemical formula 132]

,

the group represented by the formula [VI-23] is substituted with one C _1-6 alkylcarbonyl, and in addition,

it is optionally replaced by one halogen atom; And

W, ring B ¹ , R ^B11 , R ^B12 and L ¹ are as described above.

In the present aspect (G), the following aspect is more preferred.

In the above formula [I-6],

W is the structure represented by formula [III-1]:

[Chemical formula 133]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ is a C ₄ cycloalkane,

R ^A11 is C _1-2 alkoxy, and

R ^A12 represents a hydrogen atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ is C _4-5 alkanediyl, and

one carbon atom in the C _4-5 alkanediyl, which is two or more atoms away from the nitrogen atom to which R ² is attached, is optionally substituted by the formula -O-; And

R ⁴ represents the group represented by the above formula [VI-23]:

[Chemical formula 134]

,

Where

the group represented by the formula [VI-23] is replaced by one C ₁ alkylcarbonyl, and in addition,

it is optionally replaced by one halogen atom.

In the present aspect (G), another preferred aspect is as follows.

In the above formula [I-6],

W is a structure represented by formula [III-8] or [III-10]:

[Chemical formula 135]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by formula [V-12] or [V-14]:

[Chemical formula 136]

; And

R ⁴ represents a group represented by the formula [VI-24] or [VI-25]:

[Chemical formula 137]

.

Then, in the present aspect (G), one particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is one of the following:

[Chemical formula 138]

[Chemical formula 139]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 140]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 141]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 142]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 143]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 144]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 145]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 146]

.

Also in the present aspect (G), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6] is as follows:

[Chemical formula 147]

.

Another preferred aspect of the compound of the present invention is aspect (G-2) below.

Aspect (G-2):

in the present aspect (G-2), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by the formula [I-1] is the compound represented by the formula [I-6-2]:

[Chemical formula 148]

,

Where

R ⁴ is a group represented by the formula [VI-29]:

[Chemical formula 149]

, And

the group represented by the formula [VI-29] is replaced by one group selected from the group consisting of a halogen atom and a C _1-6 alkyl; And

W is as described above.

In the present aspect (G-2), the following aspect is more preferred.

In the above formula [I-6-2],

W is the structure represented by formula [III-1]:

[Chemical formula 150]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ is a C ₄ cycloalkane,

R ^A11 represents a hydrogen atom, a halogen atom or a C _1-2 alkoxy, and

R ^A12 represents a hydrogen atom or a halogen atom; And

R ⁴ represents the group represented by the above formula [VI-29]:

[Chemical formula 151]

,

Where

the group represented by the formula [VI-29] is replaced by one group selected from the group consisting of a halogen atom and a C ₁ alkyl.

In the present aspect (G-2), another preferred aspect is as follows.

In the above formula [I-6-2],

W is a structure represented by the formula [III-6], [III-8] - [III-11] or [III-13]:

[Chemical formula 152]

; And

R ⁴ represents a group represented by the formula [VI-30] or [VI-31]:

[Chemical formula 153]

.

Then, in the present aspect (G-2), one particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is one of the following:

[Chemical formula 154]

[Chemical formula 155]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 156]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 157]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 158]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 159]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 160]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 161]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 162]

.

Also, in the present aspect (G-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-6-2] is as follows:

[Chemical formula 163]

.

Another preferred aspect of the compound of the present invention is aspect (H) below.

Aspect (H):

in the present aspect (H), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-7]:

[Chemical formula 164]

,

Where

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical formula 165]

; And

X, W, ring ^B1 , ^RB11 , ^RB12 , ^L1 , ring ^B2 , ^RB21 , ^RB22 , ^L2 and ^R4 are as described above.

In the present aspect (H), the following aspect is more preferred.

In the above formula [I-7],

X represents carboxy or tetrazolyl;

W is the structure represented by formula [III-1]:

[Chemical formula 166]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ represents

C _3-4 cycloalkane,

R ^A11 represents

a hydrogen atom, a halogen atom or a C _1-2 alkoxy, and

R ^A12 is

a hydrogen atom or a halogen atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ is C _4-5 alkanediyl (C _4-5 alkanediyl is optionally substituted with two fluorine atoms), and

one carbon atom in the C _4-5 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached, optionally substituted by the formula -O-,

ring B ² is a partially saturated 9-membered fused aryl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² represents C ₂ alkanediyl; And

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 167]

,

Where

ring C is phenyl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-2 alkoxy and C ₁ alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to three groups, identical or different, selected from the group consisting of a halogen atom, C _1-3 alkyl (C _1-3 alkyl is optionally substituted with one hydroxy), C _1-2 alkoxy and C ₁ alkylcarbonyl.

In the present aspect (H), another preferred aspect is as follows.

In the above formula [I-7],

X represents carboxy or tetrazolyl;

W is a structure represented by the formula [III-5], [III-8] - [III-11] or [III-13]:

[Chemical formula 168]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by formula [V-3], [V-12] or [V-14]:

[Chemical formula 169]

,

Where

n4 represents an integer from 4, and

ring B ² is dihydroindenyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 170]

,

Where

n5 is 2; And

R ⁴ represents a group represented by the formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11] or [VI-12]:

[Chemical formula 171]

.

Then, in the present aspect (H),

One particularly preferred aspect is the case where the compound represented by the above formula [I-7] is one of the following:

[Chemical formula 172]

[Chemical formula 173]

[Chemical formula 174]

[Chemical formula 175]

[Chemical formula 176]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 177]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 178]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 179]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 180]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 181]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 182]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 183]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 184]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 185]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 186]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 187]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 188]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 189]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 190]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 191]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 192]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 193]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 194]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 195]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 196]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 197]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 198]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 199]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical Formula 200]

.

Also in the present aspect (H), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 201]

.

Another preferred aspect of the compound of the present invention is aspect (H-2) below.

Aspect (H-2):

in the present aspect (H-2), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-7]:

[Chemical formula 202]

,

Where

R ² represents a group represented by the formula [IV-1]:

[Chemical formula 203]

, And

X, W, ring B ¹ , R ^B11 , R ^B12 , L ¹ and R ⁴ are as described above.

In the present aspect (H-2), the following aspect is more preferred.

In the above formula [I-7],

X represents carboxy;

W is the structure represented by formula [III-1]:

[Chemical formula 204]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ represents

C _3-4 cycloalkane,

R ^A11 represents

a hydrogen atom, a halogen atom or a C _1-2 alkoxy, and

R ^A12 is

a hydrogen atom or a halogen atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ is C _4-5 alkanediyl, and

one carbon atom in the C _4-5 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached, optionally substituted by the formula -O-, and

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 205]

,

Where

ring C is phenyl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C ₁ alkyl, C _1-2 alkoxy and C ₁ alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to three groups, identical or different, selected from the group consisting of halogen, C ₁ alkyl, C ₃ cycloalkyl, C _1-2 alkoxy and C ₁ alkylcarbonyl.

In the present aspect (H-2), another preferred aspect is as follows.

In the above formula [I-7],

X represents carboxy;

W is a structure represented by the formula [III-5], [III-6], [III-8] to [III-11] or [III-13]:

[Chemical formula 206]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by formula [V-12] or [V-14]:

[Chemical formula 207]

, And

R ⁴ represents a group represented by the formula [VI-2], [VI-6], [VI-12], [VI-25], [VI-27], [VI-28], [VI-30] or [VI-31]:

[Chemical formula 208]

.

Then, in the present aspect (H-2),

One particularly preferred aspect is the case where the compound represented by the above formula [I-7] is one of the following:

[Chemical formula 209]

[Chemical Formula 210]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 211]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 212]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 213]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 214]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 215]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 216]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 217]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 218]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 219]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical Formula 220]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 221]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 222]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 223]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 224]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical Formula 225]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 226]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 227]

.

Also, in the present aspect (H-2), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 228]

.

Another preferred aspect of the compound of the present invention is aspect (H-3) below.

Aspect (H-3):

in the present aspect (H-3), the preferred aspect is as follows.

In the compound represented by the above formula [I-1] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I-1] is the compound represented by formula [I-7]:

[Chemical formula 229]

,

Where

R ² represents a group represented by the formula [IV-1] or [IV-2]:

[Chemical Formula 230]

; And

X, W, ring ^B1 , ^RB11 , ^RB12 , ^L1 , ring ^B2 , ^RB21 , ^RB22 , ^L2 and ^R4 are as described above.

In the present aspect (H-3), the following aspect is more preferred.

In the above formula [I-7],

X represents carboxy or tetrazolyl;

W is the structure represented by formula [III-1]:

[Chemical formula 231]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ represents

C _3-4 cycloalkane,

R ^A11 represents

a hydrogen atom, a halogen atom or a C _1-2 alkoxy, and

R ^A12 is

a hydrogen atom or a halogen atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ is C _4-5 alkanediyl (C _4-5 alkanediyl is optionally substituted with two fluorine atoms), and

one carbon atom in the C _4-5 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached, optionally substituted by the formula -O-,

ring B ² is a partially saturated 9-membered fused aryl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² represents C ₂ alkanediyl; And

R ⁴ represents a group represented by the formula [VI]:

[Chemical formula 232]

,

Where

ring C is phenyl,

phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-3 alkyl, C _1-2 alkoxy and C ₁ alkylcarbonyl, and in addition,

phenyl is optionally substituted with one to three groups, identical or different, selected from the group consisting of a halogen atom, C _1-3 alkyl (C _1-3 alkyl is optionally substituted with one hydroxy), C _1-2 alkoxy and C ₁ alkylcarbonyl.

In the present aspect (H-3), another preferred aspect is as follows.

In the above formula [I-7],

another preferred X is carboxy or tetrazolyl;

W is a structure represented by the formula [III-5], [III-6], [III-8] to [III-11] or [III-13]:

[Chemical formula 233]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is a structure represented by formula [V-3], [V-12] or [V-14]:

[Chemical formula 234]

,

Where

n4 represents an integer from 4, and

ring B ² is dihydroindenyl,

R ^B21 and R ^B22 both represent hydrogen atoms, and

L ² is the structure represented by the formula [V-20]:

[Chemical formula 235]

,

Where

n5 is 2; And

R ⁴ represents a group represented by the formula [VI-2], [VI-6], [VI-7], [VI-8], [VI-10], [VI-11], [VI-12], [VI-25], [VI-27], [VI-28], [VI-30] or [VI-31]:

[Chemical formula 236]

.

Then, in the present aspect (H-3),

One particularly preferred aspect is the case where the compound represented by the above formula [I-7] is one of the following:

[Chemical formula 237]

[Chemical formula 238]

[Chemical formula 239]

[Chemical formula 240]

[Chemical formula 241]

[Chemical formula 242]

[Chemical formula 243]

[Chemical formula 244]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 245]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 246]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 247]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 248]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 249]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 250]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 251]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 252]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 253]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 254]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 255]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 256]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 257]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 258]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 259]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical Formula 260]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 261]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 262]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 263]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 264]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 265]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 266]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 267]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 268]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 269]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 270]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 271]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 272]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 273]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 274]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 275]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 276]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 277]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 278]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 279]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 280]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 281]

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 282]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 283]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 284]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 285]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 286]

.

Also, in the present aspect (H-3), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-7] is as follows:

[Chemical formula 287]

.

Another preferred aspect of the compound of the present invention is aspect (J) below.

Aspect (J):

in the present aspect (J), the preferred aspect is as follows.

In the compound represented by the above formula [I] or a pharmaceutically acceptable salt or hydrate thereof,

the compound represented by formula [I] is the compound represented by formula [I-8]:

[Chemical formula 288]

,

Where

R ^X represents C _1-4 alkyl; And

W, ring ^B1 , ^RB11 , ^RB12 , ^L1 and ^R4 are as described above.

In the present aspect (J), the following aspect is more preferred.

In the above formula [I-8],

R ^X is C ₁ alkyl, C ₂ alkyl or C ₄ alkyl;

W is the structure represented by formula [III-1]:

[Chemical formula 289]

,

Where,

in the structure represented by formula [III-1],

ring A ¹ is a C _3-4 cycloalkane,

R ^A11 represents a hydrogen atom, a halogen atom or a C ₂ alkoxy, and

R ^A12 represents a hydrogen atom or a halogen atom;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms,

L ¹ is C ₅ alkanediyl, and

one carbon atom in the C ₅ alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-; And

R ⁴ represents a group represented by the formula [VI]:

[Chemical Formula 290]

,

Where

ring C is phenyl,

phenyl is substituted with three groups, identical or different, selected from the group consisting of C ₂ alkoxy and C ₁ alkylcarbonyl, and in addition,

phenyl is optionally substituted with one halogen atom.

In the present aspect (J), another preferred aspect is as follows.

In the above formula [I-8],

R ^X is methyl, ethyl or tert-butyl;

W is a structure represented by formula [III-5], [III-10] or [III-13]:

[Chemical formula 291]

;

ring B ¹ represents phenyl,

R ^B11 and R ^B12 both represent hydrogen atoms, and

L ¹ is the structure represented by the formula [V-14]:

[Chemical formula 292]

; And

R ⁴ represents a group represented by the formula [VI-10] or [VI-11]:

[Chemical formula 293]

.

Then, in the present aspect (J), one particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is one of the following:

[Chemical formula 294]

[Chemical Formula 295]

[Chemical formula 296]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical formula 297]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical formula 298]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical formula 299]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 300]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical formula 301]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 302]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 303]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical formula 304]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical formula 305]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 306]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 307]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 308]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 309]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical Formula 310]

.

Also in the present aspect (J), another particularly preferred aspect is the following.

In case the compound represented by the above formula [I-8] is as follows:

[Chemical formula 311]

.

The compound of the present invention is a compound having the structure of urea as the main skeleton, and may be a pharmaceutically acceptable salt thereof or a hydrate thereof.

Examples of the pharmaceutically acceptable salt include, for example, acid addition salts including salts of inorganic acids such as hydrochloride, hydrobromide, hydriodide, phosphate, sulfate and nitrate, sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and trifluoromethanesulfonate and organic salts acids such as oxalate, tartarate, citrate, maleate, succinate, acetate, trifluoroacetate, benzoate, mandelate, ascorbate, lactate, gluconate and malate, amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate , inorganic salts such as lithium salt, sodium salt, potassium salt, calcium salt and magnesium salt, and salts with organic bases such as ammonium salt, triethylamine salt, diisopropylamine salt, cyclohexylamine salt and N-methyl-D-glucamine salt. It should be noted that salt includes hydrated salt.

The compound of the present invention may have an asymmetric center, in which case various optical isomers are present. Thus, the compound of the present invention may be present as a single optically active form (R) or (S) or as a mixture of racemate or (RS). In addition, in the case of a compound having two or more centers of asymmetry, there are also diastereomers due to each optical isomerism. The compound of the present invention also includes a mixture containing all of these forms in any proportion. For example, diastereomers can be separated by methods well known to those skilled in the art, such as fractional crystallization, and the optically active forms can be prepared by organic chemistry methods well known for this purpose. In addition, geometric isomers such as cis form and trans form may be present in the compound of the present invention. Moreover, the compound of the present invention is tautomeric, and many tautomers are present. The compound of the present invention includes these isomers and a mixture containing these isomers in arbitrary proportions.

Moreover, when the compound of the present invention or a salt thereof forms a hydrate or solvate, they are also included within the scope of the present invention.

As mentioned above, the LPA1 receptor, LPA3 receptor and the like perform a wide variety of functions in a living organism.

Examples of diseases caused by LPA receptors include, for example, diseases associated with fibrosis (idiopathic pulmonary fibrosis, systemic scleroderma, chronic kidney disease, chronic hepatitis, chronic organ transplant rejection and the like), inflammatory diseases (rheumatoid arthritis, osteoarthritis of the knee and similar), diseases of the circulatory system (atherosclerosis and the like), oncological diseases (prostate cancer, breast cancer, ovarian cancer and the like), urological diseases (prostatic hyperplasia, overactive bladder and the like), and neurological diseases (neuropathic pain, diabetic neuropathy and the like).

Agents that inhibit the physiological activity of LPA receptors, in particular antagonists against the EDG family such as the LPA1 receptor and the LPA3 receptor, are considered useful as drugs for the prevention or treatment of diseases associated with organ fibrosis, such as idiopathic pulmonary fibrosis, systemic scleroderma , chronic kidney disease and chronic hepatitis, circulatory diseases such as atherosclerosis, proliferative diseases including various types of cancer, urological diseases such as prostatic hyperplasia, and central or peripheral neurological diseases.

It should be noted that the evaluation of the compound of the present invention for its LPA receptor antagonistic effect can be carried out in accordance with generally known methods, such as those described in the experimental examples that will be mentioned below.

As for the drug of the present invention, the compound contained therein which is an LPA1 receptor antagonist, which is the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, can be administered alone or together with a pharmacologically or pharmaceutically acceptable additional agent.

As the additional agent, a commonly used excipient or diluent may be used, as well as a commonly used binding agent, disintegrant, lubricant, coating agent, sugar coating agent, pH adjuster, solubilizing agent, or an aqueous or non-aqueous solvent, as necessary. Specific examples thereof may include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, corn starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate , talc, stearic acid, magnesium stearate, agar, pectin, gum acacia, glycerin, sesame oil, olive oil, soybean oil, cocoa butter, ethylene glycol, low viscosity hydroxypropyl cellulose (HPC-L), microcrystalline cellulose, carboxymethylcellulose (CMC), carboxymethylcellulose sodium (CMC-Na), and other commonly used materials.

The drug of the present invention may be in any form of solid composition, liquid composition and other compositions, and the optimal form is selected depending on the need.

The drug of the present invention can be prepared in the form of a tablet, pill, capsule, granule, powder, pulp, liquid, emulsion, suspension, injection or the like by adding the above-mentioned additional agent to the compound of the present invention and using commonly used formulation technologies.

In addition, the drug of the present invention can be formulated by forming a clathrate compound with the compound of the present invention and α-, β- or γ-cyclodextrin, methylated cyclodextrin or the like.

With respect to compounds that can be used in combination with a compound of the present invention, the drug of the present invention can be prepared as a single formulation (combination drug) or two or more formulations (concomitant drugs) prepared separately.

When these compounds are formulated separately in two or more formulations, the individual formulations can be administered simultaneously or at a specific time interval. In this case, any of them can be entered first. Two or more formulations can also be administered independently at different times during the day. In addition, two or more compositions can also be administered in different ways.

When these compounds are formulated separately in two formulations, they can be administered simultaneously or at very short intervals, and it is preferable to indicate that they are to be used in combination, for example, in package inserts, marketing brochures and other documents for commercially available drugs.

It is also preferable that these active ingredients be formulated separately in the form of a set of two formulations.

When the compound of the present invention is used as an antagonist of LPA1 receptor or the like, the compound of the present invention can be administered orally as such. Alternatively, the compound of the present invention can be administered orally in the form of an agent containing it as an active ingredient.

When the compound of the present invention is used as a drug for the prevention or treatment of systemic scleroderma or the like, the compound of the present invention can be administered orally as such. Alternatively, the compound of the present invention can be administered orally in the form of an agent containing it as an active ingredient.

The dosage of the compound of the present invention varies depending on the purpose of administration, route of administration, target disease, symptoms and the like, but, for example, when administered orally to an adult patient, the single dose is usually from 0.1 to 1000 mg, preferably from 1 to 200 mg . It is advisable to administer this dose one to three times a day or once every two to three days.

Next, methods for producing compounds [I] according to the present invention will be described in detail, but the production method is not specifically limited to the examples given.

It should be noted that when preparing compounds [I] of the present invention, the order of the corresponding steps in each production method can be changed accordingly.

In addition, the solvents used in the reactions are not particularly limited to those described below, provided that they do not interfere with each reaction.

In addition, in each production method below, the starting compound may be used in the form of a salt. In addition, the desired compound can be obtained as a salt.

Herein, examples of the salt that can be used include, for example, the “pharmaceutically acceptable salt” mentioned above.

It should be noted that the compound [Ia] of the present invention can be produced by the method for preparing compound [I] or an equivalent method thereof.

Compound [I] of the present invention can be produced by methods known per se, such as production methods 1 to 6 shown below, or methods equivalent thereto.

Particularly, among the compounds [I] of the present invention, a method for producing a compound in which X represents carboxy or C _1-4 alkoxycarbonyl is shown in Preparation Method 1, and methods for producing intermediate compounds are shown in Preparation Methods 2-8.

In addition, methods for producing a compound in which X represents tetrazolyl, a compound in which X represents a group represented by the formula [II-1] below (hereinafter may also be referred to as a compound [II-1]), a compound in in which X represents carbamoyl, a compound in which X represents a group represented by the formula [II-2], [II-3] or [II-4] below (hereinafter they may also be referred to as compound [II-2], compound [II-3] and compound [II-4], respectively), and the compound in which X represents a group represented by the following formula [II-5] (hereinafter may also be referred to as compound [II-5]) are shown in method of obtaining 9.

[Chemical Formula 312]

As used herein, in the present general production methods, "reductive amination reaction" means, for example, a reaction in which an amine compound is prepared by forming a corresponding imine compound from an aldehyde compound or a ketone compound and an amine compound in the presence or absence of an acid such as formic acid or acetic acid, in an inert solvent or under solvent-free conditions at a temperature ranging from ice-cooling to boiling, followed by exposure to a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, 2-picolineborane, or an iridium catalyst including chlorine(pentamethylcyclopentadienyl )(8-quinolinolate)iridium(III) (described, for example, in Advanced Synthesis and Catalysis, vol. 360, p. 322, 2018).

Moreover, in the present general preparation methods, "condensation reaction" means, for example, a reaction in which an amide compound is prepared by allowing a carboxylic acid compound and an amine compound to react with each other using a condensing agent, in the presence or absence of a base and an additive in an inert solvent at a temperature from room temperature to boiling temperature with reflux.

Examples of the condensing agent used in the "condensation reaction" include, for example, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-hexafluorophosphate yl-N, N,N',N'-tetramethyluronium (HBTU), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), 1,1'-carbonyldiimidazole (CDI), hexafluorophosphate (1H-benzotriazole-1 -yloxy)(tripyrrolidin-1-yl)phosphonium (PyBOP), propylphosphonic anhydride (T3P), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT -MM).

Examples of the additive used in the "condensation reaction" include, for example, N-hydroxybenzotriazole monohydrate (HOBt), and N-hydroxysuccinimide.

Examples of the base used in the "condensation reaction" include tertiary aliphatic amines such as N,N-diisopropylethylamine and triethylamine, and pyridine.

Moreover, in the present general production methods, "hydrolysis reaction" means, for example, a reaction in which a carboxylic acid compound and an alcohol compound are produced from an ester compound using a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in an inert solvent at temperatures ranging from ice cooling to reflux.

Among the compounds [I] of the present invention, compound [1-d] where X represents a carboxy group and R ¹ represents a hydrogen atom, and compound [1-f] where R ¹ represents methyl can be obtained, for example, method of obtaining 1 below or an equivalent method.

Obtaining method 1:

Scheme 1 (Method of obtaining compounds [1-d] and [1-f] from compound [1-a]):

[Chemical Formula 313]

[On the diagram,

R ² , R ³ , R ⁴ and W are as defined above, and

Alk ¹ is C _1-4 alkyl.]

Stage 1-1:

Method for preparing compound [1-c]: Compound [1-a] is used as a starting material, and is reacted with compound [1-b] in the presence of a base such as triethylamine, pyridine, 4-dimethylaminopyridine or N, N- diisopropylethylamine, and a urea derivatizing agent such as 4-nitrophenyl chloroformate, CDI or triphosgene, in an inert solvent, at a temperature from ice-cooling to reflux, to obtain compound [1-c].

Stage 1-2:

Method for producing compound [1-d]: Compound [1-c] is used as a starting material, and compound [1-d] is obtained by carrying out a “hydrolysis reaction”.

Stage 1-3:

Method for preparing compound [1-e]: Compound [1-c] is used as a starting material, and is reacted with a methylating agent such as methyl iodide in the presence of a base such as sodium hydride in an inert solvent at a temperature ranging from ice cooling to reflux to give compound [1-e].

Step 1-4:

Method for producing compound [1-f]: Compound [1-e] is used as a starting material, and by carrying out a “hydrolysis reaction” in the method described in the above-mentioned step 1-2 or an equivalent method thereto, compound [1-f] is obtained .

The compounds [1-d] and [1-f] thus obtained can be isolated and purified by generally known separation and purification methods such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

It should be noted that among the compounds [I] of the present invention, the compound in which X is C _1-4 alkoxycarbonyl can be produced as compound [1-c] or [1-e], for example, by the present production method. 1 or equivalent method.

Among the intermediates for preparing compound [I] of the present invention, compounds [1-a] and [1-b] shown in Scheme 1 can be prepared according to known methods or by purchasing commercially available products.

Alternatively, compound [1-a] can also be produced, for example, by the production method 2, which will be mentioned below, or an equivalent method thereof.

Likewise, compound [1-b] can also be produced, for example, by the production method 8, which will be mentioned below, or an equivalent method thereof.

An example of the preparation of compound [1-a], which is an intermediate for the preparation of compound [I] of the present invention, is shown in Scheme 2-1 of the production method 2 below.

Obtaining method 2:

Scheme 2-1 (Method of obtaining compound [1-a] from compound [2-a]):

[Chemical formula 314]

[On the diagram,

R ² , R ³ , R ⁴ , n12, n13, n22, n23, ring B ¹ , R ^B11 , R ^B12 , ring B ² , R ^B21 and R ^B22 are as defined above;

ring B ¹ is, as mentioned above, C _3-8 cycloalkyl, nitrogen-containing 4-8-membered saturated heterocyclyl, phenyl or nitrogen-containing 5-6-membered heteroaryl,

ring B ² is also, as mentioned above, a partially saturated 9-10 membered fused aryl or a nitrogen containing 9-10 membered fused heteroaryl, and

LG ¹ represents the leaving group,

Where

the "leaving group" represented by LG ¹ is, for example, a halogen atom such as a chlorine atom or a bromine atom; C _1-4 alkylsulfonyloxy such as methanesulfonyloxy; or arylsulfonyloxy such as p-toluenesulfonyloxy;

R ^2' represents C _5-9 alkyl, C _5-9 alkenyl, C _5-9 alkynyl, or a group represented by the formula [IV-1'] or [IV-2']:

[Chemical Formula 315]

,

Where

ring B ¹ , ring B ² , R ^B11 , R ^B12 , R ^B21 and R ^B22 are as defined above, and

L ¹ ' is a C _2-7 alkanediyl (C _2-7 alkanediyl is optionally substituted with 1-5 fluorine atoms) or the structure represented by the formula [V-1']:

[Chemical Formula 316]

,

Where

n12 and n13 are as defined above,

n11' is an integer from 1 to 2, and

if L ¹ ' is a C _2-7 alkanediyl (the C _2-7 alkanediyl is optionally substituted with 1-5 fluorine atoms), one carbon atom in the C _2-7 alkanediyl that is one or more atoms away from the carboxy or formyl, with to which R ^2' is bound is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L11 )-,

Where

R ^L11 is as defined above, and

when L ¹ ' is a C _2-7 alkanediyl (C _2-7 alkanediyl is optionally substituted with 1-5 fluorine atoms), two consecutive carbon atoms in the C _2-7 alkanediyl are optionally substituted with the formula -C(=O)N(R ^L12 ) -,

Where

R ^L12 is as defined above, and

L ^2' is C _2-7 alkanediyl (C _2-7 alkanediyl optionally substituted with 1-5 fluorine atoms) or the structure represented by the formula [V-2']:

[Chemical Formula 317]

,

Where

n22 and n23 are as defined above,

n21' represents an integer from 1 to 2, and

when L ² ' represents a C _2-7 alkanediyl (the C _2-7 alkanediyl is optionally substituted with 1-5 fluorine atoms), one carbon atom in the C _2-7 alkanediyl that is one or more atoms away from the carboxy or formyl, with to which R ^2' is bound is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L21 )-,

Where

R ^L21 represents, as mentioned above, a hydrogen atom or C _1-3 alkyl, and

two consecutive carbon atoms in the C _2-7 alkanediyl are optionally replaced by the formula -C(=O)N(R ^L22 )-,

Where

R ^L22 represents, as mentioned above, a hydrogen atom or a C _1-3 alkyl group.]

Stage 2-1:

Method for preparing compound [1-a]: Compound [2-a] is used as a starting material, and is reacted with compound [2-b] in the presence of a base in an inert solvent at a temperature from room temperature to reflux, to obtain compounds [1-a].

Examples of the base used in the present reaction include, for example, amine compounds such as triethylamine, N,N-diisopropylethylamine and 1,8-diazabicyclo[4,3,0]undec-7-ene, alkali metal hydrides such as sodium, alkali metal hydroxides such as potassium hydroxide, alkali metal carbonates such as cesium carbonate, potassium carbonate and sodium carbonate and alkoxy alkali metals such as potassium tert-butoxide.

Stage 2-2:

Another method for preparing compound [1-a]: Carry out an "amination reaction" between compound [2-a] and compound [2-c], [2-c'] or [2-c''], also to obtain compound [ 1-a].

Stage 2-3:

Method for preparing compound [2-e]: A “condensation reaction” is carried out between compound [2-a] and compound [2-d], also to obtain compound [2-e].

Stage 2-4:

Another method for preparing compound [1-a]: Compound [2-e] is used as a starting material and allowed to react with a reducing agent such as borane-tetrahydrofuran complex or borane-dimethyl sulfide complex in an inert solvent at a temperature ranging from ice cooling to reflux to obtain compound [1-a].

Alternatively, compound [1-a] is also prepared, for example, by the production method shown in Scheme 2-2 below or an equivalent method.

Scheme 2-2 (Method of obtaining compound [1-a] from compound [2-f]):

[Chemical Formula 318]

[On the diagram,

R ² , R ³ and R ⁴ are as defined above.]

Stage 2-5:

Another method for preparing compound [1-a]: An "amination reaction" is carried out between compound [2-f] and compound [2-g], to obtain compound [1-a].

In addition, the compound [1-a'], which is the compound [1-a], where R ³ represents C _1-3 alkyl, also obtained, for example, by the production method shown in Scheme 2-3 below or an equivalent method .

Scheme 2-3 (Method of obtaining compound [1-a'] from compound [2-h]):

[Chemical formula 319]

[On the diagram,

R ² and R ⁴ are as defined above, and

R ³ ' represents C _1-3 alkyl.]

Stage 2-6:

Method for preparing compound [2-j]: Compound [2-h] is used as a starting material, and is reacted with compound [2-g] in the presence or absence of an acid such as formic acid or acetic acid in an inert solvent or under solvent-free conditions, at temperatures ranging from ice-cooling to reflux, to give compound [2-j].

Stage 2-7:

Method for preparing compound [1-a']: Compound [2-j] is used as a starting material, and allowing compound [2-k] to react with it in an inert solvent at a temperature ranging from cooling on ice to room temperature, to obtain compound [ 1-a'].

In addition, step 2-6 and step 2-7 can also be carried out sequentially without isolating compound [2-j], which is the imine obtained in step 2-6 (without subsequent treatment for the reaction in step 2-6).

The compounds [1-a] and [1-a'] thus obtained can be isolated and purified by conventional separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

It should be noted that by allowing the reducing agent used in the “reductive amination reaction” to act on the compound [2-j] obtained in step 2-6, it is also possible to obtain the compound [1-a] where R ³ represents a hydrogen atom.

Among the intermediates for compound [I] of the present invention, compounds [2-a], [2-b], [2-c], [2-c'], [2-c''] and [2-d ] shown in Diagram 2-1, connections [2-f] and [2-g] shown in Diagram 2-2, and connections [2-g], [2-h] and [2-k] shown in Scheme 2-3 can be prepared by known methods or purchased as commercially available products.

Also, among these compounds, compound [2-a], the structure of which is [2-a'], which may be mentioned below (hereinafter it may also be called compound [2-a']) can also be prepared, for example, production method 3, which may be mentioned below, or an equivalent method. Compound [2-f], the structure of which is represented by [2-f'], which can be mentioned below (hereinafter, it can also be called compound [2-f']), and compound [2-h] can also be obtained, for example, by the production method 6, which may be mentioned below, or an equivalent method.

[Chemical Formula 320]

Similarly, compounds [2-b] and [2-c], compound [2-d] whose structure is represented by [5-e], which can be mentioned below (hereinafter it can also be called compound [5-e]), compound [2-d], the structure of which is represented by [5-e'], which can be mentioned below (hereinafter it can also be called compound [5-e']), and compound [2-g] can also be obtained, for example, by the method for producing 4, 5 or 7, which may be mentioned below, or an equivalent method.

[Chemical formula 321]

An example of the preparation of compound [2-a'], which is an intermediate of compound [I] of the present invention, is shown in Scheme 3-1 of Preparation Method 3 below.

Obtaining method 3:

Scheme 3-1 (Method of obtaining compound [2-a'] from compound [2-h]):

[Chemical formula 322]

[On the diagram,

R ³ ' and R ⁴ are as defined above,

M represents a lithium atom or the formula -MgX ^M ,

X ^M represents a chlorine atom, bromine atom or iodine atom,

the compound [2-k'](R ^3' -M) is an alkyl metal reagent, and

Alk ² is tert-butyl or the like.]

Stage 3-1:

Method for preparing compound [3-b]: Compound [2-h] is used as a starting material, and is reacted with compound [3-a] in the presence of a Lewis acid such as tetraethyl orthotitanate in an inert solvent at a temperature of room temperature to 160°C, obtaining compound [3-b].

Stage 3-2:

Method for preparing compound [3-c]: Compound [3-b] is used as a starting material, and reacted with compound [2-k'] in an inert solvent from -20°C to room temperature to obtain compound [3 -c].

Stage 3-3:

Method for preparing compound [2-a']: Compound [3-c] is used as a starting material, and allowed to react with an acid such as hydrochloric acid in an inert solvent at a temperature ranging from ice cooling to room temperature, to obtain the compound [2-a'].

Also, step 3-1, 3-2 and 3-3 can be carried out with reference to methods described in, for example, Journal of Combinatorial Chemistry, vol. 5, p. 590, 2003; and Organic Letters, vol. 3, p. 3707, 2001.

Moreover, in this Scheme 3-1, the optically active compound [3-a] is reacted in step 3-1 to obtain compound [2-a'] by a stereoselective method.

Compound [3-e] which is compound [2-a] in which R ⁴ is substituted phenyl and the para position of phenyl is substituted with C _1-6 alkylcarbonyl, and compound [3-f] which is compound [2-a] in wherein R ⁴ is substituted phenyl, and the para position of phenyl is substituted with C _1-6 alkyl substituted hydroxy, each can be prepared, for example, by the methods shown in Scheme 3-2 below, or an equivalent method.

Scheme 3-2 (Method of obtaining compounds [3-e] and [3-f] from compound [3-c']):

[Chemical Formula 323]

[On the diagram,

R ³ and Alk ² are as defined above,

Alk ³ and Alk ⁴ are each independently C _1-6 alkyl, halo-C _1-6 alkyl or C _3-8 cycloalkyl,

Rα ¹ is C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one hydroxy), halo-C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkylcarbonyl or halo-C _1-6 alkylcarbonyl,

Alk ⁵ is C _1-6 alkyl or C _1-6 alkyl substituted with hydroxy, and

LG ² represents the outgoing group.

Herein, the “leaving group” represented by LG ² is, for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom.]

Stage 3-4:

Method for preparing compound [3-d]: Compound [3-c'] is used as a starting material, and is reacted with a vinyl ether such as ethylene glycol monovinyl ether or butyl vinyl ether in the presence of a palladium catalyst such as palladium(II) acetate. , a phosphine ligand such as 1,3-bis(diphenylphosphino)propane or 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, and a base such as potassium carbonate or triethylamine, in an inert solvent, at a temperature of Cooling on ice to reflux to give compound [3-d].

The present step can be carried out with reference to methods described in, for example, The Journal of Organic Chemistry, vol. 66, p. 4340, 2001; and The Journal of Organic Chemistry, vol. 72, p. 6390, 2007.

Stage 3-5:

Method for preparing compound [3-e]: Compound [3-d] is used as a starting material, and allowed to react with an acid such as hydrochloric acid in an inert solvent at a temperature ranging from ice cooling to room temperature, to obtain compound [ 3-e].

It should be noted that step 3-4 and step 3-5 can also be carried out sequentially as a reaction in a single reaction vessel. Also the present stage can be carried out at a later stage.

Stage 3-6:

Method for preparing compound [3-f]: Compound [3-e] is used as a starting material, and a reducing agent such as lithium aluminum hydride (LiAlH ₄ ) or lithium borohydride (LiBH ₄ ) is allowed to react thereon in an inert solvent from -78 °C to room temperature to obtain compound [3-f].

The compounds [2-a'], [3-e] and [3-f] thus obtained can be isolated and purified by generally known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

Among the intermediates for compound [I] of the present invention, compounds [2-h] and [3-a] shown in Scheme 3-1, and compound [3-c'] shown in Scheme 3-2 can be prepared by known methods. methods or purchased as commercially available products.

Alternatively, among these compounds, compound [3-c'] can also be produced, for example, by the method described in the above-mentioned step 3-2 or an equivalent method.

Among the intermediates for compound [I] of the present invention, compound [2-b] described below in production method 2 can also be obtained, for example, by production method 4 below or an equivalent method.

[Chemical formula 324]

An example of the preparation of compound [2-b], which is an intermediate of compound [I] of the present invention, is shown in the following Scheme 4-1.

Obtaining method 4:

Scheme 4-1: Method for obtaining compound [2-b] from compound [4-a]

[Chemical Formula 325]

[On the diagram,

R ² and LG ¹ are as defined above.]

Stage 4-1:

Method for preparing compound [2-b]: Compound [4-a] is used as a starting material, and (i) reacted with an arylsulfonyl chloride such as p-toluenesulfonyl chloride or a C _1-4 alkylsulfonyl chloride such as methanesulfonyl chloride in the presence of a base such as triethylamine, and in the presence or absence of an additive such as trimethylamine hydrochloride in an inert solvent, at a temperature ranging from ice cooling to room temperature, or (ii) reacting it with a brominating agent such as lithium bromide in an inert solvent at room temperature to reflux to give compound [2-b].

The present step can be carried out with reference to the method described in, for example, Tetrahedron, vol. 55, p. 2183, 1999.

It should be noted that compound [4-a], which is used as a starting compound in the above step 4-1, can be produced by known methods or purchased as a commercially available product.

Alternatively, among compounds [4-a], the structure of which is represented by the formula [5-b], which may be mentioned below (hereinafter also may be referred to as compound [5-b]) to be obtained, for example, by the method shown in Scheme 5 -1 production method 5, which may be mentioned below, or an equivalent method.

[Chemical formula 326]

In addition, compound [4-m], which is compound [2-b] wherein R ² represents the group represented by the above formula [IV-1], and L ¹ represents C ₄ alkanediyl substituted with one fluorine atom, compound [ 4-h], which is the compound [2-b], where R ² represents the group represented by the above formula [IV-1], and L ¹ represents C ₄ alkanediyl substituted with two fluorine atoms, can also be obtained, for example , the production method shown in Scheme 4-5 below or an equivalent method.

[Chemical formula 327]

Examples of the preparation of the above compounds [4-m] and [4-h] are shown in Scheme 4-2.

Herein, compound [4-m], which is substituted with one fluorine atom, is prepared by using compound [4-b] as a starting material, and fluorinating the corresponding hydroxy compound [4-d] to obtain compound [4-j], and compound [4-h], which is substituted with two fluorine atoms, is prepared by fluorinating the corresponding ketone compound [4-e] to obtain compound [4-f].

It should be noted that, when converting a functional group, the protection and deprotection of hydroxy and the like can be carried out in a suitable manner.

Scheme 4-2 (Method of obtaining compound [4-h] or compound [4-m] from compound [4-b]):

[Chemical Formula 328]

[On the diagram,

ring B ¹ , LG ¹ , R ^B11 and R ^B12 are as defined above,

PG ¹ represents a hydroxy protecting group such as acetyl, and

LG ³ represents the outgoing group.

As used herein, the “leaving group” represented by LG ³ is, for example, C _1-6 alkoxy.]

Stage 4-2:

Method for preparing compound [4-c]: Compound [4-b] is used as a starting material, and a reducing agent is allowed to act on it in an inert solvent at a temperature ranging from cooling on ice to room temperature, to obtain compound [4-c].

As the reducing agent, when LG ³ is C _1-6 alkoxy, for example, lithium aluminum hydride or lithium borohydride can be used.

Stage 4-3:

Method for preparing compound [4-d]: Compound [4-c] is used as a starting material and reacted with acetic anhydride or the like in the presence of a base such as N,N-diisopropylethylamine in an inert solvent at a temperature ranging from cooling to ice to room temperature, selectively protecting the primary hydroxy to give compound [4-d].

Stage 4-4:

Method for preparing compound [4-e]: Compound [4-d] is used as a starting material, and an oxidizing agent such as manganese dioxide or Dess-Martin periodinane is allowed to react thereon in an inert solvent at a temperature ranging from ice-cooling to room temperature temperature to obtain compound [4-e].

Stage 4-5:

Method for preparing compound [4-f]: Compound [4-e] is used as a starting material, and a fluorinating agent such as bis(2-methoxyethyl)aminosulfur trifluoride or (diethylamino)sulfur trifluoride is allowed to react thereon in an inert solvent or under solvent-free conditions, at temperatures ranging from cooling on ice to 50°C, to obtain compound [4-f].

Stage 4-6:

Method for preparing compound [4-g]: Compound [4-f] is used as a starting material and allowed to react with a basic aqueous solution such as aqueous sodium hydroxide solution in an inert solvent at a temperature from ice cooling to room temperature, removing protecting group for hydroxy to give compound [4-g].

Stage 4-7:

Method for producing compound [4-h]: Compound [4-g] is used as a starting material, and by the method described in the above-mentioned step 4-1 or an equivalent method, compound [4-h] is obtained.

Stage 4-8:

Method for producing compound [4-j]: Compound [4-d] is used as a starting material and the method described in the above-mentioned step 4-5 or an equivalent method to obtain compound [4-j].

Stage 4-9:

Method for producing compound [4-k]: Compound [4-j] is used as a starting material and the method described in the above-mentioned step 4-6, or an equivalent method, to obtain compound [4-k].

Stage 4-10:

Method for producing compound [4-m]: Compound [4-k] is used as a starting material and the method described in the above-mentioned step 4-7, or an equivalent method, to obtain compound [4-m].

In Scheme 4-2, using compound [4-b'] as a starting material instead of compound [4-b], compound [4-m'], where R ² is a group represented by the above formula [IV-2] , and L ² is a C ₄ alkanediyl substituted with one fluorine atom, and the compound [4-h'], wherein L ² is a C ₄ alkanediyl substituted with two fluorine atoms, are prepared by methods similar to the above preparation methods for compounds [4- m] and [4-h], respectively. It should be noted that compound [4-b'] can be prepared by known methods or purchased as a commercially available product.

[Chemical formula 329]

[In formulas

ring B ² , ^RB21 , ^RB22 , LG ¹ and LG ³ are as defined above.]

In addition, the compound [4-x], which is the compound [2-b] wherein R ² represents a group represented by the above formula [IV-1], and L ¹ represents a C ₄ alkanediyl substituted with one fluorine atom, and the compound [4-u], which is the compound [2-b], where R ² represents the group represented by the above formula [IV-1], and L ¹ represents C ₄ alkanediyl substituted with two fluorine atoms, can also be obtained, for example, by the production method shown in Scheme 4-3 below or an equivalent method.

[Chemical Formula 330]

Examples of the preparation of the above compounds [4-x] and [4-u] are shown in Scheme 4-3.

Herein, a compound [4-x] that is substituted with one fluorine atom is prepared by using a compound [4-n] as a starting material and fluorinating the corresponding hydroxy compound [4-q] to obtain a compound [4-v], and compound [4-u], which is substituted with two fluorine atoms, is prepared by fluorinating the corresponding ketone compound [4-r] to obtain compound [4-s].

It should be noted that, upon conversion of the functional group, protection and deprotection of hydroxy can be carried out properly.

Scheme 4-3 (Method of obtaining connection [4-u] or connection [4-x] from connection [4-n]):

[Chemical formula 331]

[On the diagram,

ring B ¹ , R ^B11 , R ^B12 , PG ¹ , LG ¹ and LG ³ are as defined above.]

Stage 4-11:

Method for producing compound [4-p]: Compound [4-n] is used as a starting material and the method described in the above-mentioned step 4-2 or an equivalent method to obtain compound [4-p].

Stage 4-12:

Method for producing compound [4-q]: Compound [4-p] is used as a starting material and the method described in the above-mentioned step 4-3 or an equivalent method to obtain compound [4-q].

Stage 4-13:

Method for producing compound [4-r]: Compound [4-q] is used as a starting material and the method described in the above-mentioned step 4-4 or an equivalent method to obtain compound [4-r].

Stage 4-14:

Method for producing compound [4-s]: Compound [4-r] is used as a starting material and the method described in the above-mentioned step 4-5 or an equivalent method to obtain compound [4-s].

Stage 4-15:

Method for producing compound [4-t]: Compound [4-s] is used as a starting material and the method described in the above-mentioned step 4-6 or an equivalent method to obtain compound [4-t].

Stage 4-16:

Method for producing compound [4-u]: Compound [4-t] is used as a starting material and the method described in the above-mentioned step 4-7 or an equivalent method to obtain compound [4-u].

Stage 4-17:

Method for producing compound [4-v]: Compound [4-q] is used as a starting material and the method described in the above-mentioned step 4-8 or an equivalent method to obtain compound [4-v].

Stage 4-18:

Method for producing compound [4-w]: Compound [4-v] is used as a starting material and the method described in the above-mentioned step 4-9 or an equivalent method to obtain compound [4-w].

Stage 4-19:

Method for producing compound [4-x]: Compound [4-w] is used as a starting material and the method described in the above-mentioned step 4-10 or an equivalent method to obtain compound [4-x].

In Scheme 4-3, using compound [4-n'] as a starting material instead of compound [4-n], compound [4-x'], where R ² is a group represented by the above formula [IV-2] and L ² is a C ₄ alkanediyl substituted with one fluorine atom, and the compound [4-u'], wherein L ² is a C ₄ alkanediyl substituted with two fluorine atoms, are prepared by methods similar to the above preparation methods for compounds [4-x ] and [4-u], respectively. It should be noted that compound [4-n'] can be prepared by known methods or purchased as a commercially available product.

[Chemical formula 332]

[In formulas

ring B ² , ^RB21 , ^RB22 , LG ¹ and LG ³ are as defined above.]

Connections [2-b], [4-h], [4-h'], [4-m], [4-m'], [4-u], [4-u'], [4-x ] and [4-x'] thus obtained can be isolated and purified by generally known means of separation and purification, such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

Among the intermediates for compound [I] of the present invention, compound [4-a] shown in Scheme 4-1, compound [4-b] shown in Scheme 4-2 and compound [4-n] shown in Scheme 4-3 may be prepared by known methods or purchased as commercially available products.

Among the intermediates for compound [I] of the present invention, compounds [2-c] and [5-e] described below in Preparation Method 2 can also be prepared, for example, by Preparation Method 5 below or an equivalent method.

[Chemical formula 333]

Obtaining method 5:

An example of the preparation of compound [2-c], which is an intermediate of compound [I] of the present invention, is shown in the following Scheme 5-1.

Scheme 5-1 (Method of obtaining compound [2-c] from compound [2-d]):

[Chemical formula 334]

[On the diagram,

R ² ' is as defined above, and

LG ⁴ represents the outgoing group.

As used herein, the “leaving group” represented by LG ⁴ is, for example, C _1-6 alkoxy.]

Stage 5-1:

Method for preparing compound [5-a]: Compound [2-d] is used as a starting material and allowed to react with an acid such as sulfuric acid in an alcohol solvent such as methanol or ethanol at a temperature ranging from ice-cooling to boiling. with reflux to obtain compound [5-a].

Stage 5-2:

Method for producing compound [5-b]: Compound [5-a] is used as a starting material and the method described in the above-mentioned step 4-2 or an equivalent method to obtain compound [5-b].

Stage 5-3:

Another method for preparing compound [5-b]: Compound [2-d] is used as a starting material and allowed to react with a reducing agent such as borane-tetrahydrofuran complex in an inert solvent, at a temperature ranging from ice cooling to room temperature, to obtain compound [5-b].

Stage 5-4:

Method for producing compound [2-c]: Compound [5-b] is used as a starting material and the method described in the above-mentioned step 4-4 or an equivalent method to obtain compound [2-c].

It should be noted that compound [2-d], which is used as a starting compound in the above steps 5-1 and 5-3, can be produced by known methods or purchased as a commercially available product.

An example of the production of compound [5-e] is shown in the following Diagram 5-2.

Scheme 5-2 (Method of obtaining compound [5-e] from compound [5-c]):

[Chemical Formula 335]

[On the diagram,

ring B ¹ , R ^B11 and R ^B12 are as defined above,

LG ⁵ represents the outgoing group,

wherein the "leaving group" represented by LG ⁵ is, for example, a halogen atom such as a chlorine atom or a bromine atom; C _1-4 alkylsulfonyloxy such as methanesulfonyloxy; or arylsulfonyloxy, such as p-toluenesulfonyloxy,

Y ¹ is formula -O-, formula -S- or formula -N(R ^L11 )-,

where R ^L11 is as defined above,

L ^X11 is C _1-5 alkanediyl, and

L ^X12 represents a single bond or C _1-5 alkanediyl substituted with 1-5 fluorine atoms.]

Stage 5-5:

Method for preparing compound [5-e]: Compound [5-c] is used as a starting material and reacted with compound [5-d] in the presence of a base such as sodium hydride in an inert solvent such as tetrahydrofuran or N- methylpyrrolidone at temperatures ranging from ice cooling to reflux to give compound [5-e].

In Diagram 5-2, using compound [5-c'] as the starting material instead of compound [5-c], and using compound [5-d'] instead of compound [5-d], compound [5-e' ] is obtained by a method that is similar to the above method for obtaining compound [5-e]. It should be noted that compounds [5-c'] and [5-d'] can be prepared by known methods or purchased as commercially available products.

[Chemical formula 336]

[In formulas

ring B ² , ^RB21 , ^RB22 and LG ⁵ are as defined above,

Y ² is formula -O-, formula -S- or formula -N(R ^L21 )-,

where R ^L21 is as defined above,

L ^X21 is C _1-5 alkanediyl, and

L ^X22 represents a single bond or C _1-5 alkanediyl substituted with 1-5 fluorine atoms.]

The compounds [2-c], [5-e] and [5-e'] thus obtained can be isolated and purified by generally known separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

Among the intermediates for compound [I] of the present invention, compound [2-d] shown in Scheme 5-1, and compounds [5-c] and [5-d] shown in Scheme 5-2 can be prepared by known methods. methods or purchased as commercially available products.

Among the intermediates for compound [I] of the present invention, compound [2-f'] described below in production method 2 can also be obtained, for example, by production method 6 below or an equivalent method.

[Chemical formula 337]

Method 6:

An example of the preparation of compound [2-f'], which is an intermediate of compound [I] of the present invention, is shown in the following Scheme 6-1.

Scheme 6-1 (Method of obtaining compound [2-f'] from compound [6-a]):

[Chemical Formula 338]

Step

Step

[On the diagram,

R ³ ', R ⁴ and M are as defined above, and

LG ⁶ represents the outgoing group.

In this document,

The "leaving group" represented by LG ⁶ is, for example, the group represented by the formula -N(CH ₃ )OCH ₃ .]

Stage 6-1:

Method for preparing compound [2-f']: Compound [6-a] is used as a starting material and reacted with alkyllithium [2-k] in an inert solvent from -78°C to room temperature, compound [2-f' ] with receipt.

The present step can be carried out with reference to the method described in, for example, Synlett, vol. 26, p. 1395, 2015.

Stage 6-2:

Method for preparing compound [6-a']: A "condensation reaction" is carried out between compound [6-a] and an amine compound such as N,O-dimethylhydroxylamine hydrochloride to obtain compound [6-a'].

Stage 6-3:

Another method for preparing compound [2-f']: Compound [6-a'] is used as a starting material and reacted with compound [2-k'] in an inert solvent at a temperature ranging from ice cooling to room temperature to obtain connections [2-f'].

Scheme 6-2 (Method of obtaining compound [2-h] from compound [6-b]):

[Chemical formula 339]

[On the diagram,

R ⁴ is as defined above, and

LG ⁷ represents the outgoing group.

As used herein, the “leaving group” represented by LG ⁷ is, for example, hydroxy or C _1-6 alkoxy.]

Stage 6-4:

Method for preparing compound [6-c]: Compound [6-b] is used as a starting material and allowed to react with a reducing agent in an inert solvent at a temperature ranging from cooling on ice to room temperature to obtain compound [6-c].

As a reducing agent, (i) if LG ⁷ is hydroxy, a borane-tetrahydrofuran complex can be used in the same way as in the above step 5-3, for example, and (ii) if LG ⁷ is C _1-6 alkoxy, lithium aluminum hydride or lithium borohydride can be used in the same way as in the above step 4-2, for example.

Stage 6-5:

Method for producing compound [2-h]: Compound [6-c] is used as a starting material and the method described in the above-mentioned step 4-4 or an equivalent method to obtain compound [2-h].

Compound [6-g], which is compound [2-h] in which R ⁴ is substituted phenyl and the ortho position of phenyl is substituted with a chlorine atom, can also be prepared, for example, by the method shown in Scheme 6-3 below or in an equivalent way.

Scheme 6-3 (Method of obtaining compound [6-g] from compound [6-d]):

[Chemical Formula 340]

[On the diagram,

Alk ³ and Alk ⁴ are as defined above,

Alk ⁶ is C _1-6 alkyl, and

Rα ² is C _1-6 alkyl (C _1-6 alkyl is optionally substituted with one hydroxy), halo-C _1-6 alkyl, C _3-8 cycloalkyl, C _1-6 alkylcarbonyl or halo-C _1-6 alkylcarbonyl.]

Stage 6-6:

Method for preparing compound [6-e]: Compound [6-d] is used as a starting material and allowed to react with a chlorinating agent such as sulfuryl chloride or N-chlorosuccinimide (NCS) in an inert solvent from -60°C to 100°C C, yielding compound [6-e].

It should be noted that this chlorination reaction can be carried out at another stage.

Also, at this stage, by applying 2 equivalents of a chlorinating agent to compound [6-d], compound [6-e'] below, in which both ortho positions are replaced by chlorine atoms, can be obtained.

[Chemical formula 341]

Stage 6-7:

Method for producing compound [6-f]: Compound [6-e] is used as a starting material, and compound [6-f] is obtained by the method described in the above-mentioned step 4-2 or an equivalent method.

Stage 6-8:

Method for producing compound [6-g]: Compound [6-f] is used as a starting material, and compound [6-g] is obtained by the method described in the above-mentioned step 4-4 or an equivalent method.

In addition, compound [6-m], which is compound [2-h], where R ⁴ is substituted phenyl and the ortho position of phenyl is substituted with methyl, can also be prepared, for example, by the method shown in Scheme 6-4 below or equivalent.

Scheme 6-4 (Method of obtaining compound [6-m] from compound [6-d]):

[Chemical formula 342]

[On the diagram,

Alk ³ , Alk ⁴ , Alk ⁶ and Rα ² are as defined above.]

Stage 6-9:

Method for preparing compound [6-h]: Compound [6-d] is used as a starting material and allowed to react with an iodinating agent such as iodine in the presence of a silver compound such as silver trifluoroacetate in an inert solvent at a temperature ranging from cooling to ice to room temperature to obtain compound [6-h].

It should be noted that this iodination reaction can also be carried out at another stage.

Stage 6-10:

Method for preparing compound [6-j]: Compound [6-h] is used as a starting material and reacted with a methylating agent such as methylboronic acid in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), and a base such as tripotassium phosphate in an inert solvent at a temperature ranging from room temperature to 160°C to obtain compound [6-j]. It should be noted that the present methylation reaction can also be carried out in another step.

Stage 6-11:

Method for producing compound [6-k]: Compound [6-j] is used as a starting material, and compound [6-k] is obtained by the method described in the above-mentioned step 6-7 or an equivalent method.

Stage 6-12:

Method for producing compound [6-m]: Compound [6-k] is used as a starting material, and compound [6-m] is obtained by the method described in the above-mentioned step 6-8 or an equivalent method.

Scheme 6-5 (Another way to obtain compound [6-j] from compound [6-d]):

[Chemical formula 343]

[On the diagram,

Alk ³ , Alk ⁴ , Alk ⁶ and Rα ² are as defined above.]

Stage 6-13:

Method for preparing compound [6-n]: Compound [6-d] is used as a starting material and allowed to react with dichloromethyl methyl ether in the presence of a Lewis acid such as titanium(IV) chloride in an inert solvent at a temperature ranging from ice cooling to room temperature to give compound [6-n].

It should be noted that the present formylation reaction can also be carried out in another step.

Stage 6-14:

Another method for preparing compound [6-j]: Compound [6-n] is used as a starting material and allowed to react with a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid at a temperature ranging from ice cooling to room temperature, to obtain compound [6-j]. It should be noted that this melitation reaction can also be carried out at another stage.

Among the intermediates for compound [I] of the present invention, compound [2-g] described below in production method 2 can be obtained by known methods or purchased as a commercially available product, but it can also be obtained, for example, by production method 7 below or in an equivalent way.

[Chemical formula 344]

Method 7:

An example of the preparation of compound [2-g], which is an intermediate of compound [I] of the present invention, is shown in the following Scheme 7.

Scheme 7 (Method of obtaining compound [2-g] from compound [2-b]):

[Chemical Formula 345]

[On the diagram,

R ² and LG ¹ are as defined above,

PG ² is an amino protecting group such as t-butoxycarbonyl, and

PG ³ represents a hydrogen atom or an amino protecting group such as t-butoxycarbonyl, or

PG ² and PG ³ can also form a phthalimide or the like, together with an adjacent nitrogen atom, to protect the amino.]

Stage 7-1:

Method for preparing compound [7-a]: Compound [2-b] is used as a starting material and allowed to react with potassium phthalimide, di-tert-butyl iminodicarboxylate or the like in the presence or absence of a base such as potassium carbonate in an inert solvent, at a temperature from room to 120°C, compound [7-a] to obtain.

Stage 7-2:

Method for preparing compound [2-g]: Compound [7-a] is used as a starting material and under any of the following reaction conditions (i) to (ii) to obtain compound [2-g]:

(i) conditions under which an acid, such as hydrochloric acid, can react in an inert solvent at a temperature ranging from ice cooling to 100°C, or

(ii) conditions under which hydrazine monohydrate or the like can be reacted in an inert solvent at room temperature to reflux.

Compound [2-b], which is used as a starting compound in the above Step 7-1, can be produced according to methods known as such, by production according to the method shown in the above Scheme 4-1, or by purchasing commercially available products.

Compound [2-g] thus obtained can be isolated and purified by conventional separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

Among the intermediates for compound [I] of the present invention, compound [2-b] shown in Scheme 7 can be prepared by known methods or purchased as a commercially available product.

Among the intermediates of compound [I] of the present invention, the compound whose structure is represented by the formula [1-b] (hereinafter also may be referred to as compound [1-b]) can also be obtained, for example, by the preparation method 8 below or in an equivalent way.

[Chemical formula 346]

Method 8:

Compound [1-b], which is an intermediate of compound [I] of the present invention, can be prepared by known methods or purchased as a commercially available product, but it can also be prepared, for example, by the method shown in Scheme 8-1 below or equivalent way.

Scheme 8-1 (Method of obtaining compound [1-b] from compound [8-a])

[Chemical formula 347]

[On the diagram,

W and Alk ¹ are as defined above, and

PG ⁴ represents an amino protecting group such as benzyloxycarbonyl, t-butoxycarbonyl or allyloxycarbonyl.]

Stage 8-1:

Method for preparing compound [8-b]: Compound [8-a] is used as a starting material and under any of the following reaction conditions (i) to (iii) to obtain compound [8-b]:

(i) conditions under which an alkylating agent such as methyl iodide can react in the presence or absence of a base such as potassium carbonate in an inert solvent at room temperature to reflux,

(ii) conditions under which an alcohol, such as methanol or ethanol, can be reacted in the presence of p-toluenesulfonic acid, thionyl chloride and the like, in the presence or absence of an inert solvent, at a temperature ranging from room temperature to reflux, or

(iii) conditions under which an alkylating agent such as methyl iodide can react in the presence of a silver compound such as silver oxide in an inert solvent at room temperature to reflux.

Stage 8-2:

Method for preparing compound [1-b]: Compound [8-b] is used as a starting material and through the following deprotection reactions (i) - (iii) in an inert solvent to obtain compound [1-b]:

(i) a deprotection reaction in which an acid such as hydrochloric acid, hydrobromic acid or trifluoroacetic acid is used at a temperature ranging from ice cooling to 80°C,

(ii) a deprotection reaction in which palladium on carbon or the like is used in the presence or absence of acid in a hydrogen atmosphere under or without pressure, at a temperature ranging from ice cooling to room temperature, or

(iii) a deprotection reaction in which a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0) is used in the presence of an allylic acceptor such as 1,3-dimethylbarbituric acid at a temperature ranging from ice cooling to 80°C.

Compound [8-f], which is compound [1-b], where W is the structure represented by the above formula [III-1], can be produced by known methods or purchased as a commercially available product.

Alternatively, this compound can also be prepared, for example, by the method shown in Scheme 8-2 below or an equivalent method.

[Chemical formula 348]

Scheme 8-2 (Method of obtaining compound [8-f] from compound [8-c]):

[Chemical formula 349]

[On the diagram,

ring A ¹ , R ^A11 , R ^A12 , Alk ¹ and PG ⁴ are as defined above.]

Stage 8-3:

Method for preparing compound [8-d]: Compound [8-c] is used as a starting material and allowed to react with tetramethylammonium hydroxide, tetraethylammonium hydroxide or the like in an inert solvent at a temperature from ice cooling to room temperature, to obtain selective hydrolysis of only one of the two esters in compound [8-c], giving compound [8-d].

The present step can be carried out with reference to the method described in, for example, The Journal of Organic Chemistry, vol. 82, p. 12863, 2017.

Stage 8-4:

Method for preparing compound [8-e]: Compound [8-d] is used as a starting material and allowed to react with an azidating agent such as diphenylphosphoryl azide in the presence of a base such as triethylamine in an inert solvent at a temperature ranging from ice cooling to 100°C, to obtain the corresponding isocyanate, and then allowing an alcohol such as benzyl alcohol, tert-butyl alcohol or allyl alcohol to act on it, to obtain compound [8-e].

Stage 8-5:

Method for producing compound [8-f]: Compound [8-e] is used as a starting material, and compound [8-f] is obtained by the method described in the above-mentioned step 8-2 or an equivalent method.

Also, the compound [8-f'] or [8-f''], which is the compound [1-b], where W is the structure represented by the above formula [III-2] or [III-3], may be obtained by known methods or purchased as commercially available products.

Alternatively, these compounds can also be prepared, for example, by the method described in the above Scheme 8-2 or an equivalent method.

[Chemical Formula 350]

[In formulas

ring A ² , ring A ³ , R ^A21 , R ^A22 , R ^A31 , R ^A32 and Alk ¹ are as defined above.]

Compound [8-p], which is compound [1-b], where W is the structure represented by the above formula [III-1], and in this structure, ring A ¹ is a C _3-8 cycloalkane substituted by one group , selected from the group consisting of "hydroxy, C _1-6 alkoxy and nitrogen containing 4-6 membered saturated heterocyclyl" can be prepared by known methods or purchased as a commercially available product.

Alternatively, this compound can also be prepared, for example, by the method shown in Scheme 8-3 below or an equivalent method using compound [8-g], which is an oxo-substituted C _3-8 cycloalkane compound as the starting material .

[Chemical formula 351]

Scheme 8-3 (Method of obtaining compound [8-p] from compound [8-g]):

[Chemical formula 352]

[On the diagram,

Alk ¹ and PG ⁴ are as defined above,

the A ¹ ' ring is a C _3-8 cycloalkane,

PG ⁵ is C _1-3 alkyl,

Where

two PG ⁵ may form a 5-6 membered ring (the 5-6 membered ring may be substituted with one or two groups selected from the group consisting of methyl and phenyl) together with bonded oxygen atoms and a carbon atom to protect the carbonyl, and

R ^A11 ' is hydroxy, C _1-6 alkoxy or a nitrogen containing 4-6 membered saturated heterocyclyl (a nitrogen containing 4-6 member saturated heterocyclyl may be replaced by one C _1-3 alkyl).]

Stage 8-6:

Method for preparing compound [8-h]: Compound [8-g] is used as a starting material and reacted with an alcohol such as methanol, ethylene glycol or hydrobenzoin or an orthoester such as triethyl orthoformate in the presence of an acid such as p- toluenesulfonic acid in an inert solvent, at room temperature to reflux, to give compound [8-h].

Stage 8-7:

Method for producing compound [8-j]: Compound [8-h] is used as a starting material, and compound [8-j] is obtained by the method described in the above-mentioned step 8-3 or an equivalent method.

Stage 8-8:

Method for producing compound [8-k]: Compound [8-j] is used as a starting material, and compound [8-k] is obtained by the method described in the above-mentioned step 8-4 or an equivalent method.

Stage 8-9:

Method for preparing compound [8-m]: Compound [8-k] is used as a starting material and through a deprotection reaction using an acid such as hydrochloric acid or trifluoroacetic acid in an inert solvent at room temperature to reflux , join [8-m] with receive.

Stage 8-10:

Method for preparing compound [8-n]: Compound [8-m] is used as a starting material and by performing any of the following reactions (i) to (iv), compound [8-n] is obtained:

(i) a reduction reaction in which a reducing agent such as sodium borohydride, lithium borohydride, diisobutylaluminum hydride, lithium triethylborohydride, lithium tri-sec-butylborohydride or borane-tetrahydrofuran is used in the presence or absence of an additive such as zinc chloride, in inert solvent from -80°C to boiling point with reflux;

(ii) a “hydrolysis reaction” after carrying out the operation of step 8-10 (i), and subsequent reaction with 4-nitrobenzoic acid or the like, in the presence of a phosphorus compound such as triphenylphosphine and an azodicarboxylic acid diester such as bis(2- methoxyethyl azodicarboxylate, in an inert solvent at a temperature ranging from cooling on ice to boiling with a refrigerator;

(iii) reacting, after the operation of step 8-10 (i) or 8-10 (ii), using an alkyl halide such as methyl iodide or ethyl iodide in the presence of a silver compound such as silver oxide in an inert solvent at a temperature of from room temperature to boiling with refrigerator; or

(iv) a "reductive amination reaction" with an amine corresponding to RA ^11' .

The above-mentioned step 8-10 (i) can be performed with reference, for example, to the method described in Bioorganic & Medicinal Chemistry, vol. 17, p. 1982, 2009.

Moreover, in this step 8-10(i), by selecting a suitable reducing agent, compound [8-n] is prepared by a stereoselective method.

Stage 8-11:

Method for producing compound [8-p]: Compound [8-n] is used as a starting material, and compound [8-p] is obtained by the method described in the above-mentioned step 8-2 or an equivalent method.

Alternatively, the present compound [8-p] can also be prepared, for example, by the method shown in Scheme 8-4 below or an equivalent method using compound [8-m] obtained in Scheme 8-3, which is a C ₃ compound _-8 cycloalkane substituted with oxo as starting material.

Scheme 8-4 (Method of obtaining compound [8-p] from compound [8-m]):

[Chemical formula 353]

[On the diagram,

Alk ¹ , PG ⁴ , ring A ¹ ' and R ^A11 ' are as defined above.]

Stage 8-12:

Method for producing compound [1-b']: Compound [8-m] is used as a starting material, and compound [1-b'] is obtained by the method described in the above-mentioned step 8-2 or an equivalent method.

Stage 8-13:

Method for preparing compound [8-q]: Compound [1-b'] is used as a starting material and reacted with phthalic anhydride or the like in the presence of a base such as triethylamine in an inert solvent at a temperature from room temperature to reflux, to obtain compound [8-q].

Stage 8-14:

Method for producing compound [8-r]: Compound [8-q] is used as a starting material, and compound [8-r] is obtained by the method described in the above-mentioned step 8-10 or an equivalent method.

Stage 8-15:

Method for preparing compound [8-p]: Compound [8-r] is used as a starting material and allowed to react with an acid such as hydrochloric acid, hydrazine or the like in an inert solvent at a temperature ranging from ice cooling to reflux , also yielding compound [8-p].

In addition, the compound [8-p'] or [8-p''], which is the compound [1-b], where W is the structure represented by the above formula [III-2] or [III-3], and in this structure, ring A ² and ring A ³ are each a C _3-8 cycloalkane substituted by one group selected from the group consisting of "hydroxy, C _1-6 alkoxy and nitrogen-containing 4-6 membered saturated heterocyclyl" , can be prepared by known methods or purchased as commercially available products.

Alternatively, these compounds can also be prepared, for example, by the method described in the above Scheme 8-3 or 8-4, or an equivalent method.

[Chemical formula 354]

[In formulas

Alk ¹ is as defined above,

ring A ² ' and ring A ³ ' such as defined as ring A ¹ ', and each is a C _3-8 cycloalkane, and

R ^A21 ' and R ^A31 ' such as are defined as R ^A11 ' and each is hydroxy, C _1-6 alkoxy or nitrogen containing 4-6 membered saturated heterocyclyl (nitrogen containing 4-6 member saturated heterocyclyl may be substituted one C _1-3 alkyl).]

Compound [8-w], which is compound [1-b], where W is the structure represented by the above formula [III-1], and in this structure, ring A ¹ is a C _3-8 cycloalkane substituted with one hydroxy, and compound [8-z], which is compound [1-b], where W is the structure represented by the above formula [III-1], and ring A ¹ is a C _3-8 cycloalkane substituted with one C _1-6 alkoxy, can be prepared by known methods or purchased as commercially available products.

Alternatively, these compounds can also be prepared, for example, by the method shown in Scheme 8-5 below or an equivalent method using compound [8-g], which is a C _3-8 oxo-substituted cycloalkane, as a starting material.

It should be noted that when the corresponding enantiomers or diastereomers are present in compounds [8-w] and [8-z], the enantiomers or diastereomers can likewise be prepared by any of the methods known as such, by the method shown in Scheme 8-5 , or by purchasing commercially available products.

[Chemical Formula 355]

Scheme 8-5 (Method of obtaining compounds [8-w] and [8-z] from compound [8-g]):

[Chemical formula 356]

[On the diagram,

Alk ¹ , ring A ¹ ' and PG ⁴ are as defined above, and

R ^A11a is C _1-6 alkoxy.]

Stage 8-16:

Method for producing compound [8-s]: Compound [8-g] is used as a starting material and the method described in the above-mentioned step 8-10(i) or an equivalent method to obtain compound [8-s].

Stage 8-17:

Method for producing compound [8-t]: Compound [8-s] is used as a starting material and the method described in the above-mentioned step 8-3 or an equivalent method to obtain compound [8-t].

Stage 8-18:

Method for preparing compound [8-u]: Compound [8-t] is used as a starting material and allowed to react with an azide such as diphenylphosphoryl azide in the presence of a base such as triethylamine in an inert solvent at a temperature ranging from ice cooling to boiling with reflux to obtain compound [8-u].

The above step 8-18 can be carried out with reference to the method described in, for example, Journal of the Organic Chemistry, vol. 82, p. 12863, 2017.

Stage 8-19:

Method for preparing compound [8-v]: Compound [8-u] is used as a starting material and allowed to react with a base such as potassium hydroxide and water in an inert solvent at a temperature ranging from ice cooling to reflux, with receiving connection [8-v].

Stage 8-20:

Method for producing compound [8-w]: Compound [8-v] is used as a starting material, and compound [8-w] is obtained by the method described in the above-mentioned step 8-1 (ii) or an equivalent method.

Stage 8-21:

Method for preparing compound [8-x]: Compound [8-w] is used as a starting material and allowed to react with di-tert-butyl dicarbonate, allyl chloroformate, benzyl chloroformate or the like in the presence of a base such as triethylamine, sodium hydroxide or sodium carbonate in an inert solvent at a temperature ranging from cooling on ice to refluxing, compound [8-x] to give.

Stage 8-22:

Method for preparing compound [8-y]: Compound [8-x] is used as a starting material and reacted with an alkyl halide such as methyl iodide or ethyl iodide in the presence of a silver compound such as silver oxide in an inert solvent at a temperature of room temperature to reflux to give compound [8-y].

Stage 8-23:

Method for producing compound [8-z]: Compound [8-y] is used as a starting material, and compound [8-z] is also prepared by the method described in the above-mentioned step 8-2 or an equivalent method.

Compound [8-ac], which is compound [1-b], where W is the structure represented by the above formula [III-1], and in this structure, ring A ¹ is a nitrogen atom-containing 4-8 membered saturated a heterocycle substituted with one group selected from the group consisting of "C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl" can be prepared by known methods or purchased as commercially available products.

Alternatively, this compound can also be prepared, for example, by the method shown in Scheme 8-6 below, or an equivalent method using compound [8-aa], which is a nitrogen-containing 4-8 membered saturated heterocycle, as original substance.

[Chemical formula 357]

Scheme 8-6 (Method of obtaining compound [8-ac] from compound [8-aa]):

[Chemical formula 358]

[On the diagram,

Alk ¹ and PG ⁴ are as defined above,

ring A ¹ '' is a nitrogen-containing 4-8 membered saturated heterocycle, and

R ^A11 '' is C _1-4 alkylcarbonyl or C _1-4 alkoxycarbonyl.]

Stage 8-24:

Method for preparing compound [8-ac]: Compound [8-aa] is used as a starting material and the following reaction (i) or (ii) produces compound [8-ab]:

(i) a reaction in which an acyl chloride corresponding to R ^A11'' , such as acetyl chloride, or an acid anhydride corresponding to R ^A11'' , such as acetic anhydride, is used in the presence of a base in an inert solvent at a temperature ranging from ice cooling to 50° C, or

(ii) a reaction in which a chloroformate ester corresponding to R ^A11'' , such as ethyl chloroformate, is used in the presence or absence of a base in an inert solvent at a temperature ranging from ice-cooling to 50°C.

Stage 8-25:

Method for producing compound [8-ac]: Compound [8-ab] is used as a starting material, and compound [8-ac] is obtained by the method described in the above-mentioned step 8-2 or an equivalent method.

Also, the compound [8-ac'] or [8-ac''], which is the compound [1-b], where W is the structure represented by the above formula [III-2] or [III-3], and in In this structure, ring A ² and ring A ³ each represent a nitrogen atom-containing 4-8 membered saturated heterocycle substituted by one group selected from the group consisting of "C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl" may be obtained by known methods or purchased as commercially available products.

Alternatively, these compounds can also be prepared, for example, by the method described in the above Scheme 8-6, or an equivalent method.

[Chemical formula 359]

[In formulas

Alk ¹ is as defined above,

the A ^2'' ring and the A ^3'' ring are as defined as the A ^1'' ring, and each is a nitrogen atom containing 4 to 8 membered saturated heterocycle, and

R ^A21 '' and R ^A31 '' are as defined as R ^A11 '', and each is C _1-4 alkylcarbonyl or C _1-4 alkoxycarbonyl.]

Connections [1-b], [8-f], [8-f'], [8-f''], [8-p], [8-p'], [8-p''], [ 8-w], [8-z], [8-ac], [8-ac'] and [8-ac''] thus obtained can be isolated and purified by conventional separation and purification means such as concentration , concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

Among the intermediates for compound [I] of the present invention, compound [8-a] shown in Scheme 8-1, compound [8-c] shown in Scheme 8-2, compound [8-g] shown in Schemes 8-3 and 8-5, and compound [8-aa] shown in Scheme 8-6 can be prepared by known methods or purchased as commercially available products.

Among the compounds [I] of the present invention, a compound where X represents carbamoyl, a compound where X represents a group represented by the formula [II-2], [II-3], [II-4], [II-5] or [II-1] below and the compound where X is tetrazolyl is prepared, for example, by the production method of 9 below or an equivalent method.

[Chemical formula 360]

Among the compounds [I] of the present invention, an example of the preparation of compound [9-a] where X represents carbamoyl or a group represented by the formula [II-2], [II-3] or [II-4] is shown in the following diagram 9-1.

Method 9:

Scheme 9-1 (Method of obtaining compound [9-a] from compound [1-d]):

[Chemical formula 361]

[On the diagram,

R ¹ , R ² , R ³ , R ⁴ and W are as defined above, and

EQ ¹ represents a hydrogen atom or a group selected from the group of formulas [II']:

[Chemical formula 362]

]

Stage 9-1:

Preparation method of [9-a]: Compound [1-d] is used as a starting material and reacted with an amine compound such as methanesulfonamide, sulfonamide, N,N-dimethylsulfamide or ammonium chloride, in the presence or absence of a base such as as N,N-diisopropylethylamine, in the presence or absence of an additive such as 4-dimethylaminopyridine or HOBt and in the presence of a condensing agent such as EDC or CDI, in an inert solvent at a temperature ranging from ice-cooling to reflux, compound [ 9-a] with receipt.

Among the compounds [I] of the present invention, an example of the preparation of compound [9-h] where X is a group represented by the formula [II-5] is shown in the following Chart 9-2.

Scheme 9-2 (Method of obtaining compound [9-h] from compound [9-b]):

[Chemical formula 363]

[On the diagram,

R ² , R ³ , R ⁴ , R ^A11 and R ^A12 are as defined above,

ring D is a C _3-8 cycloalkane, a partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle containing a sulfur atom 4-8 membered saturated heterocycle or containing a nitrogen atom 4-8 -membered saturated heterocycle,

Where

the sulfur atom in the sulfur atom-containing 4-8-membered saturated heterocycle is optionally replaced by one to two oxos, and

the nitrogen atom in the nitrogen atom-containing 4-8 membered saturated heterocycle is optionally substituted by one group selected from the group consisting of C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl,

PG ⁵ is a protecting group for a phosphate group such as benzyl, and

PG ⁶ is an amino protecting group such as diphenylmethyl.]

Stage 9-2:

Method for preparing compound [9-e]: Compounds [9-b], [9-c] and [9-d] are used as starting materials and allowed to react with a Lewis acid such as vimsuth(III) chloride to inert them. solvent at a temperature from room to 120°C, obtaining compound [9-e].

The present step can be carried out with reference to the method described in, for example, Organic Letters, vol. 1, p. 1395, 1999.

In addition, this reaction can also be carried out under microwave irradiation.

Stage 9-3:

Method for preparing compound [9-f]: Compound [9-e] is used as a starting material and allowed to react with an oxidizing agent such as 2,3-dichloro-5,6-dicyano-1,4-benzoquinone in an inert solvent at room temperature to 100°C, thereby obtaining the corresponding imine, and then allow an acidic aqueous solution such as hydrochloric acid to react with it in an inert solvent at room temperature to 60°C, compound [9-f] with receiving.

The present step can be carried out with reference to the method described in, for example, Organic Letters, vol. 1, p. 1395, 1999.

Stage 9-4:

Method for preparing compound [9-g]: Compound [9-f] is used as a starting material and reacted with compound [1-a] in the presence of a base such as triethylamine, pyridine, 4-dimethylaminopyridine or N,N-diisopropylethylamine , and an agent that forms a urea derivative such as 4-nitrophenyl chloroformate, CDI or triphosgene, in an inert solvent, at a temperature ranging from ice cooling to reflux, to obtain the compound [9-g].

Stage 9-5:

Method for preparing compound [9-h]: Compound [9-g] is used as a starting material and through a deprotection reaction in which palladium on carbon or the like is used in the presence or absence of acid in an inert solvent under a hydrogen atmosphere under or without pressure pressure, at a temperature from cooling on ice to room temperature, compound [9-h] is obtained.

Among the compounds [I] of the present invention, a production example of compound [9-r] where X is a group represented by the formula [II-1] is shown in the following Chart 9-3.

Scheme 9-3 (Method of obtaining compound [9-q] from compound [8-a]):

[Chemical formula 364]

[On the diagram,

PG ⁴ , R ² , R ³ , R ⁴ and W are as defined above.]

Stage 9-6:

Method for producing compound [9-j]: A “condensation reaction” is carried out between compound [8-a] and an amine compound such as ammonium chloride to obtain compound [9-j].

Stage 9-7:

Method for preparing compound [9-k]: Compound [9-j] is used as a starting material and allowed to react with an arylsulfonyl chloride such as p-toluenesulfonyl chloride or a C _1-4 alkylsulfonyl chloride such as methanesulfonyl chloride in the presence of a base such as as pyridine in an inert solvent, at a temperature ranging from cooling on ice to 50°C, to give compound [9-k].

Stage 9-8:

Method for producing compound [9-m]: Compound [9-k] is used as a starting material, and compound [9-m] is obtained by the method described in the above-mentioned step 8-2 or an equivalent method.

Stage 9-9:

Method for producing compound [9-n]: Compound [9-m] is used as a starting material, and compound [9-n] is obtained by the method described in the above-mentioned step 9-4 or an equivalent method.

Stage 9-10:

Method for preparing compound [9-p]: Compound [9-n] is used as a starting material and reacted with hydroxylamine hydrochloride in the presence or absence of a base such as sodium carbonate or N,N-diisopropylethylamine in an inert solvent, at temperature from cooling on ice to 90°C, obtaining compound [9-p].

Stage 9-11:

Method for preparing compound [9-q]: Compound [9-p] is used as a starting material and reacted with CDI or the like in the presence of a base such as 1,8-diazabicyclo[5.4.0]-7-undecene, in inert solvent, at a temperature ranging from cooling on ice to room temperature, to obtain compound [9-q].

Among the compounds [I] of the present invention, an example of the preparation of compound [9-v] where X is tetrazolyl is shown in the following Scheme 9-4.

Scheme 9-4 (Method of obtaining connection [9-v] from connection [9-k]):

[Chemical Formula 365]

[On the diagram,

PG ⁴ , R ² , R ³ , R ⁴ and W are as defined above, and

PG ⁷ represents a tetrazolyl protecting group such as triphenylmethyl or benzyl.]

Stage 9-12:

Method for preparing compound [9-r]: Compound [9-k] is used as a starting material and reacted with an azide such as sodium azide in the presence of an inorganic acid salt of an amine compound such as ammonium chloride or trimethylamine hydrochloride, and in in the presence or absence of a copper catalyst, in an inert solvent at a temperature from room to 150°C, to obtain compound [9-r]. In addition, this reaction can also be carried out under microwave irradiation.

Stage 9-13:

Method for preparing compound [9-s]: Compound [9-r] is used as a starting material and allowed to react with trityl chloride, benzyl bromide or the like in the presence of a base such as triethylamine or potassium carbonate in an inert solvent at a temperature ranging from cooling on ice to room temperature, obtaining compound [9-s].

Stage 9-14:

Method for producing compound [9-t]: Compound [9-s] is used as a starting material, and compound [9-t] is obtained by the method described in the above-mentioned step 8-2 or an equivalent method.

Stage 9-15:

Method for producing compound [9-u]: Compound [9-t] is used as a starting material, and compound [9-u] is obtained by the method described in the above-mentioned step 9-4 or an equivalent method.

Stage 9-16:

Method for preparing compound [9-v]: Compound [9-u] is used as a starting material and in an inert solvent at a temperature from cooling on ice to room temperature, (i) allowing an acid such as hydrochloric acid to act on it, or (ii) ) carry out a deprotection reaction in which palladium on carbon or the like is used in the presence or absence of acid in a hydrogen atmosphere under or without pressure to obtain the compound [9-v].

Compounds [9-a], [9-h], [9-q] and [9-v] thus obtained can be isolated and purified by separation and purification means such as concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization and chromatography.

Among the intermediates for compound [I] of the present invention, compounds [9-b], [9-c] and [9-d] shown in Scheme 9-2, and compound [8-a] shown in Scheme 9- 3 may be prepared by known methods or purchased as commercially available products.

Hereinafter, the present invention will be described in detail with reference to the following reference examples, examples and experimental examples. However, they do not limit the present invention and may vary within the scope of the present invention.

In addition, the following Reference Examples and the Examples herein describe some cases where the yield exceeds the theoretical amount due to the influence of residual solvent and the like.

The following reference examples and examples use a packed column (Reveleris (registered trademark) Flash Cartridges Silica manufactured by W.R. Grace & Co. or Biotage (registered trademark) SNAP Cartridge HP-Sphere manufactured by Biotage AB) for silica gel column chromatography. For NH silica gel column chromatography, a packed column (Reveleris (registered trademark) Flash Cartridges Amino manufactured by W.R. Grace & Co. or Biotage (registered trademark) SNAP Cartridge KP-NH manufactured by Biotage AB) is used. For preparative thin-layer chromatography, a 20 x 20 cm PLC plate, silica gel 60 F254, 2 mm, manufactured by Merck KGaA, is used. The ratio of eluting solvents means the ratio by volume unless otherwise specified. The phase separator used is ISOLUTE phase separator (registered trademark), manufactured by Biotage AB.

Abbreviations used in this document have the following meanings:

s: singlet

d: doublet

t: triplet

kv: quartet

quin: quintet

skst: sextet

spt: septet

dd: double doublet

dt: double triplet

td: triple doublet

TT: triple triplet

kvd: quarter doublet

m: multiplet

w: wide

J: combination constant

Hz: Hertz

CHLORFORM-d: deuterated chloroform

DMSO-d6: deuterated dimethyl sulfoxide

METHANOL-d4: deuterated methanol

ACETONE-d6: deuterated acetone

D ₂ O: deuterated water

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

EDC: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

CDI: 1,1'-carbonyldiimidazole

DMT-MM: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride

HOBt: N-hydroxybenzotriazole monohydrate

DBU: 1,8-diazacyclo[5.4.0]-7-undecene

Rf: retardation factor

gender: positive (mode)

neg: negative (mode)

¹ H-NMR (proton nuclear magnetic resonance spectrum) is measured using Fourier transform NMR described below using tetramethylsilane as an internal standard, and all δ values are shown in ppm.

200 MHz: Gemini2000 (Agilent Technologies)

300 MHz: Inova300 (Agilent Technologies)

400 MHz: AVANCE III HD400 (Bruker)

500 MHz: JNM-ECA500 (JEOL)

600 MHz: JNM-ECA600 (JEOL)

For analysis, use ACD/Spectrus Processor 2015 ACD/Labs 2015 Release (File Version S30S41, Build 76327, 28 Feb 2015) (trade name), and the like. Very weak proton peaks such as hydroxy, amino, amide, pyrazole, urea and carboxy peaks cannot be described.

It should be noted that when analyzing compounds herein, there may be protons that were not identified due to overlap with the water or solvent peak.

MS (mass spectrum) is measured using the following device.

PlatformLC (Waters)

LCMS-2010EV (Shimadzu)

LCMS-IT-TOF (Shimadzu)

Agilent6130 (Agilent)

Agilent6150 (Agilent)

As for the ionization method, the ESI (electrospray ionization) method, the ESI (electron ionization) method, or the dual ionization method combining the ESI and APCI (atmospheric pressure chemical ionization) methods are used. For data, the measured values (found) are described. Typically molecular ion peaks are observed, but in the case of a compound containing tert-butoxycarbonyl (-Boc), the peak for which the tert-butoxycarbonyl or tert-butyl has been removed may appear as a fragment ion. Additionally, in the case of a compound containing tetrahydropyranyl (THP), a peak for which the tetrahydropyranyl has been removed may appear as a fragment ion. Additionally, in the case of a compound containing hydroxy(-OH), a peak for which the H ₂ O or OH radical has been removed may appear as a fragment peak. In the case of a salt, a free form molecular ion peak or a fragment ion peak is usually observed.

If the analytical data measurement conditions were as follows, then this is described as M mode.

Device: LCMS-IT-TOF (Shimadzu)

Ionization method: multimodal ESI/CIAD

The LC-MS in the examples and reference examples are measured under the following conditions.

HPLC: Agilent 1290 Infinity

MS: Agilent 6130 or 6150

[HPLC conditions]

Column: Acquity UPLC CSH C18, 1.7 µm, 2.1 x 50 mm (WATERS)

Solvent: solution A, water containing 0.1% formic acid and solution B, acetonitrile containing 0.1% formic acid

(method A, Normal mode)

Gradient: 0.00 min (solution A/solution B=80/20), 1.20 min (solution A/solution B=1/99), 1.40 min (solution A/solution B=1/99), 1.41 min (solution A/solution B=80/20), 1.50 min (solution A/solution B=80/20)

(method B, HP mode)

Gradient: 0.00 min (solution A/solution B=95/5), 0.80 min (solution A/solution B=60/40), 1.08 min (solution A/solution B=1/99), 1.38 min (solution A/solution B=1/99), 1.41 min (solution A/solution B=95/5), 1.50 min (solution A/solution B=80/20)

(mode C, LP mode)

Gradient: 0.00 min (solution A/solution B=70/30), 0.80 min (solution A/solution B=1/99), 1.40 min (solution A/solution B=1/99), 1.42 min (solution A/solution B=70/30), 1.50 min (solution A/solution B=70/30)

Injection volume: 0.5 µL, Flow rate: 0.8 ml/min

Detection method: UV 210 nm, 254 nm

Agilent 385-ELSD equipped with Evaporative Light Scattering Detector (ELSD)

MS terms

Ionization method: multimodal ESI or ESI/CIAD

Analytical data measurement conditions are described as follows.

[Table 1-1] Ionization method Mode LP normal HP IER A B C ESI/HIAD multimodal D E F

The preparative HPLC purification in the examples and reference examples was carried out under the following conditions.

Tool: GILSON high throughput cleaning system

Column: Triart C18, 5 µm, 30 x 50 mm (YMC) or X-Bridge Prep C18 5 µm OBD, 30 x 50 (Waters)

Solvent: solution A, water containing 0.1% formic acid and solution B, acetonitrile containing 0.1% formic acid; or solution A, water containing 0.1% trifluoroacetic acid, and solution B, acetonitrile containing 0.1% trifluoroacetic acid

(method A)

Gradient: 0.00 min (solution A/solution B=90/10), 2.00 min (solution A/solution B=90/10), 11.0 min (solution A/solution B=20/80), 12.0 min (solution A/solution B=5/95), 13.52 min (solution A/solution B=5/95), 15.0 min (solution A/solution B=90/10)

(method B)

Gradient: 0.00 min (solution A/solution B=95/5), 3.00 min (solution A/solution B=95/5), 8.53 min (solution A/solution B=80/20), 10.0 min (solution A/solution B=80/20), 11.0 min (solution A/solution B=50/50), 12.02 min (solution A/solution B=5/95), 13, 5 min (solution A/solution B=5/95), 13.65 min (solution A/solution B=95/5), 15.0 min (solution A/solution B=95/5)

(method C)

Gradient: 0.00 min (solution A/solution B=80/20), 2.00 min (solution A/solution B=80/20), 10.0 min (solution A/solution B=5/95), 11.0 min (solution A/solution B=1/99), 13.5 min (solution A/solution B=1/99), 13.55 min (solution A/solution B=80/20), 15, 0 min (solution A/solution B=80/20)

Flow rate: 40ml/min

Detection method: UV 210 nm, UV 254 nm

SoftTA MODEL 300S ELSD, if equipped with ELSD

Diastereomeric separation is carried out by preparative HPLC in the examples below.

[HPLC conditions]

[Table 2-1] Conditions Example 5-52
Example 5-53 Column: YMC Triart C18 5 µm, 30 × 50 mm
Solvent: Solution A, 0.1% formic acid-water and Solution B, 0.1% formic acid-acetonitrile
Elution conditions: solution A/solution B=80/20 → 1/99
Flow rate: 40ml/min, Temperature: room temperature Example 5-65
Example 5-66 Column: YMC Triart C18 5 µm, 30 × 50 mm
Solvent: Solution A, 0.1% formic acid-water and Solution B, 0.1% formic acid-acetonitrile
Elution conditions: solution A/solution B=80/20 → 1/99
Flow rate: 40ml/min, Temperature: room temperature Example 5-67
Example 5-68 Column: YMC Triart C18 5 µm, 30 × 50 mm
Solvent: Solution A, 0.1% formic acid-water and Solution B, 0.1% formic acid-acetonitrile
Elution conditions: solution A/solution B=80/20 → 1/99
Flow rate: 40ml/min, Temperature: room temperature Example 5-69
Example 5-70 Column: YMC Triart C18 5 µm, 30 × 50 mm
Solvent: Solution A, 0.1% formic acid-water and Solution B, 0.1% formic acid-acetonitrile
Elution conditions: solution A/solution B=80/20 → 1/99
Flow rate: 40ml/min, Temperature: room temperature Example 10-10
Example 10-11 Column: YMC Triart C18 5 µm, 30 × 50 mm
Solvent: Solution A, 0.1% formic acid-water and Solution B, 0.1% formic acid-acetonitrile
Elution conditions: solution A/solution B=80/20 → 1/99
Flow rate: 40ml/min, Temperature: room temperature

Detection method: UV 210 nm, 254 nm

Preparative isolation of chiral HPLC in the examples is carried out under the following conditions.

HPLC: GILSON high throughput purification system or Waters preparative LC system

[HPLC conditions]

[Table 3-1] Conditions Example 1-21 (2) Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=15/85
Flow rate: 10ml/min, Temperature: room temperature Example 1-30 (2) Column: CHIRALPAK ID3, 5 µm, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, n-hexane
Elution conditions: solution A/solution B=10/90
Flow rate: 10ml/min, Temperature: room temperature Example 1-35
Example 1-36 Column: CHIRALPAK IF3, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=10/90
Flow rate: 10ml/min, Temperature: room temperature Example 1-44
Example 1-45 Column: CHIRALPAK ID3, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=8/92
Flow rate: 10ml/min, Temperature: room temperature Example 1-78
Example 1-79 Column: CHIRALPAK IE, 5 µm, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 10ml/min, Temperature: room temperature Example 1-86 (1) Column: CHIRALPAK AD-H, 5 µm, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, n-hexane
Elution conditions: solution A/solution B=10/90
Flow rate: 10ml/min, Temperature: room temperature Example 1-88
Example 1-89 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=15/85
Flow rate: 10ml/min, Temperature: room temperature Example 1-98
Example 1-99 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=15/85
Flow rate: 10ml/min, Temperature: room temperature Example 1-117 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=10/90
Flow rate: 10ml/min, Temperature: room temperature Example 1-123
Example 1-124 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=5/95
Flow rate: 20ml/min, Temperature: room temperature Example 4-47
Example 4-48 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 10ml/min, Temperature: room temperature Example 4-52
Example 4-53 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 10ml/min, Temperature: room temperature

[Table 3-2]

Conditions Example 4-61
Example 4-62 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=15/85
Flow rate: 10ml/min, Temperature: room temperature Example 4-76
Example 4-77 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=30/70
Flow rate: 10ml/min, Temperature: room temperature Example 4-85
Example 4-86 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=10/90
Flow rate: 10ml/min, Temperature: room temperature Example 4-103
Example 4-104 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=30/70
Flow rate: 10ml/min, Temperature: room temperature Example 4-123
Example 4-124 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 10ml/min, Temperature: room temperature Example 4-125
Example 4-126 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 10ml/min, Temperature: room temperature Example 4-133
Example 4-134 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=30/70
Flow rate: 10ml/min, Temperature: room temperature Example 4-135
Example 4-136 Column: CHIRALPAK ID, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=30/70
Flow rate: 10ml/min, Temperature: room temperature Example 4-143
Example 4-144 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 10ml/min, Temperature: room temperature Example 5-59
Example 5-60 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=82/18
Flow rate: 10ml/min, Temperature: room temperature Example 5-61
Example 5-62 Column: CHIRALPAK IF3, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 10ml/min, Temperature: room temperature Example 5-63
Example 5-64 Column: CHIRALPAK IF, 5 µm, 20 × 250 mm
Solvent: solution A, 2-propanol and solution B, n-hexane
Elution conditions: solution A/solution B=82/18
Flow rate: 10ml/min, Temperature: room temperature

[Table 3-3]

Conditions Example 5-108
Example 5-109 Column: CHIRALPAK ID3, 5 µm, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, n-hexane
Elution conditions: solution A/solution B=5/95
Flow rate: 11 ml/min, Temperature: room temperature Example 5-110
Example 5-111 Column: CHIRALPAK ID3, 5 µm, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, n-hexane
Elution conditions: solution A/solution B=20/80
Flow rate: 11 ml/min, Temperature: room temperature Example 5-115 Column: CHIRALPAK ID3, 5 µm, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, n-hexane
Elution conditions: solution A/solution B=10/90
Flow rate: 10ml/min, Temperature: room temperature Example 5-57
Example 5-58 Column: CHIRALPAK IF3, 5 µm, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, n-hexane
Elution conditions: solution A/solution B=15/85
Flow rate: 10ml/min, Temperature: room temperature

Detection method: UV 210 nm, 254 nm

Preparative separation by chiral supercritical liquid chromatography (SLC) in the examples is carried out under the following conditions.

SLC: SFC30 from Waters Corporation

[SLC conditions]

[Table 4-1] Conditions Example 5-55
Example 5-56 Column: CHIRALCEL IC, 20 × 250 mm
Solvent: Solution A, ethanol and Solution B, carbon dioxide
Elution conditions: solution A/solution B=12/88
Flow rate: 30 ml/min, Temperature: 40°C

Detection method: UV 210 nm, 254 nm

Autopol V (Rudolph Research Analytical Corporation) is used as an apparatus for measuring optical rotation, and the sodium D line (589 nm) is used as a light source.

For X-ray diffraction analysis, the R-AXIS RAPID II apparatus (manufacturer: Rigaku Corporation) is used.

Biotage Initiator or Anton-Paar MOHOWAVE 300 is used as a microwave reaction apparatus.

Thermogravimetric differential thermal analysis (TG/DTA) was performed on a Thermo Plus Evo TG8120 (Rigaku).

Compound names were assigned by ACD/Name (ACD/Name 2017,1,3 and ACD/Name 2019,1,2, Advanced Chemistry Development, Inc.), and Pipeline Pilot 9.1 component, LexiChem (version 0.95) produced by OpenEye Scientific Software, Inc.

With regard to the asymmetric carbon atoms in the reference and example compounds, the spatial structure shown herein indicates the absolute configuration. It should be noted that the relative configuration is shown for mesoforms.

Compounds for which the absolute configuration of asymmetric carbon is indicated indicate optically active forms.

Additionally, in compounds where an asterisk (*) is indicated for the asymmetric carbon in the structural formula, the asterisk means that the ratio of one absolute configuration is greater than the other, relative to the stereoisomerism of the indicated asymmetric carbon. It should be noted that it is preferred that such connections have a substantially uniform absolute configuration. Alternatively, the absolute configuration of the asymmetric carbon may be unknown.

As used herein, the term “room temperature” refers to a temperature of 20 to 30°C unless otherwise noted. The term “ice cooling temperature” refers to a temperature between 0 and 5°C unless otherwise noted.

Next, the present invention will be described in detail with reference to the following reference examples, examples and experimental examples. However, they do not limit the present invention and may vary within the scope of the present invention.

Reference example 1-1-1

Methyl 3-methoxy-5-(methoxymethyl)benzoate

[Chemical formula 366]

To a mixed solution of methyl 3-(bromomethyl)-5-methoxybenzoate (150 mg) in methanol-tetrahydrofuran (2.9 ml-2.9 ml), potassium carbonate (168 mg) was added and the reaction solution was stirred at 55°C in for 3 hours and at room temperature overnight. The reaction solution was filtered through Celite (registered trademark) and the filtrate was concentrated to give a mixture (327 mg) containing the title compound as a colorless solid.

MS IER gender: 211 [M+H] ⁺ .

Hold time: 0.912 min (method B)

Reference example 1-1-2

Ethyl 6-ethoxy-1-ethyl-2,3-dihydro-1H-indole-4-carboxylate

[Chemical formula 367]

(1) A solution of ethyl 6-ethoxy-1H-indole-4-carboxylate (0.488 g) in N,N-dimethylformamide (4.2 ml) was cooled on ice, and sodium hydride (60% dispersion in mineral oil, 92, 0 mg), and the reaction solution was stirred at the same temperature for 30 minutes. A solution of iodoethane (0.254 ml) in N,N-dimethylformamide (3 ml) was added dropwise thereto, and the reaction solution was stirred for 30 minutes, bringing back to room temperature. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to ethyl acetate only) to give ethyl 6-ethoxy-1-ethyl-1H-indole-4-carboxylate (0.402 g) as a colorless powder.

(2) To a solution of the compound (0.2 g) obtained in (1) above in acetic acid (1 ml), sodium cyanoborohydride (0.144 g) was slowly added, and the reaction solution was stirred at room temperature for 1 hour. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to obtain the title compound (0.142 g) as a light yellow oily substance.

MS IER gender: 264 [M+H] ⁺ .

Hold time: 1.264 min (method B)

Reference example 1-2-1

Methyl 3,5-diethoxy-2,4-dimethylbenzoate

[Chemical formula 368]

(1) To a solution of methyl 3,5-dihydroxy-4-methylbenzoate (5 g) in N,N-dimethylformamide (55 ml), add potassium carbonate (3.79 g), and iodoethane (2.66 ml), and the reaction solution was stirred at room temperature for 18 hours. Water is added to the reaction solution, which is then extracted with a n-hexane/ethyl acetate (2:1) mixed solvent. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=70:30) to give methyl 3,5-diethoxy-4-methylbenzoate (2.16 g), and methyl 3-ethoxy-5- Hydroxy-4-methylbenzoate (2.02 g) each as a colorless powder.

(2) Under a nitrogen atmosphere, a solution of methyl 3,5-diethoxy-4-methylbenzoate (0.5 g) obtained in (1) above in chloroform (0.8 ml) is cooled on ice, and titanium(IV) chloride ( 0.506 ml) is added dropwise. The reaction solution was stirred at the same temperature for 30 minutes, and dichloromethyl methyl ether (0.187 ml) was added dropwise thereto. Chloroform (0.8 ml) is then added to the reaction solution, which is then stirred for 30 minutes, bringing back to room temperature. A saturated aqueous ammonium chloride solution is added to the reaction solution, which is then stirred for 1 hour. Then water is added there and extraction is carried out with chloroform. The organic layer was washed with 0.1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline successively, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=85:15) to give methyl 3,5-diethoxy-2-formyl-4-methylbenzoate (0.527 g) as a yellow oil.

(3) To a solution of the compound (0.1 g) obtained in (2) above in trifluoroacetic acid (0.3 ml), triethylsilane (0.72 ml) was added, and the reaction solution was stirred at room temperature for 1 hour . Water is added to the reaction solution, which is then extracted with chloroform. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give the title compound (0.062 g) as a colorless oil.

MS IER gender: 253 [M+H] ⁺ .

Hold time: 1.057 min (method A)

Reference example 1-2-2

Methyl 3,5-diethoxy-2-fluoro-4-methylbenzoate

[Chemical formula 369]

Under a nitrogen atmosphere, a solution of methyl 3,5-diethoxy-4-methylbenzoate (0.5 g) prepared in Reference Example 1-2-1 (1) in acetonitrile (1.0 ml) was cooled on ice, and the solution was added N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) (1.12 g) in acetonitrile (21 ml), and the reaction solution was stirred at room temperature for 23 hours. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=90:10) to obtain the title compound (0.32 g) as a yellow oily substance.

MS ESI sex: 257 [M+H] ⁺ , 279 [M+Na] ⁺ .

Hold time: 0.953 min (method A)

Reference example 1-2-3

Ethyl 2-chloro-3,5-diethoxy-4-methylbenzoate

[Chemical Formula 370]

(1) To a solution of 3,5-dihydroxy-4-methylbenzoic acid (2 g) in methanol (30 ml), N-chlorosuccinimide (1.75 g) was added, and the reaction solution was stirred at 60°C for 4 hours and at room temperature for 15 hours. Water is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain 2-chloro-3,5-dihydroxy-4-methylbenzoic acid (2.55 g) as a light yellow powder.

(2) To a solution of the compound (2.41 g) obtained in (1) above and potassium carbonate (8.22 g) in N,N-dimethylformamide (24 ml), add iodoethane (4.81 ml), and react the solution is stirred at room temperature for 18 hours. Water is added to the reaction solution, which is then extracted with a n-hexane/ethyl acetate (2:1) mixed solvent. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=90:10) to give the title compound (2.99 g) as a colorless oil.

MS ESI sex: 287 [M+H] ⁺ , 309 [M+Na] ⁺ .

Hold time: 1.023 min (method A)

Reference example 1-3-1

3-Ethoxy-5-(methoxymethyl)-4-methylbenzoic acid

[Chemical formula 371]

(1) Under a nitrogen atmosphere, to a solution of methyl 3-ethoxy-5-hydroxy-4-methylbenzoate (300 mg) obtained in Reference Example 1-2-1 (1) in chloroform (5.7 ml), add pyridine ( 0.23 ml), and trimethanesulfonic anhydride (0.288 ml), and the reaction solution was stirred at room temperature for 3 hours. After distillation of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-20:80) to obtain methyl 3-ethoxy-4-methyl-5-[(trifluoromethanesulfonyl)oxy]benzoate ( 450 mg) in the form of a colorless oily substance.

(2) The present reaction is carried out with reference to the method described in the literature (Organic Letters, vol. 14, p. 1278, 2012). Under a nitrogen atmosphere, to a mixed solution of the compound (400 mg) obtained in (1) above in 1,4-dioxane-water (2 ml-0.2 ml), add sodium carbonate (0.186 g), potassium (acetoxymethyl)trifluoroborate (0.316 g), and (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (RuPhosPdG3 , Sigma-Aldrich, 97.7 mg), the reaction solution was stirred at 100°C for 5 hours. After distillation of the solvent under reduced pressure, the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-20:80) to obtain methyl 3-ethoxy-5-(hydroxymethyl)-4-methylbenzoate (250 mg) in in the form of a colorless oily substance.

(3) To a solution of the compound (250 mg) obtained in (2) above in tetrahydrofuran (11 ml), sodium hydride (60% dispersion in mineral oil, 67 mg) was added, and the reaction solution was stirred while cooling with ice for 1 hours. Iodomethane (0.1 ml) was added and the reaction solution was stirred at room temperature overnight. Water is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with water and saturated saline sequentially, and anhydrous magnesium sulfate was added thereto. The desiccant is filtered off, followed by concentration. The residue was purified by silica gel column chromatography (n-hexane only to ethyl acetate only) to give methyl 3-ethoxy-5-(methoxymethyl)-4-methylbenzoate (84 mg) as a brown oil.

(4) To a solution of the compound (84 mg) obtained in (3) above in tetrahydrofuran (3.5 ml), add 1 mol/L aqueous sodium hydroxide solution (3.5 ml), and methanol (1.8 ml ), and the reaction solution was stirred at 60°C for 30 minutes. The reaction solution is concentrated, 1 mol/L hydrochloric acid is added to make the solution acidic, and extraction is carried out with chloroform. The organic layer was filtered through a phase separator and concentrated to give the title compound (85 mg) as a colorless powder.

MS IER floor: 225 [M+H] ⁺ .

MS IER ref: 223 [MH] ^- .

Hold time: 1.128 min (method B)

Reference example 1-4-1

4-Bromo-3,5-dimethoxybenzaldehyde

[Chemical formula 372]

(1) A solution of 4-bromo-3,5-dimethoxybenzoic acid (3.0 g) in tetrahydrofuran (7.7 ml) was cooled on ice, and a borane-tetrahydrofuran complex (0.9 mol/L tetrahydrofuran solution, 20 ml). The reaction solution was stirred at the same temperature for 30 minutes and stirred at room temperature for 2 hours. The reaction solution was cooled on ice, a saturated aqueous sodium bicarbonate solution was added thereto, and extraction was carried out with ethyl acetate. The organic layer was filtered through a phase separator and concentrated to give (4-bromo-3,5-dimethoxyphenyl)methanol (2.8 g) as a colorless powder.

(2) To a solution of the compound (2.3 g) obtained in (1) above in toluene (62 ml), manganese dioxide (8.1 g) was added, and the reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered through Celite (registered trademark) and the filtrate was concentrated to obtain the title compound (2.18 g) as a light yellow powder.

MS IER gender: 254 [M+H] ⁺ .

Hold time: 0.996 min (method B)

Reference example 1-4-2

3,5-Diethoxy-4-methylbenzaldehyde

[Chemical formula 373]

(1) A solution of methyl 3,5-diethoxy-4-methylbenzoate (1.1 g) obtained in Reference Example 1-2-1 (1) in tetrahydrofuran (18 ml) was cooled on ice, and lithium aluminum hydride (0) was added thereto. .26 g), and the reaction solution was stirred at room temperature for 1 hour. Sodium sulfate decahydrate (3 g) was added thereto, and the reaction solution was stirred for 2 hours. The reaction solution was filtered through Celite (registered trademark) and the filtrate was concentrated to give (3,5-diethoxy-4-methylphenyl)methanol (0.98 g) as a light yellow solid.

(2) Using the compound (0.98 g) obtained in (1) above, the reaction and subsequent workup were carried out in accordance with the method described in Reference Example 1-4-1 (2), and the resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=95:5-60:40) to obtain the title compound (205 mg) as a yellow solid.

MS IER gender: 209 [M+H] ⁺ .

Hold time: 1.196 min (method B)

The following Reference Examples 1-4-3-1-4-6 are synthesized by the method described in Reference Example 1-4-1 or Reference Example 1-4-2 or an equivalent method, using commercially available compounds or compounds prepared by synthesis according to the methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 5-1.

Reference example 1-5-1

1-(4-Bromo-3,5-diethoxyphenyl)ethan-1-one

[Chemical formula 374]

(1) Using 4-bromo-3,5-dihydroxybenzoic acid (4 g), the reaction and subsequent processing were carried out in accordance with the method described in Reference Example 1-2-3 (2). A mixed solution of n-hexane-ethyl acetate (4:3, 7 ml) was added to the resulting residue, which was then dissolved and further n-hexane (12 ml) was added thereto. The precipitated solid is filtered off and the filtrate is concentrated. Ethyl acetate (3 ml) was added to the resulting residue, which was then dissolved, n-hexane (16 ml) was further added thereto, and the precipitated solid was filtered off. The resulting solids were combined to give ethyl 4-bromo-3,5-diethoxybenzoate (5.11 g) as a colorless solid.

(2) Using the compound (5.11 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-3-1 (4), and 4-bromo-3,5-diethoxybenzoate the acid (4.68 g) is obtained as a colorless solid.

(3) To a solution of the compound (4.68 g) obtained in (2) above in N,N-dimethylformamide (26 ml), add N,O-dimethylhydroxylamine hydrochloride (1.65 g), HATU (9.19 d), and N,N-diisopropylethylamine (11.2 ml), and the reaction solution was stirred at room temperature for 3 hours. A saturated aqueous sodium bicarbonate solution (150 ml) was added to the reaction solution, which was then extracted with n-hexane/ethyl acetate (2:1, 100 ml) mixed solvent twice. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to give 4-bromo-3,5-diethoxy-N-methoxy-N-methylbenzamide (6.2 g) in in the form of a light yellow oily substance.

(4) Under a nitrogen atmosphere, a solution of the compound (5.36 g) obtained in (3) above in tetrahydrofuran (54 ml) was cooled on ice, and methylmagnesium bromide (3 mol/L solution in diethyl ether, 16.1 ml) was added thereto. ), and the reaction solution was stirred at the same temperature for 30 minutes and at room temperature for 4.5 hours. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. To the resulting residue, n-hexane-ethyl acetate mixed solvent (2:1, 60 ml) was added, and the precipitated solid was filtered to obtain the title compound (3.18 g) as a colorless solid.

MS IER sex: 287, 289 [M+H] ⁺ .

Hold time: 1.149 min (method B)

Reference example 1-5-2

1-(3,5-Diethoxy-4-methylphenyl)ethan-1-one

[Chemical formula 375]

(1) Using 3,5-dihydroxy-4-methylbenzoic acid (3 g), the reaction was carried out in accordance with the method described in Reference Example 1-2-3 (2), and ethyl 3,5-diethoxy-4- Methyl benzoate (4.45 g) is obtained as a light brown solid.

(2) Using the compound (4.2 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-3-1 (4), and 3,5-diethoxy-4-methylbenzoic acid (3.74 g) is obtained in the form of a colorless powder.

(3) The present reaction is carried out with reference to the method described in the literature (Synlett, vol. 26, p. 1395, 2015). Under a nitrogen atmosphere, a solution of the compound (3.7 g) obtained in (2) above in diethyl ether (130 ml) was cooled on ice, methyl lithium (1 mol/L solution in diethyl ether, 50 ml) was added thereto, and the reaction the solution is stirred at the same temperature for 10 minutes and at room temperature overnight. The reaction solution is cooled on ice, water is added slowly, and the reaction solution is acidified with 2 mol/L hydrochloric acid. The reaction solution was stirred for 30 minutes and extracted with diethyl ether three times. The organic layer was washed with saturated aqueous sodium bicarbonate (60 ml) and brine (60 ml) successively, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=88:12 to ethyl acetate only) to obtain the title compound (2.0 g) as a colorless powder.

MS IER gender: 223 [M+H] ⁺ .

Hold time: 0.931 min (method A)

The following Reference Examples 1-5-3-1-5-30 are synthesized by the method described in Reference Example 1-5-1 or Reference Example 1-5-2 or an equivalent method using the compounds obtained in Reference Examples 1-1- 1-1-1-2, Reference Examples 1-2-1-1-2-3 and Reference Example 1-3-1, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 6-1 through Table 6-6.

[Table 6-1]

Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 6-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 6-3] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 6-4] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

[Table 6-5]

Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 6-6] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 1-6-1

1-(4-Bromo-3,5-dimethoxyphenyl)ethan-1-one

[Chemical formula 376]

(1) A solution of the compound (506 mg) obtained in Reference Example 1-4-1 in tetrahydrofuran (4.1 ml) was cooled on ice, methylmagnesium bromide (3 mol/L solution in diethyl ether, 688 μL) was added thereto, and the reaction solution was stirred at room temperature for 2.5 hours. The reaction solution was cooled on ice, a saturated aqueous ammonium chloride solution (5 ml) was added thereto, and the reaction solution was extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-35:65) to obtain 1-(4-bromo-3,5-dimethoxyphenyl)ethan-1-ol (443 mg) as a colorless solid substances.

(2) Using the compound (443 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-4-1 (2), and the title compound (394 mg) was obtained as colorless powder.

MS IER gender: 259 [M+H] ⁺ .

Hold time: 1.012 min (method B)

The following Reference Example 1-6-2 is synthesized by the method described in Reference Example 1-6-1 or an equivalent method using the compound obtained in Reference Example 1-4-3, a commercially available compound, or a compound obtained by synthesis according to the methods described in literature or equivalent methods. The structure and LCMS data of the compound are shown in Table 7-1.

[Table 7-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 1-7-1

1-(3-Ethoxy-5-propylphenyl)ethan-1-one

[Chemical formula 377]

The present reaction is carried out with reference to the method described in the literature (Journal of Organic Chemistry, vol. 74, p. 3626, 2009). Toluene (2.1 ml), and water (0.206 ml) were added to the compound (0.05 g) obtained in Reference Example 1-5-8, ethyl boronic acid (22.8 mg), potassium carbonate (85.3 mg ), palladium(II) acetate (9.23 mg), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 38.4 mg), and the reaction solution was stirred at 120°C for 70 minutes under microwave irradiation. Undissolved particles in the reaction solution are filtered off, and the filtrate is concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give the title compound (32.3 mg) as a colorless oil.

MS IER gender: 207 [M+H] ⁺ .

Hold time: 1.265 min (method B)

Reference example 1-7-2

3-Acetyl-5-ethoxybenzamide

[Chemical formula 378]

To a solution of the compound (53.6 mg) obtained in Reference Example 1-5-6 in dimethyl sulfoxide (1 ml), add 1 mol/L aqueous sodium hydroxide solution (2.83 ml), hydrogen peroxide (30% aqueous solution , 86.8 μl), and ethanol (1 ml), and the reaction solution was stirred at room temperature for 4 hours. A mixed solution of saturated aqueous sodium thiosulfate-water (1:1) is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=70:30 to ethyl acetate only) to give the title compound (66.1 mg) as a colorless solid.

MS IER gender: 208 [M+H] ⁺ .

Hold time: 0.741 min (method B)

Reference example 1-7-3

3-Acetyl-5-ethoxy-N-methylbenzamide

[Chemical formula 379]

A solution of the compound (1.5 g) obtained in Reference Example 1-5-9 in tetrahydrofuran (23 ml) was cooled on ice, and methylamine (2 mol/L solution in tetrahydrofuran, 25 ml), EDC (2.8 g) was added thereto. ), and HOBt (2.2 g), and the reaction solution was stirred at room temperature for 17 hours. The reaction solution was cooled on ice with a saturated aqueous sodium bicarbonate solution, and water was added thereto, and extraction was carried out with ethyl acetate three times. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC to obtain the title compound (35 mg) as a light yellow oily substance.

MS IER/HIAD Multi gender: 222 [M+H] ⁺ .

Hold time: 0.965 min (method F)

Reference example 1-7-4

1,1'-(2-Ethoxy-6-fluoro-1,4-phenylene)di(ethan-1-one)

[Chemical formula 380]

(1) The present reaction is carried out with reference to the method described in the literature (WO 2014/191535). To a solution of 4-bromo-2,6-difluorobenzaldehyde (3 g) in N,N-dimethylformamide (14 ml), potassium carbonate (3.38 g) and water (1.2 ml) were added, and the reaction solution was stirred at 90°C for 11 hours and at room temperature overnight. Potassium carbonate (1.78 g) and iodoethane (3.91 ml) were then added to the reaction solution, which was then stirred at 65°C for 7 hours. The reaction solution is filtered through Celite (registered trademark), and water is added to the filtrate, which is then extracted with ethyl acetate twice. The organic layer was washed with 0.5 mol/L hydrochloric acid three times and brine once, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give 4-bromo-2-ethoxy-6-fluorobenzaldehyde (0.752 g) as a colorless solid.

(2) Using the compound (0.2 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-6-1 (1), and 1-(4-bromo-2- Ethoxy-6-fluorophenyl)ethan-1-ol (218 mg) is obtained as a light pink oily substance.

(3) To a solution of the compound (218 mg) obtained in (2) above in n-hexane (10 ml), manganese dioxide (0.8 g) was added, and the reaction solution was stirred at room temperature overnight. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=70:30) to give 1-(4-bromo-2-ethoxy-6-fluorophenyl)ethan-1-one (81.3 mg ) in the form of a colorless oily substance.

(4) To a mixed solution of the compound (81.3 mg) obtained in (3) above in N,N-dimethylformamide-water (1.56 ml-0.156 ml), add butyl vinyl ether (200 µl), palladium(II) acetate ) (2.10 mg), 1,3-bis(diphenylphosphino)propane (7.70 mg), and potassium carbonate (0.129 g), and the reaction solution was stirred at 120°C for 1 hour under microwave irradiation. Butyl vinyl ether (200 μL), palladium(II) acetate (6.99 mg), and 1,3-bis(diphenylphosphino)propane (25.7 mg) were further added thereto, and the reaction solution was stirred at 120°C for 1 hours under microwave irradiation. 1 mol/L hydrochloric acid (3 ml) and ethyl acetate were added to the reaction solution, which was then stirred at room temperature for 1.5 hours. The reaction solution was added to a 10% aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=70:30) to give the title compound (18.3 mg) as a light yellow oily substance.

MS IER floor: 225 [M+H] ⁺ .

Hold time: 0.879 min (method B)

Reference example 1-7-5

1-[3-Ethoxy-5-fluoro-4-(1-hydroxyethyl)phenyl]ethan-1-one

[Chemical formula 381]

Using the compound (95.3 mg) obtained in Reference Example 1-7-4 (2), the reaction was carried out in accordance with the method described in Reference Example 1-7-4 (4), and the title compound (22 .4 mg) is obtained as a colorless solid.

MS IER sex: 209 [M-OH] ⁺ .

Hold time: 0.773 min (method B)

Reference example 1-7-6

4-Ethoxy-1-ethyl-1H-indazole-6-carbaldehyde

[Chemical formula 382]

(1) To a solution of the compound (5.8 g) obtained in Reference Example 1-7-4 (1) in N-methylpyrrolidone (8.7 ml), ethylhyrrazine oxalate (3.9 g) was added, and the reaction solution was stirred at room temperature for 24 hours. N-Methylpyrrolidone (78 ml) was added to the reaction solution, which was then stirred at 200°C for 2.5 hours. By adding n-hexane, ethyl acetate, water and saturated saline solution to the reaction solution, it is separated into two layers. The aqueous layer was extracted with an n-hexane/ethyl acetate mixed solvent. The organic layers are combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40). N-hexane is added to the residue and undissolved substances are filtered off, followed by concentration. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=98:2-60:40) to obtain 6-bromo-4-ethoxy-1-ethylindazole (2.48 g) as a light green oil.

(2) Under a nitrogen atmosphere, a solution of the compound (2.48 g) obtained in (1) above and copper(I) cyanide (1.57 g) in N,N-dimethylacetamide (31 ml) was stirred at 150°C in within 30 hours. After cooling to room temperature, 10% aqueous ammonia, brine and water were added to the reaction solution, which was then extracted with ethyl acetate and concentrated. The resulting residue is purified by NH silica gel column chromatography (n-hexane:ethyl acetate=95:5 to ethyl acetate only). A mixed solution of n-hexane-ethyl acetate is added to the resulting residue. The organic layer was washed successively with water and brine and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain 4-ethoxy-1-ethylindazole-6-carbonitrile (800 mg) as a light yellow powder.

(3) Under a nitrogen atmosphere, a solution of the compound (1.54 g) obtained in (2) above in toluene (36 ml) was cooled to -40°C, and diisobutylaluminum hydride (1.0 mol/L solution in toluene, 8.6 ml), and the reaction solution was stirred at the same temperature for 1 hour. Diisobutylaluminum hydride (1.0 mol/L toluene solution, 3.0 ml) was further added thereto, and the reaction solution was stirred at the same temperature for 10 minutes. Isopropyl alcohol (6 ml) is added dropwise to the reaction solution, silica gel is added thereto, and the reaction solution is stirred for 5 minutes. After bringing the reaction solution back to room temperature, it was filtered through Celite (registered trademark) and the filtrate was concentrated to give the title compound (1.37 g) as a light yellow oily substance.

MS IER/HIAD Multi gender: 219 [M+H] ⁺ .

Hold time: 0.980 min (method E)

Reference example 1-7-7

1-[3,5-Bis(cyclopropyloxy)-4-methylphenyl]ethan-1-one

[Chemical formula 383]

(1) N-Methylpyrrolidone (15 ml) is added to methyl 3,5-dihydroxy-4-methylbenzoate (700 mg), cesium carbonate (3.76 g), potassium iodide (32 mg), and cyclopropyl bromide (1.86 g ), and the reaction solution was stirred at 200°C for 2 hours under microwave irradiation. Water is added to the reaction solution, which is then extracted with an n-hexane/ethyl acetate mixed solvent and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-80:20) to obtain a mixture (540 mg) containing methyl 3,5-bis(cyclopropoxy)-4-methylbenzoate as a colorless solid.

(2) To a solution of the mixture (540 mg) obtained in (1) above in tetrahydrofuran (21 ml), 1 mol/L sodium hydroxide aqueous solution (21 ml) and methanol (10 ml) were added, and the reaction solution was stirred at room temperature for 5 days. The reaction solution was concentrated, and the aqueous layer was washed with n-hexane. To the aqueous layer, 3 mol/L hydrochloric acid is added dropwise to adjust the pH to 5-6, and the undissolved substances are filtered off. The resulting residue was purified by preparative HPLC to obtain 3,5-bis(cyclopropoxy)-4-methylbenzoic acid (75 mg) as a colorless powder.

(3) A solution of the compound (72 mg) obtained in (2) above in tetrahydrofuran (1.5 ml) was cooled on ice, methyl lithium (1 mol/L solution in diethyl ether, 0.87 ml) was added dropwise, and the reaction solution was stirred at room temperature for 5 hours. The reaction solution is cooled on ice, isopropyl alcohol is added dropwise, 1 mol/L hydrochloric acid is added to make the solution acidic, and extraction is carried out with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=70:30) to give the title compound (92 mg) as a colorless oil.

MS IER gender: 247 [M+H] ⁺ .

Hold time: 0.942 min (method A)

Reference example 1-7-8

5-Acetyl-3-ethoxy-1-ethylpyridin-2(1H)-one

[Chemical formula 384]

(1) Under a nitrogen atmosphere, a solution of 5-bromopyridin-2,3-diol (2 g) in N,N-dimethylformamide (35 ml) was cooled on ice, and sodium hydride (60% dispersion in mineral oil, 1.0 d), and the reaction solution was stirred at the same temperature for 45 minutes. Iodomethane (2.0 ml) was added dropwise thereto, and the reaction solution was stirred at room temperature for 3 days. Water is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=92:8-34:66) to obtain 5-bromo-3-ethoxy-1-ethylpyridin-2-one (2.31 g) as light yellow oily substance.

(2) Using the compound (0.512 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-7-6 (2). However, N-methylpyrrolidone is used instead of N,N-dimethylacetamide and the reaction is carried out at a temperature of 180°C. 5-Ethoxy-1-ethyl-6-oxopyridine-3-carbonitrile (0.3 g) is obtained as a colorless oily substance.

(3) The present reaction is carried out with reference to the method described in the literature (Journal of Medicinal Chemistry, vol. 59, p. 1556, 2016). Under a nitrogen atmosphere, a solution of the compound (0.439 g) obtained in (2) above in diethyl ether (23 ml) was cooled on ice and methylmagnesium bromide (3 mol/L solution in diethyl ether, 1.5 ml) was added dropwise thereto. The reaction solution is stirred at the same temperature for 3 hours and stirred for 12 hours, gradually bringing it back to room temperature. Toluene (10 ml) was added to the reaction solution, which was then stirred at 65°C for 2 hours. The reaction solution was cooled on ice, methylmagnesium bromide (3 mol/L solution in diethyl ether, 0.53 ml) was further added thereto, and the reaction solution was stirred at room temperature for 40 minutes and at 60°C for 50 minutes. The reaction solution was cooled on ice, methylmagnesium bromide (3 mol/L solution in diethyl ether, 0.53 ml) was further added, the reaction solution was stirred at room temperature for 10 minutes and at 60°C for 80 minutes and brought back to room temperature. Water is added to the reaction solution, which is then extracted with ethyl acetate. To the aqueous layer, add 2 mol/L hydrochloric acid and 1 mol/L aqueous sodium hydroxide solution to adjust the pH to 6 to 7 and carry out extraction with ethyl acetate. The organic layers are combined, washed with brine and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=85:15 to ethyl acetate only) to obtain the title compound (0.069 g) as a colorless powder.

MS IER/HIAD Multi gender: 210 [M+H] ⁺ .

Hold time: 1.156 min (method F)

Reference example 1-7-9

1-(4-Ethoxy-1-ethyl-1H-benzimidazol-6-yl)ethan-1-one

[Chemical formula 385]

(1) To a solution of 5-bromo-1,3-difluoro-2-nitrobenzene (1.5 g) in ethanol (20 ml), potassium hydroxide (0.38 g) was added, and the reaction solution was stirred at room temperature for 2.5 days and at 90°C for 45 minutes. The reaction solution was concentrated and ethyl acetate was added thereto. The reaction solution was washed with water and saturated saline successively and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to give 5-bromo-1-ethoxy-3-fluoro-2-nitrobenzene (1.63 g) as an orange oil.

(2) A solution of the compound (1.63 g) obtained in (1) above in tetrahydrofuran (12 ml) was cooled on ice, 12 mol/L ethylamine aqueous solution (2.1 ml) was added thereto, and the reaction solution was stirred at room temperature for 23 hours. The reaction solution is concentrated and diethyl ether is added thereto. The reaction solution was washed with water and saturated saline successively and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain 5-bromo-3-ethoxy-N-ethyl-2-nitroaniline (1.79 g) as an orange powder.

(3) Using the compound (1.62 g) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-7-8 (2), and 3-ethoxy-5-(ethylamino) -4-nitrobenzonitrile (1.0 g) is obtained as a red powder.

(4) A mixture of the compound (0.5 g) obtained in (3) above, iron powder (0.593 g), saturated aqueous ammonium chloride (5 ml), and ethanol (16 ml) was stirred at room temperature for 11 hours and at 65°C for 80 minutes. To the reaction solution, 1 mol/L sodium hydroxide aqueous solution is added to adjust the pH to 9-10, the reaction solution is filtered through Celite (registered trademark), and the filtrate is concentrated. By adding water and ethyl acetate to the residue, the reaction solution was separated into two layers. A 1 mol/L aqueous solution of sodium hydroxide is added to the aqueous layer to adjust the pH to 9-10 and extraction is carried out with ethyl acetate. The organic layers are combined, washed with brine and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to obtain 4-amino-3-ethoxy-5-(ethoxyamino)benzonitrile (222 mg) as a beige powder.

(5) To a solution of the compound (0.1 g) obtained in (4) above in triethyl orthoformate (2.4 ml), p-toluenesulfonic acid monohydrate (9 mg) was added, and the reaction solution was stirred at room temperature for 17 hours. The reaction solution was diluted by adding ethyl acetate and washed by adding a saturated aqueous sodium bicarbonate solution. The aqueous layer is extracted with ethyl acetate and concentrated. The resulting residue was purified by preparative HPLC to give 7-ethoxy-3-ethylbenzimidazole-5-carbonitrile (82 mg) as a colorless gum.

(6) A solution of the compound (82 mg) obtained in (5) above in diethyl ether (3.8 ml) was cooled on ice, and methylmagnesium bromide (3 mol/L solution in diethyl ether, 0.254 ml) was added dropwise. and the reaction solution was stirred at the same temperature for 25 minutes and at room temperature for 20 hours. Tetrahydrofuran (3.8 ml) was added to the reaction solution, which was then cooled on ice. Methylmagnesium bromide (3 mol/L solution in diethyl ether, 0.254 ml) was further added thereto, and the reaction solution was stirred at the same temperature for 30 minutes and at room temperature for 90 minutes. The reaction solution was cooled on ice, methylmagnesium bromide (3 mol/L solution in diethyl ether, 1 ml) was further added thereto, and the operation of stirring the reaction solution at room temperature for 1 hour was repeated twice. Water is added to the reaction solution, which is then concentrated. The resulting residue was purified by preparative HPLC to obtain the title compound (35 mg) as a colorless solid.

MS IER sex: 233 [M+H] ⁺ .

Hold time: 0.752 min (method C)

Reference example 1-8-1

4-Acetyl-2,6-diethoxybenzonitrile

[Chemical formula 386]

To a solution of the compound (232 mg) obtained in Reference Example 1-5-1 in N,N-dimethylacetamide (3.2 ml), copper(I) cyanide (217 mg) was added, and the reaction solution was stirred at 150°C in for 1 hour under microwave irradiation. After adding ethyl acetate to the reaction solution, it is added to a 10% aqueous ammonia solution and extraction is carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give the title compound (31.7 mg) as a colorless solid.

MS IER gender: 234 [M+H] ⁺ .

Hold time: 1.004 min (method B)

Reference example 1-8-2

1-(4-Cyclopropyl-3,5-diethoxyphenyl)ethan-1-one

[Chemical formula 387]

Using the compound (50 mg) obtained in Reference Example 1-5-1 and cyclopropylboronic acid (22.4 mg), the reaction was carried out in accordance with the method described in Reference Example 1-7-1 and the title compound (34 mg) is obtained as a colorless solid.

MS IER sex: 249 [M+H] ⁺ .

Hold time: 1.199 min (method B)

The following Reference Examples 1-8-3-1-8-4 are synthesized by the method described in Reference Example 1-8-2 or an equivalent method using the compound prepared in Reference Example 1-5-1, a commercially available compound, or a compound prepared synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 8-1.

[Table 8-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 1-8-5

1,1'-(2,6-Diethoxy-1,4-phenylene)di(ethan-1-one)

[Chemical formula 388]

The present reaction is carried out with reference to the method described in the literature (Journal of Organic Chemistry, vol. 66, p. 4340, 2001). Under a nitrogen atmosphere, to a solution of the compound (0.5 g) obtained in Reference Example 1-5-1 in N,N-dimethylformamide (8.7 ml), butyl vinyl ether (1.12 ml), palladium acetate ( II) (11.7 mg), 1,3-bis(diphenylphosphino)propane (43.1 mg), potassium carbonate (722 mg), and water (0.87 ml), and the reaction solution was stirred at 120°C in for 1 hour under microwave irradiation. 1 mol/L hydrochloric acid (10 ml) is added to the reaction solution, which is then stirred at room temperature for 3 hours. A 10% aqueous solution of potassium carbonate (50 ml) is added there, and extraction is carried out with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to give the title compound (407 mg) as a colorless solid.

MS IER gender: 251 [M+H] ⁺ .

Hold time: 0.994 min (method B)

Reference example 1-8-6

1-[3,5-Diethoxy-4-(propan-2-yl)phenyl]ethan-1-one

[Chemical formula 389]

To a solution of the compound (37 mg) obtained in Reference Example 1-8-3 in methanol (3 ml), palladium-carbon (19 mg) was added, and the reaction solution was stirred at room temperature for 3 hours under a hydrogen atmosphere. Undissolved substances are filtered off and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=75:25) to give the title compound (29 mg) as a colorless solid.

MS IER gender: 251 [M+H] ⁺ .

Hold time: 1.338 min (method B)

The following Reference Example 1-8-7 was synthesized by the method described in Reference Example 1-8-2 or an equivalent method using the compound obtained in Reference Example 1-14-6 and cyclopropylboronic acid. The structure and LCMS data of the compound are shown in Table 8-2.

[Table 8-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 1-9-1

1-[3,5-Diethoxy-4-(1-hydroxycyclopropyl)phenyl]ethan-1-one

[Chemical Formula 390]

(1) To a solution of the compound (0.604 g) obtained in Reference Example 1-5-1 in toluene (21 ml), add ethylene glycol (8.42 ml), and p-toluenesulfonic acid monohydrate (40.0 mg), and the reaction solution was stirred while heating at reflux for 3 hours. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-90:10) to give 2-(4-bromo-3,5-diethoxyphenyl)-2-methyl-1,3-dioxolane (0.633 g ) as a colorless solid.

(2) The present reaction is carried out with reference to the method described in the literature (WO 2015/159233). Under a nitrogen atmosphere, to a suspension of magnesium (66 mg), and iodine (14 mg) in diethyl ether (3.6 ml), add a mixed solution of the compound (900 mg) obtained in (1) above in diethyl ether-tetrahydrofuran (1 :1, 1.8 ml), and tetrahydrofuran (3.6 ml). The temperature was gradually raised, and the reaction solution was stirred while heating at reflux for 5 hours. The reaction solution was cooled on ice, a solution of 1,3-dichloroacetone (345 mg) in tetrahydrofuran (3.6 ml) was added thereto, and the reaction solution was stirred at room temperature for 80 minutes. The reaction solution was cooled on ice, and a solution of iron(III) chloride (9 mg) in tetrahydrofuran (1.8 ml) and ethylmagnesium bromide (3 mol/L solution in diethyl ether, 4.5 ml) was added over 5 minutes and the reaction solution is stirred at room temperature for 12 hours. The reaction solution was cooled on ice, a saturated aqueous ammonium chloride solution (18 ml) was added thereto, 1 mol/L hydrochloric acid was added to acidify the solution, and the reaction solution was divided into two layers by adding ethyl acetate. The aqueous layer is extracted with ethyl acetate, and the organic layers are combined, washed with brine and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=94:6-60:40) to give 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl) phenyl]cyclopropan-1-ol (220 mg) as a light yellow solid.

(3) A solution of the compound (0.11 g) obtained in (2) above in tetrahydrofuran (2.5 ml) was cooled on ice, 1 mol/L hydrochloric acid (2.5 ml) was added thereto, and the reaction solution was stirred at room temperature for 30 minutes. Water was added to the reaction solution, which was then extracted with ethyl acetate, filtered through a phase separator and concentrated to give the title compound (0.088 g) as a light yellow oily substance.

MS ESI sex: 247 [M-OH] ⁺ .

Hold time: 0.742 min (method A)

Reference example 1-9-2

1-[3,5-Diethoxy-4-(methanesulfinyl)phenyl]ethan-1-one

[Chemical formula 391]

(1) The present reaction is carried out with reference to the method described in the literature (Journal of Medicinal Chemistry, vol. 59, p. 6772, 2016). Under a nitrogen atmosphere, a mixed solution of the compound (0.1 g) obtained in Reference Example 1-9-1 (1) in diethyl ether-tetrahydrofuran (2 ml-1 ml) was cooled to -78°C, and n-butyllithium was added thereto (1.60 mol/l n-hexane solution, 0.38 ml). The reaction solution was stirred for 30 minutes while cooling on ice and cooled to -78°C. Dimethyl sulfide (68.0 μL) was added thereto, and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added, and extraction is carried out with diethyl ether. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give 2-[3,5-diethoxy-4-(methylsulfanyl)phenyl]-2-methyl-1,3- dioxolane (75.8 mg) as a colorless solid.

(2) Under a nitrogen atmosphere, a solution of the compound (40.8 mg) obtained in (1) above in methanol (1.4 ml) was cooled on ice, and a solution of sodium periodate (29.2 mg) in water (1. 4 ml). The reaction solution was stirred at the same temperature for 1 hour and stirred at room temperature for 7 hours. The brine is added to the reaction solution, which is then extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=70:30 to ethyl acetate only) to give 2-[3,5-diethoxy-4-(methanesulfinyl)phenyl]-2-methyl-1,3-dioxolane (33.8 mg) as a colorless solid.

(3) Using the compound (33.8 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (34.0 mg ) is obtained as a colorless solid.

MS IER sex: 271 [M+H] ⁺ .

Hold time: 0.636 min (method B)

Reference example 1-9-3

1-[3,5-Diethoxy-4-(methanesulfonyl)phenyl]ethan-1-one

[Chemical formula 392]

(1) A solution of the compound (35 mg) obtained in Reference Example 1-9-2 (1) in chloroform (1.2 ml) was cooled on ice, meta-chloroperoxybenzoic acid (64.8 mg) was added thereto, and the reaction solution stir at the same temperature for 10 minutes and at room temperature for 20 minutes. The reaction solution was cooled on ice, a saturated aqueous sodium bicarbonate solution was added, and extraction was carried out with chloroform three times. The organic layer is washed with saturated aqueous sodium thiosulfate, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to ethyl acetate only) to give 2-[3,5-diethoxy-4-(methanesulfonyl)phenyl]-2-methyl-1,3-dioxolane (37.6 mg) as a colorless solid.

(2) Using the compound (37.6 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (35.6 mg ) is obtained as a colorless solid.

MS IER gender: 287 [M+H] ⁺ .

Hold time: 0.696 min (method B)

Reference example 1-10-1

1-[2,6-Diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethan-1-ol

[Chemical formula 393]

(1) Under a nitrogen atmosphere, a mixed solution of the compound (1 g) obtained in Reference Example 1-9-1 (1) in diethyl ether-tetrahydrofuran (20 ml-10 ml) was cooled to -78°C, and n- butyllithium (1.60 mol/L n-hexane solution, 2.5 ml), and the reaction solution was stirred for 30 minutes while cooling on ice. After cooling the reaction solution to -78°C, N,N-dimethylformamide (0.35 ml) was added thereto, and the reaction solution was stirred at the same temperature for 1 hour. The reaction solution was brought back to ice temperature, saturated aqueous ammonium chloride (30 ml) was added, and extraction was carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=75:25) to give 2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)benzaldehyde ( 0.602 g) as a colorless solid.

(2) Using the compound (0.1 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-6-1 (1), and 1-[2,6-diethoxy 4-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethan-1-ol (83.3 mg) was obtained as a colorless solid.

(3) Using the compound (83.3 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (68.0 mg ) is obtained as a colorless solid.

MS ESI floor: 235 [M-OH] ⁺ .

Hold time: 0.965 min (method B)

Reference example 1-10-2

1-[4-(Difluoromethyl)-3,5-diethoxyphenyl]ethan-1-one

[Chemical formula 394]

(1) To a solution of the compound (0.07 g) obtained in Reference Example 1-10-1 (1) in chloroform (1.7 ml), add bis(2-methoxyethyl)aminosulfur trifluoride (138 μL), and react the solution is stirred at room temperature for 1 hour. Bis(2-methoxyethyl)aminosulfur trifluoride (138 μL) was further added thereto, and the reaction solution was stirred at 60°C for 10 hours and at room temperature overnight. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give 2-[4-(difluoromethyl)-3,5-diethoxyphenyl]-2-methyl-1,3-dioxolane (31.3 mg) as a light yellow solid.

(2) Using the compound (31.3 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (60.6 mg ) is obtained as a colorless solid.

MS IER sex: 259 [M+H] ⁺ .

Hold time: 1.115 min (method B)

Reference example 1-10-3

(4-Acetyl-2,6-diethoxyphenyl)methyl acetate

[Chemical Formula 395]

(1) A solution of the compound (50.0 mg) obtained in Reference Example 1-10-1 (1) in methanol (2 ml) was cooled on ice, and sodium borohydride (10.1 mg) was added thereto. The reaction solution was stirred at the same temperature for 40 minutes. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to give [2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)phenyl ]methanol (43.4 mg) as a colorless solid.

(2) To a solution of the compound (43.4 mg) obtained in (1) above in chloroform (1.5 ml), add triethylamine (64.3 μL), and acetyl chloride (66.0 μL), and the reaction solution stir at room temperature for 4 hours. The reaction solution was cooled on ice, and a saturated aqueous sodium bicarbonate solution was added thereto. The reaction solution was extracted with chloroform, filtered through a phase separator and concentrated to give [2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]methyl acetate (59.7 mg) as light -yellow oily substance.

(3) Using the compound (59.7 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (30.7 mg ) is obtained as a colorless solid.

MS ESI floor: 303 [M+Na] ⁺ .

Hold time: 0.975 min (method B)

Reference example 1-10-4

1-[3,5-Diethoxy-4-(2,2,2-trifluoro-1-hydroxyethyl)phenyl]ethan-1-one

[Chemical formula 396]

(1) The present reaction is carried out with reference to the method described in the literature (Journal of the American Chemical Society, vol. 111, p. 393, 1989). Under a nitrogen atmosphere, a solution of the compound (70 mg) obtained in Reference Example 1-10-1 (1) in tetrahydrofuran (2.5 ml) was cooled on ice, and (trifluoromethyl)trimethylsilane (55.4 μl) and fluoride were added thereto. tetrabutylammonium (1 mol/L tetrahydrofuran solution, 25.0 μL), and the reaction solution was stirred at room temperature for 1.5 hours. Thereto, 1 mol/L hydrochloric acid (1 ml) was additionally added, and the reaction solution was stirred at room temperature for 3 hours. Water is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl )phenyl]-2,2,2-trifluoroethan-1-ol (42 mg) as a colorless oily substance.

(2) Using the compound (90 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (61 mg) was obtained as colorless solid.

MS IER floor: 307 [M+H] ⁺ .

Hold time: 1.053 min (method B)

Reference example 1-10-5

1-(4-Acetyl-2,6-diethoxyphenyl)-2,2,2-trifluoroethan-1-one

[Chemical formula 397]

(1) To a solution of the compound (42 mg) obtained in Reference Example 1-10-4 (1) in n-hexane (3 ml), manganese dioxide (0.8 g) was added, and the reaction solution was stirred at room temperature in for 3.5 hours and at 60 degrees for 2 hours. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl )phenyl]-2,2,2-trifluoroethan-1-one (31 mg) as a colorless solid.

(2) Using the compound (31 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (34 mg) was obtained as colorless solid.

MS IER floor: 305 [M+H] ⁺ .

Hold time: 1.145 min (method B)

Reference example 1-10-6

Methyl 4-acetyl-2,6-diethoxybenzoate

[Chemical formula 398]

(1) To a solution of the compound (266 mg) obtained in Reference Example 1-10-1 (1) in 2-methyl-2-butene (0.81 ml), add sodium dihydrogen phosphate (456 mg), tert-butyl alcohol (3.8 ml), water (1.3 ml), and tetrahydrofuran (3.8 ml), and the reaction solution was cooled on ice. Sodium chlorite (344 mg) was slowly added thereto, and the reaction solution was stirred at room temperature for 1.5 hours. The reaction solution is cooled on ice, water (50 ml) and citric acid (1 g) are added to make the solution acidic (pH 1-2), and extraction is carried out with ethyl acetate twice. The organic layer was extracted with saturated aqueous sodium bicarbonate (30 ml) twice. Citric acid (4 g) is added to the aqueous layer to make it acidic (pH 5), and extraction is carried out twice with ethyl acetate. The organic layer was washed with brine, filtered through a phase separator and concentrated to give 2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)benzoic acid (205 mg) as a colorless solid.

(2) Under a nitrogen atmosphere, a mixed solution of the compound (32 mg) obtained in (1) above in chloroform-methanol (2 ml-1 ml) was cooled on ice, and trimethylsilyldiazomethane (2 mol/L solution in diethyl ether, 162) was added thereto. µl), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution is cooled on ice, water is added thereto, and the reaction solution is extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give methyl 2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)benzoate (28.6 mg) as a colorless solid.

(3) To a mixed solution of the compound (28.6 mg) obtained in (2) above in acetone-water (920 μL-920 μL), p-toluenesulfonic acid monohydrate (17.5 mg) was added, and the reaction solution was stirred in for 2.5 hours. Thereto, p-toluenesulfonic acid monohydrate (17.5 mg) was further added, and the reaction solution was stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give the title compound (24.2 mg) as a colorless solid.

MS ESI sex: 267 [M+H] ⁺ , 289 [M+Na] ⁺ .

Hold time: 0.995 min (method B)

Reference example 1-11-1

1-[3,5-Diethoxy-4-(2-hydroxypropan-2-yl)phenyl]ethan-1-one

[Chemical formula 399]

(1) Using the compound (111 mg) obtained in Reference Example 1-8-5, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (1), and 1-[2,6-diethoxy -4-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethan-1-one (110 mg) is obtained as a colorless solid.

(2) Using the compound (45.5 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-6-1 (1), and 2-[2,6-diethoxy 4-(2-methyl-1,3-dioxolan-2-yl)phenyl]propan-2-ol (41.9 mg) is obtained as a colorless oily substance.

(3) Using the compound (41.9 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (19.7 mg ) is obtained as a colorless solid.

MS IER sex: 249 [M-OH] ⁺ .

Hold time: 1.037 min (method B)

Reference example 1-11-2

1-[3,5-Diethoxy-4-(1-hydroxypropyl)phenyl]ethan-1-one

[Chemical formula 400]

(1) Using the compound (80 mg) obtained in Reference Example 1-10-1 (1) and ethyl magnesium bromide (3 mol/L solution in diethyl ether, 143 μL), the reaction was carried out in accordance with the method described in Reference Example 1-6-1 (1), and 1-[2,6-diethoxy-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]propan-1-ol (85.0 mg ) is obtained in the form of a colorless oily substance.

(2) Using the compound (85.0 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-10-6 (3), and the title compound (71.4 mg ) is obtained in the form of a colorless oily substance.

MS IER sex: 249 [M-OH] ⁺ .

Hold time: 0.994 min (method B)

Reference example 1-11-3

1-(4-Acetyl-2,6-diethoxyphenyl)propan-1-one

[Chemical formula 401]

Using the compound (34.6 mg) obtained in Reference Example 1-11-2, the reaction was carried out in accordance with the method described in Reference Example 1-10-5 (1), and the title compound (19.2 mg ) is obtained as a colorless solid.

MS IER floor: 265 [M+H] ⁺ .

Hold time: 1.018 min (method B)

Reference example 1-12-1

4-Acetyl-2,6-diethoxybenzamide

[Chemical formula 402]

(1) To a mixed solution of the compound (50.0 mg) obtained in Reference Example 1-10-6 (1) in tetrahydrofuran-methanol (1.1 ml-0.22 ml), add ammonium chloride (13.5 mg ), triethylamine (70.6 μl), and DMT-MM (93.4 mg), and the reaction solution was stirred at room temperature for 6 hours, at 40°C for 3 hours and at room temperature overnight. Ammonium chloride (13.5 mg), triethylamine (70.6 μL), and DMT-MM (93.4 mg) were further added thereto, and the reaction solution was stirred at 40°C for 4 hours. 0.5 mol/L hydrochloric acid is added to the reaction solution, which is then extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:50 to ethyl acetate only and then chloroform only to chloroform:methanol=80:20) to give 2,6-diethoxy-4-(2-methyl-1, 3-dioxolan-2-yl)benzamide (64.0 mg) as a colorless solid.

(2) Using the compound (64.0 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (34.8 mg ) is obtained as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38-1.48 (m, 6 H) 2.59 (s, 3 H) 4.11-4.20 (m, 4 H) 7.12 (s, 2 H).

MS IER/HIAD Multi gender: 252 [M+H] ⁺ .

Reference example 1-12-2

4-Acetyl-2,6-diethoxy-N-methylbenzamide

[Chemical formula 403]

(1) Using the compound (47.7 mg) obtained in Reference Example 1-10-6 (1), the reaction and subsequent processing were carried out in accordance with the method described in Reference Example 1-7-3. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=70:30-10:90) to obtain 2,6-diethoxy-N-methyl-4-(2-methyl-1,3-dioxolane-2- yl)benzamide (47.4 mg) as a colorless solid.

(2) Using the compound (47.4 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (40.7 mg ) is obtained as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36-1.46 (m, 6 H) 2.58 (s, 3 H) 2.97-3.05 (m, 3 H) 4.07-4.18 (m, 4 H) 5.61-5.73 (m, 1 H) 7.10 (s, 2 H).

MS IER/HIAD Multi gender: 266 [M+H] ⁺ .

Reference example 1-13-1

1-(4-Acetyl-3,5-diethoxyphenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethan-1-one

[Chemical formula 404]

(1) Potassium hydroxide (1.6 g) was added to a solution of the compound (1.6 g) obtained in Reference Example 1-8-5 in methanol (32 ml), and the reaction solution was stirred for 5 minutes. The reaction solution was cooled on ice, iodobenzene diacetate (3.1 g) was added thereto, and the reaction solution was stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution (10 ml) was added to the reaction solution, which was then extracted with chloroform, filtered through a phase separator and concentrated to obtain a mixture containing 1-[2,6-diethoxy-4-(2-hydroxy-1,1- dimethoxyethyl)phenyl]ethan-1-one.

(2) To a solution of the mixture obtained in (1) above in tetrahydrofuran (21 ml), water (7.1 ml) and p-toluenesulfonic acid monohydrate (2.4 g) were added, and the reaction solution was stirred at room temperature in within 2 days. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate three times. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-30:70) to give 1-(4-acetyl-3,5-diethoxyphenyl)-2-hydroxyethan-1-one (1.15 g ) as a light yellow solid.

(3) A solution of the compound (1.15 g) obtained in (2) above in N,N-dimethylformamide (17 ml) was cooled on ice, imidazole (0.882 g), and tert-butyldimethylchlorosilane (1.95 g) were added thereto. , and the reaction solution was stirred at room temperature for 1.5 hours. Water is added to the reaction solution, which is then extracted with ethyl acetate three times. The organic layer is washed with water and brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to obtain the title compound (1.85 g) as a light yellow oily substance.

MS IER sex: 381 [M+H] ⁺ .

Hold time: 1.021 min (method A)

The following Reference Examples 1-13-2-1-13-3 were synthesized by the method described in Reference Example 1-13-1 or an equivalent method using the compounds obtained in Reference Example 1-5-2 and Reference Example 1-5-17 , commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 9-1.

[Table 9-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 1-13-4

1-(3,5-Diethoxy-4-methylphenyl)-2-methoxyethan-1-one

[Chemical Formula 405]

To a solution of the compound (100 mg) obtained in Reference Example 1-13-1 (2) in acetonitrile (2.1 ml), add iodomethane (157 μl), and silver(I) oxide (0.486 g), and the reaction solution stir at room temperature overnight. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to obtain the title compound (77 mg) as a colorless solid.

MS ESI floor: 253 [M+H] ⁺ , 275 [M+Na] ⁺ .

Hold time: 0.820 min (method A)

Reference example 1-14-1

4-Bromo-2-chloro-3,5-diethoxybenzaldehyde

[Chemical Formula 406]

(1) Under a nitrogen atmosphere, a solution of the compound (10 g) obtained in Reference Example 1-5-1 (1) in acetonitrile (105 ml) was cooled with sodium chloride-ice, and sulfuryl chloride (2.55 ml) was added thereto. internal temperature: -18°C - -16°C), and the reaction solution was stirred for 1 hour (internal temperature: -17°C - -12°C). At the same temperature, saturated aqueous sodium bicarbonate (75 ml) was added thereto (internal temperature: -17°C to -10°C, pH 7), and extraction was carried out with ethyl acetate (50 ml). The organic layer was washed with brine (50 ml), and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain ethyl 4-bromo-2-chloro-3,5-diethoxybenzoate (10.4 g) as a colorless oil.

(2) A solution of the compound (12.5 g) obtained in (1) above in tetrahydrofuran (59 ml) was cooled on ice, and lithium borohydride (1.93 g) and ethanol (3.0 ml) were slowly added thereto. and the reaction solution was stirred at the same temperature for 1.5 hours. At the same temperature, a saturated aqueous ammonium chloride solution was added thereto, and the reaction solution was extracted with chloroform, filtered through a phase separator and concentrated to give (4-bromo-2-chloro-3,5-diethoxyphenyl)methanol (10.5 g) as colorless oily substance.

(3) To a solution of the compound (9 g) obtained in (2) above in toluene (97 ml), manganese dioxide (50.5 g) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite (registered trademark) and the filtrate was concentrated to obtain the title compound (8.1 g) as a yellow powder.

MS IER floor: 307 [M+H] ⁺ .

Hold time: 0.974 min (method A)

Reference example 1-14-2

4-Bromo-3,5-diethoxy-2-methylbenzaldehyde

[Chemical formula 407]

(1) A solution of the compound (25 g) obtained in Reference Example 1-5-1 (1) in chloroform (197 ml) was cooled on ice, and silver trifluoroacetate (22.6 g) and iodine (24.0 g) were added thereto ), and the reaction solution was stirred at the same temperature for 1 hour. At the same temperature, a mixed solution of 10% sodium thiosulfate aqueous solution - saturated sodium bicarbonate aqueous solution (1:1, 260 ml) was added thereto, the reaction solution was filtered through Celite (registered trademark), and the filtrate was extracted with chloroform. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain ethyl 4-bromo-3,5-diethoxy-2-iodobenzoate (35.6 g) as a pale yellow oil.

(2) To a solution of the compound (32.2 g) obtained in (1) above in 1,4-dioxane (121 ml), add methyl boronic acid (4.57 g), and tripotassium phosphate (46.3 g), and the reaction solution is degassed under reduced pressure. Tetrakis(triphenylphosphine)palladium(0) (4.20 g) was added thereto, and the reaction solution was degassed under reduced pressure and then subjected to reflux heating for 2.5 hours. At the same temperature, water (2 ml) was added dropwise over 30 minutes, and the reaction solution was refluxed for 1.5 hours. At the same temperature, water (2 ml) was added dropwise over 30 minutes, and the reaction solution was refluxed for 5 hours. The reaction solution is cooled and filtered through Celite (registered trademark), and water is added to the filtrate, which is then extracted with ethyl acetate twice. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=93:7) to obtain ethyl 4-bromo-3,5-diethoxy-2-methylbenzoate (19.2 g) as a colorless oil. .

(3) Using the compound (21.4 g) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-14-1 (2), and a mixture (19.0 g) containing ( 4-bromo-3,5-diethoxy-2-methylphenyl)methanol is obtained in the form of a colorless oily substance.

(4) Using the mixture (19.0 g) obtained in (3) above, the reaction was carried out in accordance with the method described in Reference Example 1-14-1 (3), and the title compound (15.6 g ) is obtained as a pale yellow oily substance.

MS ESI sex: 287, 289 [M+H] ⁺ , 309 [M+Na] ⁺ .

Hold time: 0.926 min (method A)

Reference example 1-14-3

4-Bromo-2-chloro-3-ethoxybenzaldehyde

[Chemical formula 408]

(1) To a solution of 2-chloro-3-hydroxybenzaldehyde (10.0 g) in methanol (106 ml), trimethyl orthoformate (11.2 ml), and tetrabutylammonium tribromide (1.54 g) were added, and the reaction solution was stirred at room temperature for 17 hours. By adding ethyl acetate (500 ml), and 0.01 mol/L aqueous sodium bicarbonate solution (500 ml) to the reaction solution, it was separated into two layers. The organic layer was dried over anhydrous sodium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=92:8-70:30) to obtain 2-chloro-3-(dimethoxymethyl)phenol (14.8 g) as a colorless oil.

(2) The present reaction is carried out with reference to the method described in the literature (WO 2010/016230). A solution of the compound (12.9 g) obtained in (1) above in chloroform (80 ml) was cooled on ice, a solution of bromine (2.78 ml) in chloroform (11 ml) was added thereto over 1 hour, and the reaction solution was stirred. at room temperature for 17 hours. The reaction solution was cooled on ice, 5% sodium bisulfite aqueous solution (110 ml) was added thereto, and extraction was carried out with chloroform (aqueous layer pH 1). The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain 4-bromo-2-chloro-3-hydroxybenzaldehyde (14.9 g) as a light yellow solid.

(3) To the compound (14.9 g) obtained in (2) above and potassium carbonate (17.5 g), add N,N-dimethylformamide (63 ml), and iodoethane (7.67 ml), and react the solution is stirred at room temperature for 2 hours. The reaction solution was cooled on ice, water (140 ml) was added thereto, and extraction was carried out with a mixed solvent of n-hexane-ethyl acetate (3:1). The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain the title compound (17.4 g) as a light yellow oily substance.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.51-1.54 (m, 3 H) 4.12-4.16 (m, 2 H) 7.55-7.57 (m , 1 H) 7.59-7.61 (m, 1 H) 10.43 (s, 1 H).

The following Reference Examples 1-14-4-1-14-6 are synthesized by the method described in Reference Example 1-14-1(2)-(3) or Reference Example 1-14-2 or an equivalent method using the compounds prepared in Reference Example 1-2-1 and Reference Example 1-5-1 (1), commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 10-1.

[Table 10-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 1-14-7

3,5-Diethoxy-4-(1-hydroxycyclopropyl)benzaldehyde

[Chemical Formula 409]

(1) Using the compound (8.0 g) obtained in Reference Example 1-14-6, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (1), and 2-(4-bromo -3,5-diethoxyphenyl)-1,3-dioxolane (9.1 g) is obtained as a light purple oily substance.

(2) Using the compound (3.5 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (2), and 1-[4-(1,3 -dioxolan-2-yl)-2,6-diethoxyphenyl]cyclopropan-1-ol (460 mg) was obtained as a light yellow solid.

(3) Using the compound (460 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 1-9-1 (3), and the title compound (400 mg) was obtained as light yellow oily substance.

MS ESI sex: 233 [M-OH] ⁺ , 273 [M+Na] ⁺ .

Hold time: 0.733 min (method A)

Reference example 1-14-8

4-Bromo-5-ethoxy-2-methylbenzaldehyde

[Chemical formula 410]

(1) A solution of 5-hydroxy-2-methylbenzoic acid (1 g), and acetic acid (4 ml) in chloroform (32 ml) was cooled on ice, bromine (1 ml) was added, and the reaction solution was stirred at the same temperature in for 1 hour and at room temperature for 20 hours. The reaction solution is cooled on ice, a saturated aqueous solution of sodium sulfite is added thereto, and extraction is carried out successively with ethyl acetate and chloroform. The organic layer was washed with brine, filtered through a phase separator and concentrated to obtain a mixture (2.4 g) containing 4-bromo-5-hydroxy-2-methylbenzoic acid as a light yellow powder.

(2) To a solution of the mixture (2.4 g) obtained in (1) above in N,N-dimethylformamide (6.6 ml), potassium carbonate (2.7 g) was added, and the reaction solution was stirred at room temperature within 5 minutes. Iodoethane (1.6 ml) was added thereto, and the reaction solution was stirred at 60°C for 4 hours. Water is added to the reaction solution, which is then extracted with a mixed solvent of n-hexane/ethyl acetate (1:1), filtered through a phase separator and concentrated. Diethyl ether is added to the residue, the precipitated solid is filtered off, and the filtrate is concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-75:25) to obtain a mixture (2.0 g) containing ethyl 4-bromo-5-ethoxy-2-methylbenzoate as a light yellow oily substances.

(3) A solution of the mixture (2.0 g) obtained in (2) above in tetrahydrofuran (26 ml) was cooled on ice, lithium borohydride (0.429 g) was added thereto, and the reaction solution was stirred at room temperature for 12 hours and at 50°C for 3 hours. The reaction solution was cooled on ice, a saturated aqueous ammonium chloride solution (20 ml) was slowly added thereto, and the reaction solution was stirred at room temperature for 0.5 hours. The reaction solution is extracted with chloroform, filtered through a phase separator and concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-60:40) to obtain (4-bromo-5-ethoxy-2-methylphenyl)methanol (0.75 g) as a colorless oil.

(4) To a solution of the compound (0.75 g) obtained in (3) above in toluene (12 ml), manganese dioxide (3.2 g) was added, and the reaction solution was stirred at room temperature for 16 hours. The insolubles were filtered off with Celite (registered trademark) and the filtrate was concentrated to give the title compound (0.75 g) as a colorless oily substance.

MS IER sex: 243, 245 [M+H] ⁺ .

Hold time: 1.138 min (method B)

The following Reference Example 1-14-9 was synthesized by the method described in Reference Example 1-14-8(2)-(4) or an equivalent method using methyl 4-bromo-3-hydroxy-2-methylbenzoate. The structure and LCMS data of the compound are shown in Table 10-2.

[Table 10-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 1-14-10

4-Cyclopropyl-3,5-diethoxy-2-methylbenzaldehyde

[Chemical formula 411]

(1) A solution of the compound (2.27 g) obtained in Reference Example 1-8-7 in chloroform (24 ml) was cooled on ice, and silver trifluoroacetate (2.78 g) and iodine (2.95 g) were added thereto. , and the reaction solution was stirred at the same temperature for 50 minutes. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate are added dropwise to the reaction solution, which is then filtered through Celite (registered trademark), and the filtrate is separated into two layers. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-80:20) to obtain 4-cyclopropyl-3,5-diethoxy-2-iodobenzaldehyde (751 mg) as an orange oily substance.

(2) Under a nitrogen atmosphere, to a solution of the compound (1.5 g) obtained in (1) above in 1,4-dioxane (21 ml), add methyl boronic acid (0.37 g), the addition product of the dichloride [1, 1'-bis(diphenylphosphino)ferrocene]palladium(II), and dichloromethane (0.34 g), tripotassium phosphate (2.7 g), and water (2.1 ml), and the reaction solution was stirred at 100°C for 7 hours and at room temperature for 15 hours. Ethyl acetate and water are added to the reaction solution, which is then filtered through Celite (registered trademark) and the filtrate is separated into two layers. The organic layer was concentrated and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to obtain the title compound (617 mg) as a colorless oily substance.

MS IER sex: 249 [M+H] ⁺ .

Hold time: 0.968 min (method A)

The following Reference Examples 1-14-11 to 1-14-12 are synthesized by the method described in Reference Example 1-14-10 or an equivalent method using the compounds obtained in Reference Example 1-4-1 and Reference Example 1-4-3 . The structures, NMR data and LCMS data of the compounds are shown in Table 10-3 through Table 10-4.

[Table 10-3] Reference example no. Structural formula Analytical data 1-14-11 ^1H NMR (600 MHz, CHLOROFORM) δ ppm 2.60 (s, 3H), 3.83 (s, 3H), 3.95 (s, 3H), 7.18 (s, 1H), 10 .32 (s, 1H)

Reference example 1-15-1

(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethan-1-amine

[Chemical formula 412]

(1) This reaction is carried out with reference to methods described in the literature (Journal of Combinatorial Chemistry, vol. 5, p. 590, 2003; and Organic Letters, vol. 3, p. 3707, 2001). To a solution of (S)-(-)-tert-butylsulfinamide (1 g) and the compound (1.80 g) obtained in Reference Example 1-4-2 in chloroform (21 ml), add tetraethyl orthotitanate (containing 35% or less tetraisopropyl orthotitanate) (3.74 ml), and the reaction solution was stirred at 110°C for 15 minutes under microwave irradiation. The reaction solution was filtered through a mixed layer of Celite (registered trademark)-sodium sulfate decahydrate (2:1, 20 g), and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=70:30) to give (SS)-N-[(E)-(3,5-diethoxy-4-methylphenyl)methylidene]- 2-methylpropane-2-sulfinamide (2.52 g) as a light yellow solid.

(2) The present reaction is carried out with reference to the method described in the literature (Chemical Reviews, vol. 110, p. 3600, 2010). Under a nitrogen atmosphere, a solution of the compound (3.40 g) obtained in (1) above in 1,2-dichloroethane (55 ml) was cooled on ice, and methylmagnesium bromide (3 mol/L solution in diethyl ether, 18. 2 ml), and the reaction solution was stirred at room temperature for 15 hours. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added thereto, and extraction is carried out with ethyl acetate twice. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to give (SS)-N-[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl] -2-methylpropane-2-sulfinamide (2.81 g) as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 (s, 9 H) 1.37-1.44 (m, 6 H) 1.49-1.57 (m, 3 H) 2.08 (s, 3 H) 3.24-3.29 (m, 1 H) 3.95-4.06 (m, 4 H) 4.46-4.53 (m, 1 H) 6, 49 (s, 2 H).

The resulting colorless solid was recrystallized from ethyl acetate to obtain a single crystal, which was confirmed to have the desired structure below using X-ray diffraction analysis.

[Chemical formula 413]

(3) A solution of the compound (2.81 g) obtained in (2) above in methanol (43 ml) was cooled on ice, 4 mol/L solution of hydrochloride-1,4-dioxane (6.4 ml) was added thereto, and the reaction solution is stirred at room temperature for 1.5 hours. The reaction solution was concentrated, saturated aqueous sodium bicarbonate was added thereto, and extracted with a mixed solvent of chloroform-methanol (9:1). The organic layer is dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain the title compound (2.10 g) as a light yellow oily substance.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35-1.44 (m, 9 H) 2.08 (s, 3 H) 4.01-4.08 (m, 5 H) 6.51 (s, 2 H).

Reference example 1-15-2

(1R)-1-(4-Bromo-2-chloro-3,5-diethoxyphenyl)ethan-1-amine hydrochloride

[Chemical formula 414]

(1) To a solution of the compound (6.00 g) obtained in Reference Example 1-14-1 in toluene (39 ml), add (S)-(-)-tert-butylsulfinamide (2.48 g), and tetraethyl orthotitanate (containing 35% or less of tetraisopropyl orthotitanate) (6.43 ml), and the reaction solution was stirred at 100°C for 3 hours and stood at room temperature overnight. A 10% aqueous solution of disodium citrate 1,5-hydrate is added to the reaction solution, which is then stirred for 30 minutes and then filtered through Celite (registered trademark), and the filtrate is extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous solution of disodium citrate 1,5-hydrate and saturated

brine solution and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=90:10) to give (SS)-N-[(E)-(4-bromo-2-chloro-3,5-diethoxyphenyl )methylidene]-2-methylpropane-2-sulfinamide (7.06 g) as a colorless powder.

(2) Using the compound (7.06 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-15-1 (2), and (SS)-N-[(1R )-1-(4-bromo-2-chloro-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (5.93 g) was obtained as a colorless amorphous substance.

(3) To a solution of the compound (2 g) obtained in (2) above in methanol (16 ml), a 4 mol/L solution of 1,4-dioxane hydrochloride (3.5 ml) was added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain the title compound (1.36 g) as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.41-1.52 (m, 6 H) 1.56-1.66 (m, 3 H) 4.03-4.21 ( m, 4 H) 4.88-4.97 (m, 1 H) 6.99 (s, 1 H).

MS IER sex: 322, 324 [M+H] ⁺ .

Hold time: 0.953 min (method C)

The following Reference Examples 1-15-3-1-15-13 are synthesized by the method described in Reference Example 1-15-1-1-15-2 or Reference Example 1-16-1 or an equivalent method using compounds prepared in Reference Example 1-4-1, Reference Example 1-4-3 and Reference Examples 1-14-4-1-14-12, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and NMR data of the compounds are shown in Table 11-1 through Table 11-3.

[Table 11-1] Reference example no. Structural formula Analytical data 1-15-3 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.47-1.54 (m, 3H), 1.98 (s, 3H), 3.79 (s, 6H), 4.28 -4.38 (m, 1N), 6.82 (s, 2n), 8.39 (shs, 3N) 1-15-4 ^1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.21-1.90 (m, 9H), 3.84-4.13 (m, 5H), 6.38 (shs, 1H), 6.62 (shs, 2N), 8.52-9.01 (m, 3N) 1-15-5 ^1H NMR (400 MHz, METHANOL- _d4 ) δ ppm 1.36-1.46 (m, 6H), 1.51-1.62 (m, 3H), 2.12 (s, 3H) , 2.24 (s, 3H), 3.72-3.85 (m, 2H), 3.99-4.14 (m, 2H), 4.64-4.74 (m, 1H), 6 .79 (s, 1H) 1-15-6 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.34-1.39 (m, 6H), 1.48-1.52 (m, 3H), 4.08-4.15 ( m, 4H), 4.30-4.42 (m, 1H), 6.88-6.97 (m, 2H), 8.37-8.55 (m, 3H) 1-15-7 ^1H NMR (600 MHz, CHLOROFORM-d) δ ppm 0.81-0.95 (m, 2H), 1.05-1.20 (m, 2H), 1.37-1.47 (m , 6H), 1.47-1.60 (m, 3H), 3.93-4.09 (m, 4H), 4.09-4.24 (m, 1H), 6.15 (shs, 3H ), 6.58 (s, 2H), 8.24 (shs, 1H) [Table 11-2] Reference example no. Structural formula Analytical data 1-15-8 ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.39 (m, 3H), 1.40-1.50 (m, 3H), 2.27 (s, 3H), 2.62 (s, 3H), 4.07-4.23 (m, 2H), 4.31-4.43 (m, 1H), 7.13-7.76 (m, 4H). 1-15-9 ^1H NMR (600 MHz, DMSO- _d6 ) δ ppm 1.40-1.64 (m, 3H), 3.86 (s, 6H), 4.26-4.53 (m, 1H) , 6.79-7.14 (m, 2H), 8.18-8.70 (m, 3H) [Table 11-3] Reference example no. Structural formula Analytical data 1-15-10 ^1H NMR (400 MHz, CHLOROFORM) δ ppm 1.53-1.62 (m, 3H), 2.13 (s, 3H), 2.20 (s, 3H), 3.09 (s, 3H), 3.67 (s, 3H), 4.59-4.73 (m, 1H), 69.96 (s, 1H), 8.60 (shs, 3H) 1-15-11 ^1H NMR (600 MHz, CHLOROFORM) δ ppm 1.57-1.60 (m, 3H), 3.36 (s, 3H), 3.72-3.83 (s, 6H), 4, 59-4.69 (m, 1H), 7.06 (s, 1H), 8.78 (shs, 3H) 1-15-12 ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.80-0.89 (m, 2H), 0.90-1.00 (m, 2H), 1.34-1.45 ( m, 3H), 1.52-1.57 (m, 3H), 1.78-1.88 (m, 1H), 2.22 (s, 3H), 3.84-3.90 (m, 2H), 3.98-4.07 (m, 2H), 4.62-4.70 (m, 1H), 6.74 (s, 1H) 1-15-13 ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40-1.51 (m, 3H), 1.63-1.74 (m, 3H), 2.33 (s, 3H), 3.85-4.02 (m, 2H), 4.60-4.69 (m, 1H), 7.20-7.30 (m, 1H), 7.39-7.48 (m, 1H ), 8.71 (shs, 3N)

Reference example 1-16-1

1-{4-[(1R)-1-Aminoethyl]-3-chloro-2,6-diethoxyphenyl}ethan-1-one

[Chemical Formula 415]

(1) Using the compound (500 mg) obtained in Reference Example 1-15-2 (2), the reaction was carried out in accordance with the method described in Reference Example 1-8-5. However, instead of using 10% aqueous potassium carbonate, saturated aqueous sodium bicarbonate is used for the final treatment. By the above method, (SS)-N-[(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (457 mg) was obtained as a brown oily substances.

(2) To a solution of the compound (457 mg) obtained in (1) above in methanol (3.9 ml), add a 4 mol/L solution of 1,4-dioxane hydrochloride (0.88 ml), and the reaction solution stir at room temperature for 45 minutes. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol=95:5) to obtain the title compound (320 mg) as a brown amorphous solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.23-1.41 (m, 6 H) 1.63-1.72 (m, 3 H) 2.48 (s, 3 H) 3.89-4.10 (m, 4 H) 4.92-5.01 (m, 1 H) 7.20 (s, 1 H) 8.99 (shs, 2 H).

MS IER gender: 286, 288 [M+H] ⁺ .

Hold time: 0.813 min (method C)

Reference example 1-16-2

1-{4-[(1R)-1-Aminoethyl]-2,6-diethoxy-3-methylphenyl}ethan-1-one hydrochloride

[Chemical formula 416]

(1) Using the compound (15.4 g) obtained in Reference Example 1-14-2, the reaction was carried out in accordance with the method described in Reference Example 1-15-2 (1), and (SS)-N- [(E)-(4-bromo-3,5-diethoxy-2-methylphenyl)methylidene]-2-methylpropane-2-sulfinamide (19.5 g) was obtained as a yellow oily substance.

(2) Using the compound (19.5 g) obtained in (1) above, the reaction and subsequent processing were carried out in accordance with the method described in Reference Example 1-15-1 (2). To the resulting residue, ethyl acetate (5 ml) and hexane (30 ml) were added, and they were dissolved by heating and stirring. Ethyl acetate (5 ml) and hexane (160 ml) were further added thereto, and the reaction solution was stirred at room temperature for 2 hours and for 1 hour while cooling on ice. The precipitated solid is filtered off. To the resulting solid, ethyl acetate (6 ml) and hexane (14 ml) were added and dissolved by heating and stirring. Hexane (150 ml) was added thereto, and the reaction solution was stirred for 30 minutes while cooling on ice. The precipitated solid was filtered off and (SS)-N-[(1R)-1-(4-bromo-3,5-diethoxy-2-methylphenyl)ethyl]-2-methylpropane-2-sulfinamide (10.8 g ) is obtained in the form of a colorless powder.

(3) A solution of the compound (2.00 g) obtained in (2) above in methanol (16 ml) was cooled on ice, a 4 mol/L solution of 1,4-dioxane hydrochloride (3.69 ml) was added thereto, and the reaction solution is stirred at the same temperature for 1 hour. The reaction solution was concentrated and (1R)-1-(4-bromo-3,5-diethoxy-2-methylphenyl)ethan-1-amine hydrochloride (1.60 g) was obtained as a colorless powder.

(4) A solution of the compound (1.60 g) obtained in (3) above in chloroform (12 ml) was cooled on ice, and N,N-diisopropylethylamine (1.71 ml) and a solution of di-tert-butyl dicarbonate (1.71 ml) were added thereto. 1.29 g) in chloroform (4 ml), and the reaction solution was stirred at room temperature for 1 hour. Water is added to the reaction solution, which is then extracted with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:chloroform=93:2:5-71:24:5) to give tert-butyl [(1R)-1-(4-bromo-3,5-diethoxy -2-methylphenyl)ethyl]carbamate (1.63 g) as a colorless solid.

(5) To a solution of the compound (1.63 g) obtained in (4) above and butyl vinyl ether (4.05 g) in N,N-dimethylformamide (13 ml), add water (1.3 ml), acetate palladium(II) (90.8 mg), 1,3-bis(diphenylphosphino)propane (350 mg), and potassium carbonate (1.68 g), and the reaction solution was stirred at 120°C for 3 hours under microwave irradiation . Water is added to the reaction solution, which is then filtered through Celite (registered trademark), and water is added to the filtrate, which is then extracted with diethyl ether. The organic layer was washed with a mixed solution of saturated aqueous sodium bicarbonate-water (1:1), and saturated brine and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain a mixture (2.1 g) containing tert-butyl {(1R)-1-[4-(1-butoxyethenyl)-3,5-diethoxy-2-methylphenyl]ethyl}carbamate.

(6) A solution of the mixture (2.1 g) obtained in (5) above in tetrahydrofuran (10 ml) was cooled on ice, 1 mol/L hydrochloric acid (2 ml) was added thereto, and the reaction solution was stirred at the same temperature within 1 hour. There, 1 mol/L hydrochloric acid (4 ml) is additionally added to the reaction solution, which is then stirred at the same temperature for 30 minutes. The reaction solution is extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=75:25) to give tert-butyl [(1R)-1-(4-acetyl-3,5-diethoxy-2-methylphenyl) ethyl]carbamate (1.21 g) as a colorless solid.

(7) A solution of the compound (1.21 g) obtained in (6) above in 1,4-dioxane (4 ml) was cooled on ice, and a 4 mol/L solution of 1,4-dioxane hydrochloride (3. 3 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound (1.01 g) as a pale brown powder.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.18-1.38 (m, 6 H) 1.41-1.51 (m, 3 H) 2.15 (s, 3 H ) 2.39 (s, 3 H) 3.69-3.82 (m, 2 H) 4.03-4.15 (m, 2 H) 4.50-4.59 (m, 1 H) 7 .18 (s, 1 H) 8.43 (shs, 2 H).

The following Reference Example 1-16-3 is synthesized by the method described in Reference Example 1-16-2 or an equivalent method using the compound obtained in Reference Example 1-15-6, a commercially available compound, or a compound prepared by synthesis according to the methods described in the literature or equivalent methods. The structure and NMR data of the compound are shown in Table 12-1.

[Table 12-1] Reference example no. Structural formula Analytical data 1-13-3 ^1H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.26-1.40 (m, 3H), 1.60-1.67 (m, 3H), 2.45 (s, 3H), 3.97-4.12 (m, 4H), 4.17-4.36 (m, 1H), 6.72 (s, 2H), 8.70 (shs, 2H)

Reference example 1-17-1

(1R)-1-(4-Cyclopropyl-3,5-diethoxyphenyl)ethane-1-amine hydrochloride

[Chemical formula 417]

(1) N,N-Diisopropylethylamine (537 μL) was added to a solution of the compound (500 mg) obtained in Reference Example 1-15-6 in chloroform (4 ml), the reaction solution was cooled on ice, and di-tert solution was added thereto. -butyl dicarbonate (403 μg) in chloroform (2 ml), and the reaction solution was stirred at room temperature for 1 hour. Water is added to the reaction solution and the organic layer is separated, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=75:25) to give tert-butyl [(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]carbamate ( 584 mg) as a colorless solid.

(2) Using the compound (598 mg) obtained in (1) above and cyclopropylboronic acid (198 mg), the reaction was carried out in accordance with the method described in Reference Example 1-7-1 and tert-butyl [(1R)- 1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]carbamate (644 mg) was obtained as a yellow solid.

(3) A solution of the compound (644 mg) obtained in (2) above in chloroform (2.5 ml) was cooled on ice, a 4 mol/L solution of 1,4-dioxane hydrochloride (1.2 ml) was added thereto, and the reaction solution is stirred at room temperature for 1 hour. Chloroform (3 ml), methanol (2 ml), and a 4 mol/L solution of 1,4-dioxane hydrochloride (0.77 ml) were further added thereto, and the reaction solution was stirred at the same temperature for 6 hours. The reaction solution was concentrated, chloroform was added thereto, and the reaction solution was stirred at room temperature for 10 minutes. The precipitated solid was filtered to obtain the title compound (380 mg) as a colorless solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.65-0.81 (m, 2 H) 0.91-1.12 (m, 2 H) 1.33 (t, J= 6.90 Hz, 6 H) 1.41-1.54 (m, 3 H) 1.83-1.94 (m, 1 H) 4.00 (kV, J=6.90 Hz, 4 H) 4.19-4.36 (m, 1 H) 6.73 (s, 2 H) 8.32 (shs, 2 H).

The following Reference Examples 1-17-2-1-17-3 were synthesized by the method described in Reference Example 1-17-1 or an equivalent method using the compounds obtained in Reference Example 1-15-9 and Reference Example 1-15- 13. The structures and NMR data of the compounds are shown in Table 12-2.

[Table 12-2] Reference example no. Structural formula Analytical data 1-17-2 ^1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.77-0.84 (m, 2H), 0.89-0.96 (m, 2H), 1.36-1.41 (m , 3H), 1.76-1.88 (m, 1H), 3.82 (s, 6H), 4.03-4.10 (m, 1H), 8.63 (s, 2H) 1-17-3 ^1H NMR (400 MHz, METHANOL-d4) δ ppm 0.59-0.73 (m, 2H), 0.91-1.05 (m, 2H), 1.37-1.48 (m , 3H), 1.50-1.63 (m, 3H), 2.14-2.24 (m, 1H), 2.29-2.37 (m, 3H), 3.86-3.99 (m, 2H), 4.62-4.72 (m, 1H), 6.73-6.83 (m, 1H), 7.05-7.16 (m, 1H)

Reference example 1-17-4

(1R)-1-(2-Chloro-4-cyclopropyl-3-ethoxyphenyl)ethan-1-amine hydrochloride

[Chemical formula 418]

(1) To a solution of the compound (4.00 g) obtained in Reference Example 1-14-3 in toluene (30 ml), add (S)-(-)-tert-butylsulfinamide (1.93 g), and tetraethyl orthotitanate (containing 35% or less of tetraisopropyl orthotitanate) (5.00 ml), and the reaction solution was stirred at 100°C for 1 hour. After bringing the reaction solution back to room temperature, saturated saline (4 ml) was added thereto. The reaction solution was filtered through a mixed layer of Celite (registered trademark)-diatomaceous earth (1:1, 150 ml), and the filtrate was concentrated to give (SS)-N-[(E)-(4-bromo-2-chloro-3 -ethoxyphenyl)methylidene]-2-methylpropane-2-sulfinamide (5.90 g) as a light yellow oily substance.

(2) Using the compound (5.57 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 1-15-1 (2), and (SS)-N-[(1R )-1-(4-bromo-2-chloro-3-ethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (2.58 g) was obtained as a colorless solid.

(3) Under a nitrogen atmosphere, to a mixed solution of the compound (2.57 g) obtained in (2) above in toluene-water (67 ml-6.7 ml), add cesium carbonate (6.56 g), cyclopropylboronic acid (865 mg), and tetrakis(triphenylphosphine)palladium(0) (776 mg), and the reaction solution was stirred at 100°C for 14 hours, at 120°C for 20 minutes and at 130°C for 1 hour. After bringing the reaction solution back to room temperature, cyclopropylboronic acid (404 mg), and tetrakis(triphenylphosphine)palladium(0) (388 mg) were further added thereto, and the reaction solution was stirred at 130°C for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=80:20 to ethyl acetate only) to give (SS)-N-[(1R)-1-(2-chloro-4-cyclopropyl- 3-ethoxyphenyl)ethyl]-2-methylpropane-2-sulfinamide (1.89 g) as a light yellow solid.

(3) To a solution of the compound (1.89 g) obtained in (2) above in methanol (3 ml), 2 mol/L methanol hydrochloride (5.50 ml) was added, and the reaction solution was stirred at room temperature for 80 minutes. The reaction solution was concentrated, the resulting residue was suspended by adding isopropyl ether, and the solid was filtered to obtain the title compound (1.29 g) as a light yellow powder.

MS IER floor: 240 [M+H] ⁺ .

Hold time: 0.876 min (method C)

Reference example 1-18-1

1-{4-[(1R)-1-Aminoethyl]-2-ethoxy-3-methylphenyl}ethan-1-one

[Chemical formula 419]

(1) To a solution of 1-(4-benzyloxy-2-hydroxy-3-methylphenyl)ethanone (14.9 g) in N,N-dimethylformamide (58 ml), add potassium carbonate (12.0 g), and iodoethane (9.3 ml), and the reaction solution was stirred at 60°C for 10 hours and at room temperature overnight. Potassium carbonate (8.0 g) and iodoethane (4.6 ml) were further added thereto, and the reaction solution was stirred at 60°C for 20 hours. Water is added to the reaction solution, which is then extracted with an n-hexane/ethyl acetate mixed solvent. The organic layer was washed successively with water and brine and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain a mixture (18.0 g) containing 1-[4-(benzyloxy)-2-ethoxy-3-methylphenyl]ethan-1-one as a brown oil.

(2) To a solution of the mixture (18.0 g) obtained in (1) above in ethanol (58 ml), palladium on carbon (3.3 g) was added, and the reaction solution was stirred at room temperature for 20 hours under atmosphere hydrogen. The reaction solution was filtered through Celite (registered trademark) and the filtrate was concentrated to obtain a mixture (12.8 g) containing 1-(2-ethoxy-4-hydroxy-3-methylphenyl)ethan-1-one as light brown oily substance.

(3) Under a nitrogen atmosphere, pyridine (10 ml) was added to a solution of the mixture (11.3 g) obtained in (2) above in chloroform (232 ml), and the reaction solution was cooled on ice. Trimethanesulfonic anhydride (11.7 ml) was added thereto, and the reaction solution was stirred for 2 hours, gradually bringing it back to room temperature. Pyridine (1 ml) was added thereto at room temperature, and the reaction solution was stirred at the same temperature for 80 minutes. The reaction solution was cooled on ice, pyridine (2 ml) and trimethanesulfonic anhydride (2.3 ml) were added thereto, and the reaction solution was stirred at room temperature for 80 minutes. The reaction solution was concentrated, ethyl acetate was added thereto, and the reaction solution was cooled on ice. A saturated aqueous solution of sodium bicarbonate is added dropwise, and the reaction solution is stirred at room temperature until foaming stops. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution, water and brine, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=97:3-65:35) to obtain 4-acetyl-3-ethoxy-2-methylphenyl trifluoromethanesulfonate (15.9 g) as a light yellow oily substance.

(4) To a solution of the compound (15.9 g) obtained in (3) above in toluene (325 ml), ethylene glycol (122 ml), and p-toluenesulfonic acid monohydrate (0.9 g) were added, and the reaction solution was stirred at 125°C for 4.5 hours and at room temperature overnight. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer is washed successively with water and brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=97:3-78:22) to obtain 3-ethoxy-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl) trifluoromethanesulfonate. phenyl (17.3 g) as a colorless oily substance.

(5) Under a nitrogen atmosphere, to a mixed solution of the compound (17.3 g) obtained in (4) above in 1,4-dioxane-water (93 ml-9.3 ml), add sodium carbonate (7.43 d), potassium (acetoxymethyl)trifluoroborate (12.6 g), and methanesulfonate (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1' -biphenyl)]palladium(II) (RuPhosPdG3, Sigma-Aldrich, 1.95 g), and the reaction solution was stirred at 100°C for 20 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=98:2-60:40) to obtain [3-ethoxy-2-methyl-4-(2-methyl-1,3-dioxolane -2-yl)phenyl]methanol (8.3 g), and 1-[2-ethoxy-4-(hydroxymethyl)-3-methylphenyl]ethan-1-one (1.59 g), each as light yellow oily substance.

(6) To a solution of [3-ethoxy-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]methanol (8.3 g) obtained in (5) above in toluene ( 82 ml), manganese(IV) oxide (29 g) was added and the reaction solution was stirred at room temperature for 16 hours. Manganese(IV) oxide (29 g) and toluene (50 ml) were further added thereto, and the reaction solution was stirred at room temperature for 4 hours. The reaction solution was filtered through Celite (registered trademark) and the filtrate was concentrated to obtain a mixture (7.89 g) containing 3-ethoxy-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)benzaldehyde in the form of a light yellow oily substance.

(7) To a solution of the mixture (7.89 g) obtained in (6) above and (S)-(-)-tert-butylsulfinamide (3.82 g) in toluene (63 ml), add tetraethyl orthotitanate (containing 35% or less tetraisopropyl orthotitanate) (10.4 ml), and the reaction solution was stirred at room temperature for 45 minutes. Tetraethyl orthotitanate (containing 35% or less of tetraisopropyl orthotitanate) (3.9 ml) was further added thereto, and the reaction solution was stirred at room temperature for 14 hours. The reaction solution is filtered through a mixture of Celite (registered trademark) and sodium sulfate decahydrate and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=94:6-50:50) to give (SS)-N-{(E)-[3-ethoxy-2-methyl-4-(2-methyl -1,3-dioxolan-2-yl)phenyl]methylidene}-2-methylpropane-2-sulfinamide (9.56 g) as a light yellow oily substance.

(8) A solution of the compound (9.56 g) obtained in (7) above in 1,2-dichloroethane (90 ml) was cooled on ice, and methylmagnesium bromide (3 mol/L solution in diethyl ether, 27 .0 ml), and the reaction solution was stirred at the same temperature for 1 hour and at room temperature for 3 hours. The reaction solution was cooled on ice, methylmagnesium bromide (3 mol/L solution in diethyl ether, 4.5 ml) was added dropwise, and the reaction solution was stirred at the same temperature for 10 minutes, brought back to room temperature and stirred for 50 minutes. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added thereto, and the reaction solution is stirred overnight, gradually bringing it back to room temperature. Water is added to the reaction solution, which is then separated into an organic layer and an aqueous layer. The aqueous layer is extracted with chloroform and the organic layers are combined, washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate:methanol=84:16:0-0:100:0-0:90:10) to give (SS)-N-{(1R)-1-[ 3-ethoxy-2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)phenyl]ethyl}-2-methylpropane-2-sulfinamide (7.52 g) as a colorless resinous substance.

(9) A solution of the compound (7.5 g) obtained in (8) above in methanol (100 ml) was cooled on ice, 2 mol/L hydrochloric acid (100 ml) was added thereto, and the reaction solution was stirred for 2. 5 days, gradually increasing the temperature to room temperature. A saturated aqueous solution of sodium bicarbonate is added to the reaction solution to adjust the pH to 8-9 and extraction is carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was dissolved in methanol, the undissolved substances were filtered off and the filtrate was then concentrated to give the title compound (5.1 g) as a light yellow oily substance.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16-1.48 (m, 8 H) 2.30 (s, 3 H) 2.62 (s, 3 H) 3.77- 3.86 (m, 2 H) 4.38-4.46 (m, 1 H) 7.34 (d, J=8.07 Hz, 1 H) 7.46 (d, J=8.07 Hz , 1 H).

Reference example 1-18-2

(1R)-1-[3-Ethoxy-4-(2-hydroxypropan-2-yl)-2-methylphenyl]ethane-1-amine informate

[Chemical Formula 420]

(1) To a solution of 1-[2-ethoxy-4-(hydroxymethyl)-3-methylphenyl]ethan-1-one (50 mg) prepared in Reference Example 1-18-1 (5) in toluene (1.2 ml), manganese dioxide (209 mg) was added, and the reaction solution was stirred at room temperature for 18 hours and at 40°C for 2 hours. Manganese dioxide (104 mg) was further added thereto, and the reaction solution was stirred at 40°C for 4 hours. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The concentrate was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give 4-acetyl-3-ethoxy-2-methylbenzaldehyde (30.5 mg) as a yellow oil.

(2) To a solution of the compound (0.70 g) obtained in (1) above in toluene (6.8 ml), add (S)-(-)-tert-butylsulfinamide (0.41 g), and tetraethyl orthotitanate (containing 35% or less of tetraisopropyl orthotitanate) (1.1 ml), and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was filtered through a mixed layer of Celite (registered trademark)-sodium sulfate decahydrate (2:1, 15 g), and the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=94:6-60:40) to give (SS)-N-[(E)-(4-acetyl-3-ethoxy-2-methylphenyl)methylidene]- 2-methylpropane-2-sulfinamide (0.279 g) as a yellow oily substance.

(3) Under a nitrogen atmosphere, a solution of the compound (0.279 g) obtained in (2) above in 1,2-dichloroethane (3.0 ml) was cooled on ice, and methylmagnesium bromide (0.9 ml) was slowly added dropwise thereto. Thereto, 1,2-dichloroethane (3.0 ml) was further added, and the reaction solution was stirred at 0°C for 1 hour. Tetrahydrofuran (3.0 ml) was added thereto, methylmagnesium bromide (0.9 ml) was added dropwise thereto, and the reaction solution was stirred at the same temperature for 1 hour. A saturated aqueous solution of ammonium chloride is slowly added there and extraction is carried out with chloroform. The organic layers are collected, filtered through a phase separator and concentrated. The concentrate is purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to ethyl acetate only) to give (SS)-N-{(1R)-1-[3-ethoxy-4-(2-hydroxypropan-2-yl )-2-methylphenyl]ethyl}-2-methylpropane-2-sulfinamide (0.176 g) as a colorless resinous substance.

(4) A solution of the compound (174 mg) obtained in (3) above in methanol (2.5 ml) was cooled on ice, 2 mol/L hydrochloric acid (2.5 ml) was added thereto, and the reaction solution was stirred at the same temperature for 20 minutes and at room temperature for 22 hours. A saturated aqueous solution of sodium bicarbonate is added to the reaction solution to adjust the pH to 8-9, sodium chloride is added thereto and extraction is carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The concentrate was purified by preparative HPLC to obtain the title compound (53 mg) as a colorless oily substance.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.34-1.69 (m, 12 H) 2.32 (s, 3 H) 3.78-3.97 (m, 2 H ) 4.60-4.80 (m, 1 H) 7.19 (d, J=8.0 Hz, 1 H) 7.54 (d, J=8.0 Hz, 1 H) 8.53 ( shs, 1 H).

Reference example 2-1-1

4-Phenylbutyl 4-methylbenzene-1-sulfonate

[Chemical formula 421]

A solution of 4-phenyl-1-butanol (3 g) in chloroform (80 ml) was cooled on ice, trimethylamine hydrochloride (0.477 g), triethylamine (4.18 ml), and p-toluenesulfonyl chloride (4.38 g) were added. and the reaction solution was stirred at room temperature for 45 minutes. The reaction solution was cooled on ice, and a mixed solution of water-saturated aqueous ammonium chloride solution (50 ml-50 ml) was added thereto. The reaction solution is extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=65:35) to give the title compound (6.24 g) as a colorless oil.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.60-1.70 (m, 4 H) 2.44 (s, 3 H) 2.53-2.59 (m, 2 H) 4.01-4.06 (m, 2 H) 7.07-7.13 (m, 2 H) 7.14-7.21 (m, 1 H) 7.22-7.29 (m, 2 H) 7.30-7.35 (m, 2 H) 7.76-7.80 (m, 2 H).

The following Reference Examples 2-1-2 to 2-1-6 are synthesized by the method described in Reference Example 2-1-1 or an equivalent method using commercially available compounds or compounds synthesized according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 13-1.

[Table 13-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

NMR data from Reference Example 2-1-4 is shown below.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.92-2.01 (m, 2 H) 2.46 (s, 3 H) 2.60-2.68 (m, 2 H) 4.00-4.07 (m, 2 H) 7.03-7.11 (m, 2 H) 7.15-7.25 (m, 3 H) 7.31-7.38 (m, 2 H) 7.75-7.84 (m, 2 H).

Reference example 2-2-1

2-(2,3-Dihydro-1H-inden-2-yl)ethyl 4-methylbenzene-1-sulfonate

[Chemical formula 422]

(1) A solution of (2,3-dihydro-1H-inden-2-yl)acetic acid (2.60 g) in tetrahydrofuran (20 ml) was cooled on ice, and a borane-tetrahydrofuran complex (1 mol/L solution in tetrahydrofuran, 44.3 ml), and the reaction solution was stirred at room temperature for 3 days. Methanol was added to the reaction solution, which was then concentrated to obtain 2-(2,3-dihydro-1H-inden-2-yl)ethan-1-ol (2.58 g) as a colorless oily substance.

(2) Using the compound (2.58 g) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 2-1-1, and the title compound (4.15 g) was obtained in form of a colorless solid.

MS ESI floor: 339 [M+Na] ⁺ .

Hold time: 1.276 min (method B)

Reference example 2-3-1

3-(2-Fluorophenyl)propyl 4-methylbenzene-1-sulfonate

[Chemical formula 423]

(1) To a solution of 1-fluoro-2-iodobenzene (150 mg) in acetonitrile (1.7 ml), add triethylamine (0.471 ml), 2-propyn-1-ol (0.0468 ml), tris{tris[ 3,5-bis(trifluoromethyl)phenyl]phosphine}palladium(0) (SUPERSTABLE palladium(0) catalyst: FUJIFILM Wako Pure Chemical Corporation, 71.5 mg), and copper(I) iodide (12.9 mg), and the reaction solution is stirred at room temperature for 30 minutes. The reaction solution was stirred at 60°C for 5 hours and then stirred at room temperature overnight. The reaction solution was concentrated, and the resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=95:5-40:60) to obtain 3-(2-fluorophenyl)prop-2-yn-1-ol as light brown oily substance.

(2) To a solution of the compound obtained in (1) above in methanol (3.4 ml), palladium on carbon (50 mg) was added, and the reaction solution was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution is filtered through Celite (registered trademark), and NH silica gel and the filtrate are concentrated.

(3) Using the residue obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 2-1-1, and the title compound (150 mg) was obtained as a colorless oily substance.

MS ESI floor: 331 [M+Na] ⁺ .

Hold time: 0.883 min (method A)

The following Reference Examples 2-3-2-2-3-5 were synthesized by the method described in Reference Example 2-3-1 or an equivalent method using commercially available compounds or compounds synthesized according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 14-1.

[Table 14-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 2-4-1

(3E)-4-Phenylpent-3-en-1-yl 4-methylbenzene-1-sulfonate

[Chemical formula 424]

(1) A solution of triethylphosphonoacetate (3.55 ml) in acetonitrile (50 ml) was cooled on ice, and DBU (2.22 ml), lithium chloride (0.758 g), and 2-phenylpropionaldehyde (2 g) were added and the reaction solution stir at room temperature overnight. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer is washed with brine and dried over magnesium sulfate. After filtering the drying agent, the filtrate was concentrated and the resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=90:10) to give ethyl (3E)-4-phenylpent-3-enoate (2.64 g) as a colorless oily substance and ethyl (3Z)-4-phenylpent-3-enoate (53 mg) as a colorless oily substance.

(2) A solution of ethyl (3E)-4-phenylpent-3-enoate (1.51 g) obtained in (1) above in tetrahydrofuran (12 ml) was cooled on ice, lithium borohydride (0.483 g) was added thereto, and the reaction the solution is stirred at room temperature for 2 days. The reaction solution was cooled on ice, and a saturated aqueous ammonium chloride solution was slowly added thereto. The reaction solution was extracted with chloroform, filtered through a phase separator and concentrated to give (3E)-4-phenylpent-3-en-1-ol (1.21 g) as a colorless oil.

(3) Using the compound (1.21 g) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 2-1-1, and the title compound (1.61 g) was obtained in in the form of a light yellow oily substance.

MS ESI floor: 339 [M+Na] ⁺ .

Hold time: 1.224 min (method B)

Reference example 2-5-1

4,4-difluoro-4-phenylbutyl 4-methylbenzene-1-sulfonate

[Chemical Formula 425]

(1) A solution of methyl 3-benzoylpropionate (1.33 g) in tetrahydrofuran (11.5 ml) was cooled on ice, lithium borohydride (0.452 g) was added thereto, and the reaction solution was stirred at room temperature for 2 days. The reaction solution is cooled on ice, a saturated aqueous ammonium chloride solution is added thereto, and the reaction solution is stirred until no more bubbles form. The reaction solution was extracted with chloroform, filtered through a phase separator and concentrated to give 1-phenylbutane-1,4-diol (1.06 g).

(2) To a mixed solution of the compound (1.06 g) obtained in (1) above in toluene-ethyl acetate (23 ml-8 ml), manganese(IV) oxide (6.02 g) was added, and the reaction solution was stirred at room temperature for 24 hours. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to ethyl acetate only) to give 4-hydroxy-1-phenylbutan-1-one (502 mg) as a colorless oil.

(3) A solution of the compound (200 mg) obtained in (2) above in chloroform (3.0 ml) was cooled on ice, triethylamine (0.340 ml), and acetic anhydride (0.138 ml) were added thereto, and the reaction solution was stirred at room temperature for 40 hours. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added thereto, and the reaction solution is extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=75:25) to give 4-oxo-4-phenylbutyl acetate (190 mg) as a colorless oil.

(4) A solution of the compound (190 mg) obtained in (3) above in chloroform (3.0 ml) was cooled on ice, bis(2-methoxyethyl)aminosulfur trifluoride (0.674 ml) was added thereto, and the reaction solution was stirred at room temperature for 3 hours and when heated at reflux for 3 hours. Bis(2-methoxyethyl)aminosulfur trifluoride (1.12 ml) was further added thereto, and the reaction solution was stirred under reflux for 24 hours. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added thereto, and the reaction solution is extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=88:12) to give 4,4-difluoro-4-phenylbutyl acetate (104 mg) as a colorless oil.

(5) To a solution of the compound (104 mg) obtained in (4) above in methanol (2 ml), aqueous sodium hydroxide solution (1 mol/L, 0.5 ml) was added, and the reaction solution was stirred at room temperature for 1 hour. A saturated aqueous solution of ammonium chloride is added thereto, the reaction solution is extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to obtain 4,4-difluoro-4-phenylbutan-1-ol (72.8 mg) as a colorless oil.

(6) Using the compound (72.8 mg) obtained in (5) above, the reaction was carried out in accordance with the method described in Reference Example 2-1-1, and the title compound (108 mg) was obtained as pale -yellow oily substance.

MS ESI floor: 363 [M+Na] ⁺ .

Hold time: 1.155 min (method B)

Reference example 2-6-1

3,3-difluoro-4-phenylbutyl 4-methylbenzene-1-sulfonate

[Chemical formula 426]

(1) A solution of methyl 3-oxo-4-phenylbutyrate (2 g) in tetrahydrofuran (10 ml) was cooled on ice, lithium borohydride (1.13 g), and ethanol (1.0 ml) were slowly added thereto, and the reaction solution stir at room temperature for 17 hours. The reaction solution was cooled on ice, and 2 mol/L hydrochloric acid (8 ml) was added thereto to adjust the pH to 1. The reaction solution was stirred at 50°C for 1 hour and extracted with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol=95:5) to obtain 4-phenylbutane-1,3-diol (875 mg) as a colorless oil.

(2) Using the compound (200 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 2-5-1 (3), and 3-hydroxy-4-phenylbutyl acetate (188 mg ) is obtained in the form of a colorless oily substance.

(3) A solution of the compound (188 mg) obtained in (2) above in chloroform (1.0 ml) was cooled on ice, Dess-Martin reagent (0.536 g) was added thereto, and the reaction solution was gradually brought to room temperature and stirred at room temperature for 2 hours. The reaction solution was cooled on ice, and a mixed solution of saturated aqueous sodium thiosulfate-saturated aqueous sodium bicarbonate (1:1) was added thereto. The reaction solution is extracted with chloroform, then filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=75:25) to obtain 3-oxo-4-phenylbutyl acetate (175 mg) as a colorless oil.

(4) Using the compound (175 mg) obtained in (3) above, the reaction was carried out in accordance with the method described in Reference Example 2-5-1 (4), and 3,3-difluoro-4-phenylbutyl acetate (159 mg) is obtained in the form of a colorless oily substance.

(5) Using the compound (159 mg) obtained in (4) above, the reaction was carried out in accordance with the method described in Reference Example 2-5-1 (5), and 3,3-difluoro-4-phenylbutane-1 -ol (124 mg) is obtained as a colorless oily substance.

(6) Using the compound (124 mg) obtained in (5) above, the reaction was carried out in accordance with the method described in Reference Example 2-1-1, and the title compound (209 mg) was obtained as a colorless oily substance .

MS ESI floor: 363 [M+Na] ⁺ .

Hold time: 1,150 min (method B)

Reference example 2-7-1

2-[(1S)-1-Phenylethoxy]ethyl 4-methylbenzene-1-sulfonate

[Chemical formula 427]

(1) A suspension of sodium hydride (60% dispersion in mineral oil, 1.96 g) in tetrahydrofuran (60 ml) was cooled on ice, and a solution of (S)-(-)-1-phenylethyl alcohol (2 g) in tetrahydrofuran (15 ml), and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled on ice, a solution of bromoacetic acid (2.50 g) in tetrahydrofuran (15 ml) was added thereto, and the reaction solution was stirred at room temperature for 2 days. Tetrahydrofuran (20 ml) was further added to the reaction solution, which was then cooled on ice, and water (60 ml) was slowly added thereto. Diethyl ether (40 ml) is added thereto, an aqueous solution of sodium hydroxide is further added thereto to adjust the pH to 12 or higher, and extraction with water is carried out three times. The aqueous layers were combined, concentrated hydrochloric acid (4 ml) was then added to adjust the pH to 1 or less, and extracted with ethyl acetate twice. The organic layer is dried over magnesium sulfate, filtered through a phase separator and concentrated. A mixture (3.39 g) containing [(1S)-1-phenylethoxy]acetic acid was obtained as an orange oily substance.

(2) A solution of the mixture (3.39 g) obtained in (1) above in tetrahydrofuran (33 ml) was cooled on ice, thereto was added a borane-tetrahydrofuran complex (1 mol/L tetrahydrofuran solution, 49.1 ml), and the reaction the solution is stirred at room temperature for 2 hours. The reaction solution was cooled on ice, and isopropyl alcohol (10 ml) was slowly added thereto. Methanol was added thereto at room temperature and the reaction solution was stirred for 17 hours. After distillation of the solvent, ethyl acetate is added thereto and the reaction solution is washed with brine. The organic layer was concentrated to obtain a mixture (2.92 g) containing 2-[(1S)-1-phenylethoxy]ethan-1-ol as a yellow oily substance.

(3) Using the mixture (2.92 g) obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 2-1-1. However, instead of chloroform, tetrahydrofuran is used as the reaction solvent. By the above method, the title compound (4.20 g) was obtained as a yellow oily substance.

MS ESI floor: 343 [M+Na] ⁺ .

Hold time: 1.141 min (method B)

The following Reference Examples 2-7-2-2-7-5 were synthesized by the method described in Reference Example 2-7-1 or an equivalent method using commercially available compounds or compounds synthesized according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 15-1 through 15-2.

[Table 15-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 15-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 2-8-1

[(1R)-1-(2-Chlorophenyl)ethoxy]acetic acid

[Chemical formula 428]

A suspension of sodium hydride (60% dispersion in mineral oil, 192 mg) in tetrahydrofuran (4.8 ml) was cooled on ice, a solution of bromoacetic acid (266 mg) in tetrahydrofuran (1.2 ml) was slowly added thereto, and the reaction solution was stirred at room temperature for 10 minutes. The reaction solution was cooled on ice, a solution of (1R)-1-(2-chlorophenyl)ethan-1-ol (300 mg) in tetrahydrofuran (0.64 ml) was added thereto, and the reaction solution was stirred at room temperature for 7 hours. The reaction solution was cooled on ice, water (0.6 ml) was slowly added thereto, and the reaction solution was stirred at the same temperature for 30 minutes and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to methanol only) to give the title compound (340 mg) as a colorless solid.

MS ESI floor: 237 [M+Na] ⁺ .

MS IER ref: 213 [MH] ^- .

Hold time: 0.858 min (method B)

The following Reference Example 2-8-2 is synthesized by the method described in Reference Example 2-8-1 or an equivalent method using a commercially available compound. The structure and LCMS data of the compound are shown in Table 15-3.

[Table 15-3] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-1-1

N-[(3,5-dimethoxy-4-methylphenyl)methyl]-4-phenylbutan-1-amine

[Chemical formula 429]

To a solution of the compound (1 g) obtained in Reference Example 1-4-3 in chloroform (11 ml), 4-phenylbutylamine (1.32 ml) and sodium triacetoxyborohydride (1.76 g) were added, and the reaction solution was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution (5 ml) and a saturated aqueous sodium bicarbonate solution (5 ml) were added to the reaction solution, which was then extracted with chloroform (20 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (10 ml) twice, filtered through a phase separator and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=95:5-50:50) to obtain the title compound (1.65 g) as a colorless oily substance.

MS IER gender: 314 [M+H] ⁺ .

Hold time: 0.706 min (method B)

The following Reference Examples 3-1-2-3-1-21 and Reference Examples 3-1-23-3-1-79 were synthesized by the method described in Reference Example 3-1-1 or an equivalent method using the compounds prepared in Reference Example 1-4-2, Reference Examples 1-5-1-1-5-29, Reference Examples 1-6-1-1-6-2, Reference Examples 1-7-1-1-7-5, Reference examples 1-8-1-1-8-6, Reference examples 1-9-2-1-9-3, Reference examples 1-10-1-1-10-6, Reference examples 1-11-1- 1-11-2, Reference Example 1-12-2, Reference Examples 1-13-1-1-13-4, Reference Example 1-15-1 and Reference Example 1-15-4, commercially available compounds or compounds, obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 16-1 through 16-15.

[Table 16-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-3] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-4] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-5] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-6] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-7] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-8] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-9] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-10] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-11] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-12] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-13] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-14] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 16-15] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-1-80

N-{1-[3-Ethoxy-5-(methoxymethyl)-4-methylphenyl]ethyl}-4-phenylbutan-1-amine

[Chemical Formula 430]

To a solution of the compound (30 mg) obtained in Reference Example 1-5-14 and 4-phenylbutylamine (23.5 μL) in ethanol (0.67 ml), acetic acid was added to adjust the pH to 5, and the reaction solution was stirred at 60 °C for 12 hours. P-toluenesulfonic acid monohydrate (1 mg) is added to the reaction solution, which is then stirred under reflux for 2 hours. Ethanol (1 ml) is added to the reaction solution, which is then cooled on ice and sodium cyanoborohydride (25 mg) is added thereto. Acetic acid is added there to adjust the pH to 4-5 and the reaction solution is stirred at room temperature for 3 hours and kept at the same temperature for 2 days. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain the title compound (58 mg) as a yellow oily substance.

MS IER gender: 356 [M+H] ⁺ .

Hold time: 0.914 min (method B)

Reference example 3-2-1

3-Benzyl-N-[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl]cyclobutan-1-amine

[Chemical formula 431]

To a solution of the compound (50 mg) obtained in Reference Example 1-15-1 in chloroform (1.9 ml), triethylamine (80.5 μl), and 3-benzylcyclobutan-1-one (33.9 mg) were added. and the reaction solution was stirred at room temperature for 10 minutes. The reaction solution was cooled on ice, sodium triacetoxyborohydride (204 mg) was added thereto, and the reaction solution was stirred at the same temperature for 20 minutes and stirred at room temperature overnight. The reaction solution was cooled on ice, a saturated aqueous sodium bicarbonate solution was added thereto, and the reaction solution was stirred at room temperature for 1 hour and extracted with chloroform (4 ml) three times. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-70:30) to give the title compound (50 mg).

MS IER gender: 368 [M+H] ⁺ .

Hold time: 0.592 min (method A)

Reference example 3-2-2

1-(2,6-Diethoxy-4-{(1R)-1-[(4-phenylbutyl)amino]ethyl}phenyl)cyclopropan-1-ol

[Chemical formula 432]

To a solution of the compound (30 mg) obtained in Reference Example 1-15-7 and 4-phenylbutanal (17 mg) in ethanol (0.57 ml), acetic acid was added to adjust the pH to 5-6, and the reaction solution was stirred at room temperature. temperature for 20 minutes. The reaction solution was cooled on ice, sodium cyanoborohydride (21 mg) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled on ice, sodium cyanoborohydride (21 mg) was added thereto, and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was cooled on ice, 4-phenylbutanal (13 mg) was added thereto, and the reaction solution was stirred at the same temperature for 4 hours. At the same temperature, 4-phenylbutanal (3 mg) was added thereto, and the reaction solution was stirred at the same temperature for 1 hour. A saturated aqueous sodium bicarbonate solution (2 ml) was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with brine, filtered through a phase separator and concentrated to give the title compound (51 mg) as a colorless oil.

MS IER gender: 398 [M+H] ⁺ .

Hold time: 1.062 min (method C)

The following Reference Examples 3-2-3-3-2-4 were synthesized by the method described in Reference Example 3-2-2 or an equivalent method using the compounds obtained in Reference Example 2-1-1, Reference Example 2-6- 1 and Reference Examples 1-15-7-1-15-8, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 17-1.

[Table 17-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-3-1

1-(2,6-Diethoxy-4-{1-[(4-phenylbutyl)amino]ethyl}phenyl)cyclopropan-1-ol

[Chemical formula 433]

The present reaction is carried out with reference to a method described in the literature (Kanto Chemical Co., Inc.; THE CHEMICAL TIMES, vol. 228, p. 19, 2013). A solution of compound (84 mg) prepared in Reference Example 1-9-1, 4-phenylbutylamine (45.1 mg), formic acid (36.3 µl), and chloro(pentamethylcyclopentadienyl)(8-quinolinolato)iridium(III) (8.07 mg) in ethyl acetate (1.6 ml) was stirred at 40°C for 11 hours. After bringing the reaction solution back to room temperature, it was concentrated to obtain the title compound as an orange oily substance.

MS IER gender: 398 [M+H] ⁺ .

Hold time: 0.713 min (method B)

The following Reference Examples 3-3-2-3-3-4 were synthesized by the method described in Reference Example 3-3-1 or an equivalent method using the compounds obtained in Reference Example 1-7-7, Reference Example 1-7- 9 and Reference Example 1-8-4, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 18-1.

[Table 18-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-4-1

1-(2,6-Diethoxy-4-{(1R)-1-[(4-phenylbutyl)amino]ethyl}phenyl)ethan-1-one hydrochloride

[Chemical formula 434]

(1) To a solution of the compound (236 mg) obtained in Reference Example 1-16-3 in chloroform (2 ml) was added a saturated aqueous sodium bicarbonate solution, and the reaction solution was stirred at room temperature. The organic layer was filtered through a phase separator and concentrated to give 1-{4-[(1R)-1-aminoethyl]-2,6-diethoxyphenyl}ethan-1-one (217 mg).

(2) To a solution of the compound (5.25 g) obtained in (1) above in acetonitrile (105 ml), add the compound (7.00 g) obtained in Reference Example 2-1-1 and N,N-diisopropylethylamine (10.9 ml), and the reaction solution was stirred at 80°C for 39 hours. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added thereto, the reaction solution is extracted with chloroform twice, filtered through a phase separator and concentrated. The resulting residue is purified by NH silica gel column chromatography (n-hexane only to ethyl acetate only), and silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50 and then chloroform only to chloroform:methanol=80:20 ) to give 1-(2,6-diethoxy-4-{(1R)-1-[(4-phenylbutyl)amino]ethyl}phenyl)ethan-1-one (4.84 g) as a light yellow oily substances.

(3) A solution of the compound (1.87 g) obtained in (2) above in ethyl acetate (16 ml) was cooled on ice, 4 mol/L hydrochloride-ethyl acetate solution (4.9 ml) was added thereto, and the reaction solution was stirred at room temperature for 50 minutes. The reaction solution was concentrated, n-hexane-ethyl acetate mixed solution (1:1, 20 ml) was added thereto, and the precipitated solid was filtered to obtain the title compound (2.05 g) as a colorless powder.

MS IER gender: 384 [M+H] ⁺ .

Hold time: 0.732 min (method B)

Reference example 3-4-2

1-{3-Chloro-2,6-diethoxy-4-[(1R)-1-({2-[(1S)-1-phenylethoxy]ethyl}amino)ethyl]phenyl}ethan-1-one

[Chemical Formula 435]

Using the compound (214 mg) obtained in Reference Example 1-16-1 and the compound (264 mg) obtained in Reference Example 2-7-1, the reaction was carried out in accordance with the method described in Reference Example 3-4-1 (2), and the title compound (96 mg) was obtained as a light yellow oily substance.

MS IER gender: 434 [M+H] ⁺ .

Hold time: 0.794 min (method B)

Reference example 3-4-3

N-[(1R)-1-(4-Cyclopropyl-3,5-diethoxyphenyl)ethyl]-4-phenylbutan-1-amine

[Chemical formula 436]

(1) To a solution of the compound (180 mg) obtained in Reference Example 1-17-1 in chloroform (5 ml), saturated aqueous sodium bicarbonate solution (5 ml) was added, and the reaction solution was stirred at 50°C for 10 minutes . The organic layer was separated, then dried over anhydrous magnesium sulfate, filtered through a phase separator and concentrated to give (1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethan-1-amine (126 mg) as a colorless oil. .

(2) Using the compound (63 mg) obtained in (1) above and the compound (84.6 mg) obtained in Reference Example 2-1-1, the reaction was carried out in accordance with the method described in Reference Example 3- 4-1 (2), and the title compound (74.2 mg) was obtained as a brown oily substance.

MS IER gender: 382 [M+H] ⁺ .

Hold time: 0.862 min (method B)

The following Reference Examples 3-4-4-3-4-5 are synthesized by the method described in Reference Example 3-1-1, Reference Example 3-4-1, Reference Example 3-4-2 or Reference Example 3-4-3 or an equivalent method using the compounds prepared in Reference Example 1-15-1, Reference Example 1-18-1 and Reference Example 2-1-1, commercially available compounds, or compounds prepared by synthesis according to methods described in the literature or equivalent ways. The structures and LCMS data of the compounds are shown in Table 19-1.

[Table 19-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-4-6

N-[(1R)-1-(3,5-Diethoxy-4-ethylphenyl)ethyl]-4-phenylbutan-1-amine

[Chemical formula 437]

(1) Using the compound (2.96 g) obtained in Reference Example 1-15-6 and the compound (3.30 g) obtained in Reference Example 2-1-1, the reaction was carried out in accordance with the method described in Reference Example 3-4-3 and N-[(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-4-phenylbutan-1-amine (3.78 g) was obtained as a colorless oily substance .

(2) A solution of the compound (3.78 g) obtained in (1) above in ethyl acetate (30 ml) was cooled on ice, a 4 mol/L hydrochloride-ethyl acetate solution (9.0 ml) was added thereto, and the reaction solution was stirred at room temperature for 30 minutes. Ethyl acetate (20 ml) was further added to the reaction solution. The reaction solution was concentrated, a mixed solution of n-hexane-ethyl acetate (1:1, 20 ml) was added, and the precipitated solid was filtered to obtain N-[(1R)-1-(4-bromo-3,5-) hydrochloride diethoxyphenyl)ethyl]-4-phenylbutan-1-amine (2.91 g) as a colorless solid.

(3) To a chloroform solution of the compound (1.0 g) obtained in (2) above, a saturated aqueous sodium bicarbonate solution was added, and extraction was carried out with chloroform twice. The organic layer is filtered through a phase separator and concentrated to obtain a mixture containing N-[(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl]-4-phenylbutan-1-amine.

(4) To a solution of the mixture obtained in (3) above in chloroform (11 ml), di-tert-butyl dicarbonate (0.53 g) was added, and the reaction solution was stirred at room temperature for 2 hours. Triethylamine (0.61 ml) was further added to the reaction solution, which was then stirred at room temperature overnight. 0.5 mol/L hydrochloric acid is added to the reaction solution, which is then extracted with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give tert-butyl [(1R)-1-(4-bromo-3,5-diethoxyphenyl)ethyl](4 -phenylbutyl)carbamate (1.30 g) as a colorless oily substance.

(5) The present reaction is carried out with reference to the method described in the literature (Journal of Organic Chemistry, vol. 74, p. 3626, 2009). To a solution of the compound (200 mg) obtained in (4) above in toluene (3.8 ml), add ethyl boronic acid (42.6 mg), potassium carbonate (159 mg), palladium(II) acetate (17.3 mg ), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (71.7 mg), and water (384 μl), and the reaction solution was stirred at 110°C for 5 hours. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give tert-butyl [(1R)-1-(3,5-diethoxy-4-ethylphenyl)ethyl](4 -phenylbutyl)carbamate (133 mg) as a colorless oily substance.

(6) To a solution of the compound (133 mg) obtained in (5) above in ethyl acetate (2 ml), a 4 mol/L ethyl acetate hydrochloride solution (2 ml) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution is concentrated, a saturated aqueous sodium bicarbonate solution is added, and extraction is carried out with chloroform. The organic layer was filtered through a phase separator and concentrated to give the title compound (110 mg).

MS IER floor: 370 [M+H] ⁺ .

Hold time: 0.827 min (method A)

The following Reference Examples 3-4-7-3-4-51 are synthesized by the method described in Reference Example 3-4-1-3-4-3 or Reference Example 3-4-6 or by an equivalent method using the compounds prepared in Reference Example 1-15-1, Reference Example 1-15-3, Reference Example 1-15-5, Reference Example 1-15-7, Reference Examples 1-16-1-1-16-3, Reference Example 1 -17-1, Reference Examples 1-18-1-1-18-2, Reference Examples 2-1-1-2-1-6, Reference Examples 2-2-1, Reference Examples 2-3-1-2 -3-5, Reference Example 2-4-1, Reference Example 2-5-1, Reference Example 2-6-1 and Reference Examples 2-7-1 through 2-7-5, commercially available compounds or compounds prepared synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 20-1 - Table 20-10.

[Table 20-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-3] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-4] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-5] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-6] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-7] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-8] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-9] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 20-10] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-5-1

N-Benzyl-N~2~-[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl]glycinamide

[Chemical formula 438]

To a suspension of the compound (60 mg) obtained in Reference Example 1-15-1 and potassium carbonate (95.8 mg) in acetonitrile (1 ml), N-benzyl-2-chloroacetamide (50.9 mg) was added and the reaction the solution is stirred at 80°C for 9 hours. Water is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer is washed with brine and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to ethyl acetate only) to give the title compound (78.8 mg) as a colorless solid.

MS IER sex: 371 [M+H] ⁺ .

Hold time: 0.571 min (method A)

Reference example 3-6-1

N-[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl]-5-methylhexane-1-amine

[Chemical formula 439]

(1) To a solution of the compound (30 mg) obtained in Reference Example 1-15-1 in N,N-dimethylformamide (0.58 ml), add N,N-diisopropylethylamine (80.5 μL), and 5-methylhexane acid (16.4 µl), and the reaction solution was stirred for 20 minutes while cooling on ice. HATU (87.8 mg) was added to the reaction solution, which was then stirred at the same temperature for 30 minutes and stirred at room temperature overnight. Water is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-20:80) to give N-[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl]-5-methylhexanamide (38 mg) as a colorless powder.

(2) A solution of the compound (35 mg) obtained in (1) above in tetrahydrofuran (1.0 ml) was cooled on ice and stirred for 10 minutes. At the same temperature, borane-tetrahydrofuran complex (0.9 mol/L tetrahydrofuran solution, 0.3 ml) was added thereto, and the reaction solution was stirred at the same temperature for 30 minutes and at room temperature overnight. The reaction solution was cooled on ice, methanol was added thereto, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated to obtain the title compound.

MS IER gender: 322 [M+H] ⁺ .

Hold time: 0.603 min (method A)

The following Reference Examples 3-6-2-3-6-4 are synthesized by the method described in Reference Example 3-6-1 or an equivalent method using the compound obtained in Reference Example 1-15-1, a commercially available compound, or a compound obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 21-1.

[Table 21-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-6-5

N-[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl]butan-1-amine

[Chemical formula 440]

(1) Using the compound (88.5 mg) obtained in Reference Example 1-15-1 and butyric acid (30 mg), the reaction was carried out in accordance with the method described in Reference Example 3-6-1 (1), and N-[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl]butanamide (87 mg) are obtained as a colorless oily substance.

(2) A solution of lithium aluminum hydride (104 mg) in tetrahydrofuran (1.7 ml) was cooled on ice and stirred at the same temperature for 10 minutes. A solution of the compound obtained in (1) above in tetrahydrofuran (1 ml) was added thereto. The reaction solution was stirred at the same temperature for 10 minutes, while heating at reflux for 8 hours, at room temperature overnight and while heating at reflux for 4 hours. The reaction solution is cooled on ice and stirred for 10 minutes. Water is added there. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=90:10-50:50) to give the title compound (64 mg).

MS IER floor: 280 [M+H] ⁺ .

Hold time: 0.486 min (method A)

The following Reference Examples 3-6-6-3-6-13 are synthesized by the method described in Reference Example 3-6-5 or an equivalent method using the compound obtained in Reference Example 1-15-1, a commercially available compound, or a compound obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 22-1 through Table 22-2.

[Table 22-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 22-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-6-14

1-{4-[(1R)-1-{[2-(Benzyloxy)ethyl]amino}ethyl]-2,6-dimethoxyphenyl}ethan-1-one hydrochloride

[Chemical formula 441]

(1) Under a nitrogen atmosphere, to a solution of (benzyloxy)acetic acid (616 mg) in N,N-dimethylformamide (3.5 ml), add the compound (1 g) obtained in Reference Example 1-15-9 and HOBt ( 620 mg), and the reaction solution is cooled with water. EDC (776 mg) and N,N-diisopropylethylamine (1.47 ml) were added thereto, and the reaction solution was stirred at room temperature for 2 hours. Toluene (3 ml) is added to the reaction solution, which is then cooled on ice and water (6 ml) is added slowly. The reaction solution was stirred at room temperature for 10 minutes and extracted with toluene. The organic layer was washed successively with 5% aqueous potassium carbonate, 5% aqueous sodium sulfate and saturated brine, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. Methanol (20 ml) was added to the resulting residue, which was then dissolved at 65°C, and the reaction solution was stirred at room temperature for 14 hours. The precipitated solid was filtered off and 2-(benzyloxy)-N-[(1R)-1-(4-bromo-3,5-dimethoxyphenyl)ethyl]acetamide (817 mg) was obtained as a colorless powder.

(2) Under a nitrogen atmosphere, the borane-tetrahydrofuran complex (1 mol/L tetrahydrofuran solution, 6.00 ml) was cooled on ice, and a suspension of the compound (817 mg) obtained in (1) above in tetrahydrofuran (1, 8 ml), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was cooled with water, 2 mol/L hydrochloric acid (1.2 ml) was added dropwise, and the reaction solution was stirred at 60°C for 1.5 hours. Ethanol (5 ml) and water (10 ml) were added to the reaction solution and dissolved at 80°C, and the reaction solution was stirred at room temperature for 14 hours and for 30 minutes while cooling on ice. The precipitated solid was filtered off and (1R)-N-[2-(benzyloxy)ethyl]-1-(4-bromo-3,5-dimethoxyphenyl)ethane-1-amine hydrochloride (612 mg) was obtained as a colorless powder .

(3) Under a nitrogen atmosphere, to ethylene glycol monovinyl ether (255 μL), and a solution of potassium carbonate (589 mg) in toluene (3.7 ml), add the compound (612 mg) obtained in (2) above, and the reaction solution is degassed at reduced pressure. Palladium(II) acetate (6.38 mg), and 1,3-bis(diphenylphosphino)propane (23.4 mg) were added thereto, and the reaction solution was degassed under reduced pressure and stirred while heating at reflux for 18 hours. Water (1 ml) was added thereto at room temperature, and the reaction solution was stirred for 1 hour. The reaction solution was filtered through Celite (registered trademark), and a 2 mol/L ethanol hydrochloride solution (1.42 ml) was added to the filtrate, which was then stirred at room temperature for 30 minutes. The reaction solution was washed with 15% aqueous potassium carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=78:22 to ethyl acetate only) to obtain a mixture (479 mg) containing 1-{4-[(1R)-1-{[2-(benzyloxy)ethyl] amino}ethyl]-2,6-dimethoxyphenyl}ethan-1-one in the form of a yellow oily substance.

(4) To a solution of the mixture (479 mg) obtained in (3) above in ethanol (1 ml), a 2 mol/L ethanol hydrochloride solution (737 μL) was added, and the reaction solution was concentrated. Isopropyl ether (2 ml) and ethanol (0.8 ml) were added to the resulting residue, and the precipitated solid was filtered to obtain the title compound (412 mg) as a colorless powder.

MS IER gender: 358 [M+H] ⁺ .

Hold time: 0.556 min (method B)

Reference example 3-6-15

1-{4-[(1R)-1-{[2-(Benzyloxy)ethyl]amino}ethyl]-3-chloro-2,6-dimethoxyphenyl}ethan-1-one

[Chemical formula 442]

Under a nitrogen atmosphere, a solution of the compound (301 mg) obtained in Reference Example 3-6-14 in chloroform (3.8 ml) was cooled with sodium chloride-ice, sulfuryl chloride (64.8 µl) was added dropwise, and the reaction the solution is stirred at the same temperature for 1 hour. Water is slowly added there at the same temperature and extraction is carried out with chloroform. The organic layer is washed with saturated aqueous sodium bicarbonate, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=88:12 to ethyl acetate alone and then chloroform:methanol=95:5 to 80:20) and preparative HPLC to obtain the title compound (42 mg) as colorless oily substance.

MS IER sex: 392 [M+H] ⁺ .

Hold time: 0.622 min (method B)

The following Reference Examples 3-6-16-3-6-18 were synthesized by the method described in Reference Example 3-6-14-3-6-15 or an equivalent method using the compounds prepared in Reference Example 1-15-9 and Reference Example 1-15-11, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 22-3 through 22-4.

[Table 22-3] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 22-4] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-6-19

(1R)-N-[2-(Benzyloxy)ethyl]-1-(4-cyclopropyl-3,5-dimethoxy-2-methylphenyl)ethan-1-amine

[Chemical formula 443]

(1) To a solution of the compound (1 g) obtained in Reference Example 1-15-11 in N,N-dimethylformamide (13 ml), add (benzyloxy)acetic acid (475 mg), and N,N-diisopropylethylamine (1 .13 ml), and the reaction solution was cooled on ice and stirred for 5 minutes. Then, HATU (1.18 g) was added thereto, and the reaction solution was stirred at room temperature overnight. By adding water (30 ml), ethyl acetate (30 ml), and n-hexane (1 ml) to the reaction solution, it was separated into two layers. By adding water (40 ml), ethyl acetate (10 ml), and n-hexane (1 ml) to the organic layer, the organic layer was separated into two layers. The organic layer is dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:50 to ethyl acetate only) to give 2-(benzyloxy)-N-[(1R)-1-(4-bromo-3,5-dimethoxy-2 -methylphenyl)ethyl]acetamide (960 mg) as a colorless powder.

(2) Using the compound (960 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 3-6-26 (2), and (1R)-N-[2-(benzyloxy )ethyl]-1-(4-bromo-3,5-dimethoxy-2-methylphenyl)ethan-1-amine (854 mg) is obtained as a light yellow oily substance.

(3) To the compound (427 mg) obtained in (2) above, toluene (3.0 ml) and water (0.30 ml) were added, and the reaction solution was bubbled with nitrogen. Then, under a nitrogen atmosphere, cyclopropylboronic acid (118 mg), potassium carbonate (379 mg), palladium(II) acetate (20.5 mg), and 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (RuPhos, 85) are added. .3 mg), and the reaction solution was stirred at 120°C for 2 hours under microwave irradiation. Water is added to the reaction solution, which is then filtered through Celite (registered trademark) and the filtrate is separated into two layers. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=82:18 to ethyl acetate only) to give the title compound (199 mg) as a yellow oily substance.

MS IER floor: 370 [M+H] ⁺ .

Hold time: 0.789 min (method B)

The following Reference Examples 3-6-20-3-6-21 were synthesized by the method described in Reference Example 3-6-19 or an equivalent method using the compounds obtained in Reference Example 1-15-9 and Reference Example 1-15- 11, cyclopropylboronic acid, methylboronic acid, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 22-5.

[Table 22-5] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-6-22

(1R)-N-[2-(Benzyloxy)ethyl]-1-(4-cyclopropyl-3,5-dimethoxyphenyl)ethan-1-amine hydrochloride

[Chemical formula 444]

(1) To the compound (3.29 g) obtained in Reference Example 3-6-14 (2), chloroform and saturated aqueous sodium bicarbonate were added, and the reaction solution was stirred and extracted with chloroform. The organic layer was filtered through a phase separator and concentrated to give (1R)-N-[2-(Benzyloxy)ethyl]-1-(4-bromo-3,5-dimethoxyphenyl)ethan-1-amine (3.34 g) in in the form of a light yellow oily substance.

(2) A solution of the compound (3.34 g) obtained in (1) above in chloroform (26 ml) was cooled on ice, triethylamine (2.13 ml), and di-tert-butyl dicarbonate (1.83 ml) were added sequentially. d), and the reaction solution was stirred at room temperature for 1 hour. Triethylamine (639 μL), and di-tert-butyl dicarbonate (500 mg) were further added to the reaction solution, which was then stirred at room temperature for 1 hour. 4-dimethylaminopyridine (46.7 mg) was further added to the reaction solution, which was then stirred at room temperature for 30 minutes. 0.5 mol/L hydrochloric acid (20 ml) was added to the reaction solution, which was then extracted with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=80:20) to give tert-butyl [2-(benzyloxy)ethyl][(1R)-1-(4-bromo-3, 5-dimethoxyphenyl)ethyl]carbamate (3.58 g) as a colorless oily substance.

(3) Using the compound (3.50 g) obtained in (2) above and cyclopropylboronic acid (913 mg), the reaction was carried out in accordance with the method described in Reference Example 1-7-1 and tert-butyl [2- (benzyloxy)ethyl][(1R)-1-(4-cyclopropyl-3,5-dimethoxyphenyl)ethyl]carbamate (3.00 g) was obtained as a light brown oily substance.

(4) A solution of the compound (2.75 g) obtained in (3) above in a mixed solution of 1,4-dioxane-methanol (36 ml-12 ml) was cooled on ice, and a 4 mol/L solution of hydrochloride - 1 was added thereto. 4-dioxane (18 ml), and the reaction solution was stirred at room temperature for 15 hours. The reaction solution was concentrated to obtain the title compound (2.13 g) as a light yellow powder.

MS IER gender: 356 [M+H] ⁺ .

Hold time: 0.582 min (method A)

The following Reference Examples 3-6-23-3-6-25 are synthesized by the method described in Reference Example 3-6-14 (1) - (2) or Reference Example 3-6-22 (2) - (4) or equivalent method using the compound obtained in Reference Example 1-15-13, cyclopropylboronic acid, methylboronic acid, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 22-6.

[Table 22-6] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-6-26

(1R)-1-(4-Cyclopropyl-3,5-dimethoxyphenyl)-N-{2-[(1S)-1-phenylethoxy]ethyl}ethan-1-amine hydrochloride

[Chemical formula 445]

(1) To the compound (1.34 g) obtained in Reference Example 1-17-2, add a solution of [(1S)-1-phenylethoxy]acetic acid (1.20 g) in N,N-dimethylformamide (30 ml ), N,N-diisopropylethylamine (2.63 ml), and HATU (2.76 g), and the reaction solution was stirred at room temperature for 5.5 hours. Water (30 ml) and n-hexane-ethyl acetate mixed solvent (1:1, 60 ml) were added to the reaction solution, which was then separated into two layers. The aqueous layer was extracted with a mixed solvent of n-hexane/ethyl acetate (1:1, 60 ml). The organic layers were combined, washed with 0.5 mol/L hydrochloric acid and brine successively, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to ethyl acetate only) to give N-[(1R)-1-(4-cyclopropyl-3,5-dimethoxyphenyl)ethyl]-2-[( 1S)-1-phenylethoxy]acetamide (2.28 g) as a light yellow solid.

(2) Under a nitrogen atmosphere, the borane-tetrahydrofuran complex (1 mol/L tetrahydrofuran solution, 17.8 ml) was cooled on ice, and a solution of the compound (2.28 g) obtained in (1) above in tetrahydrofuran ( 20 ml). The reaction solution was stirred at room temperature for 2 hours. The reaction solution is cooled with water, 2 mol/L hydrochloric acid (3.6 ml) is slowly added dropwise, and the reaction solution is stirred at 60 degrees for 5 hours. The reaction solution was cooled on ice, and 1 mol/L aqueous sodium hydroxide solution (23.8 ml) was added thereto. The reaction solution is brought back to room temperature and extracted with toluene. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=15:85) to give (1R)-1-(4-cyclopropyl-3,5-dimethoxyphenyl)-N-{2-[ (1S)-1-phenylethoxy]ethyl}ethane-1-amine (1.95 g) as a colorless oil.

(3) A solution of the compound (1.95 g) obtained in (2) above in ethyl acetate (19.8 ml) was cooled on ice, 4 mol/L ethyl acetate hydrochloride solution (5.95 ml) was added thereto, and the reaction solution stir at room temperature for 30 minutes. The reaction solution was concentrated, suspended by adding tert-butyl methyl ether (10 ml), and ethyl acetate (5 ml), and concentrated. The resulting residue was suspended by adding tert-butyl methyl ether (10 ml), and the solid was filtered to obtain the title compound (1.61 g) as a colorless solid.

MS IER floor: 370 [M+H] ⁺ .

Hold time: 0.802 min (method B)

The following Reference Examples 3-6-27-3-6-33 were synthesized by the method described in Reference Example 3-6-26 or an equivalent method using the compounds obtained in Reference Example 1-15-10, Reference Example 1-15- 12, Reference Examples 1-17-3-1-17-4 and Reference Examples 2-8-1-2-8-2, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 22-7 22-8.

[Table 22-7] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 22-8] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-6-34

(1R)-N-[2-(Benzyloxy)ethyl]-1-(2-chloro-4-cyclopropyl-3,5-dimethoxyphenyl)ethan-1-amine

[Chemical formula 446]

A suspension of the compound (1.50 g) obtained in Reference Example 3-6-22 in toluene (23 ml) was cooled on ice, and a solution of 1,3-dichloro-5,5-dimethylhydantoin (830 mg) in toluene was added dropwise. (15 ml), and the reaction solution was stirred at the same temperature for 2 hours. A 20% aqueous solution of sodium ascorbate (12 ml) is added to the reaction solution, which is then stirred overnight, raising the temperature to room temperature. 5% aqueous sodium bicarbonate solution (15 ml) is added to the reaction solution, which is then stirred at room temperature for 15 minutes and separated into two layers. The organic layer was washed successively with 5% aqueous sodium bicarbonate (15 ml) and water (15 ml), and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=84:16 to ethyl acetate only) to give the title compound (1.30 g) as a yellow oily substance.

MS IER floor: 390 [M+H] ⁺ .

Hold time: 0.798 min (method B)

The following Reference Examples 3-6-35-3-6-37 were synthesized by the method described in Reference Example 3-6-15 or Reference Example 3-6-34 or an equivalent method using the compounds prepared in Reference Example 3-4- 32, Reference Example 3-4-45 and Reference Example 3-6-26. The structures and LCMS data of the compounds are shown in Table 22-9.

[Table 22-9] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-7-1

N-[1-(3,5-Diethoxyphenyl)ethyl]-4-phenylbutan-1-amine

[Chemical formula 447]

The compound (495 mg) obtained in Reference Example 1-14-5 and 4-phenylbutylamine (406 μl) were mixed, heated with a hairdryer and stirred at room temperature for 30 minutes. Diethyl ether (6.4 ml) was added thereto, and the reaction solution was cooled on ice. Methyl lithium (1 mol/L solution in diethyl ether, 3.06 ml) was added thereto, and the reaction solution was stirred at the same temperature for 10 minutes and at room temperature for 20 minutes. The reaction solution is cooled on ice, water is added thereto, and the reaction solution is concentrated. The resulting residue was purified by preparative HPLC to obtain the title compound (599 mg) as a colorless oily substance.

MS IER/HIAD Multi gender: 342 [M+H] ⁺ .

Hold time: 0.751 min (method E)

The following Reference Examples 3-7-2-3-7-4 are synthesized by the method described in Reference Example 3-7-1 or an equivalent method using the compounds obtained in Reference Examples 1-4-4-1-4-6, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 23-1.

[Table 23-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 3-8-1

N-[1-(4-Ethoxy-1-ethyl-1H-indazol-6-yl)ethyl]-4-phenylbutan-1-amine

[Chemical formula 448]

The compound (100 mg) obtained in Reference Example 1-7-6 and 4-phenylbutylamine (73.0 μL) were mixed and stirred at room temperature for 3 hours while reducing the pressure. Diethyl ether (2.3 ml) was added to the reaction solution, which was then cooled on ice. Methyl lithium (1 mol/L solution in diethyl ether, 550 μL) was added thereto, and the reaction solution was stirred at the same temperature for 1 hour. Water is added to the reaction solution, which is then concentrated. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=98:2-80:20), and silica gel column chromatography (n-hexane:ethyl acetate=70:30-50:50 and then chloroform only until chloroform:methanol=90 :10) to obtain the title compound (68 mg) as a light orange oily substance.

MS IER gender: 366 [M+H] ⁺ .

Hold time: 0.698 min (method B)

Reference example 3-8-2

1-[2-Ethoxy-6-(ethylamino)-4-{1-[(4-phenylbutyl)amino]ethyl}phenyl]ethan-1-one

[Chemical formula 449]

Reference example 3-8-3

2-Ethoxy-6-(ethylamino)-4-{1-[(4-phenylbutyl)amino]ethyl}benzonitrile

[Chemical Formula 450]

The compound (340 mg) obtained in Reference Example 1-7-6 and 4-phenylbutylamine (0.248 ml) were mixed and stirred at room temperature for 1 hour while reducing the pressure. Diethyl ether (7.8 ml) was added thereto, and the reaction solution was cooled on ice. Methyl lithium (1 mol/L solution in diethyl ether, 3.74 ml) was added thereto, and the reaction solution was stirred at the same temperature for 2.5 hours. Water is added to the reaction solution, which is then concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-80:20) and preparative HPLC to give the title compounds, 1-[2-ethoxy-6-(ethylamino)-4-{1-[ (4-phenylbutyl)amino]ethyl}phenyl]ethan-1-one (7 mg) (Reference Example 3-8-2), and 2-ethoxy-6-(ethylamino)-4-{1-[(4- phenylbutyl)amino]ethyl}benzonitrile (8 mg) (Reference Example 3-8-3), each as a light brown oily substance.

Reference example 3-8-2

MS IER gender: 383 [M+H] ⁺ .

Hold time: 0.781 min (method B)

Reference example 3-8-3

MS IER gender: 366 [M+H] ⁺ .

Hold time: 0.708 min (method B)

Reference example 3-8-4

1-(2-Ethoxy-6-[ethyl(methyl)amino]-4-{1-[(4-phenylbutyl)amino]ethyl}phenyl)ethan-1-one hydrochloride

[Chemical formula 451]

(1) Using the compound (30 mg) obtained in Reference Example 3-8-2, the reaction was carried out in accordance with the method described in Reference Example 1-17-1 (1), and tert-butyl {1-[4 -acetyl-3-ethoxy-5-(ethylamino)phenyl]ethyl}(4-phenylbutyl)carbamate (22 mg) is obtained as a colorless oily substance.

(2) To a solution of the compound (11 mg) obtained in (1) above in N,N-dimethylformamide (0.1 ml), add potassium carbonate (6.93 mg), and iodomethane (8.51 μl), and the reaction solution was stirred at 75°C for 17 hours. Iodomethane (8.51 μL) was further added thereto, and the reaction solution was stirred at 75°C for 1.5 hours. The reaction solution was brought back to room temperature and purified by preparative HPLC to give tert-butyl (1-{4-acetyl-3-ethoxy-5-[ethyl(methyl)amino]phenyl}ethyl)(4-phenylbutyl)carbamate (8 mg ) in the form of a colorless oily substance.

(3) To a solution of the compound (8 mg) obtained in (2) above in ethyl acetate (0.5 ml), 4 mol/L ethyl acetate hydrochloride solution (0.2 ml) was added, and the reaction solution was stirred at room temperature in for 20 hours. The reaction solution was concentrated to obtain the title compound (8 mg) as a light yellow oily substance.

MS IER sex: 397 [M+H] ⁺ .

Hold time: 0.645 min (method B)

The following Reference Example 3-8-5 is synthesized by the method described in Reference Example 3-8-4 or an equivalent method using the compound obtained in Reference Example 3-8-2, a commercially available compound, or a compound prepared by synthesis according to the methods described in the literature or equivalent methods. The structure and LCMS data of the compound are shown in Table 24-1.

[Table 24-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

1-(2,6-Diethoxy-4-{(1R)-1-[(4-phenylbutyl)amino]ethyl}phenyl)ethan-1-ol

[Chemical formula 452]

Under a nitrogen atmosphere, a solution of lithium aluminum hydride (0.588 g) in tetrahydrofuran (50 ml) was cooled on ice, and a solution of the compound (2.97 g) obtained in Reference Example 3-4-1 (2) in tetrahydrofuran (27) was added dropwise thereto. ml), and the reaction solution was stirred at the same temperature for 15 minutes. The reaction solution was cooled on ice, tetrahydrofuran-water mixed solvent (95:5, 60 ml) was added dropwise, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=10:90) to obtain the title compound (3.03 g) as a colorless oily substance.

MS IER gender: 386 [M+H] ⁺ .

Hold time: 0.719 min (method B)

The following Reference Examples 3-9-2-3-9-9 were synthesized by the method described in Reference Example 3-9-1 or an equivalent method using the compounds obtained in Reference Example 3-1-51, Reference Example 3-4- 2, Reference Example 3-4-21, Reference Example 3-4-25, Reference Example 3-4-30, Reference Example 3-4-28 and Reference Examples 3-4-37-3-4-38, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 25-1 through Table 25-2.

[Table 25-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 25-2] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 4-1-1

Ethyl 1-amino-3-methylcyclobutane-1-carboxylate trifluoroacetate

[Chemical formula 453]

(1) Under a nitrogen atmosphere, methyltriphenylphosphonium bromide (0.444 g) is heated to dryness for 10 minutes by reducing the pressure, and tetrahydrofuran (1.6 ml) and potassium tert-butoxide (0.140 g) are added thereto. The reaction solution was cooled on ice, a solution of ethyl 1-[(tert-butoxycarbonyl)amino]-3-oxocyclobutane-1-carboxylate (200 mg) in tetrahydrofuran (1.6 ml) was added thereto, and the reaction solution was stirred at the same temperature in for 1 hour and at room temperature overnight. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-40:60) to obtain ethyl 1-[(tert-butoxycarbonyl)amino]-3-methylidenecyclobutane-1-carboxylate (50 mg) as colorless oily substance.

(2) To a solution of the compound (50 mg) obtained in (1) above in methanol (3.9 ml), palladium on carbon (100 mg) was added, and the reaction solution was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered through a mixed layer of Celite (registered trademark)-NH silica gel, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to obtain a mixture containing ethyl 1-[(tert-butoxycarbonyl)amino]-3-methylcyclobutane-1-carboxylate.

(3) To a solution of the mixture obtained in (2) above in chloroform (0.98 ml), trifluoroacetic acid (0.150 ml) was added, and the reaction solution was stirred at 60°C for 10 hours and at room temperature overnight. The reaction solution was concentrated to obtain the title compound (38 mg).

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 0.89-1.47 (m, 6 H) 1.90-2.10 (m, 1 H) 2.15-2.81 ( m, 4 H) 4.18-4.31 (m, 2 H) 8.10-8.94 (m, 3 H).

Reference Example 4-2-1

Ethyl 1-amino-3-[(propan-2-yl)oxy]cyclobutane-1-carboxylate

[Chemical formula 454]

(1) A solution of ethyl 1-[(tert-butoxycarbonyl)amino]-3-oxocyclobutane-1-carboxylate (2 g) in ethanol (39 ml) was cooled on ice, and sodium borohydride (0.588 g) was added thereto. The reaction solution was stirred at the same temperature for 1 hour and at room temperature for 2 hours. The reaction solution was cooled on ice, and a saturated aqueous ammonium chloride solution (8 ml) and water (15 ml) were slowly added thereto. Ethanol in the reaction solution is distilled off under reduced pressure and extraction is carried out with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol=88:12) to obtain ethyl 1-[(tert-butoxycarbonyl)amino]-3-hydroxycyclobutane-1-carboxylate (1.94 g) as a colorless solid substances.

(2) To a solution of the compound (100 mg) obtained in (1) above in acetonitrile (7.7 ml), add silver(I) oxide (1.79 g), and 2-iodopropane (385 μl), and react the solution is stirred at 70°C for 12 hours and at room temperature overnight. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=96:4-60:40) to obtain ethyl 1-[(tert-butoxycarbonyl)amino]-3-[(propan-2-yl)oxy]cyclobutane -1-carboxylate (39 mg) as a colorless oily substance.

(3) Trifluoroacetic acid (88.9 μL) was added to a solution of the compound (35 mg) obtained in (2) above in chloroform (0.58 ml), and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated, and the resulting residue was purified by NH silica gel column chromatography (chloroform only to chloroform:methanol=80:20) to obtain the title compound (34 mg) as a colorless oily substance.

MS IER/HIAD Multi gender: 202 [M+H] ⁺ .

Hold time: 0.213 min (method F)

The following Reference Examples 4-2-2-4-2-3 were synthesized by the method described in Reference Example 4-2-1 or an equivalent method using commercially available compounds or compounds synthesized according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 26-1.

[Table 26-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 4-2-4

Ethyl 3-(acetoxy)-1-aminocyclobutane-1-carboxylate

[Chemical formula 455]

(1) To a solution of the compound (50 mg) obtained in Reference Example 4-2-1 (1) in chloroform (1.9 ml), add N,N-diisopropylethylamine (0.101 ml), and 4-dimethylaminopyridine (2. 36 mg), and the reaction solution was cooled on ice. Acetic anhydride (36.5 μL) was added thereto, and the reaction solution was stirred for 3 hours and at room temperature overnight. Ice water is added there and extraction is carried out with chloroform. The organic layer was washed with saturated aqueous sodium bicarbonate twice, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5 to ethyl acetate only) to give ethyl 3-(acetoxy)-1-[(tert-butoxycarbonyl)amino]cyclobutane-1-carboxylate (41 mg) in in the form of a colorless powder.

(2) Using the compound (40 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 4-2-1 (3), and the title compound (60 mg) was obtained as colorless oily substance.

MS IER gender: 202 [M+H] ⁺ .

Hold time: 0.211 min (method B)

Reference example 4-3-1

Ethyl trans-1-amino-3-ethoxycyclobutane-1-carboxylate hydrochloride

[Chemical formula 456]

The present reaction is carried out with reference to the method described in the literature (Bioorganic & Medicinal Chemistry, vol. 17, p. 1982, 2009).

(1) To a solution of ethyl 1-[(tert-butoxycarbonyl)amino]-3-oxocyclobutane-1-carboxylate (15 g) in 1,4-dioxane (30 ml), add a 4 mol/L solution of hydrochloride - 1,4 -dioxane (120 ml), and the reaction solution was stirred at room temperature for 14 hours. The precipitated solid was filtered to obtain ethyl 1-amino-3-oxocyclobutane-1-carboxylate hydrochloride (11.0 g) as a colorless solid.

(2) To a solution of the compound (200 mg) obtained in (1) above in toluene (5.2 ml), phthalic anhydride (306 mg), and triethylamine (288 μl) were added, and the reaction solution was stirred while heating at reflux with reflux for 4.5 hours. The reaction solution was brought back to room temperature, water and 1 mol/L hydrochloric acid were added to adjust the pH to 2, and extraction was carried out with ethyl acetate twice. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give ethyl 1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)- 3-oxocyclobutane-1-carboxylate (404 mg) as a colorless solid.

(3) Under a nitrogen atmosphere, to a solution of the compound (200 mg) obtained in (2) above in tetrahydrofuran (2 ml), add zinc chloride (0.5 mol/L tetrahydrofuran solution, 2.78 ml), and the reaction solution stir at room temperature for 30 minutes. The reaction solution was cooled to -78°C, lithium tri-sec-butylborohydride (L-Selectride (registered trademark), 1 mol/L solution in tetrahydrofuran, 1.04 ml) was slowly added dropwise, and the reaction solution was stirred at same temperature for 2 hours and at room temperature for 50 minutes. The reaction solution was cooled on ice, a saturated aqueous ammonium chloride solution (10 ml) was added thereto, and extraction was carried out with ethyl acetate twice. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give ethyl trans-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl )-3-hydroxycyclobutane-1-carboxylate (179 mg) as a colorless oily substance.

(4) To a solution of the compound (2.0 g) obtained in (3) above in acetonitrile (35 ml), silver(I) oxide (16 g) and iodoethane (2.8 ml) were added, and the reaction solution was stirred at 80°C for 24 hours, at room temperature for 2 days, at 80°C for 12 hours and at room temperature overnight. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by column chromatography in which NH silica gel column cartridge and silica gel column cartridge (n-hexane:ethyl acetate=95:5-50:50 and then chloroform:methanol=90:10) were combined to give ethyl trans-1-(1 ,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-ethoxycyclobutane-1-carboxylate (1.38 g) as a light yellow solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16-1.30 (m, 6 H) 2.76-2.96 (m, 2 H) 3.38-3.51 (m , 2 H) 3.51-3.66 (m, 2 H) 4.05-4.26 (m, 3 H) 7.71-7.79 (m, 2 H) 7.79-7.91 (m, 2 H).

The resulting light yellow solid was recrystallized from ethanol to obtain a single crystal, which was then confirmed to have the desired structure shown below using X-ray diffraction analysis.

[Chemical formula 457]

(5) To a solution of the compound (2.00 g) obtained in (4) above in ethanol (21 ml), hydrazine monohydrate (313 μL) was added, and the reaction solution was stirred at 40°C for 1.2 hours. Hydrazine monohydrate (6.14 μL) was further added thereto, and the reaction solution was stirred at 40°C for 0.8 hours, under reflux for 6.5 hours, and at room temperature overnight. Undissolved substances are filtered off and the filtrate is concentrated. Ethanol is added to the resulting residue, undissolved substances are filtered off, and the filtrate is concentrated. Chloroform (15 ml) and 1 mol/L hydrochloric acid (12 ml) were added to the resulting residue, and the aqueous layer was washed with chloroform. The organic layers are combined and extracted with 1 mol/L hydrochloric acid (10 ml). The aqueous layers were combined, then a solution of sodium hydroxide (1.4 g) in water (3.5 ml) was added to adjust the pH to 10 and extracted with chloroform. The organic layer was filtered through a phase separator and concentrated to give ethyl trans-1-amino-3-ethoxycyclobutane-1-carboxylate (475 mg) as a light brown oil.

(6) A solution of the compound (400 mg) obtained in (5) above in 2 mol/L ethanol hydrochloride (3.20 ml) was stirred at room temperature for 1 hour. The reaction solution was concentrated and toluene was added to the resulting residue. After concentration, the title compound (469 mg) was obtained as a colorless solid.

MS IER gender: 188 [M+H] ⁺ .

Hold time: 0.415 min (method C)

The following Reference Example 4-3-2 is synthesized by the method described in Reference Example 4-3-1 or an equivalent method using a commercially available compound or a compound synthesized according to methods described in the literature or equivalent methods. The structure and LCMS data of the compound are shown in Table 27-1.

[Table 27-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 4-3-3

Methyl trans-1-amino-3-ethoxycyclobutane-1-carboxylate hydrochloride

[Chemical formula 458]

(1) A suspension of the compound (100 mg) obtained in Reference Example 4-3-1 in ethyl acetate (4.5 ml) was cooled on ice, and a solution of sodium bicarbonate (308 mg) in water (3.5 ml) was slowly added thereto. and benzyl chloroformate (89.0 μl) is added dropwise. The reaction solution was stirred at room temperature for 14 hours. By adding ethyl acetate and water to the reaction solution, it is separated into two layers. The organic layer was washed successively with 1 mol/L hydrochloric acid, saturated aqueous sodium bicarbonate and saturated saline, and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=88:12 to ethyl acetate only) to give ethyl trans-1-{[(benzyloxy)carbonyl]amino}-3-ethoxycyclobutane-1-carboxylate (124 mg) in in the form of a colorless powder.

(2) To a solution of the compound (10.0 g) obtained in (1) above in methanol (39 ml), tetrahydrofuran (39 ml), and a 1 mol/L aqueous sodium hydroxide solution (31.1 ml) were added. and the reaction solution was stirred at room temperature for 3 hours. Methanol and tetrahydrofuran were distilled off under reduced pressure, the aqueous layer was washed with toluene (30 ml), and then 4 mol/L hydrochloric acid was added thereto. The aqueous layer was extracted twice with chloroform (30 ml) and the organic layers were combined, filtered through a phase separator and concentrated. Toluene (50 ml) was added to the resulting residue, followed by concentration to obtain a mixture (8.35 g) containing trans-1-{[(benzyloxy)carbonyl]amino}-3-ethoxycyclobutane-1-carboxylic acid.

(3) To a solution of the mixture (2.00 g) obtained in (2) above in methanol (2.8 ml), toluene (17 ml), and p-toluenesulfonic acid monohydrate (131 mg) were added, and the reaction solution was stirred at 100°C for 3 hours, at room temperature overnight and at 100°C for 2 hours. Toluene (10 ml) was added to the reaction solution, which was then washed sequentially twice with saturated aqueous sodium bicarbonate (8 ml) and brine (8 ml). The organic layer is dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-20:80) to give methyl trans-1-{[(benzyloxy)carbonyl]amino}-3-ethoxycyclobutane-1-carboxylate (1.65 d) as a pale brown solid.

(4) To a solution of the compound (1.00 g) obtained in (3) above in methanol (7.9 ml), palladium-carbon (0.1 g) was added, and the reaction solution was stirred at room temperature for 2 hours in a hydrogen atmosphere. The reaction solution is filtered through KC FLOCK (registered trademark), and the filtrate is concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=70:30 and then chloroform only to chloroform:methanol=80:20) to obtain a mixture containing methyl trans-1-amino-3-ethoxycyclobutane-1-carboxylate .

(5) To the mixture obtained in (4) above, a 2 mol/L methanol hydrochloride solution (3.15 ml) was added, and the reaction solution was concentrated. Toluene (10 ml) was added to the resulting residue and after concentration, the title compound (552 mg) was obtained as a colorless resinous substance.

MS IER sex: 174 [M+H] ⁺ .

Hold time: 0.239 min (method C)

Reference example 4-3-4

trans-1-{[(Benzyloxy)carbonyl]amino}-3-hydroxycyclobutane-1-carboxylic acid

[Chemical formula 459]

(1) To a solution of dipropan-2-yl 3,3-dimethoxycyclobutane-1,1-dicarboxylate (20.0 g) in isopropyl alcohol (52.9 g), add a 35% aqueous solution of tetraethylammonium hydroxide (30.7 g) , and the reaction solution was stirred at 60°C for 6 hours and at room temperature for 38 hours. The reaction solution was concentrated and toluene (60 ml) was added to the residue, thereby separating into two layers. A solution of 50% aqueous citric acid (23.5 g) was added to the aqueous layer to adjust the pH to 4 and then extracted twice with ethyl acetate. The organic layer is washed with 10% aqueous sodium sulfate and concentrated. Toluene was added to the resulting residue, and after concentration, 3,3-dimethoxy-1-{[(propan-2-yl)oxy]carbonyl}cyclobutane-1-carboxylic acid (13.9 g) was obtained as a light yellow oily substances.

(2) To a solution of the compound (4.58 g) obtained in (1) above in toluene (47.0 g), triethylamine (2.47 g) was added, and a solution of diphenylphosphoryl azide (5.42 g) was slowly added dropwise. in toluene (17.0 g) at 90°C, and the reaction solution was stirred at 90°C for 2 hours. Next, benzyl alcohol (2.42 g) was added dropwise to the reaction solution, which was then stirred at the same temperature for 7 hours and at room temperature for 80 hours. A 10% aqueous solution of potassium carbonate (16.6 g) was added to the reaction solution, which was then extracted. The organic layer was washed successively with 10% aqueous citric acid and 10% aqueous sodium sulfate and then concentrated to obtain a mixture (6.71 g) containing propan-2-yl 1-{[(benzyloxy)carbonyl]amino}-3, 3-dimethoxycyclobutane-1-carboxylate as a yellow oily substance.

(3) To a solution of the mixture (5.94 g) obtained in (2) above in isopropyl alcohol (33.2 g), a mixed solution of concentrated hydrochloric acid (4.22 g), and water (4.22 g) added dropwise at room temperature, and the reaction solution was stirred at 50°C for 2 hours and at room temperature for 22.5 hours. A solution of potassium carbonate (3.50 g) in water (21.3 g) was added to the reaction solution, isopropyl alcohol was distilled off under reduced pressure, and isopropyl acetate (37.7 g) was added thereto for extraction. The organic layer was washed with a 10% aqueous sodium sulfate solution and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain a residue (4.60 g). The resulting residue (1.00 g) was recrystallized from a mixed solvent of isopropyl acetate-n-heptane and the precipitates were filtered off to give propan-2-yl 1-{[(benzyloxy)carbonyl]amino}-3-oxocyclobutane-1-carboxylate (0.830 g ) as a colorless solid.

(4) A solution of sodium borohydride (0.128 g) in ethanol (3.79 g) was cooled on ice, and a solution of the compound (2.00 g) obtained in (3) above in ethanol (5.22 g) was added dropwise. and the reaction solution was stirred at the same temperature for 2.5 hours. A solution of ammonium chloride (0.530 g) in water (3.61 g) was added to the reaction solution, and ethanol was distilled off under reduced pressure, followed by extraction with ethyl acetate. The organic layer was washed sequentially with 10% aqueous sodium bicarbonate and 10% aqueous sodium sulfate and then concentrated to obtain a mixture (1.94 g) containing propan-2-yl trans-1-{[(benzyloxy)carbonyl]amino}- 3-Hydroxycyclobutane-1-carboxylate as a colorless solid.

(5) To a solution of the compound (1.80 g) obtained in (4) above in methanol (5.79 g), add a mixed solution of 8 mol/L sodium hydroxide aqueous solution (1.46 ml), and water (1 .46 ml), and the reaction solution was stirred at room temperature for 17.5 hours. Concentrated hydrochloric acid (0.607 g) was added to the reaction solution to adjust the pH to 5.5, and the methanol was distilled off under reduced pressure. To the resulting residue add water (4.00 g) and concentrated hydrochloric acid (0.60 g) to adjust the pH to 1.9. Then, water (3.00 g) is added thereto, and extraction with isopropyl acetate is carried out twice. The combined organic layers were washed with 10% aqueous sodium sulfate and dried over anhydrous magnesium sulfate. After filtering the desiccant, the filtrate was concentrated to obtain a residue (1.55 g). The resulting residue (1.13 g) was recrystallized from a mixed solvent of isopropyl acetate-n-heptane and the precipitates were filtered to give the title compound (0.710 g) as a colorless solid.

MS ESI sex: 266 [M+H] ⁺ , 288 [M+Na] ⁺ .

MS IER ref: 264 [MH] ^- .

Hold time: 0.539 min (method B)

Reference example 4-4-1

Ethyl cis-1-amino-3-ethoxycyclobutane-1-carboxylate hydrochloride

[Chemical Formula 460]

(1) Using dipropan-2-yl 3-oxocyclobutan-1,1-dicarboxylate (6.05 g), the reaction and subsequent workup were carried out in accordance with the method described in Reference Example 4-2-1 (1), and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-40:60) to obtain dipropan-2-yl 3-hydroxycyclobutan-1,1-dicarboxylate (3.8 g) as a colorless oil.

(2) The present reaction is carried out with reference to the method described in the literature (Journal of Organic Chemistry, vol. 82, p. 12863, 2017). To a solution of the compound (3.8 g) obtained in (1) above in isopropyl alcohol (78 ml), a 35% aqueous solution of tetraethylammonium hydroxide (7.8 ml) was added, and the reaction solution was stirred at room temperature overnight. A 35% aqueous solution of tetraethylammonium hydroxide (1.1 ml) was further added thereto, and the reaction solution was stirred at room temperature overnight. The reaction solution was concentrated, 10% sodium bisulfate aqueous solution (70 ml) was added thereto to make the solution acidic, and the reaction solution was then extracted with ethyl acetate three times. The organic layer was washed with 10% aqueous sodium bisulfate (70 ml), and saturated brine (70 ml) successively and dried over anhydrous magnesium sulfate, and the desiccant was filtered off. The filtrate was concentrated to give 3-hydroxy-1-{[(propan-2-yl)oxy]carbonyl}cyclobutane-1-carboxylic acid (2.34 g) as a light yellow solid.

(3) To the compound (100 mg) obtained in (2) above and triethylamine (103 μL), add tert-butyl alcohol (466 μL), toluene (9.9 ml), and diphenylphosphoryl azide (117 μL), and react the solution is stirred at 100°C for 5 hours and at room temperature overnight. 10% sodium bisulfate aqueous solution is added to the reaction solution to make the solution acidic, and extraction is carried out with ethyl acetate three times. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-20:80) to give propan-2-yl (1s,5s)-3-oxo-2-oxa-4-azabicyclo[3,1 ,1]heptane-5-carboxylate (86.3 mg) as a colorless powder.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24-1.37 (m, 6 H) 1.95-2.07 (m, 2 H) 2.65-2.78 (m , 2 H) 4.96-5.03 (m, 1 H) 5.05-5.20 (m, 1 H) 6.17 (shs, 1 H).

The resulting colorless powder was recrystallized from ethanol to obtain a single crystal, which was confirmed as having the desired structure below using X-ray diffraction analysis.

[Chemical formula 461]

(4) To a mixed solution of the compound (970 mg) obtained in (3) above in water-ethanol (12 ml-6.1 ml), potassium hydroxide (1.37 g) was added, and the reaction solution was stirred at 80°C within 10 hours. After bringing the reaction solution back to room temperature, ethanol was distilled off under reduced pressure. The aqueous layer is washed with diethyl ether twice and then concentrated hydrochloric acid is added little by little to neutralize it. The aqueous layer is concentrated to obtain a mixture containing cis-1-amino-3-hydroxycyclobutane-1-carboxylic acid.

(5) A solution of the mixture obtained in (4) above in ethanol (24 ml) was cooled on ice, thionyl chloride (1.07 ml) was added thereto, and the reaction solution was stirred at 70°C for 2 hours and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=60:40 to ethyl acetate only and then chloroform:methanol=95:5-60:40) to give ethyl cis-1-amino-3-hydroxycyclobutane-1- carboxylate (826 mg) as a colorless solid.

(6) A mixed solution of the compound (826 mg) obtained in (5) above in acetonitrile-water (10 ml-10 ml) was cooled on ice, triethylamine (3.59 ml), and di-tert-butyl dicarbonate ( 2.28 g), and the reaction solution was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate three times. The organic layer was washed successively with saturated aqueous sodium bicarbonate, water and brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to ethyl acetate only) to give ethyl cis-1-[(tert-butoxycarbonyl)amino]-3-hydroxycyclobutane-1-carboxylate (982 mg) as colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.19-1.35 (m, 3 H) 1.35-1.48 (m, 9 H) 2.00-2.15 ( m, 2 H) 2.81-2.94 (m, 2 H) 4.09-4.22 (m, 2 H) 4.22-4.34 (m, 1 H).

The resulting colorless powder was recrystallized from a mixed solvent of acetone-n-hexane to obtain a single crystal, which was confirmed as having the target structure below using X-ray diffraction analysis.

[Chemical formula 462]

(7) Using the compound (500 mg) obtained in (6) above, the reaction was carried out in accordance with the method described in Reference Example 4-3-1 (4), and ethyl cis-1-[(tert-butoxycarbonyl) amino]-3-ethoxycyclobutane-1-carboxylate (487 mg) is obtained as a colorless oily substance.

(8) To the compound (470 mg) obtained in (7) above, 4 mol/L ethyl acetate hydrochloride (2.0 ml) was added, and the reaction solution was stirred at room temperature for 30 minutes and concentrated. There, a 4 mol/L solution of 1,4-dioxane hydrochloride (2.0 ml) was added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain the title compound (336 mg) as a light brown powder.

MS IER/HIAD Multi gender: 188 [M+H] ⁺ .

Hold time: 0.375 min (method F)

The following Reference Examples 4-4-2-4-4-3 were synthesized by the method described in Reference Example 4-4-1 or an equivalent method using commercially available compounds or compounds synthesized according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 28-1.

[Table 28-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 4-5-1

Methyl trans-3-acetoxy-1-[(tert-butoxycarbonyl)amino]-3-methylcyclobutane-1-carboxylate

[Chemical formula 463]

(1) To trans-1-amino-3-hydroxy-3-methylcyclobutane-1-carboxylic acid (200 mg), which is prepared by the method described in the literature (Journal of Organic Chemistry, vol. 82, p. 12863, 2017) , a 2 mol/L methanol hydrochloride solution (0.276 ml) was added, and the reaction solution was stirred at 60°C overnight and then stirred at room temperature overnight. The reaction solution is concentrated to obtain a mixture containing methyl trans-1-amino-3-hydroxy-3-methylcyclobutane-1-carboxylate.

(2) To a solution of the mixture obtained in (1) above in acetonitrile (2.8 ml), triethylamine (96.0 μl), and di-tert-butyl dicarbonate (90.2 mg) were added, and the reaction solution was stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then stirred at room temperature for 1 hour and extracted with chloroform. The organic layer is filtered through a phase separator and concentrated to obtain a mixture containing methyl trans-1-[(tert-butoxycarbonyl)amino]-3-hydroxy-3-methylcyclobutane-1-carboxylate.

(3) Using the mixture obtained in (2) above, the reaction was carried out in accordance with the method described in Reference Example 4-2-4 (1), and the title compound (5 mg) was obtained as a colorless oily substance.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.39-1.54 (m, 12 H) 1.99 (s, 3 H) 2.28-2.43 (m, 2 H) 2.85-3.00 (m, 2 H) 3.68 (s, 3 H).

Reference example 4-6-1

Methyl 1-acetyl-3-aminoazetidine-3-carboxylate

[Chemical formula 464]

(1) Using methyl 3-[(tert-butoxycarbonyl)amino]azetidine-3-carboxylate hydrochloride (100 mg), the reaction was carried out according to the method described in Reference Example 4-2-4 (1), and methyl 1 -Acetyl-3-[(tert-butoxycarbonyl)amino]azetidine-3-carboxylate (79 mg) is obtained as a colorless powder.

(2) Using the compound (74 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Reference Example 4-2-1 (3), and the title compound (42 mg) was obtained as yellow oily substance.

MS IER gender: 173 [M+H] ⁺ .

Hold time: 0.209 min (method C)

The following Reference Examples 4-6-2-4-6-3 were synthesized by the method described in Reference Example 4-6-1 or an equivalent method using commercially available compounds or compounds synthesized according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 29-1.

[Table 29-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference Example 4-7-1

Ethyl 1-amino-3-(pyrrolidin-1-yl)cyclobutan-1-carboxylate

[Chemical formula 465]

(1) To a solution of ethyl 1-[(tert-butoxycarbonyl)amino]-3-oxocyclobutane-1-carboxylate (100 mg) in chloroform (2.0 ml), add pyrrolidine (48.7 μL), and the reaction solution is stirred at room temperature for 1 hour. The reaction solution was cooled on ice, sodium triacetoxyborohydride (247 mg) was added thereto, and the reaction solution was stirred at room temperature overnight. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with chloroform, filtered through a phase separator and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane:ethyl acetate=95:5 and then chloroform only to chloroform:methanol=80:20) to give ethyl 1-[(tert-butoxycarbonyl)amino]-3-(pyrrolidine- 1-yl)cyclobutan-1-carboxylate (130 mg) as a colorless oily substance.

(2) To the compound (93.0 mg) obtained in (1) above, 2 mol/L ethanol hydrochloride solution (0.744 ml) was added, and the reaction solution was stirred at 60°C for 29 hours and at room temperature for during the night. The reaction solution was concentrated to obtain the title compound (64 mg).

MS IER gender: 213 [M+H] ⁺ .

Hold time: 0.329 min (method C)

The following Reference Examples 4-7-2-4-7-3 were synthesized by the method described in Reference Example 4-7-1 or an equivalent method using commercially available compounds or compounds synthesized according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 30-1.

[Table 30-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 4-8-1

Dibenzyl (1-aminocyclopentyl)phosphonate

[Chemical formula 466]

(1) To a solution of dibenzylphosphite (500 mg), cyclopentanone (0.160 g), benzhydrylamine (0.349 g) in acetonitrile (9.5 ml), add bismuth(III) chloride (60.1 mg), and the reaction solution is stirred at 100 °C for 1 hour under microwave irradiation. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=70:30) to give dibenzyl {1-[(diphenylmethyl)amino]cyclopentyl}phosphonate (301 mg) as a brown oil.

(2) The present reaction is carried out with reference to the method described in the literature (Organic Letters, vol. 1, p. 1395, 1999). To a solution of the compound (300 mg) obtained in (1) above in toluene (2 ml), 4Å molecular sieves (300 mg) were added, and the reaction solution was stirred at room temperature for 20 minutes. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (0.146 g) was added to the reaction solution, and the reaction solution was stirred at 60°C for 3 hours while being protected from light. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (66.6 mg) was further added thereto, and the reaction solution was stirred at 60°C for 2 hours while covering from light. The reaction solution was filtered through a pad of NH silica gel, and the filtrate was concentrated.

(3) To a solution of the mixture obtained in (2) above in diethyl ether (2 ml), add 0.5 mol/L hydrochloric acid (2 ml), and the reaction solution is stirred at room temperature for 18 hours and at 40° C for 2 hours. Diethyl ether is added to the reaction solution, which is then extracted with water. The aqueous layer is concentrated, a saturated aqueous solution of sodium bicarbonate is added there, and extraction is carried out with chloroform. The organic layer was concentrated to give dibenzyl (1-aminocyclopentyl)phosphonate (20.2 mg) as a pale yellow oily substance.

MS IER/HIAD Multi gender: 346 [M+H] ⁺ .

Hold time: 0.934 min (method F)

Reference example 4-9-1

1-[2-(Triphenylmethyl)-2H-tetrazol-5-yl]cyclopropan-1-amine

[Chemical formula 467]

(1) To a mixed solution of 1-aminocyclopropanecarbonitrile hydrochloride (2.81 g) in 1,4-dioxane-water (59 ml-30 ml), potassium carbonate (9.83 g) was added, and the reaction solution was cooled on ice. Allyl chloroformate (2.76 ml) was added thereto, and the reaction solution was stirred at the same temperature for 2 hours. At the same temperature, 2 mol/L hydrochloric acid and water are added to adjust the pH to 8 and extraction is carried out with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol=90:10) to give prop-2-en-1-yl (1-cyanocyclopropyl)carbamate (3.86 g) as a colorless solid.

(2) To a solution of the compound (3.86 g) obtained in (1) above in N,N-dimethylformamide (39 ml), ammonium chloride (1.74 g) and sodium azide (2.11 g) were added. and the reaction solution was stirred at 120°C for 1 hour under microwave irradiation. The reaction solution was cooled on ice, 2 mol/L hydrochloric acid (17.4 ml) was added to adjust the pH to 3, and extraction was carried out with ethyl acetate three times. The organic layer was washed with water and brine sequentially and concentrated to obtain a mixture (10.3 g) containing prop-2-en-1-yl [1-(2H-tetrazol-5-yl)cyclopropyl]carbamate.

(3) A solution of the mixture (10.3 g) obtained in (2) above in tetrahydrofuran (116 ml) was cooled on ice, triethylamine (9.71 ml), and trityl chloride (7.12 g) were added thereto, and the reaction solution stir at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer is washed with brine, filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to give prop-2-en-1-yl {1-[2-(triphenylmethyl)-2H-tetrazol-5- yl]cyclopropyl}carbamate (5.45 g) as a colorless solid.

(4) To a solution of the compound (5.45 g) obtained in (3) above in tetrahydrofuran (121 ml), 1,3-dimethylbarbituric acid (2.07 g) was added, and the reaction solution was degassed under reduced pressure. Tetrakis(triphenylphosphine)palladium(0) (0.697 g) was added thereto, and the reaction solution was stirred at 60°C for 1 hour under a nitrogen atmosphere. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate three times. The organic layer was washed with a mixed solution of saturated saline-saturated aqueous sodium bicarbonate (2:1), and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=99:1-92:8), and NH silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to obtain the title compound (2 .32 g) as a colorless solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.00-1.13 (m, 4 H) 6.96-7.08 (m, 6 H) 7.34-7.44 ( m, 9 H).

The following Reference Examples 4-9-2-4-9-3 are synthesized by the method described in Reference Example 4-9-1 or an equivalent method using the compound obtained in Reference Example 4-3-2, commercially available compounds, or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 31-1.

[Table 31-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

NMR data of Reference Examples 4-9-2-4-9-3 are shown below.

Reference Example 4-9-2

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.75-2.89 (m, 2 H) 3.21-3.38 (m, 2 H) 7.05-7.12 (m , 6 H) 7.28-7.42 (m, 9 H).

Reference example 4-9-3

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.41-2.63 (m, 4 H) 3.26 (s, 3 H) 4.06-4.35 (m, 1 H) 6.91-7.63 (m, 15 H).

Reference example 4-10-1

1-(1-Benzyl-1H-tetrazol-5-yl)-3,3-difluorocyclobutan-1-amine hydrochloride

[Chemical formula 468]

(1) Using 1-amino-3,3-difluorocyclobutane-1-carboxylic acid (1.03 g), the reaction was carried out in accordance with the method described in Reference Example 4-5-1 (2), and 1-[ (tert-butoxycarbonyl)amino]-3,3-difluorocyclobutane-1-carboxylic acid is obtained as a colorless solid.

(2) To a solution of the compound obtained in (1) above in chloroform (15 ml), add N,N-diisopropylethylamine (3.55 ml), and ammonium chloride (0.509 g), the reaction solution is cooled on ice, HATU ( 3.88 g), and N,N-dimethylformamide (4 ml), and the reaction solution was stirred at room temperature for 4 days. Extraction is carried out with ethyl acetate, and the organic layer is washed with water and concentrated. The resulting residue was suspended by adding ethyl acetate (7 ml) and n-hexane (10 ml) at 60°C, and chloroform (5 ml) and n-hexane (60 ml) were added thereto. The suspension was stirred at room temperature for 1 hour and the solid was filtered to obtain tert-butyl (1-carbamoyl-3,3-difluorocyclobutyl)carbamate (905 mg) as a colorless powder.

(3) A suspension of the compound (300 mg) obtained in (2) above in chloroform (4.0 ml) was cooled on ice, pyridine (0.484 ml), and p-toluenesulfonyl chloride (0.457 g) were added thereto, and the reaction solution was stirred at room temperature for 18 hours. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then separated into two layers. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give tert-butyl (1-cyano-3,3-difluorocyclobutyl)carbamate (163 mg) as a colorless solid.

(4) Using the compound (490 mg) obtained in (3) above, the reaction and subsequent workup were carried out in accordance with the method described in Reference Example 4-9-1 (2), and the resulting residue was purified by silica gel column chromatography ( chloroform only to chloroform:methanol=80:20) to obtain tert-butyl [3,3-difluoro-1-(1H-tetrazol-5-yl)cyclobutyl]carbamate (1.02 g) as a colorless oily substance.

(5) A solution of the compound (1.02 g) obtained in (4) above in acetone (5.8 ml) was cooled on ice, potassium carbonate (0.478 g), and benzyl bromide (0.246 ml) were added thereto, and the reaction solution was stirred at room temperature for 18 hours. Particles undissolved in the reaction solution are filtered off and then concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to give a mixture (652 mg) of tert-butyl [1-(1-benzyl-1H-tetrazol-5-yl)- 3,3-difluorocyclobutyl]carbamate and its regioisomer as a colorless solid.

(6) To a solution of the compound (652 mg) obtained in (5) above in chloroform (3.6 ml), add a 4 mol/L solution of 1,4-dioxane hydrochloride (1.78 ml), and the reaction solution is stirred at room temperature for 2 hours. The suspension was concentrated, chloroform was added and the precipitated solid was filtered to obtain the title compound (441 mg) as a colorless powder.

MS IER sex: 266 [M+H] ⁺ .

Hold time: 0.318 min (method B)

The following Reference Example 4-10-2 is synthesized by the method described in Reference Example 4-10-1 or an equivalent method using a commercially available compound or a compound synthesized according to methods described in the literature or equivalent methods. The structure and LCMS data of the compound are shown in Table 32-1.

[Table 32-1] Reference example no. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Reference example 4-11-1

tert-butyl 1-amino-3,3-difluorocyclobutane-1-carboxylate

[Chemical formula 469]

(1) A solution of 1-amino-3,3-difluorocyclobutane-1-carboxylic acid (1.00 g) and sodium carbonate (2.10 g) in water (22 ml) was cooled on ice, and benzyl chloroformate solution ( 1.03 ml) in 1,4-dioxane (6.62 ml), and the reaction solution was stirred for 12 hours while gradually raising the temperature to room temperature. The reaction solution was cooled on ice, benzyl chloroformate (0.47 ml) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. By adding water and diethyl ether to the reaction solution, it is separated into two layers. The aqueous layer is cooled on ice, 1 mol/L hydrochloric acid is added to adjust the pH to 1, and extraction is carried out with ethyl acetate. The organic layers are combined and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate was concentrated to obtain a mixture (1.69 g) containing 1-{[(benzyloxy)carbonyl]amino}-3,3-difluorocyclobutane-1-carboxylic acid.

(2) The present reaction is carried out with reference to the method described in the literature (WO 2009/070485 A1). A solution of the mixture (1.69 g) obtained in (1) above, tert-butyl alcohol (675 μl), and 4-dimethylaminopyridine (362 mg) in chloroform (20 ml) was cooled on ice, EDC (1.25 d), and the reaction solution was stirred overnight, gradually raising the temperature to room temperature. Water was added to the reaction solution, then extracted with ethyl acetate. The organic layer was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated saline solution and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=95:5-60:40) to give tert-butyl 1-{[(benzyloxy)carbonyl]amino}-3,3-difluorocyclobutane-1-carboxylate (708 mg) in the form of a colorless powder.

(3) To a solution of the compound (200 mg) obtained in (2) above in methanol (1.5 ml), palladium on carbon (20.0 mg) was added, and the reaction solution was stirred at room temperature for 1.5 hours in a hydrogen atmosphere. The reaction solution is filtered through KC FLOCK (registered trademark), and the filtrate is concentrated. Methanol was added to the resulting residue, insoluble materials were filtered off, and the filtrate was then concentrated to obtain the title compound (92.0 mg) as a colorless oily substance.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.50 (shs, 9 H) 2.46-2.56 (m, 2 H) 3.06-3.16 (m, 2 H) .

The following Reference Examples 4-11-2 to 4-11-3 are synthesized by the method described in Reference Example 4-11-1 or an equivalent method using the compound prepared in Reference Example 4-3-3 (1), commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures, NMR data and LCMS data of the compounds are shown in Table 32-2 - Table 32-3.

[Table 32-2] Reference example no. Structural formula Analytical data 4-11-2 ¹ H NMR (400 MHz, DMSO-d ₆ ) δ -ppm 1.47-1.54 (m, 3H), 1.98 (s, 3H), 3.79 (s, 6H), 4, 28-4.38 (s, 1H), 6.82 (s, 2H), 8.39 (shs, 3H)

Example 1-1

N-{[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}-2-methylalanine

[Chemical formula 470]

(1) To a solution of ethyl 2-methylalaninate hydrochloride (13.0 mg) in tetrahydrofuran (0.5 ml) was added N,N-diisopropylethylamine (72.6 μL), and the reaction solution was stirred at room temperature for 5 minutes. The reaction solution was cooled on ice, a solution of 4-nitrophenylchloroformate (15.6 mg) in tetrahydrofuran (0.5 ml) was added thereto, and the reaction solution was stirred at room temperature for 30 minutes. The compound (25 mg) obtained in Reference Example 3-4-1 was added thereto, and the reaction solution was stirred at 60°C for 2 hours.

(2) 1 mol/L sodium hydroxide aqueous solution (595 μL), and methanol (1 ml) are added to the reaction solution of (1) above, which is then stirred at 60°C for 1 hour. The reaction solution was concentrated and the resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (26.2 mg) as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.29-1.37 (m, 6 H) 1.40-1.55 (m, 13 H) 2.41 (s, 3 H ) 2.46-2.60 (m, 2 H) 2.86-3.02 (m, 1 H) 3.04-3.18 (m, 1 H) 3.96-4.11 (m, 4 H) 5.34-5.42 (m, 1 H) 6.57 (s, 2 H) 7.08-7.16 (m, 3 H) 7.16-7.28 (m, 2 H ).

MS IER/HIAD Multi gender: 513 [M+H] ⁺ .

MS IER/HIAD Multi neg: 511 [MH] ^- .

Hold time: 0.816 min (method D)

The following Examples 1-2-1-15 are synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Examples 3-1-1-3-1-2 and Reference Example 3-4-4, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 33-1 through Table 33-3.

[Table 33-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 33-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 33-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-16

1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)cyclopropane-1-carboxylic acid

[Chemical formula 471]

Using ethyl 1-aminocyclopropane-1-carboxylate hydrochloride (17.8 mg), and the compound (30 mg) obtained in Reference Example 3-4-1, the reaction was carried out in accordance with the method described in Example 1-1, and the title compound (32 mg) is obtained as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.01-1.10 (m, 2 H) 1.26-1.39 (m, 6 H) 1.39-1.57 ( m, 9 H) 2.41 (s, 3 H) 2.47-2.56 (m, 2 H) 2.83-2.92 (m, 1 H) 3.03-3.14 (m, 2 H) 1 H) 3.99-4.10 (m, 4 H) 5.43-5.50 (m, 1 H) 6.60 (s, 2 H) 7.08-7.16 (m, 3 H ) 7.17-7.26 (m, 2 H).

MS ESI sex: 511 [M+H] ⁺ , 533 [M+Na] ⁺ .

MS IER ref: 509 [MH] ^- .

Hold time: 0.841 min (method A)

The following Examples 1-17 to 1-20 were synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Examples 3-4-1-3-4-5, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 34-1.

[Table 34-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-21

Example 1-22

1-{[{(1R)-1-[3,5-Diethoxy-4-(1-hydroxyethyl)phenyl]ethyl}(4-phenylbutyl)carbamoyl]amino}cyclobutane-1-carboxylic acid

[Chemical formula 472]

(1) To a solution of methyl 1-aminocyclobutane-1-carboxylate hydrochloride (32.9 mg) in tetrahydrofuran (0.5 ml), N,N-diisopropylethylamine (0.173 ml) was added, and the reaction solution was stirred at room temperature for 10 minutes. 4-Nitrophenyl chloroformate (40.1 mg) was added to the reaction solution, which was then stirred at room temperature for 1 hour. A solution of the compound (54.7 mg) obtained in Reference Example 3-9-1 in tetrahydrofuran (1.5 ml) was added to the reaction solution, which was then stirred at 60°C for 2 hours and concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only to ethyl acetate only) to give methyl 1-{[{(1R)-1-[3,5-diethoxy-4-(1-hydroxyethyl)phenyl]ethyl}( 4-phenylbutyl)carbamoyl]amino}cyclobutane-1-carboxylate (72.1 mg) as a colorless oily substance.

(2) The compound (72.1 mg) obtained in (1) above was separated into optical isomers using preparative HPLC equipped with a chiral column. The shorter retention time isomer (Example 1-21 (2)) (35.5 mg) is obtained as a colorless oily substance, and the longer retention time isomer (Example 1-22 (2)) (39.7 mg) obtained in the form of a colorless oily substance.

(3) To a solution of Example 1-21 (2) (35.5 mg) obtained in (2) above in methanol (1 ml), add 1 mol/L sodium hydroxide aqueous solution (0.5 ml), and react the solution is stirred at 60°C for 2 hours. The reaction solution was purified by preparative HPLC and freeze-dried to obtain one optical isomer of the title compound (Example 1-21) (19.3 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.32-1.56 (m, 16 H) 1.88-2.06 (m, 2 H) 2.18-2.28 ( m, 2 H) 2.45-2.54 (m, 2 H) 2.55-2.66 (m, 2 H) 2.84-2.94 (m, 1 H) 3.07-3, 16 (m, 1 H) 4.01-4.12 (m, 4 H) 4.57 (shs, 1 H) 5.27-5.35 (m, 1 H) 5.35-5.43 ( m, 1 H) 6.57 (s, 2 H) 7.06-7.17 (m, 3 H) 7.17-7.27 (m, 2 H).

MS ESI sex: 509 [M-OH] ⁺ , 549 [M+Na] ⁺ .

MS IER ref: 525 [MH] ^- .

Hold time: 0.936 min (method A)

(4) Using Example 1-22 (2) (39.7 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in (3) above, and another optical isomer of the title compound (Example 1-22) (18.9 mg) is obtained as a colorless amorphous substance.

¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.30-1.55 (m, 16 H) 1.87-2.08 (m, 2 H) 2.18-2.30 ( m, 2 H) 2.43-2.54 (m, 2 H) 2.54-2.65 (m, 2 H) 2.85-2.95 (m, 1 H) 3.05-3, 15 (m, 1 H) 3.94-4.18 (m, 4 H) 4.57 (shs, 1 H) 5.27-5.35 (m, 1 H) 5.35-5.42 ( m, 1 H) 6.57 (s, 2 H) 7.07-7.15 (m, 3 H) 7.18-7.26 (m, 2 H).

MS ESI sex: 509 [M-OH] ⁺ , 549 [M+Na] ⁺ .

MS IER ref: 525 [MH] ^- .

Hold time: 0.931 min (method A)

The following Examples 1-23-1-29 were synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Examples 3-1-3-3-1-6 and Reference Examples 3-4-3-3 -4-5, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 35-1 through Table 35-2.

[Table 35-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 35-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-30

1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 473]

(1) Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (328 mg), and the compound (mixture containing 624 mg in theoretical amount) obtained in Reference Example 3-1-6, the reaction was carried out in accordance with the method described in Example 1-21 (1), and methyl 1-({[1-(4-acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3 β-difluorocyclobutane-1-carboxylate (443 mg) is obtained as a colorless amorphous substance.

(2) The compound (443 mg) obtained in (1) above was separated into optical isomers using preparative HPLC equipped with a chiral column. The shorter retention time isomer (Example 1-30 (2)-1) (180 mg) is obtained as a colorless amorphous substance, and the longer retention time isomer (Example 1-30 (2)-2) (181 mg) obtained in the form of a colorless amorphous substance.

(3) To the mixed solution of Example 1-30 (2)-1 (180 mg) obtained in (2) above in methanol-tetrahydrofuran (3 ml-3 ml), add 1 mol/L sodium hydroxide aqueous solution (3 ml ), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=50:50 to ethyl acetate only and then chloroform only to chloroform:methanol=80:20) to obtain the title compound (154 mg) as colorless amorphous substance.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21-1.29 (m, 6 H) 1.35-1.52 (m, 7 H) 2.33 (s, 3 H ) 2.65-3.24 (m, 8 H) 3.94-4.09 (m, 4 H) 5.26-5.36 (m, 1 H) 6.52 (s, 2 H) 7 .09-7.20 (m, 3 H) 7.21-7.30 (m, 2 H) 12.68 (shs, 1 H).

MS ESI sex: 561 [M+H] ⁺ , 583 [M+Na] ⁺ .

MS IER ref: 559 [MH] ^- .

Hold time: 1.233 min (method B)

Example 1-31

1-({[(1S)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 474]

Using the compound (181 mg) obtained in Example 1-30 (2)-2, the reaction was carried out in accordance with the method described in Example 1-30 (3), and the title compound (154 mg) was obtained as colorless amorphous substance.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.20-1.29 (m, 6 H) 1.40-1.48 (m, 7 H) 2.33 (s, 3 H ) 2.64-3.22 (m, 8 H) 3.94-4.08 (m, 4 H) 5.27-5.37 (m, 1 H) 6.52 (s, 2 H) 7 .07-7.18 (m, 3 H) 7.19-7.28 (m, 2 H) 12.70 (shs, 1 H).

MS ESI sex: 561 [M+H] ⁺ , 583 [M+Na] ⁺ .

MS IER ref: 559 [MH] ^- .

Hold time: 1.228 min (method B)

The following Examples 1-32-1-39 were synthesized by the method described in Example 1-1 or Example 1-21 or an equivalent method using the compounds obtained in Reference Examples 3-1-7-3-1-10, Reference Example 3 -2-2, Reference Example 3-3-1 and Reference Example 3-9-1, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 36-1 to 36-2. It should be noted that Example 1-35 (shorter retention time isomer) and Example 1-36 (longer retention time isomer) are optically active compounds.

[Table 36-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 36-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-40

1-({[1-(4-Carbamoyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 475]

(1) To a solution of the compound (34.8 mg) obtained in Reference Example 1-12-1 in chloroform (1 ml), add 4-phenylbutylamine (19.6 mg), and acetic acid (1.58 μL), and the reaction solution was stirred at 60°C for 2 hours. The reaction solution was cooled on ice, sodium triacetoxyborohydride (44.0 mg) was added thereto, and the reaction solution was stirred at 60°C for 1 hour. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added, and extraction is carried out with chloroform. The organic layer was filtered through a phase separator and concentrated to obtain a mixture containing 2,6-diethoxy-4-{1-[(4-phenylbutyl)amino]ethyl}benzamide as a colorless oil.

(2) To a solution of methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (27.9 mg) in tetrahydrofuran (0.5 ml), add N,N-diisopropylethylamine (121 μL), and the reaction solution is stirred at room temperature for 10 minutes. The reaction solution was cooled on ice, 4-nitrophenyl chloroformate (27.9 mg) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled on ice, a solution of the mixture obtained in (1) above in tetrahydrofuran (1.5 ml) was added thereto, and the reaction solution was stirred at 60°C for 4 hours and at room temperature overnight.

(3) Methanol (1.4 ml), and 1 mol/L sodium hydroxide aqueous solution (1.4 ml) were added to the reaction solution, which was then stirred at 60°C for 2.5 hours. The reaction solution was concentrated and the resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (17.1 mg) as a colorless amorphous substance.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.21-1.28 (m, 6 H) 1.36-1.59 (m, 7 H) 2.71-3.21 ( m, 8 H) 3.93-4.02 (m, 4 H) 5.28-5.36 (m, 1 H) 6.49 (s, 2 H) 7.13-7.30 (m, 1 H) 5 H) 8.33 (s, 1 H) 8.78 (s, 1 H).

MS IER sex: 562 [M+H] ⁺ , 584 [M+Na] ⁺ .

MS IER ref: 560 [MH] ^- .

Hold time: 0.976 min (method B)

The following Examples 1-41-1-45 are synthesized by the method described in Example 1-1 or Example 1-30 or an equivalent method using the compounds obtained in Reference Example 3-1-2 and Reference Examples 3-1-11-3 -1-12, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 37-1. It should be noted that Example 1-44 (shorter retention time isomer) and Example 1-45 (longer retention time isomer) are optically active compounds.

[Table 37-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-46

Sodium 1-({[(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylate

[Chemical formula 476]

(1) Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (72.0 mg), and the compound (mixture containing 136 mg in theoretical amount) obtained in Reference Example 3-4-3, the reaction is carried out in accordance with the method described in Example 1-21 (1), and methyl 1-({[(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl} amino)-3,3-difluorocyclobutane-1-carboxylate (124 mg) is obtained as a colorless oily substance.

(2) To a mixed solution of the compound (124 mg) obtained in (1) above in methanol-tetrahydrofuran (2.2 ml-2.2 ml), add 1 mol/L aqueous sodium hydroxide solution (2.2 ml), and the reaction solution was stirred at room temperature for 2 hours and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=70:30 to ethyl acetate only and then chloroform only to chloroform:methanol=80:20), and preparative HPLC to give 1-({[(1R)-1- (4-cyclopropyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid (74.9 mg) as a colorless amorphous substance.

(3) To a solution of the compound (74.9 mg) obtained in (2) above in tetrahydrofuran (536 μL), 0.1 mol/L sodium hydroxide aqueous solution (1.34 ml) was added, and the reaction solution was stirred at room temperature for 30 minutes. The reaction solution was concentrated and freeze-dried to obtain the title compound (77.4 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 0.65-0.73 (m, 2 H) 0.97-1.06 (m, 2 H) 1.26-1.31 ( m, 6 H) 1.34-1.46 (m, 7 H) 1.84-1.93 (m, 1 H) 2.44-2.49 (m, 2 H) 2.77-3, 19 (m, 6 H) 3.88-3.98 (m, 4 H) 5.25-5.37 (m, 1 H) 6.43 (s, 2 H) 6.90 (s, 1 H ) 7.09-7.16 (m, 3 H) 7.20-7.28 (m, 2 H).

MS ESI sex: 559 [M+H] ⁺ , 581 [M+Na] ⁺ .

MS IER ref: 557 [MH] ^- .

Hold time: 1.087 min (method A)

The following Examples 1-47-1-49 were synthesized by the method described in Example 1-1 or Example 1-46 or an equivalent method using the compounds obtained in Reference Example 3-1-13, Reference Example 3-3-2 and Reference example 3-4-6, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 38-1.

[Table 38-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-50

1-{[{1-[3,5-Diethoxy-4-(hydroxymethyl)phenyl]ethyl}(4-phenylbutyl)carbamoyl]amino}-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 477]

(1) Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (28.7 mg), and the compound (mixture containing 45.3 mg in theoretical amount) obtained in Reference Example 3-1- 14, the reaction is carried out in accordance with the method described in Example 1-21 (1), and methyl 1-{[(1-{4-[(acetoxy)methyl]-3,5-diethoxyphenyl}ethyl)(4-phenylbutyl )carbamoyl]amino}-3,3-difluorocyclobutane-1-carboxylate (63.3 mg) is obtained as a colorless oily substance.

(2) To a solution of the compound (63.3 mg) obtained in (1) above in methanol-tetrahydrofuran (1 ml-1 ml), 1 mol/L sodium hydroxide aqueous solution (1 ml) was added, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled on ice, acetic acid (35.9 μL) was added, and extraction was carried out with chloroform three times. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to give the title compound (17.3 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.34-1.43 (m, 6 H) 1.43-1.52 (m, 7 H) 2.44-2.53 ( m, 2 H) 2.78-2.93 (m, 3 H) 3.05-3.26 (m, 3 H) 4.00-4.10 (m, 4 H) 4.67 (s, 2 H) 5.35-5.46 (m, 1 H) 6.55 (s, 2 H) 7.04-7.16 (m, 3 H) 7.16-7.26 (m, 2 H ).

MS IER sex: 531 [M-OH] ⁺ .

Hold time: 0.838 min (method A)

The following Examples 1-51 to 1-61 were synthesized by the method described in Example 1-1 or Example 1-40 or an equivalent method using the compounds obtained in Reference Example 1-11-3, Reference Example 2-1-1, Reference Example 3-1-10, Reference Examples 3-1-15-3-1-23 and Reference Example 3-9-1, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 39-1 to 39-3.

[Table 39-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 39-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 39-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-62

1-({[1-(4-Acetyl-3-ethoxy-5-hydroxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 478]

The present reaction is carried out with reference to the method described in the literature (US 2014-0148443). A solution of the compound (12.8 mg) obtained in Example 1-29 in chloroform (228 μL) was cooled on ice, boron tribromide (1 mol/L solution in n-hexane, 114 μL) was added, and the reaction solution was stirred at room temperature. temperature overnight. The reaction solution was cooled on ice, a saturated aqueous sodium bicarbonate solution (3 ml) was added thereto, and the reaction solution was stirred at the same temperature for 10 minutes. The reaction solution was concentrated, purified by preparative HPLC and freeze-dried to give the title compound (6.7 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, DMSO-d ₆ ) δ ppm 1.33-1.51 (m, 10 H) 2.43-2.54 (m, 2 H) 2.58 (s, 3 H ) 2.74-2.95 (m, 3 H) 3.01-3.21 (m, 3 H) 3.98-4.14 (m, 2 H) 5.22-5.33 (m, 1 H) 6.37 (s, 1 H) 6.41 (s, 1 H) 7.08-7.18 (m, 3 H) 7.18-7.30 (m, 2 H) 12.55 (s, 1 H) 12.75 (shs, 1 H).

MS ESI floor: 533 [M+H] ⁺ , 555 [M+Na] ⁺ .

MS IER ref: 531 [MH] ^- .

Hold time: 1.201 min (method B)

The following Examples 1-63-1-76 were synthesized by the method described in Example 1-1 or Example 1-40 or an equivalent method using the compounds obtained in Reference Example 1-5-16, Reference Example 1-5-30, Reference Example 2-1-1, Reference Example 3-1-3, Reference Example 3-1-5, Reference Example 3-1-24-3-1-28, Reference Example 3-1-80, Reference Example 3-3 -3 and Reference Example 3-4-5 - Reference Example 3-4-8, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 40-1 through 40-3.

[Table 40-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 40-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 40-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-77

1-{[{(1R)-1-[3-Ethoxy-4-(1-hydroxyethyl)-2-methylphenyl]ethyl}(4-phenylbutyl)carbamoyl]amino}-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 479]

A solution of the compound (15 mg) obtained in Example 1-75 in methanol (0.3 ml) was cooled on ice, and sodium borohydride (9 mg) was added thereto. The reaction solution was stirred at the same temperature for 10 minutes, and sodium borohydride (5 mg) was further added thereto. Water was added to the reaction solution, which was then purified by preparative HPLC to obtain the title compound (13 mg) as a colorless solid.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.65-1.71 (m, 13 H) 2.07-2.22 (m, 3 H) 2.23-2.42 ( m, 2 H) 2.73-3.41 (m, 6 H) 3.68-3.88 (m, 2 H) 5.09-5.23 (m, 1 H) 5.33-5, 54 (m, 1 H) 6.77-7.52 (m, 7 H).

MS ESI floor: 515 [M-OH] ⁺ , 555 [M+Na] ⁺ .

MS IER ref: 531 [MH] ^- .

Hold time: 1.102 to 1.113 min (method B)

Example 1-78

Example 1-79

1-{[{(1R)-1-[3-Ethoxy-4-(1-hydroxyethyl)-2-methylphenyl]ethyl}(4-phenylbutyl)carbamoyl]amino}-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 480]

The compound (9 mg) obtained in Example 1-77 was separated into optical isomers using preparative HPLC equipped with a chiral column. One optical isomer of the title compound with a shorter retention time (Example 1-78) (5.5 mg) is obtained as a colorless oily substance, and the other optical isomer of the title compound with a longer retention time (Example 1-79) (1.5 mg) is obtained as a colorless oily substance.

Example 1-78

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.66-1.55 (m, 13 H) 2.18 (s, 3 H) 2.23-2.33 (m, 2 H ) 2.81-3.03 (m, 4 H) 3.08-3.43 (m, 2 H) 3.69-3.87 (m, 2 H) 5.13-5.21 (m, 1 H) 5.42-5.52 (m, 1 H) 6.98-7.04 (m, 2 H) 7.07-7.13 (m, 1 H) 7.15-7.27 ( m, 3 H) 7.35-7.40 (m, 1 H).

MS ESI floor: 515 [M-OH] ⁺ , 555 [M+Na] ⁺ .

MS IER ref: 531 [MH] ^- .

Hold time: 0.841 min (method A)

Example 1-79

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.92-1.54 (m, 13 H) 2.17 (s, 3 H) 2.31-2.42 (m, 2 H ) 2.78-3.37 (m, 6 H) 3.69-3.80 (m, 2 H) 5.11-5.20 (m, 1 H) 5.35-5.49 (m, 1 H) 7.01-7.07 (m, 2 H) 7.07-7.14 (m, 1 H) 7.16-7.25 (m, 3 H) 7.36-7.43 ( m, 1 H).

MS ESI floor: 515 [M-OH] ⁺ , 555 [M+Na] ⁺ .

MS IER ref: 531 [MH] ^- .

Hold time: 0.850 min (method A)

The following Examples 1-80 to 1-84 were synthesized by the method described in Example 1-1, Example 1-40 or Example 1-77 or an equivalent method using the compounds obtained in Reference Example 3-1-29, Reference Example 3- 2-3, Reference Example 3-4-1 and Reference Example 4-1-1, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 41-1.

[Table 41-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-85

1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3-methoxycyclobutane-1-carboxylic acid

[Chemical formula 481]

(1) Using the compound (64.9 mg) obtained in Reference Example 4-2-3 and the compound (100 mg) obtained in Reference Example 3-4-1, the reaction was carried out in accordance with the method described in Example 1-21 (1), and ethyl 1-({[(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3-methoxycyclobutane-1-carboxylate (118 mg) is obtained as a colorless solid.

(2) Using the compound (mixture containing 27.8 mg in theoretical amount) obtained in (1) above, the reaction was carried out in accordance with the method described in Example 1-30 (3), and the title compound (19 .7 mg) is obtained in the form of a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.28-1.55 (m, 13 H) 2.14-3.66 (m, 14 H) 3.84-3.97 ( m, 1 H) 3.97-4.12 (m, 4 H) 5.37-5.45 (m, 1 H) 6.58 (s, 2 H) 7.08-7.17 (m, 1 H) 3 H) 7.17-7.28 (m, 2 H).

MS IER/HIAD Multi gender: 555 [M+H]+.

MS IER/HIAD Multi neg: 553 [M-H]-.

Hold time: 0.812 min (method D)

Example 1-86

trans-1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3-methoxycyclobutane-1-carboxylic acid

[Chemical formula 482]

(1) The compound (170 mg) obtained in Example 1-85 (1) was separated into optical isomers using preparative HPLC equipped with a chiral column. The shorter retention time isomer (Example 1-86 (1)-1) (111 mg) is obtained as a colorless gummy substance, and the longer retention time isomer (Example 1-86 (1)-2) (31 mg) obtained in the form of a light brown, gum-like substance.

(2) To a solution of Example 1-86 (1)-1 (107 mg) obtained in (1) above in methanol (459 μL), tetrahydrofuran (459 μL), and 4 mol/L aqueous sodium hydroxide solution (459 µl), and the reaction solution was stirred at 60°C for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-80:20) to obtain the title compound (98 mg) as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.25-1.39 (m, 6 H) 1.41-1.59 (m, 7 H) 2.38-2.59 ( m, 9 H) 2.85-3.00 (m, 1 H) 3.08-3.26 (m, 4 H) 3.83-3.94 (m, 1 H) 3.96-4, 12 (m, 4 H) 5.35-5.48 (m, 1 H) 6.58 (s, 2 H) 7.08-7.17 (m, 3 H) 7.17-7.28 ( m, 2 H).

MS IER floor: 555 [M+H] ⁺ .

MS IER ref: 553 [MH] ^- .

Hold time: 0.850 min (method A)

Example 1-87

cis-1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3-methoxycyclobutane-1-carboxylic acid

[Chemical formula 483]

Using the compound (28 mg) obtained in Example 1-86 (1)-2, the reaction was carried out in accordance with the method described in Example 1-86 (2), and the title compound (26 mg) was obtained as light - brown powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.26-1.38 (m, 6 H) 1.42-1.56 (m, 7 H) 2.12-2.28 ( m, 2 H) 2.41 (s, 3 H) 2.46-2.58 (m, 2 H) 2.81-3.01 (m, 3 H) 3.04-3.17 (m, 2 H) 1 H) 3.25 (s, 3 H) 3.96-4.11 (m, 5 H) 5.34-5.45 (m, 1 H) 6.58 (s, 2 H) 7.08 -7.16 (m, 3 H) 7.17-7.26 (m, 2 H).

MS IER floor: 555 [M+H] ⁺ .

MS IER ref: 553 [MH] ^- .

Hold time: 0.842 min (method A)

The following examples 1-88-1-122 are synthesized by the method described in Example 1-1, Example 1-21, Example 1-30, Example 1-40, Example 1-46 or Example 1-50 or an equivalent method using the compounds , obtained in Reference Examples 3-1-2-3-1-5, Reference Example 3-1-30, Reference Example 3-2-2, Reference Examples 3-4-1-3-4-8, Reference Example 3 -9-1, Reference examples 4-2-1-4-2-4, Reference example 4-3-1 - Reference example 4-3-2, Reference examples 4-4-1-4-4-2, Reference example Example 4-5-1 and Reference Examples 4-7-1-4-7-3, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 42-1 through 42-7. It should be noted that Example 1-88 (shorter retention time isomer), and Example 1-89 (longer retention time isomer) are optically active compounds, and Example 1-98 (shorter retention time isomer), and Example 1-99 (longer retention time isomer) are optically active compounds. Additionally, Example 1-117 is an optical isomer with a shorter retention time when isolated by preparative HPLC with a chiral column.

Table 42-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 42-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 42-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 42-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 42-5] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 42-6] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 42-7] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-123

2-({[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-2,3-dihydro-1H-indene-2-carboxylic acid

[Chemical formula 484]

(1) Using methyl 2-amino-2,3-dihydro-1H-indene-2-carboxylate hydrochloride (80 mg), and the compound (150 mg) obtained in Reference Example 3-4-4, the reaction was carried out according to with the method described in Example 1-21 (1), and methyl 2-({[1-(3,5-diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-2,3-dihydro -1H-indene-2-carboxylate (128 mg) is obtained as a colorless resinous substance.

(2) The compound (10 mg) obtained in (1) above was separated into optical isomers using preparative HPLC equipped with a chiral column. The shorter retention time isomer (Example 1-123 (2)-1) (4.0 mg) is obtained as a colorless oily substance, and the longer retention time isomer (Example 1-123 (2)-2) (4 .2 mg) is obtained in the form of a colorless oily substance.

(3) Using Example 1-123 (2)-1 (3.0 mg) obtained in (2) above, the reaction was carried out in accordance with the method described in Example 1-30 (3), and the title compound (1.8 mg) is obtained as a colorless resinous substance.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.76-1.48 (m, 13 H) 2.00 (s, 3 H) 2.31-2.45 (m, 2 H ) 2.81-3.46 (m, 4 H) 3.50-3.65 (m, 2 H) 3.86-4.03 (m, 4 H) 5.21-5.35 (m, 1 H) 6.46 (s, 2 H) 6.96-7.29 (m, 9 H).

Example 1-124

2-({[(1S)-1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-2,3-dihydro-1H-indene-2-carboxylic acid

[Chemical formula 485]

Using the compound obtained in Example 1-123 (2)-2 (4.2 mg), the reaction was carried out in accordance with the method described in Example 1-30 (3), and the title compound (3.5 mg) was obtained in the form of a colorless resinous substance.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.08-1.50 (m, 13 H) 1.99 (s, 3 H) 2.29-2.44 (m, 2 H ) 2.82-3.43 (m, 4 H) 3.51-3.67 (m, 2 H) 3.85-4.03 (m, 4 H) 5.21-5.38 (m, 1 H) 6.44 (s, 2 H) 6.96-7.30 (m, 9 H).

The following examples 1-125-1-148 are synthesized by the method described in Example 1-1, Example 1-21, Example 1-30, Example 1-40, Example 1-46 or Example 1-50 or an equivalent method using the compounds , obtained in Reference Example 3-1-2 and Reference Examples 3-4-1-3-4-5, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 43-1 through 43-5.

[Table 43-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 43-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 43-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 43-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 43-5] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-149

3-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)oxetane-3-carboxylic acid

[Chemical formula 486]

Using methyl 3-aminooxetane-3-carboxylate (8.12 mg), and the compound (20 mg) obtained in Reference Example 3-4-1, the reaction was carried out in accordance with the method described in Example 1-1, and the above The title compound (26.2 mg) is obtained as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.24-1.42 (m, 6 H) 1.43-1.60 (m, 7 H) 2.41 (s, 3 H ) 2.47-2.59 (m, 2 H) 2.84-3.02 (m, 1 H) 3.05-3.25 (m, 1 H) 3.96-4.13 (m, 4 H) 4.67-4.80 (m, 2 H) 4.88-5.04 (m, 2 H) 5.33-5.48 (m, 1 H) 6.58 (s, 2 H ) 7.08-7.16 (m, 3 H) 7.16-7.28 (m, 2 H).

MS ESI sex: 527 [M+H] ⁺ , 549 [M+Na] ⁺ .

MS IER ref: 525 [MH] ^- .

Hold time: 0.850 min (method A)

The following Examples 1-150-1-151 were synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Example 3-4-1 and Reference Example 3-4-4, commercially available compounds, or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 44-1.

[Table 44-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-152

4-{[{(1R)-1-[3,5-Diethoxy-4-(1-hydroxyethyl)phenyl]ethyl}(4-phenylbutyl)carbamoyl]amino}oxane-4-carboxylic acid

[Chemical formula 487]

A mixed solution of the compound (72.6 mg) obtained in Example 1-151 in tetrahydrofuran-ethanol (3 ml-0.15 ml) was cooled on ice, lithium borohydride (17.1 mg) was added thereto, and the reaction solution was stirred at the same time. same temperature for 3.5 hours. At the same temperature, a saturated aqueous solution of ammonium chloride is added there and extraction is carried out with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to give the title compound (61.9 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.36-1.43 (m, 6 H) 1.44-1.56 (m, 10 H) 1.87-1.95 ( m, 1 H) 1.97-2.07 (m, 2 H) 2.07-2.14 (m, 1 H) 2.50-2.58 (m, 2 H) 2.91-3, 02 (m, 1 H) 3.20-3.27 (m, 1 H) 3.39-3.50 (m, 2 H) 3.68-3.75 (m, 2 H) 4.00- 4.12 (m, 4 H) 5.28-5.38 (m, 2 H) 6.57 (s, 2 H) 7.10-7.16 (m, 3 H) 7.19-7, 25 (m, 2 H).

MS IER sex: 539 [M-OH] ⁺ .

MS IER ref: 555 [MH] ^- .

Hold time: 0.822 min (method A)

The following Examples 1-153-1-157 were synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Examples 3-2-2 and Reference Examples 3-4-3-3-4-5. commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 45-1.

[Table 45-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 1-158

3-({[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)azetidine-3-carboxylic acid

[Chemical formula 488]

Example 1-159

1-Acetyl-3-({[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)azetidine-3-carboxylic acid

[Chemical formula 489]

(1) Using the compound (19.7 mg) obtained in Reference Example 4-6-1 and the compound (32 mg) obtained in Reference Example 3-4-4, the reaction was carried out in accordance with the method described in Example 1-21 (1), and methyl 1-acetyl-3-({[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)azetidine-3- carboxylate (50 mg) is obtained as a colorless oily substance.

(2) To a solution of the compound (50 mg) obtained in (1) above in methanol (1 ml), add tetrahydrofuran (1 ml), water (0.8 ml), and lithium hydroxide (39.1 mg), and the reaction solution is stirred at room temperature overnight. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=95:5-60:40) and preparative HPLC to give the title compounds, 3-({[(1R)-1-(3, 5-diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)azetidine-3-carboxylic acid (Example 1-158) (5 mg) as a colorless resinous substance, and 1-acetyl-3-({ [(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)azetidine-3-carboxylic acid (Example 1-159) (36 mg) as a colorless resinous substance .

Example 1-158

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.28-1.54 (m, 13 H) 2.03 (s, 3 H) 2.43-2.54 (m, 2 H ) 3.02-3.19 (m, 2 H) 3.91-4.07 (m, 4 H) 4.28-4.37 (m, 2 H) 4.56-4.68 (m, 2 H) 5.36-5.52 (m, 1 H) 6.52 (s, 2 H) 7.05-7.15 (m, 3 H) 7.15-7.27 (m, 2 H ) 8.47 (shs, 1 H).

MS IER sex: 498 [M+H] ⁺ .

MS IER ref: 496 [MH] ^- .

Hold time: 0.720 min (method A)

Example 1-159

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.30-1.54 (m, 13 H) 1.90 (s, 3 H) 2.04 (s, 3 H) 2.36 -2.57 (m, 2 H) 2.82-3.01 (m, 1 H) 3.02-3.17 (m, 1 H) 3.90-4.12 (m, 5 H) 4 .16-4.37 (m, 2 H) 4.56-4.70 (m, 1 H) 5.26-5.49 (m, 1 H) 6.41-6.62 (m, 2 H ) 7.00-7.15 (m, 3 H) 7.15-7.26 (m, 2 H).

MS IER floor: 540 [M+H] ⁺ .

MS IER ref: 538 [MH] ^- .

Hold time: 0.941 min (method A)

The following Examples 1-160-1-167 were synthesized by the method described in Example 1-1 or Example 1-158 or an equivalent method using the compounds obtained in Reference Examples 3-4-1-3-4-2, Reference Example 3 -4-4 and Reference Examples 4-6-2-4-6-3, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 46-1 through 46-3.

[Table 46-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 46-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 46-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 2-1

1-[{[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}(methyl)amino]-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical Formula 490]

(1) Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (162 mg), and the compound (300 mg) obtained in Reference Example 3-4-4, the reaction was carried out in accordance with the method described in Example 1-21 (1), and methyl 1-({[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane -1-carboxylate (290 mg) is obtained as a colorless oily substance.

(2) A solution of the compound (10 mg) obtained in (1) above in N,N-dimethylformamide (0.37 ml) was cooled on ice, and sodium hydride (50% dispersion in mineral oil, 1.76 mg) was added thereto. in a nitrogen atmosphere. Iodomethane (2.28 μL) was added thereto, and the reaction solution was stirred at the same temperature for 10 minutes and at room temperature for 2 hours. The reaction solution was cooled on ice, water was added thereto, and extraction was carried out with ethyl acetate three times. The organic layer was washed successively with water and brine. The organic layer is filtered through a phase separator and concentrated to give methyl 1-[{[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}(methyl)amino]-3. 3-difluorocyclobutane-1-carboxylate (7.4 mg) as a colorless resinous substance.

(3) Using the compound (7.2 mg) obtained in (2) above, the reaction and subsequent workup were carried out in accordance with the method described in Example 1-21 (3), and the resulting residue was purified by silica gel column chromatography (chloroform :methanol=98:2-90:10) to obtain the title compound (7.0 mg) as a colorless resinous substance.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.82-0.93 (m, 2 H) 1.26-1.31 (m, 2 H) 1.31-1.43 ( m, 6 H) 1.43-1.50 (m, 2 H) 1.55 (d, J=7.0 Hz, 3 H) 2.03 (s, 3 H) 2.45-2.53 (m, 2 H) 2.57-2.76 (m, 1 H) 2.76-2.92 (m, 2 H) 2.92-3.03 (m, 1 H) 3.07 (s , 3 H) 3.91-4.04 (m, 4 H) 4.98 (kV, J=7.0 Hz, 1 H) 6.49 (s, 2 H) 7.04-7.16 ( m, 3 H) 7.16-7.27 (m, 2 H).

MS IER/HIAD Multi gender: 547 [M+H] ⁺ .

MS IER/HIAD Multi neg: 545 [MH] ^- .

Hold time: 1.081 min (method D)

Example 3-1

1-({[(3,5-dimethoxy-4-methylphenyl)methyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 491]

(1) To a solution of methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (30 mg) in tetrahydrofuran (0.5 ml), N,N-diisopropylethylamine (0.130 ml) was added, and the reaction solution was stirred at room temperature for 10 minutes. The reaction solution was cooled on ice, a solution of 4-nitrophenylchloroformate (30.0 mg) in tetrahydrofuran (0.5 ml) was added thereto, and the reaction solution was stirred at room temperature for 1 hour. The compound (56.0 mg) obtained in Reference Example 3-1-1 was added to the reaction solution, which was then stirred at 60°C for 4 hours.

(2) 1 mol/L sodium hydroxide aqueous solution (1.5 ml), and methanol (1.5 ml) were added to the reaction solution (1) above, which was then stirred at 60°C for 2 hours. The reaction solution is concentrated, 1 mol/L hydrochloric acid is added to make the solution acidic, and extraction with chloroform is carried out twice. The organic layer is concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=98:2-90:10) to obtain the title compound (21 mg) as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.50-1.63 (m, 4 H) 2.00 (s, 3 H) 2.53-2.61 (m, 2 H ) 2.78-2.91 (m, 2 H) 3.16-3.28 (m, 4 H) 3.77 (s, 6 H) 4.44 (s, 2 H) 6.48 (s , 2 H) 7.09-7.16 (m, 3 H) 7.16-7.27 (m, 2 H).

MS IER/HIAD Multi gender: 491 [M+H] ⁺ .

MS IER/HIAD Multi neg: 489 [MH] ^- .

Hold time: 0.929 min (method D)

The following Examples 3-2-3-3 were synthesized by the method described in Example 3-1, or an equivalent method, using the compounds obtained in Reference Examples 3-1-31-3-1-32, commercially available compounds, or compounds obtained synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 47-1.

[Table 47-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 3-4

1-({[1-(4-Acetyl-3,5-diethoxyphenyl)-2-hydroxyethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 492]

(1) A solution of 4-nitrophenylchloroformate (38.3 mg) in chloroform (1 ml) was cooled on ice, and methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (36.5 mg) and N were added. N-diisopropylethylamine (69.4 μl), and the reaction solution was stirred at room temperature for 1 hour and concentrated. To a solution of the resulting residue in N,N-dimethylformamide (2 ml), the compound (88 mg) obtained in Reference Example 3-1-33 and N,N-diisopropylethylamine (32.8 μl) were added, and the reaction solution was stirred at 60° C for 1 hour and at room temperature overnight. Water is added to the reaction solution, which is then extracted with ethyl acetate three times. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC to give methyl 1-({[1-(4-acetyl-3,5-diethoxyphenyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl](4-phenylbutyl)carbamoyl} amino)-3,3-difluorocyclobutane-1-carboxylate (30 mg) as a light yellow oily substance.

(2) A solution of the compound (30 mg) obtained in (1) above in tetrahydrofuran (0.5 ml) was cooled on ice, 1 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (0.128 ml) was added thereto, and the reaction solution was stirred at that same temperature for 3 hours.

(3) Methanol (0.43 ml), and 1 mol/L sodium hydroxide aqueous solution (0.43 ml) were added to the reaction solution obtained in (2) above, which was then stirred at 65°C for 1 hour. The reaction solution was concentrated and purified by preparative HPLC to obtain the title compound (16 mg) as a colorless amorphous substance.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14-1.45 (m, 10 H) 2.35-2.57 (m, 6 H) 2.60-2.77 (m , 1 H) 2.84-3.05 (m, 1 H) 3.05-3.29 (m, 2 H) 3.33-3.54 (m, 1 H) 3.75-4.14 (m, 6 H) 5.24-5.51 (m, 1 H) 6.23-6.41 (m, 2 H) 6.96-7.09 (m, 2 H) 7.09-7 .23 (m, 3 H).

MS IER/HIAD Multi gender: 577 [M+H] ⁺ .

MS IER/HIAD Multi neg: 575 [MH] ^- .

Hold time: 0.794 min (method D)

The following Examples 3-5-3-10 are synthesized by the method described in Example 3-1 or Example 3-4 or an equivalent method using the compounds obtained in Reference Examples 3-1-34-3-1-36, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 48-1 through 48-2.

[Table 48-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 48-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-1

1-({Butyl[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl]carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 493]

Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (44 mg), and the compound (64 mg) obtained in Reference Example 3-6-5, the reaction was carried out in accordance with the method described in Example 1 -1 and the title compound (48 mg) was obtained as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.75-0.85 (m, 3 H) 1.11-1.24 (m, 2 H) 1.38 (t, J= 6.9 Hz, 6 H) 1.48-1.57 (m, 3 H) 2.03 (s, 3 H) 2.78-2.92 (m, 3 H) 3.02-3.12 (m, 1 H) 3.16-3.37 (m, 4 H) 4.02 (kV, J=6.9 Hz, 4 H) 5.34-5.47 (m, 1 H) 6, 52 (s, 2 H).

MS ESI sex: 457 [M+H] ⁺ , 479 [M+Na] ⁺ .

MS IER ref: 455 [MH] ^- .

Hold time: 0.929 min (method A)

The following Examples 4-2 to 4-3 are synthesized by the method described in Example 1-1 or an equivalent method, using the compounds obtained in Reference Examples 3-6-1-3-6-2, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 49-1.

[Table 49-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-4

1-({[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl][3-(2-fluorophenyl)propyl]carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 494]

Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (27.9 mg), and the compound (mixture containing 41.5 mg in theoretical amount) obtained in Reference Example 3-4-9, the reaction was carried out in accordance with the method described in Example 1-1, and the title compound (19 mg) was obtained as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.37 (t, J=6.9 Hz, 6 H) 1.40 -1.46 (m, 3 H) 1.52-1 .69 (m, 1 H) 1.69-1.83 (m, 1 H) 2.03 (s, 3 H) 2.41-2.57 (m, 2 H) 2.77-2.99 (m, 3 H) 2.99-3.13 (m, 1 H) 3.14-3.29 (m, 2 H) 3.96 (kV, J=6.9 Hz, 4 H) 5, 32-5.46 (m, 1 H) 6.44 (s, 2 H) 6.91-7.08 (m, 3 H) 7.11-7.23 (m, 1 H).

MS ESI sex: 537 [M+H] ⁺ , 559 [M+Na] ⁺ .

MS IER ref: 535 [MH] ^- .

Hold time: 0.963 min (method A)

The following Examples 4-5-4-17 were synthesized by the method described in Example 1-1 or Example 1-40 or an equivalent method using the compounds obtained in Reference Example 1-5-2, Reference Example 1-5-17, Reference Examples 3-1-37-3-1-41 and Reference Examples 3-4-10-3-4-14, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 50-1 through 50-3.

[Table 50-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 50-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 50-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-18

1-({[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl][4-(3-methoxyphenyl)butyl]carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 495]

(1) Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (119 mg), and the compound (148 mg) obtained in Reference Example 3-4-15, the reaction was carried out in accordance with the method described in Example 1-21 (1), and methyl 1-({(but-3-yn-1-yl)[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl]carbamoyl}amino) -3,3-difluorocyclobutane-1-carboxylate (214 mg) is obtained as a colorless amorphous substance.

To a solution of the compound (30 mg) obtained in (1) above, add 3-iodanisole (18.1 mg), copper(I) iodide (1.23 mg), and bis(triphenylphosphine)palladium(II) dichloride (4 .51 mg) in acetonitrile (1 ml), triethylamine (26.9 µl), and the reaction solution was stirred at 80°C for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=75:25) to give methyl 1-({[(1R)-1-(3,5-diethoxy-4 -methylphenyl)ethyl][4-(3-methoxyphenyl)but-3-yn-1-yl]carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylate (23.8 mg) as a brown oil.

(3) To a solution of the compound (23.8 mg) obtained in (2) above in methanol (2 ml), palladium on carbon (5 mg) was added, and the reaction solution was stirred at room temperature for 3 days under a hydrogen atmosphere.

(4) 1 mol/L sodium hydroxide aqueous solution (0.5 ml) was added to the reaction solution obtained in (3) above, which was then stirred at room temperature for 18 hours. For neutralization, 2 mol/L hydrochloric acid is added to the reaction solution, which is then filtered through Celite (registered trademark) and passed through a phase separator, and the filtrate is concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (8.33 mg) as a colorless powder.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=6.81 Hz, 6 H) 1.49-1.71 (m, 7 H) 2.09 (s, 3 H) 2.32-2.54 (m, 2 H) 2.54-2.67 (m, 2 H) 2.99-3.47 (m, 4 H) 3.79 (s, 3 H ) 3.97 (kV, J=6.81 Hz, 4 H) 4.68-5.29 (m, 2 H) 6.41 (s, 2 H) 6.66-6.77 (m, 3 H) 7.15-7.23 (m, 1 H).

MS ESI sex: 563 [M+H] ⁺ , 585 [M+Na] ⁺ .

MS IER ref: 561 [MH] ^- .

Hold time: 0.985 min (method A)

The following Examples 4-19-4-20 were synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Example 3-4-16 and Reference Example 3-6-3, commercially available compounds, or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 51-1.

[Table 51-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-21

1-({[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl][2-(2,3-dihydro-1H-inden-2-yl)ethyl]carbamoyl}amino)-3 ,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 496]

Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (22 mg), and the compound (35 mg) obtained in Reference Example 3-6-6, the reaction was carried out in accordance with the method described in Example 1 -1, and the title compound (28 mg) was obtained as a colorless resinous substance.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.31-1.41 (m, 6 H) 1.42-1.57 (m, 4 H) 1.59-1.72 ( m, 1 H) 2.02 (s, 3 H) 2.17-2.27 (m, 1 H) 2.29-2.47 (m, 2 H) 2.79-2.94 (m, 1 H) 4 H) 2.95-3.06 (m, 1 H) 3.08-3.18 (m, 1 H) 3.20-3.28 (m, 2 H) 3.90-4.11 ( m, 4 H) 5.34-5.45 (m, 1 H) 6.55 (s, 2 H) 6.98-7.16 (m, 4 H).

MS ESI floor: 545 [M+H] ⁺ , 567 [M+Na] ⁺ .

MS IER ref: 543 [MH] ^- .

Hold time: 1.011 min (method A)

The following Examples 4-22-4-33 were synthesized by the method described in Example 1-1 or Example 1-40 or an equivalent method using the compounds obtained in Reference Example 1-5-17, Reference Examples 3-4-17-3 -4-18, Reference Example 3-6-4, Reference Examples 3-6-7-3-6-12, Reference Example 4-3-2 and Reference Example 4-4-2, commercially available compounds or compounds prepared synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 52-1 to 52-3.

[Table 52-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 52-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 52-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-34

1-({[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl][4-(piperidin-4-yl)butyl]carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 497]

(1) To a solution of the compound (30 mg) obtained in Example 4-18 (1) and 4-iodopyridine (15.8 mg) in acetonitrile (0.3 ml), add tris{tris[3,5-bis (trifluoromethyl)phenyl]phosphine}palladium(0) (SUPERSTABLE palladium(0) catalyst: manufactured by FUJIFILM Wako Pure Chemical Corporation, 6.81 mg), copper(I) iodide (1.23 mg), and triethylamine (44.8 µl), and the reaction solution was stirred at 80°C for 2 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=40:60) to give methyl 1-({[(1R)-1-(3,5-diethoxy-4 -methylphenyl)ethyl][4-(pyridin-4-yl)but-3-yn-1-yl]carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylate (9.1 mg) as a yellow amorphous substance .

(2) To a methanol solution of the compound (9.1 mg) obtained in (1) above, palladium-carbon (10 mg) was added, and the reaction solution was stirred at room temperature for 6 hours under a hydrogen atmosphere.

(3) 1 mol/L sodium hydroxide aqueous solution (0.5 ml) was added to the reaction solution obtained in (2) above, which was then stirred at room temperature for 18 hours. For neutralization, a 2 mol/L hydrochloric acid solution is added to the reaction, which is then filtered through Celite (registered trademark), and passed through a phase separator and the filtrate is concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to give the title compound (4.70 mg) as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.01-2.01 (m, 11 H) 1.39 (pcs, J=6.81 Hz, 4 H) 1.50 (s, 3 H) 2.06 (s, 3 H) 2.62-3.22 (m, 11 H) 3.26-3.38 (m, 2 H) 3.99 (sq, J=6.81 Hz , 4 H) 5.23-5.51 (m, 1 H) 5.82-6.03 (m, 1 H) 6.46 (s, 2 H).

MS IER floor: 540 [M+H] ⁺ .

MS IER ref: 538 [MH] ^- .

Hold time: 0.691 min (method B)

Example 4-35

1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](3-phenylpropyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 498]

Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (27.5 mg), and the compound (45.8 mg) obtained in Reference Example 3-4-19, the reaction was carried out in accordance with the method described in Example 1-1, and the title compound (38.5 mg) was obtained as a colorless powder.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=6.89 Hz, 6 H) 1.48-1.54 (m, 3 H) 1.62-1, 94 (m, 2 H) 2.25-2.43 (m, 2 H) 2.44-2.65 (m, 2 H) 2.48 (s, 3 H) 2.86-3.08 ( m, 2 H) 3.13-3.32 (m, 2 H) 3.99 (kV, J=6.89 Hz, 4 H) 4.41-4.56 (m, 1 H) 5.26 -5.62 (m, 1 H) 6.40 (s, 2 H) 7.11-7.17 (m, 2 H) 7.22-7.27 (m, 1 H) 7.29-7 .35 (m, 2 H).

MS ESI sex: 547 [M+H] ⁺ , 569 [M+Na] ⁺ .

MS IER ref: 545 [MH] ^- .

Hold time: 1.123 min (method B)

The following Examples 4-36-4-39 were synthesized by the method described in Example 1-1 or Example 1-40 or an equivalent method using the compounds obtained in Reference Example 1-5-2 and Reference Examples 3-1-42-3 -1-43, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 53-1.

[Table 53-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-40

1-({[(1R)-1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylpentyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 499]

(1) Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (69.9 mg), and the compound (116 mg) obtained in Reference Example 3-4-20, the reaction was carried out in accordance with the method , described in Example 1-21 (1), and methyl 1-({[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl][(3E)-4-phenylpent-3-ene- 1-yl]carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylate (124 mg) is obtained as a colorless amorphous substance.

(2) To a solution of the compound (16 mg) obtained in (1) above in methanol (2 ml), palladium on carbon (4 mg) was added, and the reaction solution was stirred at room temperature for 17 hours under a hydrogen atmosphere. The undissolved substances are filtered off and the filtrate is then concentrated to obtain a mixture containing methyl 1-({[(1R)-1-(3,5-diethoxy-4-methylphenyl)ethyl](4-phenylpentyl)carbamoyl}amino)-3,3 -difluorocyclobutane-1-carboxylate.

(3) To a solution of the mixture obtained as described above in methanol (1 ml), 1 mol/L sodium hydroxide aqueous solution (0.4 ml) was added, and the reaction solution was stirred at 60°C for 1 hour. In the reaction solution, 2 mol/L hydrochloric acid is added to adjust the pH to 3 and extraction is carried out with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (12.1 mg) as a colorless powder.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00-1.79 (m, 13 H) 1.18-1.28 (m, 3 H) 2.08 (s, 3 H) 2.22-2.54 (m, 2 H) 2.55-2.73 (m, 1 H) 2.92-3.14 (m, 1 H) 3.14-3.44 (m, 3 H) 3.84-4.06 (m, 4 H) 4.61-4.79 (m, 1 H) 4.79-5.33 (m, 1 H) 6.37 (s, 2 H) 7.02 (s, 5 H).

MS IER gender: 547 [M+H] ⁺ .

Hold time: 1,080 min (method A)

The following Examples 4-41-4-43 were synthesized by the method described in Example 1-1, or an equivalent method, using the compounds obtained in Reference Example 3-2-1, Reference Example 3-4-20 and Reference Example 3-6 -13, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 54-1.

[Table 54-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-44

trans-1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4,4-difluoro-4-phenylbutyl)carbamoyl}amino)-3-ethoxycyclobutane-1-carboxylic acid

[Chemical formula 500]

Using the compound (20.6 mg) obtained in Reference Example 4-3-1 and the compound (30 mg) obtained in Reference Example 3-4-21, the reaction was carried out in accordance with the method described in Example 1-1 , and the title compound (32.1 mg) was obtained as a colorless amorphous substance.

¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.18 (t, J=7.02 Hz, 3 H) 1.30-1.36 (m, 6 H) 1.46-1 .58 (m, 5 H) 2.00-2.11 (m, 2 H) 2.41 (s, 3 H) 2.46-2.50 (m, 1 H) 2.50-2.57 (m, 3 H) 2.94-3.02 (m, 1 H) 3.12-3.20 (m, 1 H) 3.41 (kV, J=7.02 Hz, 2 H) 3, 94-3.99 (m, 1 H) 3.99-4.08 (m, 4 H) 5.36-5.44 (m, 1 H) 6.57 (s, 2 H) 7.40- 7.44 (m, 5 H).

MS IER floor: 605 [M+H] ⁺ .

MS IER ref: 603 [MH] ^- .

Hold time: 0.891 min (method A)

The following Examples 4-45-4-96 were synthesized by the method described in Example 1-1 or Example 1-21 or an equivalent method using the compounds obtained in Reference Example 3-2-4, Reference Examples 3-4-21-3 -4-27, Reference Examples 3-9-2-3-9-3, Reference Examples 4-3-1-4-3-2 and Reference Examples 4-4-1-4-4-2, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 55-1 through 55-11. It should be noted that the following pairs are optically active compounds:

Example 4-47 (shorter retention time isomer), and Example 4-48 (longer retention time isomer);

Example 4-52 (shorter retention time isomer), and Example 4-53 (longer retention time isomer);

Example 4-61 (shorter retention time isomer), and Example 4-62 (longer retention time isomer);

Example 4-76 (shorter retention time isomer), and Example 4-77 (longer retention time isomer); And

Example 4-85 (shorter retention time isomer), and Example 4-86 (longer retention time isomer).

[Table 55-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-5] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-6] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-7] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-8] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-9] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-10] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 55-11] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 4-97

trans-1-[([(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1 -carboxylic acid

[Chemical formula 501]

Using the compound (23.3 mg) obtained in Reference Example 4-3-1 and the compound (29.7 mg) obtained in Reference Example 3-4-28, the reaction was carried out in accordance with the method described in Example 1 -1, and the title compound (30.4 mg) was obtained as a colorless amorphous substance.

¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.13-1.20 (m, 3 H) 1.27-1.51 (m, 12 H) 2.34-2.60 ( m, 7 H) 3.12-3.37 (m, 4 H) 3.37-3.46 (m, 3 H) 3.91-4.14 (m, 5 H) 5.47-5, 56 (m, 1 H) 6.51-6.62 (m, 2 H) 7.22-7.38 (m, 5 H).

MS ESI floor: 585 [M+H] ⁺ , 607 [M+Na] ⁺ .

MS IER ref: 583 [MH] ^- .

Hold time: 0.924 min (method A)

It should be noted that the title compound can also be prepared by the method indicated below.

(1) To a solution of the compound (672 mg) obtained in Reference Example 4-3-1 in tetrahydrofuran (15 ml), N,N-diisopropylethylamine (2.18 ml) was added, and the reaction solution was stirred at room temperature for 5 minutes. The reaction solution was cooled on ice, a solution of 4-nitrophenylchloroformate (605 mg) in tetrahydrofuran (5 ml) was slowly added thereto, and the reaction solution was stirred at room temperature for 1 hour. The reaction solution was cooled on ice, a solution of the compound (1.00 g) obtained in Reference Example 3-4-28 in tetrahydrofuran (5 ml) was added thereto, and the reaction solution was stirred at 60°C for 30 minutes and overnight, bringing back to room temperature. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with ethyl acetate. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. Ethyl acetate was added to the resulting residue, and the precipitated solid was filtered to obtain ethyl trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)- 1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate (648 mg) as a colorless powder.

(2) Ethanol (3.4 ml) was added to the compound (422 mg) obtained in (1) above, which was then dissolved at 60°C. A 3 mol/L aqueous solution of potassium hydroxide (689 μL) was added thereto, and the reaction solution was stirred at room temperature for 3 days. The reaction solution was cooled on ice, and a 0.5 mol/L aqueous citric acid solution (3 ml) (pH 3-4) was added thereto, followed by concentration. Water was added to the resulting residue, and the precipitated solid was filtered to obtain the title compound (371 mg) as a colorless powder. If the resulting powder is subjected to thermogravimetry-differential thermal analysis (TG/DTA) and the endothermic peak is observed at 95.5°C.

The following Examples 4-98-4-163 were synthesized by the method described in Example 1-1, Example 1-21, Example 1-40 or Example 1-46 or an equivalent method using the compounds obtained in Reference Example 1-5-2 , Reference Example 3-1-44, Reference Example 3-4-28-3-4-35, Reference Example 3-4-46-3-4-48, Reference Example 3-5-1, Reference Example 3-9 -4-3-9-5, Reference Examples 4-3-1-4-3-2 and Reference Examples 4-4-1-4-4-2, commercially available compounds or compounds prepared by synthesis according to the methods described in literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 56-1 through 56-14. It should be noted that the following pairs are optically active compounds:

Example 4-103 (shorter retention time isomer), and Example 4-104 (longer retention time isomer);

Example 4-123 (shorter retention time isomer), and Example 4-124 (longer retention time isomer);

Example 4-125 (shorter retention time isomer), and Example 4-126 (longer retention time isomer);

Example 4-133 (shorter retention time isomer), and Example 4-134 (longer retention time isomer);

Example 4-135 (shorter retention time isomer), and Example 4-136 (longer retention time isomer); And

Example 4-143 (shorter retention time isomer), and Example 4-144 (longer retention time isomer).

[Table 56-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-5] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-6] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-7] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-8] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-9] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-10] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-11] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-12] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-13] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-14] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

It should be noted that sodium salt cis-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino] The -3-methoxycyclobutane-1-carboxylic acid obtained in Example 4-129 can be prepared by the method shown below.

(1) To a solution of the compound (49.8 mg) obtained in Example 4-129 in acetonitrile (0.5 ml), add 1 mol/L aqueous sodium hydroxide solution (87.6 μL), and water (0.5 ml), and the reaction solution was freeze-dried to obtain a yellow amorphous substance (53.7 mg).

(2) n-Heptane (0.2 ml), and tetrahydrofuran (10 μl) were added to the compound (39 mg) obtained in (1) above, which was then dissolved at 45°C, and the reaction solution was stirred overnight to back to room temperature. n-Heptane (1 ml) was added to the solution and the precipitated solid was filtered to obtain a colorless powder (23 mg). If the resulting powder is subjected to thermogravimetry-differential thermal analysis (TG/DTA), an endothermic peak is observed at 77.0°C.

In addition, trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3- The ethoxycyclobutane-1-carboxylic acid obtained in Example 4-138 can also be prepared by the method indicated below.

(1) Using the compound (75.5 mg) obtained in Reference Example 4-3-1 and the compound (114 mg) obtained in Reference Example 3-4-32, the reaction was carried out according to the method described in Example 4-97 (1), and ethyl trans-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl )amino]-3-ethoxycyclobutane-1-carboxylate (145 mg) is obtained as a colorless powder.

(2) Ethanol (3.6 ml) was added to the compound (145 mg) obtained in (1) above, which was then dissolved at 60°C. A 3 mol/L aqueous solution of potassium hydroxide (237 μL) was added thereto, and the reaction solution was stirred at room temperature for 18 hours, at 50°C for 1 hour, and at 60°C for 1 hour. The reaction solution was cooled on ice, and a 0.5 mol/L aqueous citric acid solution (1 ml) was added thereto. The reaction solution was concentrated, and water (10 ml) was added to the resulting residue (pH 4), which was then stirred at room temperature for 15 minutes. The precipitated solid was filtered to obtain a colorless powder (121 mg). If the resulting powder is subjected to thermogravimetry-differential thermal analysis (TG/DTA), an endothermic peak is observed at 86.9°C.

In addition, the potassium salt cis-1-[([(1R)-1-(4-cyclopropyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]- The 3-ethoxycyclobutane-1-carboxylic acid obtained in Example 4-139 can be prepared by the method shown below.

(1) To a solution of the compound (32.1 mg) obtained in Example 4-139 in acetonitrile (0.5 ml), add 3 mol/L aqueous solution of potassium hydroxide (18.4 μL) and water (0.5 ml ), and the reaction solution was freeze-dried to obtain a colorless amorphous substance (36.4 mg).

(2) Tetrahydrofuran (10 μL) and n-heptane (200 μL) were added to the compound (27 mg) obtained in (1) above, and the reaction solution was stirred at room temperature. Tetrahydrofuran (50 μl), and n-heptane (1 ml) are added to the solution and dissolved at 60°C. The reaction solution was stirred at room temperature for 16.5 hours. The precipitated solid was filtered to obtain a colorless powder (22 mg). If the resulting powder is subjected to thermogravimetry-differential thermal analysis (TG/DTA), an endothermic peak is observed at 81.1°C.

The following Examples 4-164-4-181 were synthesized by the method described in Example 1-1, or an equivalent method, using the compounds obtained in Reference Examples 3-4-50-3-4-51, Reference Example 3-6-21 , Reference Examples 3-6-23-3-6-25, Reference Examples 3-6-31-3-6-33, and Reference Example 4-3-1, commercially available compounds or compounds prepared by synthesis according to the methods described in literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 56-15-56-18.

[Table 56-15] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-16] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-17] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 56-18] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 5-1

1-({[1-(3,5-Diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 502]

(1) Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (101 mg), and the compound (132 mg) obtained in Reference Example 3-7-1, the reaction and post-workup were carried out in accordance with method described in Example 1-21 (1), and purification by preparative HPLC is carried out to obtain methyl 1-({[1-(3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3- difluorocyclobutane-1-carboxylate (110 mg) as a colorless oily substance.

(2) Using the compound (15 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Example 1-21 (3), and the title compound (13 mg) was obtained as a colorless oily substance .

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.02 Hz, 6 H) 1.49-1.56 (m, 3 H) 1.56-1, 65 (m, 4 H) 2.39-2.55 (m, 2 H) 2.56-2.65 (m, 2 H) 3.03-3.18 (m, 1 H) 3.21- 3.36 (m, 3 H) 3.98 (kv, J=7.02 Hz, 4 H) 4.74-5.33 (m, 1 H) 4.81-4.89 (m, 1 H ) 6.37-6.39 (m, 1 H) 6.39-6.41 (m, 2 H) 7.14 (d, J=7.20 Hz, 2 H) 7.19 (t, J =7.20 Hz, 1 H) 7.28 (t, J=7.20 Hz, 2 H).

MS IER/HIAD Multi gender: 519 [M+H] ⁺ .

MS IER/HIAD Multi neg: 517 [MH] ^- .

Hold time: 1,260 min (method E)

The following Examples 5-2 to 5-25 were synthesized by the method described in Example 1-1 or Example 1-40 or an equivalent method using the compounds obtained in Reference Examples 3-1-45-3-1-65 and Reference Example 3 -9-7, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 57-1 through 57-5.

[Table 57-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 57-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 57-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 57-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 57-5] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 5-26

trans-1-[([(1R)-1-(4-Acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3 -ethoxycyclobutane-1-carboxylic acid

[Chemical Formula 503]

Using the compound (24.7 mg) obtained in Reference Example 4-3-1 and the compound (40 mg) obtained in Reference Example 3-4-2, the reaction was carried out in accordance with the method described in Example 1-1, and the title compound (31.2 mg) was obtained as a colorless powder.

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.14-1.20 (m, 3 H) 1.30-1.37 (m, 6 H) 1.38-1.42 ( m, 3 H) 1.44-1.48 (m, 3 H) 2.32-2.50 (m, 6 H) 2.54-2.63 (m, 1 H) 2.64-2, 76 (m, 1 H) 3.03-3.16 (m, 1 H) 3.23-3.47 (m, 4 H) 3.94-4.03 (m, 2 H) 4.03- 4.13 (m, 3 H) 4.27-4.37 (m, 1 H) 5.55-5.63 (m, 1 H) 6.86 (s, 1 H) 7.20-7, 34 (m, 5 H).

MS IER sex: 619 [M+H] ⁺ , 641 [M+Na] ⁺ .

MS IER ref: 617 [MH] ^- .

Hold time: 0.947 min (method A)

It should be noted that N-methyl-D-glucamine hydrate of the title compound can be prepared by the method shown below.

(1) To the title compound (500 mg) and N-methyl-D-glucamine (158 mg), acetonitrile (2 ml) and water (2 ml) were added, and the resulting solution was freeze-dried to obtain a colorless powder (654 mg ).

(2) A mixed solvent of tert-butyl methyl ether-water (100:1, 500 μL), and n-heptane (50 μL) was added to the compound (50 mg) obtained in (1) above, which was then dissolved at 40°C and the reaction solution is stirred at room temperature overnight. The precipitated solid was filtered to obtain a colorless solid (46 mg). If the resulting solid is subjected to thermogravimetry-differential thermal analysis (TG/DTA), endothermic peaks are observed at 50.1°C and 76.3°C.

It should be noted that the solid of the title compound described above was identified as a hydrate by X-ray diffraction.

The following Examples 5-27-5-51 were synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Example 3-4-2, Reference Examples 3-4-36-3-4-39, Reference Example 4-2-3, Reference Example 4-3-2 and Reference Examples 4-4-1-4-4-2, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 58-1 to 58-5.

[Table 58-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 58-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 58-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 58-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 58-5] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

It should be noted that the potassium salt 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl) The amino]cyclopropane-1-carboxylic acid obtained in Example 5-31 can be produced by the method shown below.

(1) To a mixed solution of the compound (603 mg) obtained in Example 5-31 in tetrahydrofuran-water (11 ml-2.7 ml), 3 mol/L potassium hydroxide aqueous solution (358 μL) was added, and the reaction solution was stirred at room temperature for 1 hour and concentrate. A mixed solvent of acetonitrile-water (3 ml-3 ml) was added to the resulting residue, which was then freeze-dried to obtain a colorless amorphous substance (648 mg).

(2) Acetonitrile (0.5 ml), tert-butyl methyl ether (10 ml) and ethyl acetate (1 ml) were added to the compound (648 mg) obtained in (1) above, and the reaction solution was stirred at room temperature overnight . The precipitated solid was filtered to obtain a colorless solid (315 mg). If the resulting solid is subjected to thermogravimetry-differential thermal analysis (TG/DTA), an endothermic peak is observed at 95.9°C.

Example 5-52

Example 5-53

1-{[{(1R)-1-[2-Chloro-3,5-diethoxy-4-(1-hydroxyethyl)phenyl]ethyl}(4-phenylbutyl)carbamoyl]amino}-3,3-difluorocyclobutane-1 -carboxylic acid

[Chemical formula 504]

A mixed solution of the compound (9 mg) obtained in Example 5-46 in tetrahydrofuran-ethanol (0.3 ml-15 μl) was cooled on ice, lithium borohydride (0.988 mg) was added thereto, and the reaction solution was stirred at the same temperature for 2 hours. At the same temperature, lithium borohydride (0.988 mg) was further added thereto, and the reaction solution was stirred at the same temperature for 2 hours. At the same temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, which was then extracted with a chloroform-methanol (4:1) mixed solvent. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC, and one optical isomer of the title compound with a shorter retention time (Example 5-52) (3.40 mg) was obtained as a colorless amorphous substance, and the other optical isomer of the title compound with a longer retention time retention (Example 5-53) (4.11 mg) is obtained as a colorless amorphous substance.

Example 5-52

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.90-1.62 (m, 16 H) 2.28-2.45 (m, 2 H) 2.76-2.94 ( m, 2 H) 2.95-3.10 (m, 2 H) 3.11-3.27 (m, 2 H) 3.87-4.01 (m, 2 H) 4.07-4, 23 (m, 2 H) 5.22-5.33 (m, 1 H) 5.44-5.59 (m, 1 H) 6.89 (s, 1 H) 7.01-7.16 ( m, 3 H) 7.16-7.29 (m, 2 H).

MS ESI sex: 579 [M-OH] ⁺ , 619 [M+Na] ⁺ .

MS IER ref: 595 [MH] ^- .

Hold time: 0.864 min (method A)

Example 5-53

¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.99-1.60 (m, 16 H) 2.32-2.48 (m, 2 H) 2.76-2.94 ( m, 2 H) 2.95-3.10 (m, 2 H) 3.10-3.28 (m, 2 H) 3.88-4.03 (m, 2 H) 4.07-4, 23 (m, 2 H) 5.21-5.32 (m, 1 H) 5.43-5.55 (m, 1 H) 6.88 (s, 1 H) 6.99-7.15 ( m, 3 H) 7.15-7.29 (m, 2 H).

MS ESI sex: 579 [M-OH] ⁺ , 619 [M+Na] ⁺ .

MS IER ref: 595 [MH] ^- .

Hold time: 0.895 min (method A)

The following Examples 5-54-5-66 are synthesized by the method described in Example 1-1, Example 1-21, Example 1-152 or Example 5-52 or an equivalent method using the compounds obtained in Reference Examples 3-4-37- 3-4-39, Reference Example 3-9-6, Reference Example 3-9-9, Reference Examples 4-3-1-4-3-2 and Reference Examples 4-4-1-4-4-2. commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 59-1 through 59-3. It should be noted that the following pairs are optically active compounds:

Example 5-55 (shorter retention time isomer), and Example 5-56 (longer retention time isomer);

Example 5-57 (shorter retention time isomer), and Example 5-58 (longer retention time isomer);

Example 5-59 (shorter retention time isomer), and Example 5-60 (longer retention time isomer);

Example 5-61 (shorter retention time isomer), and Example 5-62 (longer retention time isomer);

Example 5-63 (shorter retention time isomer), and Example 5-64 (longer retention time isomer); And

Example 5-65 (shorter retention time isomer), and Example 5-66 (longer retention time isomer).

[Table 59-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 59-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 59-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 5-67

Example 5-68

4-{[{(1R)-1-[2-Chloro-3,5-diethoxy-4-(1-hydroxyethyl)phenyl]ethyl}(3,3-difluoro-4-phenylbutyl)carbamoyl]amino}oxan- 4-carboxylic acid

[Chemical Formula 505]

(1) Using methyl 4-aminoxan-4-carboxylate hydrochloride (26 mg), and the compound (50 mg) obtained in Reference Example 3-9-8, the reaction and post-working were carried out in accordance with the method described in Example 1 -21 (1), and preparative HPLC purification was carried out to obtain the shorter retention time isomer (Example 5-67 (1)) (18 mg) as a colorless amorphous substance, and the longer retention time isomer (Example 5-68 (1)) (22 mg) as a colorless amorphous substance.

(2) Using Example 5-67 (1) (18 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Example 1-21 (3), and one isomer of the title compound (Example 5-67) (12 mg) is obtained as a colorless powder.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.57 (m, 12 H) 1.78-1.87 (m, 2 H) 2.18-2.32 (m , 2 H) 2.98-3.12 (m, 2 H) 3.32-3.50 (m, 4 H) 3.59-3.67 (m, 1 H) 3.69-3.81 (m, 2 H) 3.89-3.99 (m, 1 H) 3.99-4.15 (m, 3 H) 4.54 (s, 1 H) 5.13-5.26 (m , 1 H) 5.35-5.50 (m, 1 H) 6.63 (s, 1 H) 7.12-7.19 (m, 2 H) 7.28-7.34 (m, 3 H).

MS ESI sex: 609 [M-OH] ⁺ , 649 [M+Na] ⁺ .

MS IER ref: 625 [MH] ^- .

Hold time: 0.832 min (method A)

(3) Using Example 5-68 (1) (22 mg) obtained in (1) above, the reaction was carried out in accordance with the method described in Example 1-21 (3), and the other isomer of the title compound (Example 5-68) (13 mg) is obtained as a colorless powder.

MS ESI sex: 609 [M-OH] ⁺ , 649 [M+Na] ⁺ .

MS IER ref: 625 [MH] ^- .

Hold time: 0.858 min (method A)

The following Examples 5-69 to 5-84 were synthesized by the method described in Example 1-1 or Example 5-52 or an equivalent method using the compounds obtained in Reference Examples 3-1-67-3-1-68, Reference Examples 3- 4-37-3-4-44, Reference Examples 4-3-1-4-3-2 and Reference Example 4-4-2, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 60-1 through 60-4. It should be noted that Example 5-69 (shorter retention time isomer) and Example 5-70 (longer retention time isomer) are optically active compounds.

[Table 60-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 60-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 60-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 60-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

It should be noted that the potassium salt trans-1-[([(1R)-1-(3,5-diethoxy-2,4-dimethylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl) The amino]-3-ethoxycyclobutane-1-carboxylic acid obtained in Example 5-82 can be prepared by the method shown below.

(1) To a solution of the compound (101 mg) obtained in Example 5-82 in acetonitrile (0.5 ml), add 3 mol/L aqueous potassium hydroxide solution (59 μL) and water (0.5 ml), dissolve and the reaction solution was freeze-dried to obtain a colorless amorphous substance (110 mg).

(2) tert-butyl methyl ether and water are mixed and then separated into two layers.

(3) To the compound (80 mg) obtained in (1) above, the organic layer (240 μL) obtained in (2) above and n-heptane (1.2 ml) were added, and the reaction solution was stirred at room temperature in within 14 hours. n-Heptane (2 ml) was added to the solution and the precipitated solid was filtered to obtain a colorless powder (71 mg). If the resulting powder is subjected to thermogravimetry-differential thermal analysis (TG/DTA), an endothermic peak is observed at 76.2°C.

Example 5-85

1-({[1-(4,6-Diethoxypyridin-2-yl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutan-1-carboxylic acid

[Chemical formula 506]

Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (36 mg), and the compound (41 mg) obtained in Reference Example 3-7-2, the reaction was carried out in accordance with the method described in Example 1 -1, and the title compound (48 mg) was obtained as a colorless resinous substance.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.36 (t, J=7.03 Hz, 3 H) 1.42 (t, J=7.03 Hz, 3 H) 1.48 -1.57 (m, 4 H) 1.58-1.66 (m, 3 H) 2.50-2.63 (m, 2 H) 2.63-2.84 (m, 2 H) 3 .16-3.27 (m, 1 H) 3.27-3.48 (m, 3 H) 4.03 (kV, J=6.97 Hz, 4 H) 4.45-4.77 (m , 1 H) 6.10 (d, J=1.71 Hz, 1 H) 6.36 (d, J=1.71 Hz, 1 H) 7.08-7.33 (m, 5 H) 8 .51-9.38 (m, 1 H).

MS IER/HIAD Multi gender: 520 [M+H] ⁺ .

MS IER/HIAD Multi neg: 518 [MH] ^- .

Hold time: 1.225 min (method E)

The following Examples 5-86-5-98 were synthesized by the method described in Example 1-1 or Example 1-40 or an equivalent method using the compounds obtained in Reference Example 1-7-8, Reference Examples 3-1-69-3 -1-77, Reference Example 3-3-4 and Reference Examples 3-7-3-3-7-4, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 61-1 to 61-3.

[Table 61-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 61-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 61-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 5-99

1-({[1-(4-Ethoxy-1-ethyl-1H-indazol-6-yl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 507]

Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (6.6 mg), and the compound (8 mg) obtained in Reference Example 3-8-1, the reaction was carried out in accordance with the method described in Example 1-1 and the title compound (2.5 mg) were obtained as a colorless oily substance.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22-1.53 (m, 10 H) 1.60-1.70 (m, 3 H) 2.37-2.62 (m , 4 H) 2.89-3.16 (m, 1 H) 3.16-3.37 (m, 3 H) 4.04-4.22 (m, 2 H) 4.33-4.43 (m, 2 H) 4.83-4.94 (m, 1 H) 5.13-5.53 (m, 1 H) 6.33 (s, 1 H) 6.86 (s, 1 H) 7.05-7.12 (m, 2 H) 7.15-7.25 (m, 3 H) 8.04 (s, 1 H).

MS IER/HIAD Multi gender: 543 [M+H] ⁺ .

MS IER/HIAD Multi neg: 541 [MH] ^- .

Hold time: 1,140 min (method E)

The following Examples 5-100-5-115 are synthesized by the method described in Example 1-1, Example 1-30, Example 1-40 or Example 1-62 or an equivalent method using the compounds obtained in Reference Examples 3-8-1 -3-8-5, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 62-1 through 62-4. It should be noted that the following pairs are optically active compounds:

Example 5-108 (shorter retention time isomer), and Example 5-109 (longer retention time isomer); And

Example 5-110 (shorter retention time isomer), and Example 5-111 (longer retention time isomer).

Additionally, Example 5-115 is an optical isomer with a shorter retention time when isolated by preparative HPLC with a chiral column.

[Table 62-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 62-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 62-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 62-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 5-116

1-{[(4,6-dichloro-2,3-dihydro-1H-inden-1-yl)(4-phenylbutyl)carbamoyl]amino}-3,3-difluorocyclobutane-1-carboxylic acid

[Chemical formula 508]

Using methyl 1-amino-3,3-difluorocyclobutane-1-carboxylate hydrochloride (12 mg), and the compound (20 mg) obtained in Reference Example 3-1-78, the reaction and subsequent workup were carried out in accordance with the method described in Example 1-1. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:90 to ethyl acetate only and then chloroform only to chloroform:methanol=80:20) to obtain the title compound (3 mg) as a colorless amorphous substance.

MS IER gender: 511 [M+H] ⁺ .

MS IER ref: 509 [MH] ^- .

Hold time: 1.054 min (method A)

The following Example 5-117 is synthesized by the method described in Example 1-1 or an equivalent method using the compound obtained in Reference Example 3-1-79, a commercially available compound, or a compound obtained by synthesis according to methods described in the literature or equivalent methods. The structure and LCMS data of the compound are shown in Table 63-1.

[Table 63-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 5-118

trans-1-[([(1R)-1-(4-Acetyl-3,5-diethoxy-2-methylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3 -ethoxycyclobutane-1-carboxylic acid

[Chemical formula 509]

(1) Solution of the compound (272 mg) obtained in Reference Example 4-3-1. and 4-nitrophenylchloroformate (292 mg) in tetrahydrofuran (12 ml) are cooled with sodium chloride-ice and stirred for 5 minutes. Then, N,N-diisopropylethylamine (1.05 ml) was added dropwise thereto, and the reaction solution was stirred at the same temperature for 3 hours. A solution of the compound (500 mg) obtained in Reference Example 3-4-40 in tetrahydrofuran (1 ml) was added to the reaction solution, which was then stirred at room temperature for 22 hours. A saturated aqueous sodium bicarbonate solution is added to the reaction solution, which is then extracted with toluene. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by column chromatography, in which NH silica gel column cartridge and silica gel column cartridge (n-hexane:ethyl acetate=50:50) were combined to obtain ethyl trans-1-[([(1R)-1-(4-acetyl-3 ,5-diethoxy-2-methylphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate (617 mg) as a colorless powder.

(2) To a solution of the compound (617 mg) obtained in (1) above in ethanol (4.9 ml), add 3 mol/L aqueous potassium hydroxide solution (984 μL), and the reaction solution is stirred at room temperature for 3 days . The reaction solution was cooled on ice, and a 0.5 mol/L aqueous citric acid solution (3 ml) was added thereto, followed by concentration. Chloroform and water are added to the resulting residue, which is then extracted with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to give the title compound (513 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, METHANOL-d ₄ ) δ ppm 1.10-1.24 (m, 3 H) 1.24-1.53 (m, 12 H) 2.18 (s, 3 H ) 2.28-2.40 (m, 2 H) 2.40-2.50 (m, 5 H) 2.64-2.69 (m, 1 H) 2.99-3.04 (m, 1 H) 3.18-3.24 (m, 1 H) 3.28-3.48 (m, 3 H) 3.79-3.87 (m, 2 H) 3.97-4.15 ( m, 3 H) 4.19-4.24 (m, 1 H) 5.55-5.60 (m, 1 H) 6.79 (s, 1 H) 7.14-7.36 (m, 1 H) 5 H).

MS IER/HIAD Multi gender: 599 [M+H] ⁺ .

MS IER/HIAD Multi neg: 597 [MH] ^- .

Hold time: 0.830 min (method D)

The following Example 5-119 is synthesized by the method described in Example 5-118 or an equivalent method using the compounds obtained in Reference Example 3-4-40 and Reference Example 4-4-3, commercially available compounds or compounds obtained by synthesis according to the methods described in the literature or equivalent methods. The structure and LCMS data of the compound are shown in Table 64-1.

[Table 64-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 5-120

trans-1-[([(1R)-1-(4-Acetyl-2,6-dichloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino] -3-ethoxycyclobutane-1-carboxylic acid

[Chemical Formula 510]

(1) Using the compound (18.5 mg) obtained in Reference Example 4-3-1 and the compound (30 mg) obtained in Reference Example 3-4-28, the reaction and subsequent processing were carried out in accordance with the method described in Example 5-118 (1). The resulting residue was purified by preparative HPLC and freeze-dried to give ethyl trans-1-[([(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl }carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate (20 mg) as a colorless powder.

(2) Under a nitrogen atmosphere, a solution of the compound (100 mg) obtained in (1) above in chloroform (0.8 ml) was cooled on ice, and a solution of sulfuryl chloride (14.4 μL) in chloroform (0.8 ml) was added dropwise thereto. ml) and the reaction solution was stirred at the same temperature for 30 minutes. The reaction solution is cooled with a mixture of sodium chloride and ice, a saturated aqueous solution of sodium bicarbonate is added thereto, and extraction is carried out with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=50:50) to give ethyl trans-1-[([(1R)-1-(4-acetyl-2,6-dichloro- 3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]-3-ethoxycyclobutane-1-carboxylate (46 mg) as a colorless amorphous substance.

(3) To a solution of the compound (17 mg) obtained in (2) above in ethanol (0.5 ml), 3 mol/L potassium hydroxide aqueous solution (24.9 μL) was added, and the reaction solution was stirred at room temperature for 16 hours. A 3 mol/L aqueous solution of potassium hydroxide (12.5 μL) was further added to the reaction solution, which was then stirred at room temperature for 55 hours. The reaction solution was cooled on ice, and a solution of citric acid (10.5 mg) in water (0.5 ml) was added thereto. The reaction solution is concentrated and extracted with toluene. The organic layer was washed with water, filtered through a phase separator, concentrated and freeze-dried to give the title compound (12 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.14-1.20 (m, 3 H) 1.31-1.44 (m, 9 H) 1.51-1.62 (m , 3 H) 2.22-2.32 (m, 1 H) 2.45-2.61 (m, 6 H) 3.05-3.15 (m, 1 H) 3.29-3.43 (m, 3 H) 3.55-3.69 (m, 2 H) 3.90-4.03 (m, 5 H) 4.27-4.35 (m, 1 H) 5.71-5 .81 (m, 1 H) 7.14-7.22 (m, 2 H) 7.27-7.32 (m, 1 H) 7.32-7.39 (m, 2 H).

MS IER sex: 653, 655 [M+H] ⁺ .

MS IER ref: 651, 653 [MH] ^- .

Hold time: 1.024 min (method A)

The following Examples 5-121-5-128 were synthesized by the method described in Example 1-1 or Example 5-118 or an equivalent method using the compounds obtained in Reference Examples 3-6-14-3-6-17 and Reference Examples 4 -3-1-4-3-2, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 65-1 through 65-2.

[Table 65-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 65-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

The following Examples 5-129-5-228 were synthesized by the method described in Example 1-1 or an equivalent method using the compounds obtained in Reference Examples 3-4-36-3-4-37, Reference Example 3-4-39, Reference examples 3-4-41-3-4-42, Reference examples 3-4-44-3-4-45, Reference example 3-4-49, Reference examples 3-6-14-3-6-15, Reference examples 3-6-18-3-6-20, Reference example 3-6-22, Reference examples 3-6-26-3-6-30, Reference examples 3-6-34-3-6-37, Reference Examples 4-3-1-4-3-2 and Reference Examples 4-4-1-4-4-2, commercially available compounds or compounds prepared by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 66-1 through 66-20.

[Table 66-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-4] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-5] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-6] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-7] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-8] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-9] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-10] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

[Table 66-11]

Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-12] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-13] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-14] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-15] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-16] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-17] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-18] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-19] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 66-20] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 6-1

1-({[1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)cyclopentane-1-carboxamide

[Chemical formula 511]

To a solution of the compound (50 mg) obtained in Example 1-112 in N,N-dimethylformamide (1 ml), ammonium chloride (26.2 mg) and N,N-diisopropylethylamine (75.9 mg) were added and the reaction solution was stirred at room temperature for 30 minutes. EDC (37.5 mg), and HOBt (30.0 mg) were further added to the reaction solution, which was then stirred at room temperature for 7 hours. Water is added to the reaction solution, which is then extracted with chloroform. The organic layer was concentrated and the resulting residue was purified by silica gel column chromatography (chloroform only to chloroform:methanol=95:5) to obtain the title compound (30.7 mg) as a colorless solid.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.24-1.81 (m, 20 H) 2.03-2.14 (m, 3 H) 2.14-2.27 (m , 2 H) 2.54-2.66 (m, 2 H) 3.01-3.19 (m, 1 H) 3.25-3.38 (m, 1 H) 3.92-4.03 (m, 4 H) 4.36-4.51 (m, 1 H) 4.96-5.11 (m, 1 H) 5.11-5.27 (m, 1 H) 6.41-6 .48 (m, 2 H) 7.07-7.32 (m, 5 H).

MS ESI/HIAD Multi sex: 510 [M+H] ⁺ , 532 [M+Na] ⁺ .

Hold time: 0.968 min (method D)

Example 6-2

Methyl 1-({[1-(3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)cyclopentane-1-carboxylate

[Chemical formula 512]

Using methyl 1-aminocyclopentanecarboxylate hydrochloride (139 mg) and the compound (189 mg) obtained in Reference Example 3-7-1, the reaction and subsequent workup were carried out in accordance with the method described in Example 1-21 (1), and purification Preparative HPLC was carried out to obtain the title compound (115 mg) as a colorless oily substance.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.39 (t, J=7.02 Hz, 6 H) 1.47-1.57 (m, 5 H) 1.58-1, 60 (m, 2 H) 1.61-1.78 (m, 5 H) 1.80-1.97 (m, 1 H) 2.11-2.25 (m, 2 H) 2.53- 2.61 (m, 2 H) 2.92-3.06 (m, 1 H) 3.11-3.24 (m, 1 H) 3.68 (s, 3 H) 3.99 (sq, J=7.02 Hz, 4 H) 4.54-4.59 (m, 1 H) 5.19-5.35 (m, 1 H) 6.34 (t, J=2.27 Hz, 1 H) 6.45 (d, J=2.27 Hz, 2 H) 7.11-7.18 (m, 3 H) 7.24-7.29 (m, 2 H).

MS IER/HIAD Multi gender: 511 [M+H] ⁺ .

Hold time: 1.374 min (method E)

Example 6-3

Methyl 1-[([(1R)-1-(4-acetyl-2-chloro-3,5-diethoxyphenyl)ethyl]{2-[(1S)-1-phenylethoxy]ethyl}carbamoyl)amino]cyclopropane-1 -carboxylate

[Chemical formula 513]

A solution of methyl 1-aminocyclopropane-1-carboxylate hydrochloride (27.1 mg) and 4-nitrophenylchloroformate (36.0 mg) in tetrahydrofuran (1.5 ml) was cooled on ice and stirred for 10 minutes, then N, N was added -diisopropylethylamine (130 μl), and the reaction solution was stirred at the same temperature for 2 hours. The compound (70 mg) obtained in Reference Example 3-4-2 was added to the reaction solution, which was then stirred at room temperature for 18 hours. The reaction solution was concentrated, purified by preparative HPLC and freeze-dried to give the title compound (64.3 mg) as a colorless amorphous substance.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.03-1.13 (m, 2 H) 1.31-1.64 (m, 14 H) 2.47 (s, 3 H) 2.70-2.78 (m, 1 H) 3.04-3.17 (m, 2 H) 3.28-3.37 (m, 1 H) 3.71 (s, 3 H) 3, 97-4.05 (m, 4 H) 4.29-4.37 (m, 1 H) 5.63-5.72 (m, 1 H) 6.69 (s, 1 H) 7.11- 7.36 (m, 6 H).

MS ESI sex: 575 [M+H] ⁺ , 597 [M+Na] ⁺ .

Hold time: 0.936 min (method A)

The following Examples 6-4 to 6-17 were synthesized by the method described in Example 6-2 or an equivalent method using the compounds obtained in Reference Example 3-4-2, Reference Example 3-4-28, Reference Examples 4-3- 1-4-3-3 and Reference Examples 4-11-1-4-11-3, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 67-1 through 67-3.

[Table 67-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 67-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 67-3] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 7-1

1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluoro-N-(methanesulfonyl)cyclobutane-1-carboxamide

[Chemical formula 514]

A solution of the compound (31 mg) obtained in Example 1-30 in tetrahydrofuran (0.8 ml) was cooled on ice, N,N-diisopropylethylamine (77.1 μl) and CDI (17.9 mg) were added thereto, and the reaction solution stir at 50°C for 1 hour. A solution of methanesulfonamide (21.0 mg) in tetrahydrofuran (0.4 ml) was added to the reaction solution, which was then stirred at 60°C for 5 hours. N,N-diisopropylethylamine (77.1 μL) and CDI (17.9 mg) were further added thereto, and the reaction solution was stirred at 60°C for 1 hour. Then, methanesulfonamide (21.0 mg) was further added thereto, and the reaction solution was stirred at 60°C for 2 hours. To the reaction solution, 2 mol/L hydrochloric acid was added to adjust the pH to 3, and purification by preparative thin layer chromatography (chloroform:methanol=85:15, Rf=0.55), and preparative HPLC was carried out to obtain the title compound (15, 5 mg) as a colorless solid.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.24-1.39 (m, 6 H) 1.48-1.68 (m, 7 H) 2.44-2.62 (m , 7 H) 2.97-3.05 (m, 1 H) 3.07-3.20 (m, 1 H) 3.20-3.35 (m, 5 H) 3.95-4.03 (m, 4 H) 4.81-4.93 (m, 1 H) 5.04-5.50 (m, 1 H) 6.40 (s, 2 H) 7.12-7.16 (m , 2 H) 7.18-7.32 (m, 3 H) 11.21 (shs, 1 H).

MS ESI floor: 638 [M+H] ⁺ , 660 [M+Na] ⁺ .

MS IER ref: 636 [MH] ^- .

Hold time: 0.951 min (method A)

The following Examples 7-2-7-3 are synthesized by the method described in Example 1-1 or Example 7-1 or an equivalent method using the compounds obtained in Reference Example 3-9-1 and Example 1-112, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 68-1.

[Table 68-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 7-4

1-({[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-3,3-difluoro-N-sulfamoylcyclobutane-1-carboxamide

[Chemical formula 515]

Using the compound (31 mg) obtained in Example 1-30 and sulfamide (42.5 mg), the reaction was carried out in accordance with the method described in Example 7-1, 2 mol/L hydrochloric acid was added to adjust the pH to 1 and extraction is carried out with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC and preparative thin layer chromatography (chloroform:methanol=85:15, Rf=0.55), and freeze-dried to obtain the title compound (5.63 mg) as a colorless powder.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.32-1.40 (m, 6 H) 1.49-1.54 (m, 3 H) 1.54-1.69 (m , 4 H) 2.42-2.57 (m, 5 H) 2.59-2.63 (m, 2 H) 2.92-3.09 (m, 1 H) 3.10-3.19 (m, 1 H) 3.19-3.36 (m, 3 H) 3.95-4.05 (m, 4 H) 4.84 (shs, 1 H) 5.17-5.35 (m , 2 H) 6.41 (s, 2 H) 7.13-7.16 (m, 2 H) 7.17-7.25 (m, 1 H) 7.27-7.33 (m, 2 H) 11.03 (shs, 1 H).

MS ESI sex: 639 [M+H] ⁺ , 661 [M+Na] ⁺ .

MS IER ref: 637 [MH] ^- .

Hold time: 0.919 min (method A)

Example 7-5

1-({[1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)-N-(dimethylsulfamoyl)cyclopentane-1-carboxamide

[Chemical formula 516]

A solution of the compound (80 mg) obtained in Example 1-112 and N,N-dimethylsulfamide (38.9 mg) in N,N-dimethylformamide (1 ml) was cooled on ice, EDC (90.1 mg) was added thereto, and 4-dimethylaminopyridine (57.4 mg) and the reaction solution were stirred at 60°C for 14 hours. Water is added to the reaction solution, which is then extracted with diethyl ether. The organic layer was washed with saline and dried over anhydrous magnesium sulfate. After filtering the drying agent, the filtrate is concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to give the title compound (11.1 mg) as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.38-1.44 (m, 6 H) 1.49-1.65 (m, 13 H) 2.08 (s, 3 H) 2.13-2.27 (m, 2 H) 2.55-2.65 (m, 2 H) 2.93 (s, 6 H) 3.01-3.15 (m, 1 H) 3, 24-3.41 (m, 1 H) 3.92-4.02 (m, 4 H) 4.38-4.44 (m, 1 H) 4.94-5.13 (m, 1 H) 6.41 (s, 2 H) 7.11-7.24 (m, 3 H) 7.27-7.33 (m, 2 H) 10.52 (shs, 1 H).

MS ESI/CIAD Multi sex: 617 [M+H] ⁺ , 639 [M+Na] ⁺ .

MS IER/HIAD Multi neg: 615 [MH] ^- .

Hold time: 1.061 min (method D)

Example 8-1

[1-({[1-(3,5-Diethoxy-4-methylphenyl)ethyl](4-phenylbutyl)carbamoyl}amino)cyclopentyl]phosphonic acid

[Chemical formula 517]

(1) To a solution of the compound (20 mg) obtained in Reference Example 4-8-1 in tetrahydrofuran (1 ml), add N,N-diisopropylethylamine (50.4 μL), 4-nitrophenylchloroformate (11.7 mg) and a solution of the compound (22.6 mg) obtained in Reference Example 3-1-2 in tetrahydrofuran (0.5 ml) and the reaction solution was stirred at room temperature for 3 hours. Water is added to the reaction solution, which is then extracted with chloroform, and the organic layer is concentrated. The resulting residue was purified by NH silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=60:40) to give dibenzyl [1-({[1-(3,5-diethoxy-4-methylphenyl)ethyl](4 -phenylbutyl)carbamoyl}amino)cyclopentyl]phosphonate (7.9 mg) as a colorless resinous substance.

(2) To a solution of the compound (7.9 mg) obtained in (1) above in methanol (2 ml), palladium on carbon (4 mg) was added, and the reaction solution was stirred at room temperature for 2 hours under a hydrogen atmosphere. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by preparative thin layer chromatography (chloroform:methanol=70:30, Rf=0.15) and preparative HPLC to obtain the title compound (3.08 mg) as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.06-1.32 (m, 3 H) 1.37 (t, J=6.60 Hz, 6 H) 1.47 (shs, 8 H) 1.74-1.96 (m, 2 H) 1.99-2.18 (m, 5 H) 2.43-2.59 (m, 2 H) 2.89-3.07 ( m, 1 H) 3.07-3.25 (m, 1 H) 3.95 (kV, J=6.60 Hz, 4 H) 4.40-4.68 (m, 1 H) 5.03 -5.29 (m, 1 H) 6.40 (s, 2 H) 7.05-7.24 (m, 5 H).

MS IER/HIAD Multi gender: 547 [M+H] ⁺ .

MS IER/HIAD Multi neg: 545 [MH] ^- .

Hold time: 1.020 min (method D)

The following Example 8-2 is synthesized by the method described in Example 8-1 or an equivalent method using the compounds obtained in Reference Example 3-4-4 and Reference Example 4-8-1, commercially available compounds or compounds obtained by synthesis according to the methods described in the literature or equivalent methods. The structure and LCMS data of the compound are shown in Table 69-1.

[Table 69-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 9-1

N-[1-(3,5-Diethoxy-4-methylphenyl)ethyl]-N'-[1-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopentyl] -N-(4-phenylbutyl)urea

[Chemical Formula 518]

(1) Using 1-aminocyclopentane-1-carbonitrile hydrochloride (193 mg), and the compound (400 mg) obtained in Reference Example 3-1-2, the reaction was carried out in accordance with the method described in Example 1-21 (1) , and N'-(1-cyanocyclopentyl)-N-[1-(3,5-diethoxy-4-methylphenyl)ethyl]-N-(4-phenylbutyl)urea (278 mg) were obtained as a colorless oily substance.

(2) To a solution of the compound (96.0 mg) obtained in (1) above in ethanol (976 μL), add water (244 μL), hydroxylamine hydrochloride (40.7 mg) and sodium carbonate (62.1 mg) , and the reaction solution was stirred at 80°C for 1 hour. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (n-hexane only to n-hexane:ethyl acetate=30:70) to give 1-({[1-(3,5-diethoxy-4-methylphenyl)ethyl] (4-phenylbutyl)carbamoyl}amino)-N'-hydroxycyclopentane-1-carboximidamide (22.4 mg) as a colorless oily substance.

(3) To a solution of the compound (22.4 mg) obtained in (2) above in tetrahydrofuran (427 μL), CDI (8.31 mg), and DBU (7.01 μL) were added, and the reaction solution was stirred at room temperature for 17 hours. The reaction solution was concentrated and the resulting residue was purified by preparative HPLC to obtain the title compound (11.4 mg) as a colorless solid.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20-1.64 (m, 16 H) 1.65-1.78 (m, 2 H) 1.81-1.99 (m , 2 H) 2.08 (s, 3 H) 2.11-2.31 (m, 2 H) 2.52-2.69 (m, 2 H) 2.95-3.20 (m, 1 H) 3.20-3.45 (m, 1 H) 3.87-4.04 (m, 4 H) 4.39-4.54 (m, 1 H) 4.87-5.14 (m , 1 H) 6.40 (s, 2 H) 7.08-7.23 (m, 3 H) 7.23-7.31 (m, 2 H).

MS IER/HIAD Multi gender: 551 [M+H] ⁺ .

MS IER/HIAD Multi neg: 549 [MH] ^- .

Hold time: 1.051 min (method D)

Example 10-1

N-[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl]-N-{2-[(1S)-1-phenylethoxy]ethyl}-N'-[1-(2H-tetrazole -5-yl)cyclopropyl]urea

[Chemical formula 519]

(1) A solution of the compound (25.3 mg) obtained in Reference Example 4-9-1 in tetrahydrofuran (1 ml) was cooled on ice, and N,N-diisopropylethylamine (59.9 μL) and 4-nitrophenyl chloroformate were added thereto. (13.9 mg), and the reaction solution was stirred at room temperature for 1.5 hours. The compound (25 mg) obtained in Reference Example 3-4-28 was added to the reaction solution, which was then stirred at 60°C for 1.5 hours. The reaction solution is cooled on ice, a saturated aqueous sodium bicarbonate solution is added thereto, and extraction is carried out with ethyl acetate. The organic layer was washed with each of saturated sodium bicarbonate solution and brine, then filtered through a phase separator and concentrated to obtain a mixture containing N-[(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]-N -{2-[(1S)-1-phenylethoxy]ethyl}-N'-{1-[2-(triphenylmethyl)-2H-tetrazol-5-yl]cyclopropyl}urea.

(2) A solution of the mixture (11.4 mg) obtained in (1) above in isopropyl alcohol (0.5 ml) is cooled on ice, 2 mol/L solution of isopropyl alcohol hydrochloride (0.2 ml) is added and the reaction The solution is stirred for 1 hour, gradually bringing it back to room temperature. The reaction solution is cooled on ice and a saturated aqueous sodium bicarbonate solution (pH 7 or more) is neutralized, 2 mol/L hydrochloric acid (pH 5-3) is added, and extraction is carried out with chloroform. The organic layer is filtered through a phase separator and concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (6.7 mg) as a colorless powder.

¹ H NMR (600 MHz, CHLOROFORM-d) δ ppm 1.13-1.19 (m, 1 H) 1.22-1.27 (m, 1 H) 1.30-1.38 (m , 12 H) 1.50-1.63 (m, 2 H) 2.46 (s, 3 H) 3.00-3.07 (m, 1 H) 3.09-3.19 (m, 2 H) 3.19-3.25 (m, 1 H) 3.90-4.05 (m, 4 H) 4.20-4.30 (m, 1 H) 5.65-5.75 (m , 1 H) 6.43 (s, 2 H) 7.01-7.11 (m, 2 H) 7.22-7.36 (m, 3 H) 7.70 (shs, 1 H) 13, 84-14.30 (m, 1 H).

MS ESI sex: 551 [M+H] ⁺ , 573 [M+Na] ⁺ .

MS IER ref: 549 [MH] ^- .

Hold time: 0.802 min (method A)

The following Examples 10-2 to 10-6 were synthesized by the method described in Example 10-1 or an equivalent method using the compounds obtained in Reference Example 3-4-1, Reference Example 3-4-21, Reference Example 3-4- 30 and Reference Example 4-9-1, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 70-1.

[Table 70-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 10-7

N-[(1R)-1-(4-Acetyl-3,5-diethoxyphenyl)ethyl]-N'-[3,3-difluoro-1-(1H-tetrazol-5-yl)cyclobutyl]-N-( 4-phenylbutyl)urea

[Chemical Formula 520]

(1) Using the compound (40 mg) obtained in Reference Example 4-10-1 and the compound (50 mg) obtained in Reference Example 3-4-1, the reaction was carried out in accordance with the method described in Example 10- 1 (1), and N-[(1R)-1-(4-acetyl-3,5-diethoxyphenyl)ethyl]-N'-[1-(2-benzyl-2H-tetrazol-5-yl)-3 ,3-difluorocyclobutyl]-N-(4-phenylbutyl)urea (64 mg) is obtained as a colorless oily substance.

(2) To a solution of the compound (64 mg) obtained in (1) above in methanol (4 ml), palladium on carbon (32 mg) was added, and the reaction solution was stirred at room temperature for 20 hours under a hydrogen atmosphere. The reaction solution is filtered through Celite (registered trademark) and the filtrate is concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (23 mg) as a colorless powder.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.30-1.40 (m, 6 H) 1.45-1.66 (m, 7 H) 2.46 (s, 3 H) 2.56-2.65 (m, 2 H) 2.81-3.07 (m, 3 H) 3.07-3.23 (m, 1 H) 3.41-3.61 (m, 2 H) 3.84-4.04 (m, 4 H) 4.91-5.05 (m, 1 H) 5.10-5.35 (m, 1 H) 6.36 (s, 2 H) 7.26 (s, 5 H).

MS IER floor: 585 [M+H] ⁺ .

Hold time: 0.873 min (method A)

The following Example 10-8 is synthesized by the method described in Example 10-7 or an equivalent method using the compounds obtained in Reference Example 3-4-39 and Reference Example 4-10-1, commercially available compounds or compounds obtained by synthesis according to the methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Table 71-1.

[Table 71-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

Example 10-9

N-{(1R)-1-[3,5-Diethoxy-4-(1-hydroxyethyl)phenyl]ethyl}-N'-[3,3-difluoro-1-(1H-tetrazol-5-yl)cyclobutyl ]-N-(4-phenylbutyl)urea

[Chemical formula 521]

A solution of the compound (10 mg) obtained in Example 10-7 in tetrahydrofuran (2 ml) was cooled on ice, lithium borohydride (7.45 mg) was added thereto, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution is cooled on ice, methanol, water and acetic acid are added thereto, and the reaction solution is stirred for a while and concentrated. The resulting residue was purified by preparative HPLC and freeze-dried to obtain the title compound (6.69 mg) as a colorless powder.

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15-1.57 (m, 16 H) 2.56-2.64 (m, 2 H) 2.77-2.91 (m , 2 H) 2.95-3.08 (m, 2 H) 3.15-3.21 (m, 1 H) 3.42-3.57 (m, 2 H) 3.80-3.89 (m, 1 H) 3.89-4.06 (m, 4 H) 4.88-4.97 (m, 1 H) 5.24-5.36 (m, 1 H) 6.38 (s , 2 H) 7.08-7.15 (m, 2 H) 7.17-7.32 (m, 3 H).

MS ESI sex: 569 [M-OH] ⁺ , 609 [M+Na] ⁺ .

MS IER ref: 585 [MH] ^- .

Hold time: 0.869 min (method A)

Example 10-10

Example 10-11

N-{(1R)-1-[3,5-Diethoxy-4-(1-hydroxyethyl)phenyl]ethyl}-N'-[3,3-difluoro-1-(1H-tetrazol-5-yl)cyclobutyl ]-N-(4-phenylbutyl)urea

[Chemical formula 522]

Using the compound (8.5 mg) obtained in Example 10-8, the reaction was carried out in accordance with the method described in Example 10-9. Preparative HPLC purification and freeze drying were carried out to obtain one optical isomer of the title compound with a shorter retention time (Example 10-10) (2.67 mg) as a colorless powder, and another optical isomer of the title compound with a longer retention time. retention time (Example 10-11) (3.59 mg) as a colorless powder.

Example 10-10

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.20-1.59 (m, 16 H) 2.45-2.57 (m, 2 H) 2.81-2.99 (m , 2 H) 3.03-3.17 (m, 2 H) 3.35-3.51 (m, 1 H) 3.53-3.69 (m, 1 H) 3.88-4.15 (m, 5 H) 4.90-5.00 (m, 1 H) 5.14-5.24 (m, 1 H) 5.35-5.48 (m, 1 H) 6.62 (s , 1 H) 7.08-7.14 (m, 2 H) 7.16-7.30 (m, 3 H).

MS ESI sex: 603 [M-OH] ⁺ , 643 [M+Na] ⁺ .

MS IER ref: 619 [MH] ^- .

Hold time: 0.848 min (method A)

Example 10-11

¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17-1.60 (m, 16 H) 2.45-2.57 (m, 2 H) 2.81-3.11 (m , 5 H) 3.37-3.54 (m, 1 H) 3.54-3.72 (m, 1 H) 3.89-3.99 (m, 2 H) 4.02-4.16 (m, 2 H) 4.96-5.04 (m, 1 H) 5.10-5.30 (m, 1 H) 5.40-5.53 (m, 1 H) 6.64 (s , 1 H) 7.06-7.13 (m, 2 H) 7.16-7.30 (m, 3 H).

MS ESI sex: 603 [M-OH] ⁺ , 643 [M+Na] ⁺ .

MS IER ref: 619 [MH] ^- .

Hold time: 0.868 min (method A)

The following Examples 10-12-10-18 were synthesized by the method described in Example 1-152, Example 10-1, Example 10-7 or Example 10-9 or an equivalent method using the compounds obtained in Reference Example 3-1-2 , Reference Example 3-4-1, Reference Example 3-4-28, Reference Example 3-4-32, Reference Example 3-4-38, Reference Example 3-4-45, Reference Examples 4-9-2-4 -9-3 and Reference Examples 4-10-1-4-10-2, commercially available compounds or compounds obtained by synthesis according to methods described in the literature or equivalent methods. The structures and LCMS data of the compounds are shown in Tables 72-1 through 72-2.

[Table 72-1] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way [Table 72-2] Example No. Structural formula MS floor m/z
MS neg m/z Holding time (min) Way

The LPA1 receptor antagonistic activity of the compounds of the present invention was assessed by the method shown in Experimental Example 1 below.

Experimental example 1

(1) Generation of RH7777 cells stably expressing human LPAR1.

The human LPAR1 expression vector was transfected into RH7777 cells to generate cells expressing human LPAR1.

(2) Test for antagonism of the response to LPA-induced increase in intracellular Ca ²⁺ concentration.

Cells stably expressing human LPAR1 were used to test for antagonism of the response to LPA-induced increases in intracellular Ca ²⁺ concentration.

Cells are seeded onto a 96-well black poly-D-lysine plate and incubated overnight. After incubation in medium without FBS for 2 hours or longer, the medium is removed by suction and 100 μl loading buffer (1xHBSS, 20 mM HEPES, 2.5 mM probenecid, 0.05% BSA, 0.25 mg/ml Amaranth, 0. 05% Pluronic F-127, 2 µM Fluo-4, pH 7.4) and incubated for 60 minutes. Add 50 μl of basic buffer (1xHBSS, 20 mM HEPES, 2.5 mM Probenecid, 0.05% BSA, 0.25 mg/ml Amaranth, pH 7.4) containing the test compound, followed by incubation at 37°C within 30 minutes. LPA was added to FDSS6000 (Hamamatsu Photonics KK), and the change in intracellular Ca ²⁺ concentration was determined using a fluorescence value of 540 nm at an excitation wavelength of 480 nm as an indicator. The ratio (Rmax) between the basal fluorescence value and the maximum fluorescence value is determined and the concentration that produces 50% antagonism of the response to the LPA-induced increase in intracellular Ca ²⁺ concentration (IC ₅₀ value) is calculated. Rmax when stimulated with basal buffer without test compound is used as a control value. The reference value is Rmax when stimulated with the starting buffer without LPA or test compounds.

The fraction (%) increase in intracellular Ca ²⁺ concentration is calculated by dividing the value obtained by subtracting the basal value from Rmax in the presence of LPAs and each test compound concentration by the value obtained by subtracting the basal value from the control value. The concentration of each test compound is plotted on the X-axis, the fraction (%) increase in intracellular Ca ²⁺ concentration is plotted on the Y-axis, and the IC ₅₀ value is calculated using non-linear regression using XLfit. The test results are shown in Table 73-1 - Table 73-6.

[Table 73-1]

[Table 73-2]

[Table 73-3]

[Table 73-4]

[Table 73-5]

[Table 73-6]

In addition, the LPA3 receptor antagonistic activity of the compounds of the present invention can also be assessed by the method shown in Experimental Example 2 below.

Experimental example 2

(1) Antagonism test for response to LPA-induced increase in intracellular Ca ²⁺ concentration

Cells stably expressing human LPAR3 are used to test for antagonism of the response to LPA-induced increases in intracellular Ca ²⁺ concentration.

Cells are seeded onto a 96-well black poly-D-lysine plate and incubated overnight. After washing with PBS, add 100 μl of loading buffer (1xHBSS, 20 mM HEPES, 2.5 mM probenecid, 0.05% BSA, 0.25 mg/ml amaranth, 0.05% Pluronic F-127, 200 nM Fluo-8, pH 7.4) and incubate for 60 minutes. Add 50 μl of basal buffer (1xHBSS, 20 mM HEPES, 2.5 mM probenecid, 0.05% BSA, 0.25 mg/ml amaranth, pH 7.4) containing the test compound, followed by incubation at 37°C in within 30 minutes. LPA was added to FDSS6000 (Hamamatsu Photonics KK), and the change in intracellular Ca ²⁺ concentration was determined using a fluorescence value of 540 nm at an excitation wavelength of 480 nm as an indicator. The ratio (Rmax) between the basal fluorescence value and the maximum fluorescence value is determined and the concentration that produces 50% antagonism of the response to the LPA-induced increase in intracellular Ca ²⁺ concentration (IC ₅₀ value) is calculated. Rmax when stimulated with basal buffer without test compound is used as a control value. The reference value is Rmax when stimulated with the starting buffer without LPA or test compounds.

The fraction (%) increase in intracellular Ca ²⁺ concentration is calculated by dividing the value obtained by subtracting the basal value from Rmax in the presence of LPAs and each test compound concentration by the value obtained by subtracting the basal value from the control value. The concentration of each test compound is plotted on the X-axis, the fraction (%) increase in intracellular Ca ²⁺ concentration is plotted on the Y-axis, and the IC ₅₀ value is calculated using non-linear regression using XLfit.

INDUSTRIAL APPLICABILITY

The compound of the present invention has excellent LPA1 receptor antagonistic activity, and it is expected that the present invention will provide a medical product effective for the prevention or treatment of diseases associated with fibrosis and the like, such as systemic scleroderma, thereby reducing the burden on patients and promoting progress in the pharmaceutical industry.

Claims (281)

1. The compound represented by formula [I] [Chemical formula 1] or a pharmaceutically acceptable salt or hydrate thereof, where X represents carboxy, C _1-4 alkoxycarbonyl, carbamoyl, tetrazolyl or a group selected from the group of formulas [II]: [Chemical formula 2] W represents a linear C _1-3 alkanediyl or a structure selected from the group of formulas [III]: [Chemical formula 3] wherein the linear C _1-3 alkanediyl is optionally substituted by one group selected from the group consisting of C _1-6 alkyl, optionally substituted by one group selected from the group consisting of hydroxy and carboxy, halo-C _1-6 alkyl, C _{3- 8} cycloalkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and, if a linear C _1-3 alkanediyl is substituted with one methyl, it is optionally further substituted with one methyl, ring A ¹ , ring A ² and ring A ³ are each a C _3-8 cycloalkane, a partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle containing a sulfur atom 4-8- membered saturated heterocycle or 4-8 membered saturated heterocycle containing a nitrogen atom, where the sulfur atom in the 4-8-membered saturated heterocycle containing a sulfur atom is optionally replaced by one or two oxo, the nitrogen atom in the nitrogen atom-containing 4-8 membered saturated heterocycle is optionally substituted by one group selected from the group consisting of C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl, and R ^A11 , R ^A21 and R ^A31 each independently represent a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl or a nitrogen-containing 4-6 membered saturated heterocyclyl , optionally substituted with one C _1-3 alkyl, and R ^A12 , R ^A22 and R ^A32 each independently represent a hydrogen atom, a halogen or methyl atom, or R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally together form an oxo, or R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally form a C _3-6 cycloalkane together with carbon atoms in the adjacent ring; R ¹ represents a hydrogen atom or methyl; R ² represents C _6-10 alkyl, C _6-10 alkenyl, C _6-10 alkynyl, or a group represented by formula [IV-1] or [IV-2]: [Chemical formula 4] where ring B ¹ represents C _3-8 cycloalkyl, nitrogen-containing 4-8-membered saturated heterocyclyl, phenyl or nitrogen-containing 5-6-membered heteroaryl, R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy, L ¹ is a C _3-8 alkanediyl, optionally substituted with 1-5 fluorine atoms, the structure represented by the formula [V-6] -CH ₂ CH ₂ CH=C(CH ₃ )-, or the structure represented by the formula [V-1 ] [Chemical formula 5] where n11 represents an integer from 0 to 3, n12 represents an integer from 0 to 5, n13 is an integer from 0 to 3, and one carbon atom in the C _3-8 alkanediyl, which is two or more atoms from the nitrogen atom to which R ² is attached, is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L11 )- and, in addition Togo, two consecutive carbon atoms in a C _3-8 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L12 )-, R ^L11 represents a hydrogen atom or C _1-3 alkyl and R ^L12 represents a hydrogen atom or C _1-3 alkyl, ring B ² is a partially saturated 9-10 membered fused ring aryl or a nitrogen-containing 9-10 membered fused ring heteroaryl, R ^B21 and R ^B22 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy, L ² is C _1-2 alkanediyl, optionally substituted with 1-4 fluorine atoms, C _3-6 alkanediyl, optionally substituted with 1-5 fluorine atoms, or the structure represented by the formula [V-2] [Chemical formula 6] where n21 represents an integer from 0 to 3, n22 represents an integer from 0 to 5, n23 is an integer from 0 to 3, and one carbon atom in the C _3-6 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-, the formula -S-, or the formula -N(R ^L21 )-, and, Besides, two consecutive carbon atoms in a C _3-6 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L22 )-, R ^L21 represents a hydrogen atom or C _1-3 alkyl and R ^L22 represents a hydrogen atom or C _1-3 alkyl; R ³ represents a hydrogen atom or C _1-3 alkyl, optionally substituted by one group selected from the group consisting of hydroxy and methoxy; And R ⁴ represents a group represented by the formula [VI] [Chemical formula 7] where ring C is a phenyl containing a nitrogen atom, a 6-membered heteroaryl or a 9-10-membered fused ring heteroaryl, phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition, phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl, optionally substituted with one group selected from the group consisting of hydroxy and C _{1 -6} alkoxy, halogen-C _1-6 alkyl, optionally substituted with one hydroxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, optionally substituted with one hydroxy, C _1-6 alkoxy, halogen-C _{1 -6} alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylcarbonyl, halogen-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, mono-C _1-6 alkylaminocarbonyl and di-C _1-6 alkylaminocarbonyl, the nitrogen-containing 6-membered heteroaryl is replaced by one C _1-6 alkoxy, and, in addition, the nitrogen atom-containing 6-membered heteroaryl is optionally substituted with one to two groups, the same or different, selected from the group consisting of cyano, C _1-6 alkyl, C _1-6 alkoxy and oxo, and The 9-10 membered fused ring heteroaryl is optionally substituted with one to four groups, identical or different, selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and oxo; or R ³ and R ⁴ together with their adjacent carbon atom optionally form a partially substituted 9-10 membered fused hydrocarbon aromatic ring or a partially substituted oxygen atom containing 9-10 membered fused heteroaromatic ring, wherein the partially saturated 9-10 membered fused hydrocarbon aromatic ring is optionally substituted with one to two halogen atoms, and the partially saturated oxygen atom containing 9-10 membered fused heteroaromatic ring is optionally substituted with one or two halogen atoms. 2. A compound according to claim 1 or a pharmaceutically acceptable salt or hydrate thereof, where, in the formula of group [III] for W, R ^A11 , R ^A21 and R ^A31 each independently represent a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy or a nitrogen-containing 4-6 membered saturated heterocyclyl, optionally substituted with a single C _{1 -3} alkyl, and R ^A12 , R ^A22 and R ^A32 each independently represent a hydrogen atom, a halogen or methyl atom, or R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally together form an oxo, or R ^A11 and R ^A12 , R ^A21 and R ^A22 and R ^A31 and R ^A32 each optionally form a C _3-6 cycloalkane together with carbon atoms in the adjacent ring, and where, in formula [IV-1] for R ² , L ¹ represents a C _3-8 alkanediyl, optionally substituted with 1-5 fluorine atoms, or the structure represented by the formula [V-1], wherein the one carbon atom in the C _3-8 alkanediyl that is two or more atoms away from the nitrogen atom to which R ² is attached is optionally substituted by the formula -O-, the formula -S- or the formula -N(R ^L11 )- and, Besides, two consecutive carbon atoms in a C _3-8 alkanediyl that is one or more atoms away from the nitrogen atom to which R ² is attached are optionally substituted by the formula -C(=O)N(R ^L12 )-, R ^L11 represents a hydrogen atom or C _1-3 alkyl and R ^L12 represents a hydrogen atom or C _1-3 alkyl. 3. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], W represents a linear C _1-3 alkanediyl or a structure selected from the group of formulas [III]: [Chemical formula 8] wherein the linear C _1-3 alkanediyl is optionally substituted by one group selected from the group consisting of C _1-6 alkyl, optionally substituted by one group selected from the group consisting of hydroxy and carboxy, halo-C _1-6 alkyl, C _{3- 8} cycloalkyl, phenyl-C _1-3 alkyl and pyridyl-C _1-3 alkyl, and, if a linear C _1-3 alkanediyl is substituted with one methyl, it is optionally further substituted with one methyl, ring A ¹ is a C _3-8 cycloalkane, dihydroindene, oxetane, tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, azetidine, pyrrolidine or piperidine, ring A ² is a C _3-8 cycloalkane or tetrahydropyran and ring A ³ is a C _3-8 cycloalkane, dihydroindene or tetrahydropyran, wherein the sulfur atom in the tetrahydrothiopyran is optionally replaced by one to two oxos, and the nitrogen atom in each of azetidine, pyrrolidine and piperidine is optionally replaced by one C _1-4 alkylcarbonyl, and R ^A11 represents a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy, C _1-6 alkylcarbonyl or a nitrogen-containing 4-6 membered saturated heterocyclyl, optionally substituted with a single C _1-3 alkyl, and R ^A12 represents a hydrogen atom, a halogen or methyl atom, or R ^A11 and R ^A12 optionally together form oxo, R ^A21 and R ^A22 both represent hydrogen atoms, R ^A31 and R ^A32 both represent hydrogen atoms and, in addition, R ^A11 and R ^A12 optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent ring; R ² represents a C _6-10 alkyl or a group represented by the formula [IV-1] or [IV-2]: [Chemical formula 9] where ring B ¹ represents C _3-8 cycloalkyl, piperidinyl, phenyl, pyrazolyl or pyridyl, R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy and L ¹ is any of the structures represented by formulas [V-3] - [V-12] and [V-14] - [V-19]: [Chemical formula 10] where n4 represents an integer from 3 to 5, n12' represents an integer from 0 to 3, n12'' is an integer from 0 to 3, and ring B ² is dihydroindenyl, indolyl or isoindolinyl, R ^B21 and R ^B22 both represent hydrogen atoms and L ² is the structure represented by the formula [V-20] [Chemical formula 11] , where n5 is an integer from 1 to 2; And R ⁴ represents a group represented by the formula [VI] [Chemical formula 12] where ring C is phenyl, pyridyl, pyrimidinyl, dihydropyridinyl, dihydrobenzofuranyl, benzodioxanyl, indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl, indolinyl or dihydroquinazolinyl, where phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition, phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl, optionally substituted with one group selected from the group consisting of hydroxy and C _{1 -6} alkoxy, halogen-C _1-6 alkyl, optionally substituted with one hydroxy, C _2-6 alkenyl, C _3-8 cycloalkyl, optionally substituted with one hydroxy, C _1-6 alkoxy, halogen-C _1-6 alkoxy, C _{3 -8} cycloalkoxy, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl and mono-C _1-6 alkylaminocarbonyl, pyridyl is substituted with one C _1-6 alkoxy and, in addition, pyridyl is optionally substituted with one group selected from the group consisting of cyano and C _1-6 alkoxy, pyrimidinyl is substituted with one C _1-6 alkoxy and, in addition, pyrimidinyl is optionally substituted with one C _1-6 alkoxy, dihydropyridinyl is substituted with one C _1-6 alkoxy and, in addition, The dihydropyridinyl is optionally substituted with one to two groups, the same or different, selected from the group consisting of C _1-6 alkyl and oxo, dihydrobenzofuranyl and benzodioxanyl are optionally substituted with one C ₁ - ₆ alkoxy, indolyl, indazolyl, benzimidazolyl, pyrazolopyridinyl and indolinyl are optionally substituted with one or two groups, the same or different, selected from the group consisting of C _1-6 alkyl and C _1-6 alkoxy, and dihydroquinazolinyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy and oxo; or the fused ring formed by R ³ and R ⁴ together with their adjacent carbon atom is dihydroindene or dihydrobenzofuran, and The dihydroindene and dihydrobenzofuran are optionally substituted with one or two halogen atoms. 4. A compound according to claim 1 or 2 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], X represents carboxy, C _1-4 alkoxycarbonyl or tetrazolyl; R ¹ represents a hydrogen atom; And R ² represents a group represented by the above formula [IV-1] or [IV-2]: [Chemical formula 13] 5. Connection according to any one of paragraphs. 1, 2 and 4 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], W represents methandiyl or the structure represented by the formula [III-1] [Chemical formula 14] wherein the methanediyl is optionally substituted by one group selected from the group consisting of C _1-6 alkyl, optionally substituted by one group selected from the group consisting of hydroxy and carboxy, halo-C _1-6 alkyl, C _3-8 cycloalkyl, phenyl- C _1-3 alkyl and pyridyl-C _1-3 alkyl, and, if methandiyl is substituted with one methyl, it is optionally further substituted with one methyl, and where, in the structure represented by formula [III-1], ring A ¹ is a C _3-8 cycloalkane, a partially substituted 9-10 membered fused hydrocarbon aromatic ring containing an oxygen atom 4-8 membered saturated heterocycle, containing a sulfur atom 4-8 membered saturated heterocycle or containing a nitrogen atom 4- 8-membered saturated heterocycle, where the sulfur atom in the sulfur atom-containing 4-8-membered saturated heterocycle is optionally replaced by one to two oxos, and the nitrogen atom in the nitrogen atom-containing 4-8 membered saturated heterocycle is optionally substituted by one group selected from the group consisting of C _1-4 alkylcarbonyl and C _1-4 alkoxycarbonyl, and R ^A11 represents a hydrogen atom, hydroxy, carboxy, halogen atom, C _1-6 alkyl, C _1-6 alkoxy or a nitrogen-containing 4-6 membered saturated heterocyclyl, optionally substituted with one C _1-3 alkyl, and R ^A12 represents a hydrogen atom, a halogen or methyl atom or R ^A11 and R ^A12 optionally together form oxo and, in addition, R ^A11 and R ^A12 optionally form a C _3-6 cycloalkane together with the carbon atoms in the adjacent ring. 6. Connection according to any one of paragraphs. 1, 2, 4 and 5 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], R ⁴ represents a group represented by the formula [VI] [Chemical formula 15] where ring C represents phenyl, phenyl is substituted by one group selected from the group consisting of a halogen atom, C _1-6 alkyl, C _1-6 alkoxy and C _1-6 alkylcarbonyl, and in addition, phenyl is optionally substituted with one to four groups, the same or different, selected from the group consisting of hydroxy, carboxy, carbamoyl, cyano, halogen atom, C _1-6 alkyl, optionally substituted with one group selected from the group consisting of hydroxy and C _{1 -6} alkoxy, halogen-C _1-6 alkyl, optionally substituted with one hydroxy, C _2-6 alkenyl, C _2-6 alkynyl, C _3-8 cycloalkyl, optionally substituted with one hydroxy, C _1-6 alkoxy, halogen-C _{1 -6} alkoxy, C _3-8 cycloalkoxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, mono-C _1-6 alkylamino, di-C _1-6 alkylamino, C _1-6 alkylcarbonyl, halo-C _1-6 alkylcarbonyl, C _1-6 alkoxycarbonyl, mono-C _1-6 alkylaminocarbonyl and di-C _1-6 alkylaminocarbonyl. 7. Connection according to any one of paragraphs. 1, 2 and 4-6 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], R ² represents a group represented by the formula [IV-1] or [IV-2]: [Chemical formula 16] where ring B ¹ represents phenyl, R ^B11 and R ^B12 each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl or a C _1-6 alkoxy and L ¹ is any of the structures represented by formulas [V-3] - [V-5], [V-7] - [V-8], [V-11] - [V-12] and [V-14] - [V-16]: [Chemical formula 17] where n4 is an integer between 3 and 5, and ring B ² is dihydroindenyl, indolyl or isoindolinyl, R ^B21 and R ^B22 both represent hydrogen atoms and L ² is the structure represented by the formula [V-20] [Chemical formula 18] where n5 represents an integer between 1 and 2. 8. Connection according to any one of paragraphs. 4-7 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], X represents carboxy; W is any of the structures represented by formulas [III-4] - [III-17]: [Chemical formula 19] R ² represents a group represented by the formula [IV-1] or [IV-2]: [Chemical formula 20] where ring B ¹ represents phenyl, R ^B11 and R ^B12 both represent hydrogen atoms and L ¹ is a structure represented by the formula [V-3], [V-8], [V-12], [V-14] or [V-15]: [Chemical formula 21] where n4 is an integer between 3 and 4, and ring B ² is dihydroindenyl, R ^B21 and R ^B22 both represent hydrogen atoms and L ² is the structure represented by the formula [V-20] [Chemical formula 22] where n5 is 2; R ³ represents methyl having the spatial configuration represented by the formula [VII] [Chemical formula 23] And R ⁴ represents a group represented by any of the formulas [VI-1] - [VI-21]: [Chemical formula 24] [Chemical formula 25] [Chemical formula 26] 9. Connection according to any one of paragraphs. 4-7 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], X represents carboxy; W is a structure represented by any of the formulas [III-4] - [III-11], [III-13] - [III-14] and [III-18] - [III-19]: [Chemical formula 27] R ² represents a group represented by the formula [IV-1] or [IV-2]: [Chemical formula 28] where ring B ¹ represents phenyl, R ^B11 and R ^B12 both represent hydrogen atoms and L ¹ is a structure represented by formula [V-3], [V-8] or [V-14]: [Chemical formula 29] where n4 is equal to, and ring B ² is dihydroindenyl, R ^B21 and R ^B22 both represent hydrogen atoms and L ² is the structure represented by the formula [V-20] [Chemical formula 30] where n5 is 2; R ³ represents methyl having the spatial configuration represented by the formula [VII] [Chemical formula 31] And R ⁴ represents a group represented by the formula [VI-2], [VI-3], [VI-8], [VI-10] - [VI-12], [VI-16], [VI-19] or [VI-21]: [Chemical formula 32] [Chemical formula 33] 10. Connection according to any one of paragraphs. 4-7 or a pharmaceutically acceptable salt or hydrate thereof, where, in the above formula [I], X represents carboxy or tetrazolyl; W is a structure represented by the formula [III-5], [III-8] - [III-11] or [III-13]: [Chemical formula 34] R ² represents a group represented by the formula [IV-1] or [IV-2]: [Chemical formula 35] where ring B ¹ represents phenyl, R ^B11 and R ^B12 both represent hydrogen atoms and L ¹ is a structure represented by formula [V-3], [V-12] or [V-14]: [Chemical formula 36] where n4 represents an integer from 4, and ring B ² is dihydroindenyl, R ^B21 and R ^B22 both represent hydrogen atoms and L ² is the structure represented by the formula [V-20] [Chemical formula 37] where n5 is 2; R ³ represents methyl having the spatial configuration represented by the formula [VII] [Chemical formula 38] And R ⁴ represents a group represented by the formula [VI-2], [VI-7], [VI-8], [VI-10], [VI-11] or [VI-12]: [Chemical formula 39] 11. A compound according to claim 1, which is any of the following: [Chemical formula 40] [Chemical formula 41] [Chemical formula 42] [Chemical formula 43] [Chemical formula 44] or a pharmaceutically acceptable salt or hydrate thereof. 12. A compound according to claim 1, which is any of the following: [Chemical formula 45] [Chemical formula 46] [Chemical formula 47] or a pharmaceutically acceptable salt or hydrate thereof. 13. A medicinal product for the prevention or treatment of a disease caused by LPA1, containing a compound according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt or hydrate thereof as the active ingredient. 14. An LPA1 receptor antagonist containing a compound according to any one of claims. 1-12 or a pharmaceutically acceptable salt or hydrate thereof as the active ingredient. 15. A medicinal product for the prevention or treatment of systemic scleroderma, containing a compound according to any one of paragraphs. 1-12 or a pharmaceutically acceptable salt or hydrate thereof as the active ingredient.