JP2018087189A - Pharmaceutical application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide pharmaceutical compositions containing as an active ingredient a compound having antagonistic activity against EPreceptor, in the prevention and/or treatment of various diseases attributed to the activation of EPreceptor.SOLUTION: The present invention provides a compound represented by general formula (I), its salt, its N-oxide body, its solvate, or their prodrugs. L1 is alkylene and the like, L2 is-CH2CH2- and the like, X1 and X2 are nitrogen and the like, X3 is methylene, oxygen and the like.SELECTED DRAWING: None

Description

  The present invention relates to the following general formula (I)

(Wherein all symbols have the same meaning as described below), a tricyclic spiro compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof (hereinafter referred to as the present invention). And a therapeutic and / or prophylactic agent for diseases related to EP ₄ receptor.

Prostaglandin E ₂ (PGE ₂ ) is known as a metabolite in the arachidonic acid cascade, and has a cytoprotective action, a uterine contraction action, a pain threshold lowering action, a gastrointestinal peristaltic action promoting action, a waking action, a gastric acid It is known to have a secretion inhibitory action, a blood pressure lowering action, a diuretic action, and the like.

In recent studies, it has been found that PGE ₂ receptors have subtypes with different roles. There are roughly four subtypes known at the present time, which are called EP ₁ , EP ₂ , EP ₃ , and EP ₄ , respectively (Non-patent Document 1).

Among these subtypes, EP ₄ receptor is an anti-inflammatory agent by inhibiting MCP-1 production from macrophages, inhibiting TNF-α, IL-2, and IFN-γ production from lymphocytes, and enhancing IL-10 production. , Vasodilation, angiogenesis, suppression of elastic fiber formation, and MMP-9 expression control. Furthermore, the EP ₄ receptor is considered to be involved in cancer immunoregulation via myeloid derived suppressor cells, regulatory T cells, and natural killer cells.

From these facts, compounds that bind strongly to the EP ₄ receptor and have an antagonistic action can be used for diseases caused by activation of the EP ₄ receptor, such as bone disease, cancer, systemic granulomas, immune diseases, allergies, atopy. , Asthma, alveolar pyorrhea, gingivitis, periodontal disease, Alzheimer, Kawasaki disease, burns, multiple organ failure, chronic headache, pain, vasculitis, venous insufficiency, varicose vein, aneurysm, aortic aneurysm, hemorrhoids, diabetes insipidus It is considered useful for prevention and / or treatment of diseases such as stress, endometriosis, adenomyosis, neonatal patent ductus arteriosus, and cholelithiasis (Non-patent Documents 2-7).

On the other hand, in Patent Document 1, a compound represented by the following general formula (A) is used as a compound used for treatment of diseases related to prostaglandin E receptor, such as pain, inflammation, and cancer. It is described.

  General formula (A) is

Wherein Ar ^1a is an aryl or heteroaryl group optionally substituted with R ^1a or R ^3a ;
R ^1a is CN, NO ₂ , CON (R ^5a ) ₂ or the like;
W ^a represents a 3 to 6 membered linking group containing 0 to 2 heteroatoms selected from O, N and S, wherein the linking group is optionally CO, S (O) _na , C═C, Or contains an acetylene group;
Ar ^2a is an aryl or heteroaryl group optionally substituted with R ^3a ;
R ^3a is halogen, CN or the like;
X ^a is a linker attached to the ortho of Ar ^2a to the binding site of W ^a ;
Q ^a is COOH or the like. (Partial definition is excerpted.)).

Patent Document 2 discloses that the compound of the following general formula (B) binds to PGE ₂ receptor, particularly EP ₃ and / or EP ₄ and has an antagonistic action. It is described as being useful for prevention and / or treatment.

  General formula (B) is

(Wherein R ^1b represents —COOH or the like;
A ^b represents (i) a single bond, (ii) Cl to 6 alkylene, and (iii) C2-6 alkenylene or (iv) C2-6 alkynylene;
B ^b ring represents a monocyclic or bicyclic heterocyclic monocyclic or bicyclic carbon ring of C3~12 or 3-12 membered;
R ^2b represents nitro, cyano or the like;
Q ^b represents C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkyl substituted by 1 to 3 halogen atoms, cyano, nitro, or the like;
D ^b is a connecting chain composed of one or two atoms selected from a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom, and the chain may contain a double bond or a triple bond, and the connecting chain ^May be substituted with 1 to 4 R ^40b ;
R ^40b represents oxo or halogen;
R ^3b is (1) C 1-6 alkyl, or (2) 1 to 5 R ^42b substituted or unsubstituted C 3-15 monocyclic, bicyclic or tricyclic carbocycles, or 3 Represents a -15 membered monocyclic, bicyclic or tricyclic heterocycle;
R ^42b is C 1-6 alkyl, C 1-6 alkoxy, halogen, cyano, —NR ^46b.
It represents COR ^47b or Cyc10 ^b . (Partial definition is excerpted.)).

  Furthermore, in Patent Document 3, a compound represented by the following general formula (C) is used as a compound used for treatment of diseases associated with prostaglandin E receptor, such as pain, inflammation, and cancer. It is described.

  General formula (C) is

Wherein HET ^c is a 5-12 membered monocyclic or bicyclic aromatic ring having 0-3 heteroatoms selected from O, S (O) _nc , and N (O) _mc Represents the system, mc is 0 or 1, nc is 0, 1 or 2;
^Ac is a 1- or 2-atom moiety and is selected from the group consisting of —W ^c — or —C (O) —, etc., and W ^c is O, S (O) _nc , or NR ^17c ;
X ^c represents a 5- to 10-membered monocyclic or bicyclic aryl or heteroaryl group having 1 to 3 heteroatoms selected from O, S (O) _nc , and N (O) _mc Represent,
Y ^c represents O, S (O) _nc , NR ^17c , or a bond;
B ^c is — (C (R ^18c ) ₂ ) _pc —Y ^c — (C (R ^18c ) ₂ ) _qc —;
pc and qc are independently 0-3;
Z ^c is OH or the like;
R ^1c , R ^2c , and R ^3c independently represent halogen, —CO ₂ R ^9c , —CON (R ^6c ) ₂ or the like. (Partial definition is excerpted.)).

  In any of the prior art documents, there is no description or suggestion about a tricyclic spiro compound which is a compound used in the present invention.

International Publication No. 2000/020371 Pamphlet International Publication No. 2003/016254 Pamphlet International Publication No. 1999/047497 Pamphlet

Journal of Lipid Mediators and Cell Signaling, Vol. 12, pages 379-391, 1995 Pharmacological Reviews, 65, 1010-1052, July, 2013 105th American Association for Cancer Research (AACR), Abstract No .: LB-265, Presentation Title: ONO-AE3-208 inhibitory suppressors cells and month 14 Day FEBS Letters, 364, 339-341, 1995 Cancer Science, 105, 1142-1151, 2014 Cancer Research, 70, 1606-1615, 2010 Cancer Research, 62, 28-32, 2002

An object of the present invention is to provide a pharmaceutical composition containing a compound having a strong antagonistic activity against EP ₄ receptor and exhibiting good pharmacokinetics, and prevention and / or prevention of diseases caused by activation of EP ₄ receptor. Or to provide a therapeutic agent.

In order to solve the above-mentioned problems, the present inventors have intensively studied to find a compound having a strong antagonistic activity against the EP ₄ receptor and exhibiting good pharmacokinetics. As a result, the following general formula (I) The present invention was completed by finding that the compound represented by the above formula strongly antagonizes the EP ₄ receptor.

That is, the present invention
[1] General formula (I)

(Where
R ¹ represents COOR ⁸ , tetrazole, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHR ^8-1 , CONHSO ₂ R ^8-1 , SO ₂ NHCOR ^8-1 , or hydroxamic acid,
R ⁸ represents a hydrogen atom, C 1-4 alkyl, or benzyl,
R ^8-1 represents C 1-4 alkyl, C 1-4 haloalkyl, a C 3-10 carbocycle, or a 3-10 membered heterocyclic ring, each of the C 3-10 carbocycle and 3-10 membered heterocyclic ring being C 1 -4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -O (C1-4 haloalkyl), C1-4 alkylthio, -S (C1-4 haloalkyl), halogen, or nitrile ("-CN" is shown below; The same)),
L ¹ represents C 1-5 alkylene, C 2-5 alkenylene, or C 2-5 alkynylene,
R ² is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C ^2-4 alkenyl, C ^2-4 alkynyl, —O (C 1-4 haloalkyl), —S (C 1-4 haloalkyl), — C (O) (C1-4 alkyl), —SO ₂ (C1-4 alkyl), —CONH (C1-4 alkyl), —CON (C1-4 alkyl) ₂ , —NHC (O) (C1-4 alkyl) ), - N (C1-4 alkyl) C (O) (C1-4 alkyl), _- NHSO 2 (C1-4 alkyl), - N (C1-4 _alkyl) SO 2 (C1-4 alkyl), - SO ₂ NH (C1-4 alkyl), —SO ₂ N (C1-4 alkyl) ₂ , —NR ¹⁷ R
^{17 represents} nitro, nitrile, hydroxyl group, aldehyde (indicating formyl; the same shall apply hereinafter) or carboxyl, each C1-4 alkyl may be substituted with halogen,
The in ^{R 2} and (C1-4 _{alkyl) 2,} independently represents a two C1-4 alkyl, each of C1-4 alkyl may be the same or different,
X ¹ represents CR ⁶ or a nitrogen atom, R ⁶ represents a hydrogen atom or R ² ,
X ² represents CR ⁷ or a nitrogen atom, R ⁷ represents a hydrogen atom, R ² , or —L ³ —R ⁹ , and L ³ represents a methylene, oxygen atom, or an optionally oxidized sulfur atom. R ⁹ represents a 4-10 membered heterocyclic ring optionally substituted with a substituent selected from the group consisting of halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
L ² _{is, -CH 2 CH 2 -, -} CH = CH -, - CH 2 O -, - OCH 2 -, - CH 2 S -, - SCH 2 -, - CH 2 S (O) -, - S _{(O) CH 2 -, -} CH 2 SO 2 -, - SO 2 CH 2 -, - CH 2 NH -, - NHCH 2 -, - NHCO -, - CONH -, - NHSO 2 -, or _-SO 2 NH -
R ³ represents C 1-4 alkyl or halogen,
R ⁴ represents halogen, C ^1-4 alkyl, or C ^1-4 haloalkyl,
X ³ represents methylene, an oxygen atom, an optionally oxidized sulfur atom, or NR ¹⁰ , and R ¹⁰ represents C 1-4 alkyl, —C (O) (C 1-4 alkyl), —C (O). O (C1-4 alkyl), or _-SO 2 represents (C1-4 alkyl), each of which C1-4 alkyl may be substituted by halogen,
ring represents a benzene ring or a 5-6 membered monocyclic aromatic heterocycle;

Represents a single bond or a double bond,
R ⁵ is (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5) -CONHR ¹¹ , (6) -C (O) R ¹² , (7) -OR ¹⁴ , (8) -S (O) _t R ¹⁵ , (9) —CH ₂ R ¹⁶ , (10) —NR ¹⁷ R ¹⁷ , (11) —NHCOR ¹¹ , (12) C 4-10 carbocyclic ring, or ( 13) Represents a 4-10 membered heterocyclic ring, and the C4-10 carbocyclic ring or 4-10 membered heterocyclic ring may be substituted with 1 to 3 R ^{18 s} , and when R ¹⁸ is plural, ¹⁸ may be independently the same or different,
R ¹¹ is, C1-6 alkyl, represents C3-6 cycloalkyl, phenyl, or a 4-6 membered heterocyclic ^{ring, R 11} may be optionally substituted with 1-3 ^{R 13,} wherein ^{R 13} is more Each R ¹³ may independently be the same or different,
R ¹³ represents halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, hydroxyl group, —NR ²⁰ R ²¹ , benzene, or a 4-6 membered heterocyclic ring;
R ²⁰ and R ²¹ each independently represents a hydrogen atom or C 1-4 alkyl;
R ¹² represents C 1-6 alkyl, C 3-6 cycloalkyl, benzene, or a 4-6 membered heterocyclic ring, and the C 3-6 cycloalkyl, benzene, or 4-6 membered heterocyclic ring each independently represents: Optionally substituted with halogen, C1-4 alkyl, or C1-4 alkoxy;
R ¹⁴ is a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, benzene or a benzyl, wherein the C1-6 alkyl may be optionally substituted with 1-3 ^{R 19,} wherein ^{R 19} is When there are a plurality of R ^{19 s} , each R ¹⁹ may be independently the same or different;
R ¹⁹ is substituted with a substituent selected from the group consisting of C 1-4 alkoxy, —CONH (C 1-4 alkyl), —CON (C 1-4 alkyl) ₂ , or C 1-4 alkyl and C 1-4 haloalkyl. Represents a 5-6 membered monocyclic aromatic heterocycle which may have
(C1-4 alkyl) ₂ in R ¹⁹ represents two independent C1-4 alkyl, and each C1-4 alkyl may be the same or different;
R ¹⁵ represents C 1-6 alkyl, C 3-6 cycloalkyl, benzene, or benzyl,
R ¹⁶ represents a hydroxyl group or C 1-4 alkoxy;
R ¹⁷ each independently represents a hydrogen atom, C 1-6 alkyl, or C 3-6 cycloalkyl;
R ¹⁸ is halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, oxo, nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C 1-4 alkyl) SO ₂ —, 4-6 membered heterocyclic ring, (C1-4 alkyl) NH-, or (C1-4 _alkyl) 2 N-a represents,
(C1-4 alkyl) ₂ in R ¹⁸ represents two independent C1-4 alkyl, and each C1-4 alkyl may be the same or different;
m represents an integer of 1 to 4, n represents an integer of 0 to 4, p represents an integer of 0 to 2, q represents an integer of 0 to 6, r represents an integer of 0 to 6, s represents an integer of 0 to 4, t represents an integer of 0 to 2,
However, when p, q, r, and s each represent an integer of 2 or more, R ² , R ³ , R ⁴ , and R ⁵ may be independently the same or different. ), A salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof,
[2] The compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is represented by the general formula (I-1)

(In the formula, na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, X ^3a represents a methylene or oxygen atom, and the other symbols are those described above. [1] represents the same meaning as the symbol described above), a pharmaceutical composition according to the above [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.
[3] The pharmaceutical composition according to the above [1] or [2], wherein at least one R ⁵ is —CONHR ¹¹ ;
[4] The pharmaceutical composition according to any one of [1] to [3], wherein L ² is —NHCO— or —CONH—,
[5] The compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is represented by the general formula (I-2)

Wherein R ^2a represents halogen, R ^6a represents a hydrogen atom or halogen, and other symbols have the same meanings as described in the above [1] or [2], and salts thereof , An N-oxide thereof, a solvate thereof, or a prodrug thereof, the pharmaceutical composition according to any one of [1] to [4] above,
[6]
(1) 4- [4-Cyano-2-({[(2′R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(2) 4- {4-cyano-2-[({(2′R, 4S) -6-[(cyclopropylmethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(3) 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(4) 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-methyl-2-propanyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(5) 4- [4-cyano-2-({[(2′R, 4S) -6-{[(2S) -1-methoxy-2-propanyl] carbamoyl} -2,3-dihydrospiro [chromene] -4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(6) 4- {4-cyano-2-[({(2′R, 4S) -6-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] -2,3-dihydrospiro [chromene -4,1'-cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(7) 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(8) 4- [4-cyano-2-({[(2′R, 4S) -6- (isopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(9) 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclopentylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(10) 4- {2-[({(2′R, 4S) -6-[(2S) -2-butanylcarbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl} carbonyl) amino] -4-cyanophenyl} butanoic acid,
(11) 4- {4-cyano-2-[({(2′R, 4S) -6-[(trans-4-hydroxycyclohexyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1
'-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(12) 4- {4-cyano-2-[({(2′R, 4S) -6-[(cis-4-hydroxycyclohexyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(13) 4- [4-Cyano-2-({[(2′R, 4S) -6- (2-pyridinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(14) 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridazinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(15) 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclobutylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(16) 4- [4-cyano-2-({[(2′R, 4S) -6-{[1- (2-methyl-2-propanyl) -1H-pyrazol-4-yl] carbamoyl}- 2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(17) 4- [4-cyano-2-({[(2′R, 4S) -6- (tetrahydro-2H-pyran-4-ylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(18) 4- [4-cyano-2-({[(2'R, 4S) -6- (propylcarbamoyl) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2 ' -Yl] carbonyl} amino) phenyl] butanoic acid,
(19) 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-ethoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(20) 4- [4-cyano-2-({[(2′R, 4S) -6- (ethylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(21) 4- [4-Cyano-2-({[(1R, 2R) -6 ′-(methylcarbamoyl) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -2 -Yl] carbonyl} amino) phenyl] butanoic acid,
(22) 4- {4-cyano-2-[({(1R, 2R) -6 ′-[(2-methoxyethyl) carbamoyl] -2 ′, 3′-dihydrospiro [cyclopropane-1,1 ′ -Indene] -2-yl} carbonyl) amino] phenyl} butanoic acid,
(23) 4- {4-cyano-2-[({(1R, 2R) -6 ′-[(1-methyl-1H-pyrazol-4-yl) carbamoyl] -2 ′, 3′-dihydrospiro [ Cyclopropane-1,1′-indene] -2-yl} carbonyl) amino] phenyl} butanoic acid,
(24) 4- [4-cyano-2-({[(2′R, 4S) -7-fluoro-6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(25) 4- {4-cyano-2-[({(2′R, 4S) -7-fluoro-6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4, 1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid,
(26) 4- [4-cyano-2-({[(2′R, 4S) -7-fluoro-6- (isopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(27) 4- [4-cyano-2-({[(2′R, 4S) -7- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(28) 4- {4-cyano-2-[({(2′R, 4S) -7-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(29) 4- [4-cyano-2-({[(2′R, 4S) -7-methoxy-6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(30) 4- {4-cyano-2-[({(2'R, 4S) -7-methoxy-6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4, 1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid,
(31) 4- [4-cyano-2-({[(2′R, 3S) -5- (methylcarbamoyl) -2H-spiro [1-benzofuran-3,1′-cyclopropane] -2′- Yl] carbonyl} amino) phenyl] butanoic acid,
(32) 4- {4-cyano-2-[({(2′R, 3S) -5-[(2-methoxyethyl) carbamoyl] -2H-spiro [1-benzofuran-3,1′-cyclopropane] ] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(33) 4- [4-cyano-2-({[(1S, 2R) -6 ′-[(2-methoxyethyl) carbamoyl] -3 ′, 3′-dimethyl-2 ′, 3′-dihydrospiro [Cyclopropane-1,1′-indene] -2-yl] carbonyl} amino) phenyl] butanoic acid, or (34) 4- [4-cyano-2-({[(1S, 2R) -3 ′, 3′-dimethyl-6 ′-(methylcarbamoyl) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -2-yl] carbonyl} amino) phenyl] butanoic acid, its salt, its The pharmaceutical composition according to the above [1], which contains an N-oxide, a solvate thereof, or a prodrug thereof,
[7] at least one of ^{R 5} may be substituted with 1-3 ^{R 18,} a C4-10 carbocyclic or 4-10 membered heterocyclic ring, if the ^{R 18} is plural, R ¹⁸ is a pharmaceutical composition according to the above [1] or [2], which may be independently the same or different;
[8] The pharmaceutical composition according to the above [7], wherein L ² is —NHCO— or —CONH—, [9] the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, Solvates, or prodrugs thereof, have the general formula (I-3)

^{(Wherein, R 5a} is optionally substituted with 1-3 ^{R 18,} a C4-10 carbocyclic or 4-10 membered heterocyclic ring, if the ^{R 18} is ^{plural, R 18} is Each may be independently the same or different, and the other symbols have the same meanings as those described in the above [1], [2], or [5])), compounds thereof, salts thereof, N— The pharmaceutical composition according to any one of [1], [2], [7], or [8], which is an oxide, a solvate thereof, or a prodrug thereof,
[10]
(1) 4- [4-Cyano-2-({[(2′R, 4S) -6- (5-methyl-1,3,4-oxadiazol-2-yl) -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(2) 4- [4-cyano-2-({[(2′R, 4S) -6- (5-cyclopropyl-1,3,4-oxadiazol-2-yl) -2,3- Dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(3) 4- [4-cyano-2-({[(2′R, 4S) -6- (3-methyl-1,2,4-oxadiazol-5-yl) -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(4) 4- [4-Cyano-2-({[(2′R, 4S) -6- (3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(5) 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-1-yl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(6) 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-5-yl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(7) 4- [4-cyano-2-({[(2′R, 4S) -6- (4-pyridazinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(8) 4- [4-cyano-2-({[(2′R, 4S) -6- (2-oxo-1-pyrrolidinyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(9) 4- [4-Cyano-2-({[(2′R, 4S) -6- (6-methoxy-3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(10) 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (1H-pyrazol-1-yl) -3-pyridinyl] -2,3-dihydrospiro [ Chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid,
(11) 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (dimethylamino) -3-pyridinyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(12) 4- [4-cyano-2-({[(2′R, 4S) -6- (6-methyl-3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(13) 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (methylamino) -3-pyridinyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(14) 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(15) 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-thiazol-2-yl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(16) 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-oxazol-2-yl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(17) 4- [4-cyano-2-({[(2′R, 4S) -6- (1-methyl-1H-1,2,3-triazol-4-yl) -2,3-dihydro Spiro [chromene-4,1 '
-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(18) 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridazinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(19) 4- [4-Cyano-2-({[(2′R, 3S) -5- (3-pyridinyl) -2H-spiro [1-benzofuran-3,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid or (20) 4- [4-cyano-2-({[(1S, 2R) -3 ′, 3′-dimethyl-6 ′-(3-pyridinyl)] -2 ', 3'-dihydrospiro [cyclopropane-1,1'-inden] -2-yl] carbonyl} amino) phenyl] butanoic acid, its salt, its N-oxide, its solvate, or they The pharmaceutical composition according to the above [1], comprising a prodrug of
[11] The pharmaceutical composition according to the above [1], which is an EP ₄ receptor antagonist,
[12] A pharmaceutically acceptable carrier comprising the compound represented by the general formula (I) described in [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. comprising a prophylactic and / or therapeutic agent for diseases caused by the activation of EP ₄ receptor, [13] EP ₄ disease caused by receptor activation, bone diseases, cancer, systemic granulomatosis Tumor, immune disease, alveolar pyorrhea, gingivitis, periodontal disease, Kawasaki disease, multiple organ failure, chronic headache, pain, vasculitis, venous failure, varicose vein, aneurysm, aortic aneurysm, hemorrhoids, diabetes insipidus, newborn The agent according to the above [12], which is patent ductus arteriosus or cholelithiasis,
[14] Cancer is breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, malignant lymphoma, uveal malignant melanoma, thymoma, mesothelioma, esophageal cancer, stomach cancer, Duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis / ureteral cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vagina The agent according to the above [13], which is cancer, vulvar cancer, skin cancer, malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, or multiple myeloma,
[15] The compound represented by the general formula (I) described in [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, an alkylating agent, an antimetabolite, and an anticancer agent Antibiotics, botanical preparations, hormone agents, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteasome inhibitors, HDAC inhibitors, and immunomodulators A pharmaceutical comprising a combination of at least one selected from the group consisting of:
[16] The compound represented by the general formula (I) described in [1], a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, an HMG-CoA reductase inhibitor, an antihypertensive agent And a pharmaceutical comprising a combination of at least one selected from the group consisting of tetracycline antibiotics, or [17] the compound represented by the general formula (I) described in [1], a salt thereof, and an N-oxide thereof Body, its solvate, or prodrug thereof, at least one selected from the group consisting of an N-type calcium channel inhibitor, a nitric oxide synthase (NOS) inhibitor, and a cannabinoid-2 receptor stimulator It relates to a medicine comprising a combination of

Since the compound used in the present invention has a strong antagonistic activity against the EP ₄ receptor and exhibits better pharmacokinetics, the pharmaceutical composition containing the compound used in the present invention is an EP ₄ receptor. It becomes a preventive and / or therapeutic agent for a disease caused by activation of.

It is the figure which showed the anti-tumor effect of the compound used for this invention in the allograft model of mouse | mouth colon cancer cell line CT26.

  Hereinafter, the present invention will be described in detail.

  In the present invention, “C1-4 alkyl” is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, and isobutyl.

  In the present invention, “C1-3 alkyl” is, for example, methyl, ethyl, n-propyl, and isopropyl.

  In the present invention, “C 1-5 alkylene” is, for example, methylene, ethylene, propylene, butylene, and pentylene.

  In the present invention, “C2-5 alkenylene” means, for example, ethenylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene, 2-pentenylene, 3 -Pentenylene, 4-pentenylene and the like.

  In the present invention, “C2-5 alkynylene” means, for example, ethynylene, 1-propynylene, 2-propynylene, 1-butynylene, 2-butynylene, 3-butynylene, 1-pentynylene, 2-pentynylene, and 3-pentynylene. 4-pentynylene and the like.

  In the present invention, “halogen” is fluorine, chlorine, bromine, and iodine.

  In the present invention, “C1-4 alkoxy” includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, tert-butoxy, isobutoxy and the like.

  In the present invention, “C1-4 alkylthio” includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, 1-methylpropylthio, tert-butylthio, isobutylthio and the like.

  In the present invention, “C2-4 alkenyl” includes, for example, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl and the like.

  In the present invention, “C2-4 alkynyl” includes, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and the like.

In the present invention, “C1-4 haloalkyl” refers to C1-4 alkyl substituted with halogen, such as monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 2, 2-difluoroethyl, 1,2-difluoroethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, 1,2,2-trifluoroethyl, 1,1,2-trifluoroethyl, 1 , 2,2,2-tetrafluoroethyl, 1,1,2,2-tetrafluoroethyl, pentafluoroethyl, 1,2-dibromo-1,2,2-trifluoroethyl, 1-chloro-1,2 2,2-tetrafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2-fluoropropyl, 2-chloropropyl, 1-fluoropropyl Pill, 1-chloropropyl, 3,3-difluoropropyl, 2,3-difluoropropyl, 1,3-difluoropropyl, 1,2-difluoropropyl, 2,2-difluoropropyl, 1,1-difluoropropyl, 3 , 3,3-trifluoropropyl, 2,3,3-trifluoropropyl, 1,3,3-trifluoropropyl, 1,2,2-trifluoropropyl, 1,1,2-trifluoropropyl, , 1
, 3-trifluoropropyl, 1,1,2,2-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4-fluorobutyl, 4-chlorobutyl, 3-fluorobutyl, 3-chlorobutyl 2-fluorobutyl, 2-chlorobutyl, 1-fluorobutyl, 1-chlorobutyl, 3,3-difluorobutyl, 2,3-difluorobutyl, 1,3-difluorobutyl, 1,2-difluorobutyl, 2,2 -Difluorobutyl, 1,1-difluorobutyl, 3,3,3-trifluorobutyl, 2,3,3-trifluorobutyl, 1,3,3-trifluorobutyl, 1,2,2-trifluorobutyl 1,1,2-trifluorobutyl, 1,1,3-trifluorobutyl, 1,1,2,2-tetrafluorobutyl, and 2,2,3 3,3-pentafluoro-butyl, and the like.

In the present invention, the “optionally oxidized sulfur atom” refers to sulfur (S), sulfoxide (S (O)), and sulfone (SO ₂ ).

In the present invention, the “4-10 membered heterocyclic ring” is a 4-10 membered monocyclic or bicyclic heterocyclic ring containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. For example, oxetane, azetidine, pyrrolidine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, piperidine, piperazine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, furan, pyran, oxepin, thiophene, Thiopyran, thiepine, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, oxazine, oxadiazine, oxazepine, oxadiazepine, thiadiazole, thiazine, thiadiazine, thiazepine, thiadiazepine, indole, isoindole, i Dridine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, quinoline, isoquinoline, quinolidine, purine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, benzoxazole, benzothiazole, benzimidazole, benzodioxol, benzo Oxathiol, chromene, benzofurazan, benzothiadiazole, benzotriazole, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, dihydropyrazine, tetrahydropyrazine, dihydropyrimidine, tetrahydropyrimidine , Perhydropyrimidine , Dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihydrooxepin, Tetrahydrooxepin, perhydrooxepin, dihydrothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydrothiepin, tetrahydrothiepine, perhydrothiepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), dihydroisoxazole , Tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (Thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), dihydrooxazine, tetrahydrooxazine, dihydrooxadiazine, tetrahydro Oxadiazine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadiazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), dihydrothiazine , Tetrahydrothiazine, dihydrothiadiazine, tetrahydrothiadiazine, dihydrothiazepine, tetrahydrothiazepine, Hydrothiazepine, dihydrothiadiazepine, tetrahydrothiadiazepine, perhydrothiadiazepine, tetrahydrotriazolopyrazine, morpholine, thiomorpholine, oxathian, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydro Isobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, Dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydride Naphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzooxathiane, dihydrobenzoxazine, Dihydrobenzothiazine, pyrazinomorpholine, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxolane, dioxane, dioxaindane, benzodioxane, thiochroman, dihydrobenzodioxin , Dihydrobenzoxanthine, chroman , Pyrazolopyrimidine, imidazopyridazine, imidazopyridine, imidazopyrimidine, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, imidazopyrazine, pyrazolopyridine, pyrazolopyrimidine, triazolopyridine, and dihydropyridoxazine rings.

  In the present invention, the “3-10 membered heterocyclic ring” means a 3-10 membered monocyclic or bicyclic heterocyclic ring containing 1 to 5 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. For example, aziridine, oxirane, thiirane, and the heterocyclic ring described in the above “4-10 membered heterocyclic ring”.

  In the present invention, the “5-10 membered aromatic heterocycle” means a 5-10 membered monocyclic or bicyclic ring containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. Means aromatic heterocycle, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, thiadiazole, pyridine, pyrazine, pyrimidine, pyridazine, Indole, isoindole, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, purine, benzoxazole, benzothiazole, benzimidazole, benzofurazan, benzothiadiazole, benzotriazole, quinoline, isoquine Phosphorus is phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, and cinnoline like.

  In the present invention, “5-6-membered monocyclic aromatic heterocycle” means, for example, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, thiophene, oxazole, isoxazole, thiazole. , Isothiazole, furazane, oxadiazole, and thiadiazole rings.

  In the present invention, the “C4-10 carbocycle” means a C4-10 monocyclic or bicyclic carbocycle, for example, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopentene. , Cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cyclohexadiene, cycloheptadiene, cyclooctadiene, benzene, pentalene, perhydropentalene, azulene, perhydroazulene, indene, perhydroindene, indane, naphthalene, dihydronaphthalene, Tetrahydronaphthalene and perhydronaphthalene ring.

  In the present invention, the “C3-10 carbocycle” means a C3-10 monocyclic or bicyclic carbocycle such as cyclopropane and the carbocycle described in the above “C4-10 carbocycle”. It is.

  In the present invention, “C 1-6 alkyl” means, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3 -Methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1- Dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 1-methyl-1-ethylpropyl, 2-methyl-2-ethylpropyl, 1 -Ethylbutyl, 2-ethylbutyl and the like.

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

  In the present invention, the “4-6 membered heterocycle” means a 4-6 membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. For example, oxetane, azetidine, pyrrolidine, piperidine, pyrazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrimidine, pyridazine, furan, thiophene, oxazole, iso Such as oxazole, thiazole, isothiazole, furazane, oxadiazole, and thiadiazole rings.

In the present invention, R ¹ is preferably COOR ⁸ .

In the present invention, R ⁸ is preferably a hydrogen atom or C1-4 alkyl, and more preferably a hydrogen atom.

In the present invention, R ^8-1 is preferably C1-4 alkyl, benzene or pyridine, and the benzene and pyridine are C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -O (C1-4 haloalkyl). ), C1-4 alkylthio, -S (C1-4 haloalkyl), halogen, or nitrile.

In the present invention, L ¹ is preferably C 1-5 alkylene or C 2-5 alkenylene, more preferably C 1-5 alkylene, and particularly preferably propylene.

In the present invention, R ² is preferably fluorine.

In the present invention, ^{X 1} is preferably a CR ^6.

In the present invention, R ⁶ is preferably a hydrogen atom or fluorine, more preferably a hydrogen atom.

In the present invention, preferably as ^{X 2} is CR ^7.

In the present invention, R ⁷ is preferably fluorine, nitrile, —CH ₂ R ⁹ , or —OR ⁹ , more preferably nitrile.

In the present invention, R ⁹ is preferably a 4-10 membered heterocyclic ring optionally substituted with methyl or trifluoromethyl, and the 4-10 membered heterocyclic ring is preferably a 5-10 membered aromatic heterocyclic ring. , More preferably a 5- to 10-membered nitrogen-containing aromatic heterocycle (eg, pyrazole, imidazole, triazole, pyrrolopyridine, pyrrolopyrimidine, pyrrolopyridazine, imidazopyridazine, imidazopyridine, imidazopyrimidine, imidazopyrazine, pyrazolopyridine, pyrazolo Pyrimidines, etc.).

In the present invention, L ² is preferably —CH═CH—, —NHCO—, —CONH—, —NHSO ₂ —, or —SO ₂ NH—, more preferably —NHCO— or —CONH—, Particularly preferred is -NHCO-.

In the present invention, R ³ is preferably fluorine.

In the present invention, R ⁴ is preferably methyl, ethyl, or trifluoromethyl, more preferably methyl.

In the present invention, X ³ is preferably a methylene or oxygen atom, more preferably an oxygen atom.

In the present invention, R ¹⁰ is preferably methyl, ethyl, methylcarbonyl, ethylcarbonyl, methylsulfonyl, ethylsulfonyl, or tert-butoxycarbonyl.

  In the present invention, the ring is preferably a benzene, thiophene, or pyrazole ring, and more preferably a benzene ring.

In the present invention, R ⁵ is preferably —CONHR ¹¹ , fluorine, methoxy, a benzene ring, or a 4-10 membered heterocyclic ring, and the 4-10 membered heterocyclic ring is preferably azetidine, pyrrolidine, piperidine, oxazolidine, oxadi An azole, triazole, thiophene, furan, pyrazole, thiazole, oxazole, imidazole, pyridine, pyrazine, pyridazine, pyrimidine, pyrazolopyrimidine, pyrrolopyrimidine, pyrazolopyridine, pyrrolopyridine, or dihydropyridooxazine ring.

In the present invention, R ¹¹ is preferably C 1-6 alkyl, C 3-6 cycloalkyl, pyran, pyrrolidine, piperidine, pyrazole, thiazole, oxazole, isoxazole, pyridine, pyridazine, or pyrimidine ring, and more preferably C 1- 6 alkyl.

In the present invention, R ¹³ is preferably a halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, hydroxyl group, —NR ²⁰ R ²¹ , benzene, oxetane, pyridine, pyrazole, or oxazole ring. More preferably, fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, cyclopentyl, cyclobutyl, oxetane, hydroxyl group, methoxy, ethoxy, propoxy, isopropoxy, dimethylamino, benzene , Pyridine, pyrazole, or oxazole ring.

In the present invention, R ²⁰ is preferably a hydrogen atom or methyl.

In the present invention, R ²¹ is preferably a hydrogen atom or methyl.

In the present invention, R ¹² is preferably C 1-3 alkyl, C 3-6 cycloalkyl, benzene, or a 4-6 membered heterocyclic ring. The 4-6 membered heterocyclic ring is preferably oxetane, azetidine, pyrrolidine, piperidine, pyrazine, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, Pyridazine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, furazane, oxadiazole, or thiadiazole ring. The 4-6 membered heterocyclic ring may be substituted with C1-4 alkoxy.

In the present invention, R ¹⁴ is preferably a hydrogen atom, methyl, ethyl, benzene, or benzyl.

In the present invention, R ¹⁹ is preferably methoxy, —CONHCH ₃ , —CON (CH ₃ ) ₂ , oxazole, thiazole, pyrazole, or pyridine ring.

In the present invention, R ¹⁵ is preferably methyl, cyclopropyl, or benzene.

In the present invention, R ¹⁶ is preferably a hydroxyl group.

In the present invention, R ¹⁷ is preferably methyl, ethyl, or cyclopropyl, more preferably methyl.

In the present invention, R ¹⁸ is preferably fluorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, cyclopropyl, methoxy, ethoxy, n-propoxy, isopropoxy, oxo. , Nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, methylsulfonyl, pyridine, dimethylamino.

  In the present invention, m is preferably an integer of 1 to 2, and more preferably 1.

  In the present invention, n is preferably an integer of 0 to 1, more preferably 1.

  In the present invention, p is preferably 0.

  In the present invention, q is preferably 0.

  In the present invention, r is preferably an integer of 0 to 4, more preferably an integer of 0 to 2.

  In the present invention, s is preferably an integer of 0 to 2, more preferably 1 or 2.

  In the present invention, t is preferably an integer of 0 to 2.

In the present invention, X ^3a is preferably an oxygen atom.

  In the present invention, na is preferably an integer of 0 to 1, more preferably 1.

  In the present invention, qa is preferably 0.

  In the present invention, ra is preferably an integer of 0 to 2.

In the present invention, the general formula (I) is preferably the ring, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ^8-1 , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁶ , R ¹⁷ , R ¹⁸ , R ¹⁹ , R ²⁰ , R ²¹ , L ¹ , L ² , L ³ , X ¹ , X ² , A preferred definition combination of each of X ³ , m, n, p, q, r, s, and t.

  In the present invention, the compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is preferably represented by formula (Ia).

(Wherein all symbols have the same meanings as described in [1] and [2] above), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof And more preferably the general formula (I-1)

(Wherein all symbols have the same meanings as described in [1] and [2] above), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof It is.

  In the present invention, as another embodiment of the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, more preferably, the general formula (Ib)

(Wherein all symbols have the same meanings as described in [1] and [2] above), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof More preferably, the formula (Ic)

(Wherein all symbols have the same meanings as described in [1] and [2] above), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof And preferably still the general formula (Id)

(Wherein all symbols have the same meanings as described in [1] and [2] above), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof And more preferably still the general formula (Ie)

(Wherein all symbols have the same meanings as described in [1] and [2] above), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof And particularly preferably the formula (I-2)

(Wherein all symbols have the same meanings as those described in [1], [2] and [5]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof, most preferably a general formula (I-4)

(Wherein all symbols have the same meanings as those described in [1], [2] and [5]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof.

  In the present invention, as still another embodiment of the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, more preferably, the general formula (If )

(Wherein all symbols have the same meanings as those described in [1], [2], and [9]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof, more preferably a general formula (Ig)

(Wherein all symbols have the same meanings as those described in [1], [2], and [9]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof, preferably a compound represented by the general formula (Ih)

(Wherein all symbols have the same meanings as those described in [1], [2], and [9]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof, and still more preferably a compound of the general formula (Ii)

(Wherein all symbols have the same meanings as those described in [1], [2], and [9]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof, particularly preferably a general formula (I-3)

(Wherein all symbols have the same meanings as those described in [1], [2], and [9]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof, most preferably a compound represented by the general formula (I-5)

(Wherein all symbols have the same meanings as those described in [1], [2], and [9]), a salt thereof, an N-oxide thereof, a solvate thereof, Or a prodrug thereof.

In the present invention, the above general formula (Ia), general formula (Ib), general formula (Ic), general formula (Id), general formula (Ie), general formula (I) -F), general formula (Ig), general formula (Ih), general formula (Ii), and general formula selected from the group of general formula (I-1), each independently Preferably, L ¹ is propylene and L ² is —CH═CH—, —NHCO—, —CONH—, —NHSO ₂ —, or —SO ₂ NH—. More preferably, L ¹ is propylene and L ² is —NHCO— or —CONH—. More preferably, L ¹ is propylene and L ² is —NHCO—.

In the present invention, each of the general formulas selected from the group of the general formula (I-2), general formula (I-3), general formula (I-4), and general formula (I-5) is independent of each other. Preferably, L ¹ is propylene.

  In the present invention, as another embodiment of the compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, it is most preferably described in the synthesis examples described later. A compound, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof.

  In the present invention, all isomers are included unless otherwise specified. For example, an alkyl group, an alkoxy group, an alkylene group, and the like include a straight chain group and a branched chain group. Furthermore, isomers (E, Z, cis, trans isomers) in double bonds, rings, condensed rings, isomers due to the presence of asymmetric carbons (R, S isomers, α, β isomers, enantiomers, diastereomers) , Optically active substances having optical activity (D, L, d, l form), polar bodies (high polar bodies, low polar bodies) by chromatographic separation, equilibrium compounds, rotamers, mixtures of these in any proportions, All racemic mixtures are included in the present invention. In the present invention, all isomers by tautomerism are also included.

  In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Represents binding to the other side of the page (ie α-configuration),

Represents binding to the near side of the page (ie β-configuration),

Represents an arbitrary mixture of α-configuration and β-configuration.

[salt]
The compound represented by the general formula (I) is converted into a salt by a known method.

  The salt is preferably a pharmaceutically acceptable salt.

  The salt is preferably water-soluble.

  Examples of the pharmaceutically acceptable salt include acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts, and amine salts.

  Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, or acetate, lactate, tartrate, benzoic acid. Organic acid salts such as salt, citrate, methanesulfonate, ethanesulfonate, trifluoroacetate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, or gluconate Can be mentioned.

  Examples of the alkali metal salt include potassium and sodium.

  Examples of the alkaline earth metal salt include calcium and magnesium.

  Examples of the ammonium salt include tetramethylammonium.

  Examples of amine salts include triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) aminomethane, lysine, arginine, and N-methyl-D-. Examples include glucamine.

  Moreover, the compound used for this invention can be made into an N-oxide body by arbitrary methods. The N-oxide form represents an oxidized form of the nitrogen atom of the compound represented by the general formula (I).

  The compound represented by the general formula (I) and a salt thereof can also be converted into a solvate.

  The solvate is preferably non-toxic and water-soluble. Suitable solvates include, for example, solvates such as water or alcohol solvents (for example, ethanol).

[Prodrug]
The prodrug of the compound represented by the general formula (I) refers to a compound that is converted into a compound represented by the general formula (I) by a reaction with an enzyme, gastric acid or the like in a living body. As a prodrug of the compound represented by the general formula (I), for example, when the compound represented by the general formula (I) has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, The amino group of the compound represented by the general formula (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranyl , Pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated, tert-butylated compounds, etc.); when the compound represented by formula (I) has a hydroxyl group, the hydroxyl group is acylated, alkyl , Phosphorylated, and borated compounds (for example, the hydroxyl group of the compound represented by the general formula (I) is acetylated, palmitoyl Propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compound, etc.); when the compound represented by the general formula (I) has a carboxy group, Esterified, amidated compounds (for example, the carboxy group of the compound represented by the general formula (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified 1-{(ethoxycarbonyl) oxy} ethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, 1-{[(cyclohexyloxy) Carbonyl] oxy} ethyl esterification, methylamidation Such compounds), and the like. These compounds can be produced by a method known per se. The prodrug of the compound represented by the general formula (I) may be either a hydrate or a non-hydrate. In addition, the prodrug of the compound represented by the general formula (I) is a compound represented by the general formula under physiological conditions as described in Yodogawa Shoten 1990, “Development of Drugs”, Volume 7, “Molecular Design”, pages 163 to 198. It may be changed to the compound represented by (I).

Further, each atom constituting the compound represented by the general formula (I) is an isotope (for example, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁶ N, ¹⁷ O, ¹⁸ O, ¹⁸ F , ³⁵ S, ³⁶ Cl, ⁷⁷ Br, ¹²⁵ I, etc.).

[Method for producing compound used in the present invention]
The compound represented by the general formula (I) can be produced according to a known method, for example, a method shown below, a method analogous thereto, or a method shown in Examples. In each of the following production methods, the raw material compound may be used as a salt. As such salts, those described as pharmaceutically acceptable salts of the compounds represented by formula (I) are used.

In the compound represented by the general formula (I), the compound represented by the general formula (IVa) in which L ² is —NHCO— or the compound represented by the general formula (IVb) in which L ² is —CONH— It can be produced by the method shown in the following reaction process formula (Ia) or reaction process formula (Ib).

(In the formula, all symbols have the same meanings as those described in [1].)
Or

(In the formula, all symbols have the same meanings as those described in [1].)
That is, the compound represented by the general formula (IVa) can be produced by subjecting the compound represented by the general formula (IIa) and the compound represented by the general formula (IIIa) to an amidation reaction. The compound represented by the general formula (IVb) can be produced by subjecting the compound represented by the general formula (IIb) and the compound represented by the general formula (IIIb) to an amidation reaction.

Amidation reactions are known, for example
(1) a method using an acid halide,
(2) a method using a mixed acid anhydride,
(3) A method using a condensing agent may be mentioned.

Specifically explaining these methods,
(1) The method using an acid halide includes, for example, carboxylic acid in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without solvent, and an acid halide agent (oxalyl chloride, thionyl chloride, etc.) and about − The reaction is carried out at 20 ° C. to reflux temperature, and the obtained acid halide is present in the presence of a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropylethylamine, etc.) and an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.). ) At a temperature of about 0 to 40 ° C. Alternatively, the obtained acid halide can be reacted with an amine at about 0 to 40 ° C. in an organic solvent (dioxane, tetrahydrofuran, etc.) using an aqueous alkali solution (such as sodium bicarbonate water or sodium hydroxide solution). .

  (2) A method using a mixed acid anhydride is, for example, a method in which a carboxylic acid is used in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.) or without a solvent, and a base (pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, diisopropyl). Obtained by reacting with acid halide (pivaloyl chloride, tosyl chloride, mesyl chloride, etc.) or acid derivatives (ethyl chloroformate, isobutyl chloroformate, etc.) at about 0-40 ° C. in the presence of ethylamine, etc. The reaction is carried out by reacting the mixed acid anhydride with an amine at about 0 to 40 ° C. in an organic solvent (chloroform, dichloromethane, diethyl ether, tetrahydrofuran, etc.).

(3) A method using a condensing agent includes, for example, carboxylic acid and amine in an organic solvent (chloroform, dichloromethane, dimethylformamide, dimethylacetamide, diethyl ether, tetrahydrofuran, etc.) or without solvent, with a base (pyridine, triethylamine, In the presence or absence of dimethylaniline, dimethylaminopyridine, etc.), a condensing agent (1,3-dicyclohexylcarbodiimide (DCC), 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (EDC), 1 , 1′-carbonyldiimidazole (CDI), 2-chloro-1-methylpyridinium iodine, 1-propylphosphonic acid cyclic anhydride (T3P), etc., and 1-hydroxybenztriazole ( HOBt) Without using, it carried out by reacting at about 0 ° C. ~ reflux.

  These reactions (1), (2), and (3) are all desirably carried out under an inert gas (argon, nitrogen, etc.) atmosphere under anhydrous conditions.

In the compound represented by the general formula (I), a compound represented by the general formula (IVc) in which L ² is —NHSO ₂ —, or a compound represented by the general formula (IVd) in which L ² is —SO ₂ NH— Can be produced by the methods shown in the following reaction process formula (Ic) or reaction process formula (Id), respectively.

(In the formula, all symbols have the same meanings as those described in [1].)
Or

(In the formula, all symbols have the same meanings as those described in [1].)
That is, the compound represented by the general formula (IVc) can be produced by subjecting the compound represented by the general formula (IIc) and the compound represented by the general formula (IIIc) to a sulfonamidation reaction. The compound represented by the general formula (IVd) can be produced by subjecting the compound represented by the general formula (IId) and the compound represented by the general formula (IIId) to a sulfonamidation reaction.

  Sulfonamidation reactions are known, for example, acid halides (oxalyl chloride, thionyl chloride) in an organic solvent (chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) or without solvent. , Phosphorus pentachloride, phosphorus trichloride, etc.) at −20 ° C. to reflux temperature, and the resulting sulfonyl halide in the presence of a base (diisopropylethylamine, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine, etc.) in an organic solvent It is carried out by reacting with an amine at about 0 to 40 ° C. in chloroform, dichloromethane, dichloroethane, diethyl ether, tetrahydrofuran or the like.

In the compound represented by the general formula (I), a compound represented by the general formula (IVe) in which L ² is —NHCH ₂ —, or a compound represented by the general formula (IVf) in which L ² is —CH ₂ NH—. Can be produced by the methods shown in the following reaction process formula (Ie) or reaction process formula (If), respectively.

(In the formula, all symbols have the same meanings as those described in [1].)
Or

(In the formula, all symbols have the same meanings as those described in [1].)
That is, the compound represented by the general formula (IVe) can be produced by subjecting the compound represented by the general formula (IIe) and the compound represented by the general formula (IIIe) to a reductive amination reaction. The compound represented by the general formula (IVf) can be produced by subjecting the compound represented by the general formula (IIf) and the compound represented by the general formula (IIIf) to a reductive amination reaction.

  Reductive amination reactions are known, for example, reducing agents (sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, in organic solvents such as dichloroethane, dichloromethane, dimethylformamide, acetic acid and mixtures thereof). In the presence of sodium, etc.) at a temperature of about 0-40 ° C.

In the compound represented by the general formula (I), a compound represented by the general formula (IVg) in which L ² is —OCH ₂ —, or a compound represented by the general formula (IVh) in which L ² is —CH ₂ O—. Can be produced by the methods shown in the following reaction process formula (Ig) or reaction process formula (Ih), respectively.

(In the formula, Xg is halogen, tosylate, or mesylate, and other symbols have the same meanings as those described in [1].)
Or

(In the formula, Xh is halogen, tosylate or mesylate, and other symbols have the same meanings as those described in [1].)
That is, the compound represented by the general formula (IVg) can be produced by subjecting the compound represented by the general formula (IIg) and the compound represented by the general formula (IIIg) to an etherification reaction. The compound represented by the general formula (IVh) can be produced by subjecting the compound represented by the general formula (IIh) and the compound represented by the general formula (IIIh) to an etherification reaction.

  This etherification reaction is known, for example, an alkali metal hydroxide (sodium hydroxide, hydroxide) in an organic solvent (dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.). Potassium, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.), aqueous solutions thereof or mixtures thereof, about 0 It is carried out by reacting at ~ 100 ° C.

In the compound represented by the general formula (I), a compound represented by the general formula (IVj) in which L ² is —SCH ₂ —, or a compound represented by the general formula (IVk) in which L ² is —CH ₂ S—. Can be produced by the methods shown in the following reaction process formula (Ij) or reaction process formula (Ik), respectively.

(In the formula, Xj is halogen, tosylate, or mesylate, and other symbols have the same meanings as those described in [1].)
Or

(In the formula, Xk is halogen, tosylate, or mesylate, and other symbols have the same meanings as the symbols described in [1].)
That is, the compound represented by the general formula (IVj) can be produced by subjecting the compound represented by the general formula (IIj) and the compound represented by the general formula (IIIj) to a thioetherification reaction. Further, the compound represented by the general formula (IVk) can be produced by subjecting the compound represented by the general formula (IIk) and the compound represented by the general formula (IIIk) to a thioetherification reaction.

  This thioetherification reaction is known, for example, an alkali metal hydroxide (sodium hydroxide, hydroxide) in an organic solvent (dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.). Potassium, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.) or carbonates (sodium carbonate, potassium carbonate, etc.) or their aqueous solutions or mixtures thereof, 0 to The reaction is carried out at 100 ° C.

In the compound represented by the general formula (I), the compound in which L ² is —S (O) CH ₂ — or —SO ₂ CH ₂ — represents the sulfur atom of the compound represented by the above general formula (IVj) as appropriate. It can be produced by subjecting it to an oxidation reaction.

In the compound represented by the general formula (I), the compound in which L ² is —CH ₂ S (O) — or —CH ₂ SO ₂ — represents the sulfur atom of the compound represented by the above general formula (IVk) as appropriate. It can be produced by subjecting it to an oxidation reaction.

This oxidation reaction (sulfoxidation reaction: —SCH ₂ — → —S (O) CH ₂ —, or —CH ₂ S— → —CH ₂ S (O) —) is known, for example, an organic solvent (dichloromethane, 1) to 1.2 equivalents of oxidizing agent (in chloroform, benzene, hexane, methanol, t-butyl alcohol, acetone, acetonitrile, tetrahydrofuran, acetic acid, N, N-dimethylformamide, etc.), water or a mixed solvent thereof. Hydrogen peroxide, sodium periodate, acyl nitrite, sodium perborate, sodium hypochlorite, peracid (3-chloroperbenzoic acid, peracetic acid, etc.), oxone (trade name, hereinafter abbreviated as oxone) Potassium peroxymonosulfate), potassium permanganate, chromic acid, dimethyldioxolane, etc.) in the presence of about -4 It carried out by reacting at a temperature of ~0 ° C..

This oxidation reaction (sulfonation reaction: —SCH ₂ — → —SO ₂ CH ₂ —, or —CH ₂ S— → —CH ₂ SO ₂ —) is known, for example, an appropriate organic solvent (dichloromethane, chloroform, Excess oxidizing agent (hydrogen peroxide, periodic acid) in benzene, hexane, methanol, t-butyl alcohol, acetone, acetonitrile, tetrahydrofuran, acetic acid, N, N-dimethylformamide, etc.), in water or in a mixed solvent thereof. Sodium, acyl nitrite, sodium perborate, sodium hypochlorite, peracid (3-chloroperbenzoic acid, peracetic acid, etc.), oxone (trade name: potassium peroxymonosulfate), potassium permanganate, In the presence of chromic acid, dimethyldioxolane, etc.) at a temperature of about 20-60 ° C. Done.

In the compound represented by the general formula (I), the compound represented by the general formula (IVm) in which L ² is —CH═CH— can be produced by the method shown in the following reaction process formula (Im).

(In the formula, all symbols have the same meanings as those described in [1].)
That is, the compound represented by the general formula (IVm) is prepared by subjecting the compound represented by the general formula (IIIm) to a vinylation reaction and the compound represented by the general formula (Vm) and the general formula (IIm). It can manufacture by attaching | subjecting the compound shown by Hecking reaction.

  This vinylation reaction is known and, for example, using a compound represented by the general formula (IIIm) and methyltriphenylphosphonium bromide, an organic solvent (for example, acetonitrile, methylene chloride, tetrahydrofuran, toluene, benzene, or these In a solvent in which an organic solvent is appropriately mixed), for example, potassium carbonate, sodium hydride, potassium hydride, n-butyl lithium, tert-butoxy potassium, 1,8-diazabicyclo [5.4.0] undeca In the presence of 7-entylethylamine (DBU) and the like, at a temperature of about 0 ° C to 120 ° C.

This Hecking reaction is known, for example, in a base (for example, triphosphate) in an organic solvent (for example, toluene, diethyl ether, benzene, dichlorobenzene, dimethylformamide, or a solvent obtained by appropriately mixing these organic solvents). Potassium, sodium bicarbonate, triethylamine, etc.) and catalysts (eg, palladium catalysts (eg, palladium chloride, palladium acetate, tetrakis (triphenylphosphine) palladium (0)), nickel catalysts (eg, tetrakis (triphenylphosphine) nickel) , Bis (triphenylphosphine) nickel (II), etc.), cobalt catalyst (eg, cobalt chloride, etc.)
In addition, a phosphorus reagent (for example, 1,3-bis (diphenylphosphino) propane) in the presence of a copper catalyst (for example, copper chloride), a zinc catalyst (for example, zinc or the like), or a catalyst in which these catalysts are appropriately mixed) (Dppp), Ph ₂ P— (CH ₂ ) ₆ -PPh _2, etc.) in the presence or absence, and the reaction is carried out at a temperature of about 0 ° C. to 120 ° C.

In the compound represented by the general formula (I), the compound in which L ² is —CH ₂ CH ₂ — is appropriately subjected to the reduction reaction of “—CH═CH—” of the compound represented by the above general formula (IVm). Can be manufactured.

  This reduction reaction is known, for example, an organic solvent (eg, tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, methanol, ethanol, benzene, toluene, acetone, methyl ethyl ketone, acetonitrile, dimethylformamide, water, ethyl acetate, acetic acid, or In the presence of a hydrogenation catalyst (palladium-carbon, palladium black, palladium, palladium hydroxide, platinum dioxide, platinum-carbon, nickel, Raney nickel, ruthenium chloride, etc.) (Hydrochloric acid, sulfuric acid, hypochlorous acid, boric acid, tetrafluoroboric acid, acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid, formic acid, etc.) In a hydrogen atmosphere, in the presence of ammonium formate or Under hydrazine presence, at a temperature of about 0 to 200 ° C..

  In the compound represented by the general formula (IIIa) in the reaction process formula (Ia), the compound represented by the general formula (IIIaa) in which q is 0 and m is 1 is represented by the following reaction process formula (Iaa). It can be manufactured by the method.

(In the formula, Raa is C1-4 alkyl, and other symbols have the same meanings as the symbols described in [1] and [2] above.)
That is, the compound represented by the general formula (IIIaa) is subjected to a cyclization reaction of the compound represented by the general formula (VIaa) produced by subjecting the compound represented by the general formula (Vaa) to a vinylation reaction, It can be produced by subjecting it to a hydrolysis reaction.

This vinylation reaction is known and, for example, using a compound represented by the general formula (Vaa) and methyltriphenylphosphonium bromide, an organic solvent (for example, acetonitrile, methylene chloride, tetrahydrofuran, toluene, benzene, or these In a solvent in which an organic solvent is appropriately mixed), for example, potassium carbonate, sodium hydride, potassium hydride, n-butyl lithium, tert-butoxy potassium, 1,8-diazabicyclo [5.4.0] undeca In the presence of 7-entylethylamine (DBU) and the like, at a temperature of about 0 ° C to 120 ° C.

This cyclization reaction is known. For example, using a compound represented by the general formula (VIaa) and a diazo compound, an organic solvent (for example, toluene, benzene, methylene chloride, dichloroethane, methanol, ethanol, hexane, tetrahydrofuran, Catalysts (ruthenium catalysts (for example, dichloro (cymene) ruthenium dimer ([Ru (p-cymene) Cl ₂ ] ₂ ), RuCl ₂ (PPh ₃ ) ₃ ) , RuCl (Cp) (PPh ₃ ) ₂ ), rhodium catalyst (for example, Rh ₂ (O—CO-hepty) ₄ , Rh ₂ (O—CO—tBu) ₄ , Rh ₂ (OAc) ₄ , Rh ₂ ( _{O-Piv) 4, Rh 2} ((S) -PTTL) 4, Rh 2 ((S) -DOSP) 4, Rh 2 ( _sp), such as _{2, Rh 2 ((S)} -NTTL) 4), a silver catalyst (e.g., such as silver tetrafluoroborate (I)), copper catalysts _{(e.g., CuOTf, Cu (OAc) 2} , [Cu (MeCN ) ₄ ] PF ₆ etc.), tin catalyst (eg Sn (tpp) (OTf) ₂ etc.), iron catalyst (eg [Fe (Cp) (CO) ₂ (thf)] BF ₄ etc.), cobalt catalyst, 2,6-bis (4-isopropyl-4,5-dihydrooxazol-2-yl) pyridine, 2,6-bis ((S) -4-isopropyl-4,5-dihydrooxazol-2-yl) pyridine, The reaction is carried out in the presence of 2,6-bis ((R) -4-isopropyl-4,5-dihydrooxazol-2-yl) pyridine) at a temperature of about -78 ° C to 120 ° C. In this cyclization reaction, by using a known optically active asymmetric catalyst, an optically active tricyclic spiro compound (an optically active substance of a compound represented by the general formula (VIIaa)) can be produced. .

  This hydrolysis reaction (carboxyl group deprotection reaction) is known, and examples thereof include alkaline hydrolysis. The deprotection reaction by alkaline hydrolysis can be carried out, for example, in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.), alkali metal hydroxide (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal water, etc. It is carried out at a temperature of 0 to 100 ° C. using an oxide (barium hydroxide, calcium hydroxide, etc.) or carbonate (sodium carbonate, potassium carbonate, etc.), an aqueous solution thereof or a mixture thereof.

A compound represented by general formula (IIIb) in reaction scheme (Ib), a compound represented by general formula (IIId) in reaction scheme (Id), or represented by general formula (IIIf) in reaction scheme (If) In the compound, m is 1, the compound represented by the general formula (IIIaa) in the above reaction process formula (Iaa) is converted into a known method, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard) C. Larock, John Wiley & Sons Inc, 1999) ”.

In the compound represented by the general formula (IIIc) in the reaction process formula (Ic), the compound represented by the general formula (IIIaa) in the reaction process formula (Iaa) is known as the compound in which m is an integer of 1. Methods such as “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition” (Richard C. Larock, John Wiley
& Sons Inc, 1999) ”.

In the compound represented by the general formula (IIIe) in the reaction process formula (Ie) or the compound represented by the general formula (IIIm) in the reaction process formula (Im), the compound in which m is 1 is represented by the above reaction process formula (Iaa) The compound represented by the general formula (IIIaa) in a known method, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Pre
parations 2nd Edition "(Richard C. Larock, John Wiley & Sons Inc, 1999)" can be used for the reduction reaction.

In the compound represented by the general formula (IIIg) in the reaction process formula (Ig) or the compound represented by the general formula (IIIj) in the reaction process formula (Ij), the compound in which m is 1 is represented by the above reaction process formula (Iaa) The compound represented by the general formula (IIIaa) in a known method, for example, the method described in “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)” Can be prepared by reducing the carboxylic acid to a primary alcohol derivative and then converting the alcohol derivative to a halogen derivative, a tosylate derivative, or a mesylate derivative.

In the compound represented by the general formula (IIIh) in the reaction process formula (Ih), the compound in which m is 1 is obtained by converting the compound represented by the general formula (IIIaa) in the reaction process formula (Iaa) into a known method, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition” (Richard C. Larock, John Wiley & Sons Inc, 1999) or “Tetrahedron Letter”, Vol. 28, 4489.
-4492, 1987 "can be used.

In the compound represented by the general formula (IIIk) in the reaction process formula (Ik), the compound in which m is 1 is obtained by converting the compound represented by the general formula (IIIaa) in the reaction process formula (Iaa) by a known method, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition” (Richard C. Larock, John Wiley & Sons Inc, 1999) or “Tetrahedron Letter”, Vol. 28, 4489.
It can be produced by converting the alcohol derivative into a thiol derivative after making it into a secondary alcohol derivative using the method described in "-4492, 1987".

General formula (IIIa), general formula (IIIb), general formula (IIIc), general formula (IIId), general formula (IIIe), general formula (IIIf), general formula (IIIg) used as starting materials in the reaction process formula In the compound represented by formula (IIIh), formula (IIIj), formula (IIIk), or formula (IIIm), m is 1, and q is an integer of 1 to 3, or m Is an integer of 2 to 4 and q is an integer of 1 to 6 is known or known, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley &
Sons Inc, 1999) ”can be used for easy production.

General formulas (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh), (IIj), (IIk) used as starting materials in the reaction process formula , (IIm), and (Vaa) are known or known methods such as "Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc. , 1999) ”can be easily produced.

In addition, a compound having an amino group, a carboxyl group, or a hydroxyl group can be used, if necessary, as a protective group widely used for these groups, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C . Larock, John
Using the compound protected by the protecting group described in “Wiley & Sons Inc, 1999)”, the amidation reaction described in the above reaction scheme (Ia) or (Ib), the above reaction scheme (Ic ) Or (Id), the reductive amination reaction described in the above reaction scheme (Ie) or (If), the above reaction scheme (Ig) or (Ih) Or after the reaction up to the Heck reaction described in the above reaction process formula (Im) or the thioetherification reaction described in the above reaction process formula (Ij) or (Ik) After a simple reaction step, a known deprotection reaction or a deprotection described in, for example, “Comprehensive Organic Transformations: A Guide to Functional Group Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999)”. It can be produced by carrying out a protective reaction.

  Among the compounds represented by the general formula (I), compounds other than those shown above may be used in the examples described in the present specification or known methods such as “Comprehensive Organic Transformations: A Guide to Functional Group”. Preparations 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999) ”can be used in combination.

  Among the compounds used in the present invention, compounds having optical activity are produced using optically active starting materials or reagents, or optically resolving racemic intermediates, and then into compounds used in the present invention. Alternatively, it can be produced by optical resolution of a racemic compound.

  This optical resolution method is known. For example, after forming a salt / complex with another optically active compound and recrystallizing it, the target compound is isolated or directly using a chiral column or the like. And a method of separating them.

  In each reaction in the present specification, the reaction involving heating can be performed using a water bath, an oil bath, a sand bath, or a microwave, as will be apparent to those skilled in the art.

  In each reaction in the present specification, a solid-phase-supported reagent supported on a high molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

  In each reaction in the present specification, the reaction product is obtained by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography, ion exchange resin, It can be purified by scavenger resin, column chromatography, washing or recrystallization. Purification may be performed for each reaction or after completion of several reactions.

[toxicity]
Since the compound used in the present invention has low toxicity, it can be safely used as an active ingredient of a pharmaceutical product.

[Application to pharmaceutical products]
An object of the present invention is to provide a pharmaceutical composition containing a compound having a strong antagonistic activity against EP ₄ receptor and exhibiting good pharmacokinetics, and prevention and / or prevention of diseases caused by activation of EP ₄ receptor. Or to provide a therapeutic agent.

Compound used in the present invention exhibits antagonistic activity against EP ₄ receptor, diseases caused by the activation of EP ₄ receptor, for example, bone diseases, cancer, systemic granuloma, immune diseases, allergy Sexual diseases, asthma, alveolar pus effusion, gingivitis, periodontal disease, Alzheimer, Kawasaki disease, burns, multiple organ failure, chronic headache, pain, vasculitis, venous failure, varicose vein, aneurysm, aortic aneurysm, hemorrhoid It is useful as an active ingredient of a preventive and / or therapeutic agent for insomnia, stress, endometriosis, adenomyosis, neonatal patent ductus arteriosus, cholelithiasis and the like.

  More specifically, examples of the bone disease include osteoporosis, rheumatoid arthritis, osteoarthritis, and bone dysplasia. Examples of cancer include breast cancer, ovarian cancer, colon cancer (for example, colon cancer), lung cancer (for example, non-small cell lung cancer), prostate cancer, head and neck cancer (for example, oral squamous epithelium). Cancer, head and neck squamous cell carcinoma, pharyngeal cancer, laryngeal cancer, tongue cancer, thyroid cancer, acoustic schwannoma, etc.), malignant lymphoma (eg B cell lymphoma, T cell lymphoma, etc.), uveal malignant black Tumor, thymoma, mesothelioma, esophageal cancer, stomach cancer, duodenal cancer, hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis / ureteral cancer, bladder Cancer, penile cancer, testicular cancer, uterine cancer, vaginal cancer, vulvar cancer, skin cancer (eg, malignant melanoma), malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia (eg, acute bone marrow) Leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia), bone marrow Forming syndrome or the like multiple myeloma. Examples of immune diseases include amyotrophic lateral sclerosis (ALS), multiple sclerosis, Sjogren's syndrome, systemic lupus erythematosus, AIDS, and the like. Examples of allergic diseases include allergic conjunctivitis, allergic rhinitis, contact dermatitis, psoriasis and the like. Examples of chronic headache include migraine, tension-type headache or a mixed headache thereof, or cluster headache.

The compound used in the present invention is:
1) complementation and / or enhancement of the prophylactic and / or therapeutic effect of the compound,
2) Improving the kinetics / absorption of the compound, reducing the dose, and / or 3) reducing the side effects of the compound may be combined with other drugs and administered as a concomitant drug.

  The combination agent of the compound used in the present invention and another drug may be administered in the form of a combination drug in which both components are mixed in one preparation, or may be administered in separate preparations. When administered as separate preparations, simultaneous administration and administration by time difference are included. In addition, administration by time difference may be such that the compound used in the present invention is administered first, and another drug is administered later, or the other drug is administered first and the compound used in the present invention is administered later. May be. Each administration method may be the same or different.

  The disease that exerts a preventive and / or therapeutic effect by the above-mentioned concomitant drug is not particularly limited as long as it is a disease that complements and / or enhances the preventive and / or therapeutic effect of the compound used in the present invention.

  Examples of other drugs for complementing and / or enhancing the preventive and / or therapeutic effects of the compounds used in the present invention on aortic aneurysms include, for example, HMG-CoA reductase inhibitors, antihypertensives, and tetracycline antibiotics. Is mentioned.

  Examples of the HMG-CoA reductase inhibitor include pravastatin (sodium), simvastatin, fluvastatin (sodium), cerivastatin (sodium), itavastatin, atorvastatin (calcium hydrate), lovastatin, pitavastatin (calcium) and the like. It is done.

  Examples of the antihypertensive agent include calcium antagonists, angiotensin II antagonists, angiotensin converting enzyme inhibitors, phosphodiesterase 4 inhibitors, diuretics, prostaglandins, aldosterone antagonists, and sympathetic nerve inhibitors.

Examples of calcium antagonists include nifedipine, benidipine hydrochloride, diltiazem hydrochloride, verapamil hydrochloride, nisoldipine, nitrendipine hydrochloride, bepridil hydrochloride, amlodipine besylate, lomelidine hydrochloride, efonidipine hydrochloride, and the like.

  Examples of angiotensin II antagonists include losartan (potassium), candesartan (cilexetil), valsartan, irbesartan, olmesartan (medoxomil), telmisartan, and the like.

  Examples of the angiotensin converting enzyme inhibitor include alacepril, imidapril hydrochloride, quinapril hydrochloride, temocapril hydrochloride, delapril hydrochloride, benazepril hydrochloride, captopril, trandolapril, perindopril, erbumine, enalapril maleate, and lisinopril.

  Examples of the phosphodiesterase 4 inhibitor include cilomilast, roflumilast, allophylline, atizolam, cypamfilin, rolipram and the like.

  Examples of the diuretic include acetazolamide, aminophylline, isosorbide, dichlorophenamide, spironolactone, trichloromethiazide, furosemide, mannitol, metazolamide, and mefluside.

  Examples of aldosterone antagonists include drospirenone, mercyrapone, potassium canrenoate, canrenone, eplerenone and the like.

  Examples of tetracycline antibiotics include doxycycline.

  Examples of other drugs for supplementing and / or enhancing the preventive and / or therapeutic effect on cancer of the compound used in the present invention include, for example, alkylating agents, antimetabolites, anticancer antibiotics, botanical preparations. , Hormone agents, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteasome inhibitors, HDAC inhibitors, and immunomodulators.

  Examples of the alkylating agent include cyclophosphamide, ifosfamide, dacarbazine, temozolomide, nimustine hydrochloride, ranimustine, bendamustine, thiotepa, and carbocon.

  Antimetabolites include, for example, methotrexate, pemetrexed, fluorouracil, tegafur, tegafur uracil, tegafur gimestat otastat potassium, doxyfluridine, capecitabine, cytarabine, gemcitabine hydrochloride, fludarabine, nelarabine, carmofur and the like .

  Examples of the anticancer antibiotics include mitomycin C, doxorubicin hydrochloride, aclarubicin hydrochloride, pirarubicin hydrochloride, epirubicin, chromomycin A3, bleomycin, pepromycin sulfate, and terarubicin.

  Examples of botanical preparations include irinotecan hydrochloride, etoposide, vincristine sulfate, vinblastine sulfate, vindesine sulfate, vinorelbine tartrate, docetaxel hydrate, eribulin mesylate, and paclitaxel.

Examples of the hormone agent include estramustine phosphate sodium, flutamide, bicalutamide, goserelin acetate, leuprorelin acetate, tamoxifen citrate, toremifene citrate, anastrozole, letrozole, exemestane, mepithiostane, medroxyprogesterone acetate, Examples include epithiostanol, phosfestol, fadrozol hydrochloride hydrate, abiraterone, fulvestrant, and aminoglutethimide.

  Examples of the platinum compound include carboplatin, cisplatin, nedaplatin, oxaliplatin, and the like.

  Examples of topoisomerase inhibitors include topotecan and sobuzoxane.

  Examples of the kinase inhibitor include EGFR inhibitor erlotinib, gefitinib, afatinib, HER2 inhibitor lapatinib, BCR-ABL inhibitor imatinib, ALK inhibitor crizotinib, multikinase inhibitor regorafenib, And dasatinib.

  Examples of the anti-CD20 antibody include rituximab, ibritumomab, ibritumomab tiuxetan, and ocrelizumab.

  Examples of the anti-HER2 antibody include trastuzumab, trastuzumab emtansine, and pertuzumab.

  Examples of the anti-EGFR antibody include cetuximab and panitumumab.

  Examples of the anti-VEGF antibody include bevacizumab.

  Examples of proteasome inhibitors include bortezomib.

  Examples of HDAC inhibitors include vorinostat.

  Examples of immunomodulators include thalidomide, lenalidomide, and pomalidomide.

  Examples of other drugs for complementing and / or enhancing the preventive and / or therapeutic effect on pain of the compound used in the present invention include, for example, N-type calcium channel inhibitors, nitric oxide synthase (NOS) inhibitors, And cannabinoid-2 receptor stimulants.

  Examples of the N-type calcium channel inhibitor include cilnidipine.

Examples of nitric oxide synthase (NOS) inhibitors include D-arginine and N ^G -monomethyl-L-arginine.

  The mass ratio of the compound used for this invention and another chemical | medical agent is not specifically limited.

  Other drugs may be administered in combination of any two or more.

  In addition, other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compounds used in the present invention will be found in the future as well as those that have been found so far based on the above-described mechanism. Also included.

  It is an active ingredient for use in the prevention and / or treatment of the above-mentioned diseases as a single agent of the compound used in the present invention or as a concomitant combination of the compound used in the present invention and another drug. The substance is usually formulated with a pharmaceutically acceptable carrier such as various additives or solvents, and then administered systemically or locally in an oral or parenteral form. Here, the pharmaceutically acceptable carrier means a substance other than the active ingredient generally used for pharmaceutical preparations. The pharmaceutically acceptable carrier is preferably one that does not exhibit pharmacological action at the dosage of the preparation, is harmless, and does not interfere with the therapeutic effect of the active ingredient. A pharmaceutically acceptable carrier can also be used for the purpose of enhancing the usefulness of active ingredients and preparations, facilitating preparation, stabilizing quality, improving usability, and the like. Specifically, substances described in Yakuji Nippo Co., Ltd. 2016 “Pharmaceutical Additives Encyclopedia 2016” (edited by the Japan Pharmaceutical Additives Association) may be appropriately selected according to the purpose.

  Examples of the dosage form used for administration include oral preparations (eg: tablets, capsules, granules, powders, oral solutions, syrups, oral jelly, etc.), oral preparations (eg: oral tablets, Oral sprays, semi-solid oral preparations, mouthwashes, etc., injectable preparations (eg, injections, etc.), dialysis preparations (eg, dialysis preparations, etc.), inhalation preparations (eg, inhalants, etc.), Ophthalmic preparations (eg, eye drops, eye ointments, etc.), otologic preparations (eg, ear drops, etc.), nasal preparations (eg, nasal drops, etc.), rectal preparations (eg, suppositories, Rectal semi-solid preparations, intestinal preparations, etc., vaginal preparations (eg, vaginal tablets, vaginal suppositories), and skin preparations (eg, external solid preparations, external preparations, sprays, ointments, creams) , Gels, patches, etc.).

[Formulation for oral administration]
Preparations for oral administration include, for example, tablets, capsules, granules, powders, oral solutions, syrups, oral jelly and the like. In addition, preparations for oral administration include fast-disintegrating preparations in which the release of active ingredients from the preparation is not particularly adjusted, and release adjustments tailored to the purpose by specific formulation design and manufacturing method, for example, enteric properties There are controlled-release preparations such as preparations and sustained-release preparations. Enteric preparations are designed not to release the active ingredient in the stomach but mainly in the small intestine for the purpose of preventing the active ingredient from breaking down in the stomach or reducing the irritation of the active ingredient in the stomach. In general, it can be produced by applying a film using an acid-insoluble enteric base. A sustained-release preparation is a preparation in which the release rate, release time, and release site of an active ingredient are adjusted for the purpose of reducing the number of administrations or reducing side effects, and is usually an appropriate sustained-release agent. It can manufacture by using. Among the preparations for oral administration, capsules, granules, tablets, etc. are coated with appropriate coating agents such as sugars, sugar alcohols, and polymer compounds for the purpose of facilitating taking or preventing the decomposition of active ingredients. A coating can also be applied.

(1) Tablet A tablet is a solid preparation having a certain shape to be administered orally, and is generally referred to as a tablet such as a plain tablet, a film-coated tablet, a sugar-coated tablet, a multilayer tablet, and a dry-coated tablet. In addition, intraoral rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets and the like are included. When manufacturing an uncoated tablet, usually, the following method (a), (b), or (c):
(A) Additives such as excipients, binders, and disintegrants are added to the active ingredients and mixed to homogenize, and then granulated by an appropriate method using water or a solution containing a binder, followed by a lubricant. Etc. are added and mixed and compression molded;
(B) An active ingredient and additives such as excipients, binders and disintegrants are added to the active ingredient and mixed into a homogeneous mixture. Add a mixture of ingredients to mix and homogenize, and then compression mold;
(C) Add additives such as excipients and binders to the active ingredient and mix to homogenize, cast the kneaded material wetted with a solvent into a fixed mold, and then dry by an appropriate method ;
Is used. Film-coated tablets can be usually produced by thinly coating a plain tablet with an appropriate coating agent such as a polymer compound. Sugar-coated tablets can be usually produced by coating a plain tablet with a coating agent containing sugar or sugar alcohol. Multi-layer tablets can be produced by stacking powders having different compositions in layers and compressing them by an appropriate method. The dry-coated tablet can be produced by covering the inner core tablet with an outer layer having a different composition. Moreover, a tablet can also be used as an enteric tablet or a sustained release tablet using a known appropriate technique. Intraoral rapidly disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, and dissolving tablets are tablets that have been given unique functions by appropriate selection of additives, and should be manufactured according to the manufacturing method for the tablets. Can do. Intraoral rapidly disintegrating tablets are tablets that can be rapidly dissolved or disintegrated in the oral cavity; chewable tablets are tablets that are chewed and taken; effervescent tablets are rapidly foaming in water Dissolving or dispersing tablet: Dispersed tablet refers to a tablet dispersed in water and taken; Dissolved tablet refers to a tablet dissolved in water and taken. The effervescent tablet can be produced by using an appropriate acidic substance, carbonate, bicarbonate or the like as an additive.

(2) Capsule A capsule is a preparation filled in a capsule or encapsulated with a capsule base, and includes hard capsules and soft capsules. Hard capsules are made by adding additives such as excipients to the active ingredient and mixing them into homogenous or granular or molded products by an appropriate method. Can be manufactured. Soft capsules are manufactured by encapsulating an active ingredient with additives into a certain shape with an appropriate capsule base such as gelatin with increased plasticity by adding glycerin, D-sorbitol, etc. can do. Capsules can be made enteric capsules or sustained-release capsules using a known appropriate technique, and coloring agents or preservatives can be added to the capsule base.

(3) Granules A granule is a granulated preparation, and includes what is generally called a granule, as well as effervescent granules. When producing a granule, the following method (a), (b), or (c) is usually used:
(A) An excipient, a binder, a disintegrant, or other additives are added to the powdered active ingredient, mixed and homogenized, and then granulated by an appropriate method;
(B) An additive such as an excipient is added to the active ingredient previously granulated and mixed to make homogeneous;
(C) Additives such as excipients and the like to the active ingredient prepared in advance in a granular form and mix, and granulate by an appropriate method;
Is used. The granules can be coated as necessary, and enteric granules or sustained-release granules can be prepared by using a known appropriate technique. The foamed granule can be produced by using an appropriate acidic substance, carbonate, bicarbonate or the like as an additive. The foaming granules are granules that dissolve or disperse while rapidly foaming in water. Granules can be made into fine granules by adjusting the size of the particles.

(4) Powder A powder is a powder-form preparation, and can be usually produced by adding an excipient or other additive to an active ingredient, mixing and homogenizing.

(5) Oral liquids Oral liquids are liquid or fluid viscous gel-like preparations. In addition to what are commonly referred to as oral liquids, elixirs, suspensions, emulsions, limonades, etc. included. Oral solutions can be usually produced by adding an additive and purified water to an active ingredient, mixing and dissolving homogeneously, or emulsifying or suspending, and filtering if necessary. An elixir refers to a clear liquid oral solution containing sweet and fragrant ethanol. Usually, the solid active ingredient or its exudate is mixed with ethanol, purified water, flavoring agent, white sugar, other sugars, or It can be produced by adding a sweetening agent to dissolve and then making a clear liquid by filtration or other methods. Suspension refers to an oral solution in which the active ingredient is finely suspended. Usually, the solid active ingredient is added with a suspending agent or other additives and purified water or oil, and suspended by an appropriate method. It can be produced by making the whole homogeneous. An emulsion refers to an oral solution in which an active ingredient is finely and uniformly emulsified. Usually, it can be produced by adding an emulsifier and purified water to a liquid active ingredient, emulsifying it by an appropriate method, and homogenizing the whole. . Note that the limonade agent is a clear liquid oral solution with sweet and sour taste.

(6) Syrup The syrup is a viscous liquid or solid preparation containing saccharides or sweeteners, and includes syrup preparations. A syrup is usually a solution of sucrose, other sugars or sweeteners, or a simple syrup in which an active ingredient is added, dissolved, blended, suspended, or emulsified. It can manufacture by filtering. The syrup preparation refers to a granular or powder preparation that becomes a syrup when water is added, and is sometimes referred to as a dry syrup preparation. The syrup preparation can be usually produced according to the above-mentioned method for producing granules or powders using saccharides or sweeteners as additives.

(7) Oral jelly agent An oral jelly agent is a non-flowable, gel-form preparation. Usually, an active ingredient is mixed with an additive and a polymer gel base, and the mixture is gelled by an appropriate method. It can be manufactured by molding into a certain shape.

[Oral preparation]
(1) Oral tablets Oral tablets are solid preparations of a certain shape applied to the oral cavity, and include lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums and the like. Oral tablets can be usually manufactured according to the manufacturing method of the said tablet. A lozenge is an oral tablet that is gradually dissolved or disintegrated in the oral cavity and applied locally to the oral cavity, pharynx, etc .; Oral tablets to be absorbed from; buccal tablets are oral tablets in which active ingredients are gradually dissolved between the molar teeth and cheeks and absorbed from the oral mucosa; A tablet is an oral tablet that releases an active ingredient by chewing.

(2) Oral sprays Oral sprays are formulations in which the active ingredient is sprayed in the form of a mist, powder, foam, or paste, and the active ingredient and additives are usually dissolved or suspended in a solvent. After turbidity and filtration, if necessary, fill the container with liquefied gas or compressed gas, or prepare a solution or suspension using active ingredients and additives, fill the container, and then spray pump It can be manufactured by mounting.

(3) Oral semi-solid preparations Oral semi-solid preparations are preparations applied to the oral mucosa, and include creams, gels, ointments and the like. Oral semi-solid preparations are usually homogenized by emulsifying active ingredients with additives and oily ingredients such as petrolatum, or mixing with active ingredients and additives based on polymer gels or fats. Can be manufactured. The cream refers to a semi-solid preparation emulsified in an oil-in-water type or a water-in-oil type, and a lipophilic preparation emulsified in a water-in-oil type is sometimes called an oily cream. Creams are usually petrolatum, higher alcohols, etc. as they are or added with additives such as emulsifiers to form an oil phase. Separately, purified water is used as is, or additives such as emulsifiers are added to form an aqueous phase. The active ingredient can be added to this phase, heated, and the oil phase and the aqueous phase are combined and stirred until the whole is homogeneous and emulsified. The gel agent refers to a gel-like preparation, and includes an aqueous gel agent and an oily gel agent. An aqueous gel can be produced by adding a polymer compound, other additives and purified water to an active ingredient to dissolve or suspend, and heating and cooling, or adding a gelling agent to crosslink. The oily gel can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them. An ointment refers to a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base, and includes an oily ointment, a water-soluble ointment and the like. Oily ointments are usually homogeneous by heating and melting oily bases such as fats, waxes, and hydrocarbons such as paraffin, adding active ingredients, mixing and dissolving or dispersing them. It can be manufactured by mixing and kneading until. A water-soluble ointment can be usually produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole becomes homogeneous.

(4) Mouthwash The mouthwash is a liquid preparation that is applied locally to the oral cavity, pharynx, etc., and includes solid preparations that are dissolved upon use. The gargle can usually be produced by adding a solvent and an additive to the active ingredient, mixing and dissolving homogeneously, and filtering if necessary. In the case of a solid preparation which is dissolved at the time of use, it can usually be produced according to the production method of the tablet or granule.

[Injection preparation]
(1) Injection The injection is a solution, suspension, or emulsion that is administered directly to a body tissue or organ such as subcutaneous, intramuscular, or blood vessel, or a solid that is dissolved or suspended at the time of use. In addition to what is commonly referred to as injections, it includes lyophilized injections, powdered injections, filled syringes, cartridges, infusions, implantable injections, and sustained injections. It is. When producing an injection, the following method (a) or (b) is usually used:
(A) The active ingredient as it is or with the additive added to the active ingredient is dissolved, suspended, or emulsified in water for injection, other aqueous solvent, or non-aqueous solvent, and the mixture is homogeneous for injection Filled in a container, sealed and sterilized;
(B) Aseptically filter the active ingredient as it is or after adding the additive to the active ingredient, dissolving, suspending or emulsifying it in water for injection, other aqueous solvent, or non-aqueous solvent. Or aseptically prepared and homogenized, filled into an injectable container and sealed;
Is used. The freeze-dried injection is usually the active ingredient as it is, or the active ingredient and excipients such as excipients are dissolved in water for injection, sterile filtered, filled into a container for injection and freeze-dried, or It can be produced by lyophilization in a dedicated container and then filling directly into the container. A powder injection can be usually produced by processing by aseptic filtration, and then adding a sterilized additive to the powder obtained by crystallization or filling the powder into a container for injection. The filled syringe preparation can be usually produced by preparing a solution, suspension, or emulsion using the active ingredient as it is or using the active ingredient and additives and filling the syringe. The cartridge agent refers to an injection that is used by putting a cartridge filled with a chemical solution into a dedicated syringe, and the cartridge filled with a chemical solution is usually a solution containing an active ingredient as it is or using an active ingredient and an additive, It can be produced by preparing a suspension or emulsion and filling the cartridge. An infusion means an injection that is usually administered 100 mL or more intravenously. An implantable injection refers to a solid or gel injection that is applied subcutaneously, intramuscularly, etc., or by surgery for the purpose of releasing an active ingredient over a long period of time. Implantable injections can usually be produced by using biodegradable polymer compounds and making them into pellets, microspheres, or gels. A sustained injection is an injection that is applied intramuscularly for the purpose of releasing an active ingredient over a long period of time. Usually, the active ingredient is dissolved or suspended in vegetable oil or the like, or a biodegradable polymer compound. It can be produced by making a suspension of microspheres using

[Dialysis preparations]
(1) Dialysis agent The dialysis agent is a liquid preparation used for peritoneal dialysis or hemodialysis or a solid preparation that dissolves during use, and includes a peritoneal dialysis agent and a hemodialysis agent. A peritoneal dialysis agent is a sterile dialysis agent used for peritoneal dialysis. Usually, an additive is added to the active ingredient and dissolved in a solvent to a constant volume, or an additive is added to the active ingredient. Can be produced by filling the container in a container, sealing the container, and sterilizing as necessary. In the case of a solid preparation which dissolves at the time of use, it can be usually produced according to the production method of the tablet or granule. A hemodialysis agent is a dialysis agent used for hemodialysis. Usually, an additive is added to the active ingredient and dissolved in a solvent to a constant volume, or an active ingredient is added to the container. It can be manufactured by filling. In the case of a solid preparation which dissolves at the time of use, it can be usually produced according to the production method of the tablet or granule.

[Inhalation preparation]
(1) Inhalant An inhalant is a preparation for inhaling an active ingredient as an aerosol and applied to the bronchus or lung, and includes powder inhalers, inhalants, inhaled aerosols and the like. A powder inhalant is a preparation that is inhaled as a solid particle aerosol prepared so that the amount of inhalation is constant. Usually, the active ingredient is made into fine particles and mixed with additives such as lactose as necessary. And can be manufactured by homogenizing. An inhalation solution is a liquid inhaler that is applied with a nebulizer or the like. Usually, a solvent and an appropriate isotonic agent, pH adjuster, etc. are added to the active ingredient, and mixed to dissolve or suspend uniformly. Accordingly, it can be produced by filtering. An inhalation aerosol is a metered dose inhaler that sprays a certain amount of active ingredient together with a propellant filled in a container. Inhalation aerosols are usually prepared by adding a solvent and appropriate dispersant, stabilizer, etc. to the active ingredient to form a solution or suspension, filling a pressure-resistant container with a liquid propellant, and mounting a metering valve. Can be manufactured.

[Ophthalmic formulation]
(1) Eyedrops Eyedrops are liquid or solid aseptic preparations that are applied to ocular tissues such as the conjunctival sac and dissolved or suspended at the time of use. Eye drops can be usually produced by adding an additive to an active ingredient and dissolving or suspending it in a solvent or the like to make a constant volume, or filling an active ingredient with an additive into a container. .

(2) Eye ointment An eye ointment is a semi-solid, sterile preparation that is applied to ocular tissues such as the conjunctival sac. Usually, a base such as petrolatum and a solution of active ingredients or a fine powder are mixed and made homogeneous. It can be manufactured by filling a container.

[Ophthalmic preparations]
(1) Eardrops Eardrops are liquid, semi-solid, or solid preparations that are dissolved or suspended at the time of use for administration to the outer ear or middle ear. Ear drops are usually manufactured by adding an additive to an active ingredient and dissolving or suspending it in a solvent or the like to make a fixed volume, or filling an active ingredient with an additive into a container. it can.

[Nasal formulation]
(1) Nasal drops Nasal drops are preparations administered to the nasal cavity or nasal mucosa, and include nasal powders, nasal drops and the like. Nasal powder refers to a finely powdered nasal spray that is administered to the nasal cavity, and is usually manufactured by making the active ingredient into moderately fine particles and mixing with additives as necessary to make it homogeneous. Can do. Nasal solution refers to a liquid nasal solution that is administered into the nasal cavity or a solid nasal solution that is dissolved or suspended at the time of use. Usually, it is dissolved or suspended by adding a solvent or an additive to the active ingredient, and is necessary. It can manufacture by filtering according to. As an additive for the nasal solution, an isotonic agent, a pH adjuster and the like can be used.

[Rectal preparation]
(1) Suppositories A suppository is a semi-solid preparation of a certain shape that is applied into the rectum, melts with body temperature, or slowly dissolves or disperses in water to release the active ingredient. Suppositories are usually obtained by adding additives such as dispersants and emulsifiers to active ingredients and mixing them uniformly, and then dissolving or uniformly dispersing them in a base liquefied by heating or the like. It is possible to manufacture by filling a certain amount into and solidifying / molding. As a suppository base, an oleaginous base or a hydrophilic base is usually used.

(2) Rectal semi-solid preparations Rectal semi-solid preparations are preparations applied around or within the anus, and include rectal creams, rectal gels, rectal ointments and the like. A rectal semi-solid preparation is usually homogenized by emulsifying the active ingredient with additives and an oily ingredient such as petroleum jelly, or by mixing with the active ingredient and additives based on a polymer gel or fat. Can be manufactured. Rectal cream is usually used as petrolatum, higher alcohol, or the like as an oil phase by adding an additive such as an emulsifier, and separately as purified water or an additive such as an emulsifier as an aqueous phase. It can be produced by adding an active ingredient to any phase, heating each, and stirring and emulsifying the oil phase and the aqueous phase together until the whole becomes homogeneous. The rectal gel refers to a gel-like preparation, and includes an aqueous gel and an oily gel. An aqueous gel can be produced by adding a polymer compound, other additives and purified water to an active ingredient to dissolve or suspend, and heating and cooling, or adding a gelling agent to crosslink. The oily gel can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them. A rectal ointment refers to a semi-solid preparation in which an active ingredient is dissolved or dispersed in a base, and includes an oily ointment, a water-soluble ointment and the like. Oily ointments are usually homogeneous by heating and melting oily bases such as fats, waxes, and hydrocarbons such as paraffin, adding active ingredients, mixing and dissolving or dispersing them. It can be manufactured by mixing and kneading until. A water-soluble ointment can be usually produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole becomes homogeneous.

(3) Enema Intestinal infusion is a liquid or viscous gel preparation that is applied through the anus. Usually, purified water or an appropriate aqueous solvent is used, and the active ingredient is dissolved or suspended in a solvent. It can be manufactured by filling the container with a constant volume. Dispersants, stabilizers, pH adjusters, and the like can be used as additives for enteric preparations.

[Vaginal preparation]
(1) Tablets Tablets are solid preparations of a fixed shape that are applied to the tablet and release active ingredients by gradually dissolving or dispersing in water, and are usually manufactured according to the manufacturing method of the tablets. can do.

(2) Vaginal suppositories Vaginal suppositories are semi-solid preparations of a certain shape that release active ingredients by applying to vaginal, melting by body temperature, or gradually dissolving or dispersing in water Usually, it can be produced according to the production method of the rectal suppository and the like.

[Skin preparation]
(1) External solid agent An external solid agent is a solid preparation that is applied or sprayed to the skin or nails including the scalp, and includes an external powder. The powder for external use refers to a powdered external solid preparation, which can be usually produced by adding an additive such as an excipient to the active ingredient and mixing to make it homogeneous, and then powdered.

(2) External liquid preparations External liquid preparations are liquid preparations applied to the skin or nails including the scalp, and include liniments, lotions and the like. A liquid preparation for external use can be usually produced by adding a solvent, an additive or the like to an active ingredient, dissolving, emulsifying, or suspending, and filtering as necessary. A liniment refers to a liquid or mud external liquid used by being rubbed into the skin. A lotion refers to a solution for external use in which an active ingredient is dissolved or emulsified or finely dispersed in an aqueous liquid. Usually, the active ingredient, additive, and purified water are used to form a solution, suspension, or emulsion. It can be manufactured by homogenizing the whole as a liquid.

(3) Spray agent A spray agent is a formulation which sprays an active ingredient on the skin as a mist form, a powder form, a foam form, or a paste form, and includes an aerosol for external use, a pump spray, and the like. The spray can be usually produced by preparing a solution or suspension of the active ingredient, filtering it if necessary, and filling the container. An external aerosol agent refers to a spray agent that sprays an active ingredient together with a liquefied gas or a compressed gas filled in a container. An aerosol for external use can be usually produced by preparing a solution or suspension of an active ingredient, filling a pressure-resistant container together with a liquid propellant, and mounting a continuous injection valve. Additives such as dispersants and stabilizers may be added to the external aerosol as needed. A pump spray refers to a spray that sprays the active ingredients in a container with a pump. A pump spray can be usually produced by dissolving or suspending active ingredients and additives and attaching a pump to a container after filling.

(4) Ointment An ointment is a semisolid preparation in which an active ingredient is dissolved or dispersed in a base and is applied to the skin, and includes an oily ointment, a water-soluble ointment and the like. Oily ointments are usually homogeneous by heating and melting oily bases such as fats, waxes, and hydrocarbons such as paraffin, adding active ingredients, mixing and dissolving or dispersing them. It can be manufactured by mixing and kneading until. A water-soluble ointment can be usually produced by heating and melting a water-soluble base such as macrogol, adding an active ingredient, and mixing and kneading until the whole becomes homogeneous.

(5) Cream The cream is a semi-solid preparation emulsified in the oil-in-water or water-in-oil type applied to the skin, and the lipophilic preparation emulsified in the water-in-oil type is also called an oily cream. Sometimes. Creams are usually petrolatum, higher alcohols, etc. as they are or added with additives such as emulsifiers to form an oil phase. Separately, purified water is used as is, or additives such as emulsifiers are added to form an aqueous phase. The active ingredient can be added to this phase, heated, and the oil phase and the aqueous phase are combined and stirred until the whole is homogeneous and emulsified.

(6) Gel agent A gel agent is a gel-like preparation applied to the skin, and includes an aqueous gel agent and an oily gel agent. An aqueous gel can be produced by adding a polymer compound, other additives and purified water to an active ingredient to dissolve or suspend, and heating and cooling, or adding a gelling agent to crosslink. The oily gel can be produced by adding a liquid oily base such as glycols and higher alcohols and other additives to the active ingredient and mixing them.

(7) Patches Patches are preparations that are applied to the skin, and include tapes and poultices. The patch is usually produced by using a polymer compound or a mixture thereof as a base, mixing the active ingredient with the base and making it homogeneous, and spreading and molding on a support or liner (release body). it can. Moreover, it can also be set as a percutaneous absorption type preparation using a controlled release membrane. In the patch, additives such as an adhesive and an absorption accelerator can be used as necessary. The tape preparation refers to a patch using a base containing almost no water, and includes plaster, plaster and the like. Tapes are usually based on water-insoluble natural or synthetic polymer compounds such as resins, plastics, and rubbers, and the active ingredients are used as they are, or additives are added to the active ingredients to make the whole homogeneous and spread on the cloth. It can be manufactured by spreading or encapsulating in a rolled or plastic film. It can also be produced by encapsulating and molding a mixture comprising an active ingredient and a base or other additive in a release body made of a release-controlling membrane, a support and a liner (peeling body). A cataplasm is a patch that uses a base containing water. Usually, the active ingredient is mixed with purified water, a liquid substance such as glycerin, and the whole is homogenized, water-soluble polymer, water-absorbing high It can be produced by mixing natural or synthetic polymer compounds such as molecules with purified water and kneading them, adding the active ingredients, homogenizing the whole, and spreading and molding on a cloth or the like.

  Unless defined otherwise, all technical and scientific terms and abbreviations used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

  In addition, the contents of all patent documents and non-patent documents or references explicitly cited in the present specification can be cited herein as a part of the present specification.

  EXAMPLES Hereinafter, although this invention is explained in full detail according to a synthesis example, this invention is not limited to these.

  The location of separation by chromatography and the solvent in parentheses shown in TLC indicate the elution solvent or developing solvent used, and the ratio indicates the volume ratio.

  The solvent in parentheses shown in the NMR part indicates the solvent used for the measurement.

  The compound name used in this specification is a computer program, ACD / Name (registered trademark), which is generally named in accordance with the rules of IUPAC, or Chemdraw Ultra (version 12.0, manufactured by Cambridge Soft). Or named according to the IUPAC nomenclature.

Reference Example 1: 4-methylene chroman

Under a nitrogen stream, a solution of lithium bistrimethylsilylamide in THF (1.3 mol / L, 931 mL) in tetrahydrofuran (1500 mL) in methyltriphenylphosphonium bromide (435 g) was added dropwise under ice cooling. Then, it stirred at room temperature for 1 hour. A solution of 4-chromanone (150 g) in THF (180 mL) was added dropwise at −5 ° C., and the mixture was stirred at room temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture under ice cooling, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (75.9 g) having the following physical property values.
TLC: Rf 0.62 (hexane: ethyl acetate = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 2.59-2.75, 4.18-4.31, 4.89, 5.51, 6.79-6.94, 7.12-7.20, 7.56.

Reference Example 2: Ethyl (2'R, 4S) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-carbochelate

Under a nitrogen stream, a solution of the compound prepared in Reference Example 1 (75.9 g) in dichloromethane (2500 mL) was added to dichloro (p-cymene) ruthenium (II) dimer (15.8 g), (S,
S) -2,6-bis (4-isopropyl-2-oxazolin-2-yl) pyridine (15.6 g) was added. A solution of ethyl diazoacetate (containing 13% dichloromethane, 134 g) in dichloromethane (150 mL) was slowly added dropwise at room temperature, followed by stirring for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with dichloromethane. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (91.2 g) having the following physical property values.
¹ H-NMR (CDCl ₃ ): δ 1.26, 1.54-1.67, 2.07-2.22, 4.05-4.21, 4.27, 6.68, 6.78-6.89, 7.04-7.12.

Reference Example 3: (2'R, 4S) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-carboxylic acid

To a solution of the compound (91.2 g) produced in Reference Example 2 in methanol (400 mL) and 1,2-dimethoxyethane (400 mL), a solution of lithium hydroxide monohydrate (29.6 g) in water (160 mL) was added. Stir at room temperature overnight. A 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from dichloromethane to give the title compound (55.2 g) having the following physical data.
¹ H-NMR (CDCl ₃ ): δ 1.59-1.67, 1.68-1.76, 2.15, 2.21-2.29, 4.12-4.23, 4.25-4.36, 6.70, 6.80-6.92, 7.06-7.16;
HPLC retention time: 6.9 minutes (CHIRALPAK IC 4.6 mm x 250 mm hexane: ethyl acetate: formic acid = 97: 3: 1).

Reference Example 4: Methyl (2'R, 4S) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-carbochelate

Under a nitrogen stream, potassium carbonate (28.5 g) was added to an N, N-dimethylformamide (hereinafter abbreviated as DMF) (200 mL) solution of the compound (40.0 g) prepared in Reference Example 3 and then iodomethane ( 31.9 g) was added dropwise and stirred at room temperature overnight. The reaction mixture was poured into ice water and extracted with a hexane-ethyl acetate mixed solution. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (40.1 g) having the following physical data.
TLC: Rf 0.30 (hexane: ethyl acetate = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.57-1.69, 2.09-2.22, 3.71, 4.07-4.17, 4.27, 6.68, 6.78-6.90, 7.04-7.14.

Reference Example 5: Methyl (2'R, 4S) -6-iodo-2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-carbochelate

Under a nitrogen stream, 1,3-diiodo-5,5-dimethylhydantoin (35.6 g) and 3 drops of concentrated sulfuric acid were added to a methanol (320 mL) solution of the compound prepared in Reference Example 4 (40.1 g) under ice cooling. After the addition, the mixture was stirred for 1.5 hours and at room temperature for 2.5 hours. The reaction mixture was diluted with a hexane-ethyl acetate mixed solution, washed with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with a hexane-ethyl acetate mixed solution. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (63.8 g) having the following physical data.
TLC: Rf 0.33 (hexane: ethyl acetate = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.60, 2.06-2.19, 3.71, 4.09, 4.20-4.31, 6.59, 6.93, 7.36.

Reference Example 6: (2'R, 4S) -6-iodo-2,3-dihydrospiro [chromene-4,1
'-Cyclopropane] -2'-carboxylic acid

To a solution of the compound prepared in Reference Example 5 (15.0 g) in methanol (60 mL) and 1,2-dimethoxyethane (60 mL) was added an aqueous sodium hydroxide solution (2 mol / L, 44 mL), and the mixture was stirred at room temperature for 1.5 hours. Stir. Hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (14.4 g) having the following physical data.
TLC: Rf 0.42 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.57-1.74, 2.11, 2.16-2.25, 4.10-4.20, 4.23-4.33, 6.59, 6.94, 7.37.

Reference Example 7: Ethyl 4- (4-formyl-2-nitrophenyl) butanoate

Under a nitrogen stream, iodine (26.0 g) was added to a solution of zinc powder (99.2 g) in N, N-dimethylacetamide (hereinafter abbreviated as DMA) (700 mL) and stirred for 10 minutes. After dropwise addition of ethyl 4-bromobutyrate (200 g), a zinc reagent was prepared by stirring at 80 ° C. for 2 hours. Under a nitrogen stream, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (7.14 g) and palladium acetate (1.96 g) were added to a THF (500 mL) solution of 3-nitro-4-bromobenzaldehyde (100 g). After the addition, a zinc reagent (500 mL) prepared under ice cooling was added dropwise, and the mixture was stirred at room temperature for 30 minutes. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (91.2 g) having the following physical property values.
TLC: Rf 0.61 (hexane: ethyl acetate = 2: 1);
¹ H-NMR (CDCl ₃ ): δ 1.27, 1.97-2.09, 2.42, 3.01, 4.15, 7.57, 8.04, 8.38, 10.03.

Reference Example 8: Ethyl 4- (4-cyano-2-nitrophenyl) butanoate

Hydroxylamine hydrochloride (26.0 g) was added to a DMF (350 mL) solution of the compound produced in Reference Example 7 (92.0 g), and the mixture was stirred at 50 ° C. for 1 hour. Acetyl chloride (30 mL) was added and stirred at 90 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (81.0 g) having the following physical property values.
TLC: Rf 0.65 (hexane: ethyl acetate = 2: 1);
¹ H-NMR (CDCl ₃ ): δ 1.27, 1.92-2.10, 2.37-2.45, 2.91-3.06, 4.15, 7.55, 7.81, 8.21.

Reference Example 9: Ethyl 4- (2-amino-4-cyanophenyl) butanoate

To a solution of the compound (17.0 g) produced in Reference Example 8 in ethanol (80 mL) was added palladium carbon (50% wet, 8.0 g), and the mixture was stirred at room temperature for 9 hours in a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated to give the title compound (12.0 g) having the following physical data.
TLC: Rf 0.56 (hexane: ethyl acetate = 2: 1);
¹ H-NMR (CDCl ₃ ): δ 1.28, 1.79-1.95, 2.38-2.45, 2.50-2.60, 4.09-4.30, 6.89, 6.93-6.98, 7.04-7.10.

Reference Example 10: Ethyl 4- [4-cyano-2-({[(2′R, 4S) -6-iodo-2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′- Yl] carbonyl} amino) phenyl] butanoate

To a solution of the compound prepared in Reference Example 6 (14.4 g) and the compound prepared in Reference Example 9 (10.0 g) in DMA (90 mL) was added 4-methylmorpholine (24.0 mL), 4-dimethylaminopyridine (5 .33 g) and propylphosphonic acid anhydride cyclic trimer (hereinafter abbreviated as T3P) (1.7 mol / L, 46.5 mL) were added, and the mixture was stirred overnight at room temperature. Ethyl acetate, water, and aqueous hydrochloric acid solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed with a mixed solution of hexane-ethyl acetate to obtain the title compound (19.3 g) having the following physical property values.
TLC: Rf 0.42 (hexane: ethyl acetate = 2: 1);
¹ H-NMR (CDCl ₃ ): δ 1.20, 1.61, 1.66-1.79, 1.83, 2.18-2.28, 2.39-2.49, 2.60, 3.66, 3.90, 4.00-4.12, 4.26, 6.58, 7.05, 7.15-7.22, 7.26- 7.31, 7.33, 8.72, 9.39.

Reference Example 11: (2'R, 4S) -2 '-{[5-cyano-2- (4-ethoxy-4-oxy)
Sobutyl) phenyl] carbamoyl} -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -6-carboxylic acid

To a solution of the compound prepared in Reference Example 10 (7.40 g) in DMF (60 mL), sodium acetate (3.35 g), [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (555 mg) ) Under a carbon monoxide atmosphere.
Stir at 0 ° C. for 6 hours. After adding potassium carbonate aqueous solution to the reaction mixture and stirring for a while, tert-butyl methyl ether and water were added and filtered through Celite (trade name). To the filtrate was added aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification device) to obtain the title compound (6.14 g) having the following physical property values.
TLC: Rf 0.48 (dichloromethane: ethyl acetate: methanol = 8: 4: 1);
¹ H-NMR (CDCl ₃ ): δ 1.08, 1.65-1.80, 1.83-1.92, 2.25-2.36, 2.37-2.49, 2.55-2.66, 2.71, 3.55, 3.79, 4.12-4.23, 4.37, 6.88, 7.15-7.22, 7.27-7.32, 7.61, 7.83, 8.73, 9.40.

Reference Example 12: Ethyl 4- [4-cyano-2-({[(2′R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane]- 2′-yl] carbonyl} amino) phenyl] butanoate

The compound prepared in Reference Example 11 (60.0 mg) was used instead of the compound prepared in Reference Example 6, and methylamine hydrochloride (87.5 mg) was used instead of the compound prepared in Reference Example 9. The same operation as in Example 10 was performed to give the title compound (53.0 mg) having the following physical data.
¹ H-NMR (CDCl ₃ ): δ 1.07, 1.64-1.79, 1.81-1.89, 2.20-2.35, 2.40, 2.60, 2.69, 2.98, 3.44-3.59, 3.68-3.83, 4.07-4.19, 4.27-4.38, 6.05, 6.82, 7.15-7.22, 7.27-7.32, 7.35-7.44, 8.72, 9.37.

Example 1: 4- [4-cyano-2-({[(2'R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2 '-Il]
Rubonyl} amino) phenyl] butanoic acid

The title compound (45 mg) having the following physical data was obtained by conducting the same operation as in Reference Example 6 using the compound (53 mg) produced in Reference Example 12 and ethanol instead of methanol.
TLC: Rf 0.45 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.21-1.30, 1.55, 1.65-1.82, 2.06-2.26, 2.38-2.67, 2.67-2.76, 3.02, 3.57, 4.33, 4.49-4.58, 6.25, 6.81, 7.19, 7.23- 7.30, 7.94, 8.87, 9.93.

Example 2
Using the corresponding amine compound in place of methylamine hydrochloride, the same operation as in Reference Example 12 → Example 1 was performed to obtain the title compound having the following physical property values.

Example 2-1: 4- {4-cyano-2-[({(2′R, 4S) -6-[(cyclopropylmethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.45 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 0.23-0.31, 0.52-0.63, 0.96-1.14, 1.22-1.30, 1.55, 1.66-1.81, 2.06-2.24, 2.38-2.66, 2.66-2.76, 3.31, 3.57, 4.34, 4.49-4.59, 6.31, 6.83, 7.19, 7.24-7.29, 7.32, 7.95, 8.87, 9.93.

Example 2-2: 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.51 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.26, 1.55, 1.67-1.84, 2.06-2.27, 2.39-2.67, 2.67-2.78, 3.39, 3.51-3.78, 4.33, 4.49-4.59, 6.62, 6.82, 7.19, 7.24- 7.29, 7.32, 7.92, 8.86, 9.88.

Example 2-3: 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-methyl-2-propanyl) carbamoyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.63 (chloroform: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.37, 1.57, 1.64-1.85, 2.04-2.25, 2.42-2.48,
2.60-2.71, 4.01-4.15, 4.24-4.38, 6.80, 7.34-7.45, 7.52-7.66, 7.88, 9.89, 12.11
.

Example 2-4: 4- [4-cyano-2-({[(2′R, 4S) -6-{[(2S) -1-methoxy-2-propanyl] carbamoyl} -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.62 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CD ₃ OD): δ 1.22, 1.65-1.89, 2.12-2.26, 2.33, 2.62-2.77, 3.30-3.32, 3.37, 3.41, 3.47, 4.21-4.39, 6.82, 7.37-7.51, 7.58, 8.05 .

Example 2-5: 4- {4-cyano-2-[({(2′R, 4S) -6-[(1-methyl-1H-pyrazol-4-yl) carbamoyl] -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.51 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.61, 1.66-1.87, 2.08-2.25, 2.50, 2.59-2.73,
3.81, 4.06-4.19, 4.28-4.42, 6.90, 7.41, 7.49-7.61, 7.73, 7.88, 7.99, 9.91, 10.19, 12.10.

Example 2-6: 4- {4-cyano-2-[({(2′R, 4S) -6-[(3-methoxy-1-azetidinyl) carbamoyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.54 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.56, 1.67-1.80, 2.04-2.26, 2.45, 2.58-2.72,
3.21, 3.74-3.91, 4.06-4.27, 4.30, 4.37-4.51, 6.83, 7.15, 7.34-7.44, 7.57, 7.88,
9.89, 12.11.

Example 2-7: 4- {4-cyano-2-[({(2′R, 4S) -6-[(1,3-oxazol-2-ylmethyl) carbamoyl] -2,3-dihydrospiro [ Chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.64 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.63, 1.65-1.83, 2.07-2.25, 2.48, 2.58-2.70, 4.03-4.16, 4.27-4.40, 4.47-4.64, 6.87, 7.15, 7.40, 7.48, 7.56, 7.67, 7.87,
8.04, 9.02, 9.90, 12.10.

Example 2-8: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-oxazol-2-ylcarbamoyl) -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.40 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.61, 1.66-1.80, 1.86, 2.11-2.25, 2.52, 2.61-2.72, 4.14, 4.38, 6.93, 7.19, 7.42, 7.54-7.65, 7.76, 7.88, 7.96, 9.92, 11.38, 12.10.

Example 2-9: 4- {4-cyano-2-[({(2′R, 4S) -6-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.62 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.59, 1.67-1.81, 1.92, 2.10-2.25, 2.54, 2.60-2.72, 3.77, 4.12, 4.35, 6.59, 6.89, 7.42, 7.55-7.62, 7.68, 7.77, 7.88, 9.92, 10.75, 12.10.

Example 2-10: 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.65 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 0.49-0.59, 0.65-0.75, 1.58, 1.66-1.82, 2.06-2.26, 2.47, 2.61-2.71, 2.81, 4.09, 4.34, 6.83, 7.36-7.45, 7.54- 7.65, 7.88, 8.30,
9.89, 12.09.

Example 2-11: 4- [2-({[(2′R, 4S) -6- (butylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′- Yl] carbonyl} amino) -4-cyanophenyl] butanoic acid TLC: Rf 0.79 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CDCl ₃ ): δ 0.93-1.00, 1.21-1.83, 2.06-2.25, 2.37-2.77, 3.41-3.50, 3.51-3.63, 4.33, 4.54, 6.18, 6.81, 7.15-7.31, 7.94, 8.87, 9.93.

Example 2-12: 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclohexylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.86 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CDCl ₃ ): δ 1.10-1.87, 1.94-2.26, 2.38-2.79, 3.50-3.64, 3.85-4.04, 4.33, 4.54, 6.04, 6.81, 7.14-7.31, 7.93, 8.87, 9.93.

Example 2-13: 4- [4-cyano-2-({[(2′R, 4S) -6- (isopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.74 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CDCl ₃ ): δ 1.27, 1.34-1.92, 2.01-2.30, 2.38-2.80, 3.50-3.61, 4.18-4.43, 4.54, 6.00, 6.81, 7.15-7.31, 7.94, 8.87, 9.93.

Example 2-14: 4- [4-cyano-2-({[(2'R, 4S) -6- (cyclopentyl
Rucarbamoyl) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.83 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CDCl ₃ ): δ 1.20-1.86, 2.00-2.26, 2.38-2.79, 3.50-3.64, 4.25-4.45, 4.46-4.61, 6.13, 6.81, 7.13-7.31, 7.94, 8.87, 9.93.

Example 2-15: 4- [4-cyano-2-({[(2′R, 4S) -6- (isobutylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.83 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CDCl ₃ ): δ 0.84-1.03, 1.21-2.01, 2.06-2.26, 2.37-2.79, 3.20-3.38, 3.51-3.62, 4.34, 4.49-4.59, 6.18-6.32, 6.82, 7.14-7.32, 7.94, 8.87, 9.93
.

Example 2-16: 4- {2-[({(2'R, 4S) -6-[(2S) -2-butanylcarbamoyl] -2,3-dihydrospiro [chromene-4,1'- Cyclopropane] -2'-yl} carbonyl) amino] -4-cyanophenyl} butanoic acid

TLC: Rf 0.84 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 0.95, 1.18-1.91, 2.05-2.25, 2.39-2.78, 3.50-3.64, 4.03-4.20, 4.33, 4.48-4.60, 5.97, 6.81, 7.13-7.32, 7.94, 8.87, 9.93.

Example 2-17: 4- {2-[({(2'R, 4S) -6-[(2R) -2-butanylcarbamoyl] -2,3-dihydrospiro [chromene-4,1'- Cyclopropane] -2′-yl} carbonyl) amino] -4-cyanophenyl} butanoic acid TLC: Rf 0.84 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 0.98, 1.18-1.32, 1.49-1.86, 2.05-2.25, 2.39-2.81, 3.57, 4.11, 4.33, 4.54, 5.95, 6.81, 7.13-7.33, 7.93, 8.81, 8.86, 9.93.

Example 2-18: 4- [2-({[(2'R, 4S) -6- (benzylcarbamoyl) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'- Il] Carbo
Nyl} amino) -4-cyanophenyl] butanoic acid TLC: Rf 0.84 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.20-1.86, 2.06-2.26, 2.40-2.79, 3.58, 4.34, 4.48-4.72, 6.47, 6.80, 7.15-7.42, 7.99, 8.87, 9.92.

Example 2-19: 4- {4-cyano-2-[({(2'R, 4S) -6-[(3R) -tetrahydro-3-furanylcarbamoyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.56 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.59, 1.67-1.83, 1.90, 2.07-2.26, 2.46, 2.61-2.71, 3.58, 3.72, 3.82-3.92, 4.10, 4.33, 4.48, 6.85, 7.38-7.48, 7.58, 7.67, 7.88, 8.39, 9.91, 12.11.

Example 2-20: 4- {4-cyano-2-[({(2′R, 4S) -6-[(trans-4-hydroxycyclohexyl) carbamoyl] -2,3-dihydrospiro [chromene-4 , 1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.57 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 0.77-1.85, 1.95-2.26, 2.38-2.77, 3.48-3.77, 3.83-4.04, 4.33, 4.54, 5.97, 6.81, 7.15-7.35, 7.92, 8.87, 9.92.

Example 2-21: 4- {4-cyano-2-[({(2′R, 4S) -6-[(cis-4-hydroxycyclohexyl) carbamoyl] -2,3-dihydrospiro [chromene-4 , 1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.64 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.20-1.31, 1.51-1.86, 2.05-2.24, 2.38-2.79, 3.51-3.62, 3.94-4.09, 4.33, 4.54, 6.16, 6.82, 7.13-7.31, 7.92, 8.87, 9.92.

Example 2-22: 4- [4-cyano-2-({[(2′R, 4S) -6-{[2- (dimethylamino) ethyl] carbamoyl} -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.17 (ethyl acetate: methanol = 9: 1, chromatolex diol TLC plate (Fuji Silysia));
¹ H-NMR (CDCl ₃ ): δ 1.19-1.34, 1.59, 1.66-1.84, 2.09-3.16, 3.38, 3.62-3.81, 4.33, 4.52, 6.85, 7.15-7.31, 7.52-7.64, 7.87, 8.80, 9.55.

Example 2-23: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyridinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′- Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.83 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.58, 1.73, 1.88-1.99, 2.10-2.24, 2.60-2.70,
4.06-4.18, 4.30-4.40, 6.90, 7.14, 7.41, 7.57, 7.72, 7.77-7.90, 8.18, 8.38, 9.91, 10.78, 12.09.

Example 2-24: 4- {4-cyano-2-[({(2'R, 4S) -6-[(2-pyridinylmethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 ' -Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.62 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.58, 1.63-1.84, 2.01-2.24, 2.59-2.69, 4.04-4.16, 4.27-4.39, 4.55, 6.87, 7.22-7.33, 7.40, 7.55, 7.66-7.80, 7.87, 8.45-8.55, 9.01, 9.90, 12.09.

Example 2-25: 4- [4-cyano-2-({[(2′R, 4S) -6-{[(2R) -1-methoxy-2-propanyl] carbamoyl} -2,3-dihydro Spiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.76 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.12, 1.59, 1.67-1.83, 2.08-2.25, 2.47, 2.61-2.70, 3.23-3.31, 3.40, 4.09, 4.20, 4.33, 6.85, 7.39-7.46, 7.58, 7.65, 7.89, 8.09, 9.90, 12.11.

Example 2-26: 4- {4-cyano-2-[({(2′R, 4S) -6-[(3-oxetanylmethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.56 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.59, 1.66-1.80, 2.09-2.25, 2.46, 2.61-2.71,
3.15, 3.52, 4.10, 4.28-4.39, 4.63, 6.85, 7.37-7.47, 7.57-7.64, 7.89, 8.50, 9.92, 12.10.

Example 2-27: 4- {4-cyano-2-[({(2'R, 4S) -6-[(3S) -tetrahydro-3-furanylcarbamoyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.50 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.63, 1.64-1.97, 2.04-2.28, 2.41-2.47, 2.60-2.70, 3.58, 3.64-3.77, 3.80-3.92, 4.02-4.16, 4.26-4.38, 4.38-4.53, 6.84, 7.36-7.48, 7.58, 7.67, 7.87, 8.37, 9.91, 12.10.

Example 2-28: 4- {4-cyano-2-[({(2′R, 4S) -6-[(cyclobutylmethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.63 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.52-1.62, 1.62-1.88, 1.88-2.06, 2.06-2.24, 2.60-2.70, 3.23-3.30, 4.01-4.14, 4.26-4.37, 6.83, 7.36-7.45, 7.59, 7.88, 8.31, 9.91, 12.10.

Example 2-29: 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridazinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.65 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.59, 1.72, 1.87-1.99, 2.05-2.24, 2.54-2.70,
4.05-4.23, 4.30-4.44, 6.93, 7.41, 7.57, 7.72, 7.76-7.93, 8.38, 9.00, 9.99, 11.45, 12.11.

Example 2-30: 4- {4-cyano-2-[({(2′R, 4S) -6-[(1-methyl-4-piperidinyl) carbamoyl] -2,3-dihydrospiro [ Chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.21 (dichloromethane: methanol: 28% aqueous ammonia = 4: 1: 0.
. 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.49-1.83, 1.90-2.06, 2.06-2.24, 2.65, 2.81,
3.73, 4.02-4.15, 4.26-4.37, 6.83, 7.37-7.46, 7.56, 7.63, 7.90, 8.14, 10.01.

Example 2-31: 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-4-ylcarbamoyl) -2,3-dihydrospiro [chromene-4, 1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.45 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CD ₃ OD): δ 1.65-1.90, 2.24, 2.35, 2.60-2.80, 4.20-4.42, 6.89, 7.39-7.50, 7.59, 7.70, 7.89, 8.03.

Example 2-32: 4- {4-cyano-2-[({(2'R, 4S) -6-[(2,2-difluoroethyl) carbamoyl] -2,3-dihydrospiro [chromene-4 , 1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.76 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.81, 2.06-2.25, 2.41-2.47, 2.58-2.71, 3.55-3.78, 4.04-4.17, 4.25-4.40, 5.84-6.36, 6.87, 7.41, 7.48, 7.55, 7.67, 7.87, 8.73, 9.91, 12.10.

Example 2-33: 4- [4-cyano-2-({[(2'R, 4S) -6-{[(3S) -1-methyl-3-pyrrolidinyl] carbamoyl} -2,3-dihydro Spiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.33 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.50-1.59, 1.62-1.84, 2.06-2.23, 2.37, 2.64,
2.74-2.84, 4.14, 4.24-4.36, 4.45, 6.83, 7.35-7.48, 7.55, 7.63, 7.98, 8.45, 10.09.

Example 2-34: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-thiazol-2-ylcarbamoyl) -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.68 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.56-1.64, 1.65-1.81, 1.86-1.96, 2.10-2.24, 2.60-2.70, 4.07-4.19, 4.32-4.43, 6.94, 7.26, 7.41, 7.53-7.60, 7.79, 7.82-7.90, 9.92, 12.11, 12.53.

Example 2-35: 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′- Cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.53 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.58-1.65, 1.72, 1.83, 2.08-2.24, 2.61-2.70,
4.30-4.43, 6.94, 7.35-7.45, 7.57, 7.79, 7.88, 8.11-8.18, 8.30, 8.90, 9.93, 10.24, 12.09.

Example 2-36: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyrimidinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.56 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.63, 1.63-1.80, 1.84-1.95, 2.07-2.24, 2.60-2.70, 4.06-4.19, 4.29-4.43, 6.90, 7.24, 7.41, 7.57, 7.64, 7.75, 7.86, 8.72,
9.91, 10.94, 12.08.

Example 2-37: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,2-oxazol-3-ylcarbamoyl) -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.65 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.36-1.50, 1.62, 1.86-2.15, 2.53-2.68, 2.68-2.89, 4.19-4.37, 6.85, 6.91, 7.31-7.41, 7.41-7.49, 7.62, 7.79, 8.36, 8.75, 11.61, 12.62.

Example 2-38: 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclobutylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.72 (ethyl acetate);
¹ H-NMR (CD ₃ OD): δ 1.62-1.90, 2.02-2.44, 2.59-2.80, 4.19-4.30, 4.33, 4.49, 6.82, 7.37-7.51, 7.58, 8.04.

Example 2-39: 4- [4-cyano-2-({[(2′R, 4S) -6-{[1- (2-methyl-2-propanyl) -1H-pyrazol-4-yl]] Carbamoyl} -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.64 (ethyl acetate);
¹ H-NMR (CD ₃ OD): δ 1.59, 1.67-1.92, 2.16-2.29, 2.30-2.41, 2.62-2.78, 4.21-4.32, 4.33-4.46, 6.88, 7.37-7.51, 7.58, 7.65-7.74, 8.03 , 8.11.

Example 2-40: 4- [4-cyano-2-({[(2′R, 4S) -6- (tetrahydro-2H-pyran-4-ylcarbamoyl) -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.62 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.44-1.86, 2.02-2.24, 2.59-2.70, 3.35-3.44, 3.80-4.15, 4.25-4.37, 6.84, 7.37-7.46, 7.57, 7.64, 7.87, 8.13, 9.90, 12.09.

Example 2-41: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,2-oxazol-5-ylcarbamoyl) -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.71 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.56-1.66, 1.73, 1.87, 2.06-2.25, 2.60-2.70,
4.06-4.19, 4.31-4.44, 6.39, 6.94, 7.41, 7.57, 7.67, 7.81, 7.87, 8.50, 9.92, 11.90, 12.09.

Example 2-42: 4- [4-cyano-2-({[(2′R, 4S) -6- (4-pyridinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′- Cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.53 (dichloromethane: methanol = 4: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.57-1.66, 1.73, 1.83, 2.09-2.24, 2.60-2.70,
4.08-4.21, 4.31-4.42, 6.95, 7.41, 7.52-7.61, 7.74-7.91, 8.42-8.52, 9.91, 10.38,
12.09.

Example 2-43: 4- {4-cyano-2-[({(2'R, 4S) -6-[(1-methyl-1H-pyrazol-5-yl) carbamoyl] -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.58 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.55-1.65, 1.66-1.90, 2.06-2.29, 2.50, 2.60-2.74, 3.66, 4.06-4.22, 4.30-4.46, 6.17, 6.93, 7.35-7.45, 7.52- 7.61, 7.77, 7.88, 9.91, 10.15, 12.10.

Example 2-44: 4- [4-cyano-2-({[(2′R, 4S) -6- (propylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.75 (ethyl acetate);
¹ H-NMR (DMSO-d ₆ ): δ 0.88, 1.45-1.63, 1.68-1.82, 2.07-2.25, 2.45,
2.61-2.72, 3.15-3.26, 4.10, 4.32, 6.85, 7.39-7.46, 7.57-7.63, 7.88, 8.32, 9.90,
12.11.

Example 2-45: 4- {4-cyano-2-[({(2'R, 4S) -6-[(2-ethoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.51 (ethyl acetate);
¹ H-NMR (DMSO-d ₆ ): δ 1.11, 1.59, 1.67-1.83, 2.07-2.26, 2.47, 2.61-2.71, 3.35-3.52, 4.10, 4.33, 6.85, 7.38-7.48, 7.57-7.64, 7.88, 8.42, 9.90, 12.09.

Example 2-46: 4- [4-cyano-2-({[(2′R, 4S) -6- (ethylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.59 (ethyl acetate);
¹ H-NMR (DMSO-d ₆ ): δ 1.10, 1.58, 1.65-1.80, 2.07-2.24, 2.45, 2.58-2.69, 3.19-3.33, 4.09, 4.32, 6.84, 7.37-7.45, 7.57, 7.62, 7.88, 8.33, 9.89, 12.09.

Example 2-47: 4- {4-cyano-2-[({(2'R, 4S) -6-[(1-methoxy-2-methyl-2-propanyl) carbamoyl] -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.72 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (DMSO-d ₆ ): δ 1.33, 1.57, 1.67-1.86, 2.08-2.25, 2.47, 2.62-2.71, 3.27, 3.53, 4.09, 4.32, 6.82, 7.35-7.45, 7.48, 7.57-7.62, 7.88, 9.89, 12.10.

Reference Example 13: Ethyl 4- [4-cyano-2-({[(2′R, 4S) -6- (5-methyl-1,3,4-oxadiazol-2-yl) -2,3 -Dihydrospiro [chromene-4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoate

Triethylamine (60 μL) and T3P (1.7 mol / L ethyl acetate solution, 95 μL) were added to a solution of the compound prepared in Reference Example 11 (50 mg) and acetylhydrazine (16 mg) in dichloromethane (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purifier) to a solution of the compound obtained in THF (5 mL) to Burgess Reagent (methyl N- (triethylammoniosulfonyl) carbamate) (117 mg). ) Was added at room temperature. It stirred at 100 degreeC for 1 hour using the microwave reaction apparatus (made by Biotage). Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification device) to obtain the title compound (22 mg) having the following physical property values.
TLC: Rf 0.53 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (CDCl ₃ ): δ 0.94, 1.65-1.83, 1.89, 2.26-2.34, 2.35-2.44, 2.56-2.63, 2.66-2.76, 3.12-3.28, 3.36-3.55, 3.58-3.74, 4.07-4.23, 4.30-4.41, 6.92, 7.18, 7.28, 7.54, 7.70, 8.72, 9.39.

Example 3: 4- [4-cyano-2-({[(2′R, 4S) -6- (5-methyl-1,3,4-oxadiazol-2-yl) -2,3- Dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

Using the compound produced in Reference Example 13 instead of the compound produced in Reference Example 12, the same operation as in Example 1 was performed to obtain the title compound having the following physical property values.
TLC: Rf 0.93 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.27, 1.54, 1.70-1.91, 2.17, 2.32, 2.45-2.90, 3.64, 4.35-4.48, 4.56-4.66, 6.92, 7.20, 7.28, 7.58, 8.15, 8.92, 9.91, 12.68.

Example 4
Using the corresponding hydrazine compound instead of acetyl hydrazine, the same operation as in Reference Example 13 → Example 1 was performed to obtain the title compound having the following physical property values.

Example 4-1: 4- [4-cyano-2-({[(2′R, 4S) -6- (5-cyclopropyl-1,3,4-oxadiazol-2-yl) -2 , 3-Dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.64 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CDCl ₃ ): δ 1.14-1.32, 1.78, 2.07-2.41, 2.43-2.91, 3.63, 4.33-4.49, 4.61, 6.86-6.96, 7.16-7.32, 7.54, 8.13, 8.92, 9.91.

Example 4-2: 4- {4-cyano-2-[({(2′R, 4S) -6- [5- (2-methyl-2-propanyl) -1,3,4-oxadiazole -2-yl] -2,3-dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.83 (ethyl acetate: methanol = 19 : 1);
¹ H-NMR (CDCl ₃ ): δ 1.19-1.32, 1.44-1.52, 1.64-1.87, 2.10-2.40, 2.44-2.90, 3.64, 4.35-4.49, 4.56-4.67, 6.93, 7.16-7.35, 7.60, 8.15, 8.92, 9.92.

Example 4-3: 4- [4-cyano-2-({[(2′R, 4S) -6- (5-ethyl-1,3,4-oxadiazol-2-yl) -2, 3-dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.53 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.32, 1.60, 1.66-1.82, 2.10-2.24, 2.60-2.70,
2.92, 4.09-4.21, 4.31-4.42, 6.99, 7.41, 7.46, 7.57, 7.71, 7.88, 9.91, 12.08.

Reference Example 14: Ethyl 4- [4-cyano-2-({[(2′R, 4S) -6- (3-methyl-1,2,4-oxadiazol-5-yl) -2,3 -Dihydrospiro [chromene-4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoate

Triethylamine (0.144 mL) and T3P (1.7 mol / L ethyl acetate solution, 0.380 mL) were added to a solution of the compound prepared in Reference Example 11 (80 mg) and acetamide oxime (32 mg) in ethyl acetate (0.5 mL). Added at room temperature. The reaction mixture was heated to reflux for 4 days and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification device) to obtain the title compound (49 mg) having the following physical property values.
TLC: Rf 0.55 (hexane: ethyl acetate = 1: 1);
¹ H-NMR (CDCl ₃ ): δ 0.92, 1.64-1.83, 1.86-1.95, 2.22-2.35, 2.36-2.44, 2.45, 2.54-2.65, 2.72, 3.39-3.54, 3.59-3.73, 4.10-4.23, 4.32- 4.44, 6.94, 7.20,
7.28, 7.59, 7.84, 8.74, 9.39.

Example 5: 4- [4-cyano-2-({[(2′R, 4S) -6- (3-methyl-1,2,4-oxadiazol-5-yl) -2,3- Dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

Using the compound produced in Reference Example 14 instead of the compound produced in Reference Example 12, the same operation as in Example 1 was performed to obtain the title compound having the following physical property values.
TLC: Rf 0.74 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.55-1.64, 1.67-1.83, 2.11-2.29, 2.39, 2.51-2.60, 2.61-2.73, 4.11-4.25, 4.31-4.44, 7.02, 7.41, 7.52-7.62, 7.83, 7.88, 9.90, 12.10.

Reference Example 15: Ethyl 4- [4-cyano-2-({[(2′R, 4S) -6- (4-fluorophenyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoate

To a solution of the compound produced in Reference Example 10 (70 mg) in 1,2-dimethoxyethane (0.4 mL) at room temperature, cesium carbonate (84 mg), 4-fluorophenylboronic acid (36 mg), and purified water (0. 4 mL) was added to replace with argon. [1,1′-Bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (5 mg) was added and stirred at 85 ° C. overnight. The reaction mixture was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purifier) to give the title compound (54 mg) having the following physical data.
TLC: Rf 0.48 (hexane: ethyl acetate = 2: 1);
¹ H-NMR (CDCl ₃ ): δ 0.83, 1.64-1.79, 1.82-1.93, 2.29, 2.33-2.43, 2.48-2.74, 3.30, 3.49, 4.06-4.19, 4.26-4.38, 6.84-6.91, 6.97, 7.04- 7.15, 7.15-7.22,
7.22-7.32, 7.39-7.51, 8.73, 9.30.

Example 6: 4- [4-cyano-2-({[(2′R, 4S) -6- (4-fluorophenyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

The title compound having the following physical data was obtained by conducting the same operation as in Example 1, except that the compound prepared in Reference Example 15 was used instead of the compound prepared in Reference Example 12.
TLC: Rf 0.58 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.50-1.60, 1.72, 1.87, 2.06-2.24, 2.60-2.69,
4.03-4.15, 4.24-4.35, 6.87, 7.11, 7.19-7.29, 7.32-7.44, 7.56, 7.61-7.70, 7.87, 9.88, 12.09.

Example 7
Using the corresponding boronic acid compound or heterocyclic ring instead of 4-fluorophenylboronic acid, the same operation as in Reference Example 15 → Example 1 was performed to obtain the title compound having the following physical property values.

Example 7-1: 4- [4-cyano-2-({[(2′R, 4S) -6-phenyl-2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.53 (dichloromethane: methanol = 9: 1)
¹ H-NMR (CDCl ₃ ): δ 1.58-1.81, 2.14-2.27, 2.36-2.46, 2.49-2.71, 2.78, 4.22-4.37, 6.92, 7.15, 7.16-7.22, 7.26-7.51, 7.52-7.61, 8.69, 8.95.

Example 7-2: 4- [4-cyano-2-({[(2′R, 4S) -6- (4-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.36 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.52-1.63, 1.64-1.79, 1.87-1.99, 2.08-2.30, 2.43-2.73, 3.99-4.20, 4.25-4.41, 6.93, 7.31, 7.40, 7.56, 7.66- 7.71, 7.87, 8.51-8.62, 9.88, 11.90-12.18.

Example 7-3: 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.36 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.56, 1.65-1.77, 1.88-2.00, 2.06-2.30, 2.34-2.75, 4.03-4.19, 4.25-4.39, 6.92, 7.22, 7.37-7.51, 7.57, 7.87, 7.99-8.09, 8.48-8.53, 8.87, 9.87.

Example 7-4: 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-1-yl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.45 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.23-1.34, 1.62, 1.66-1.83, 2.05-2.23, 2.40-2.59, 2.61-2.82, 3.37-3.47, 4.22-4.35, 4.44-4.52, 6.49, 6.88, 7.11, 7.20, 7.28, 7.41, 7.71, 8.86, 9.95.

Example 7-5: 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-5-yl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.35 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.62, 1.63-1.86, 2.04-2.33, 2.34-2.75, 3.98-4.14, 4.23-4.35, 6.65, 6.82, 7.29, 7.40, 7.48-7.60, 7.63, 7.87, 9.91, 12.47.

Example 7-6: 4- [4-cyano-2-({[(2′R, 4S) -6- (4-pyridazinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane ] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.62, 1.63-1.80, 1.95-2.06, 2.09-2.33, 2.34-2.78, 4.01-4.22, 4.28-4.42, 6.97, 7.42, 7.47, 7.57, 7.71, 7.87, 7.94-8.04, 9.20, 9.60, 9.87, 12.1.

Example 7-7: 4- [4-cyano-2-({[(2′R, 4S) -6- (1-methyl-1H-pyrazol-4-yl) -2,3-dihydrospiro [chromene -4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.25 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CDCl ₃ ): δ 1.44-1.88, 2.22-2.33, 2.48, 2.58-2.76, 3.70, 4.16-4.36, 6.81-6.95, 7.11-7.34, 7.39, 7.56, 8.73, 9.16.

Example 7-8: 4- [4-cyano-2-({[(2′R, 4S) -6- (5-pyrimidinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.44 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.57, 1.65-1.79, 1.92-2.03, 2.06-2.35, 2.36-2.77, 4.01-4.17, 4.27-4.40, 6.94, 7.33, 7.40, 7.50-7.61, 7.87, 9.12, 9.86, 12.08.

Example 7-9: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-thienyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.44 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.61, 1.65-1.78, 1.79-1.88, 2.05-2.31, 2.40-2.76, 3.98-4.14, 4.23-4.36, 6.83, 7.04-7.16, 7.30-7.49, 7.57, 7.86, 9.90, 12.08.

Example 7-10: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-oxo-1-pyrrolidinyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.47 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.50-1.59, 1.60-1.80, 1.93-2.12, 2.19, 2.31-2.51, 2.54-2.78, 3.78, 3.93-4.09, 4.19-4.31, 6.78, 7.09, 7.29, 7.40, 7.56, 7.85,
9.91, 12.08.

Example 7-11: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-thiazol-5-yl) -2,3-dihydrospiro [chromene-4 , 1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.53 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.20-1.30, 1.58, 1.73-1.90, 2.26-2.37, 2.52, 2.64-2.82, 4.19-4.41, 6.81-6.97, 7.13-7.35, 7.77, 8.60, 8.69, 9.25.

Example 7-12: 4- [4-cyano-2-({[(2′R, 4S) -6- (pyrazolo [1,5-a] pyridin-3-yl) -2,3-dihydrospiro [Chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.59-1.70, 1.76-1.84, 2.31, 2.43-2.53, 2.60-2.80, 4.15-4.44, 6.72, 6.89, 6.97, 7.09-7.36, 7.68, 7.89, 8.43, 8.70, 9.15.

Example 7-13: 4- [4-cyano-2-({[(2′R, 4S) -6- (6-methoxy-3-pyridinyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.56 (ethyl acetate);
¹ H-NMR (CD ₃ OD): δ 1.65-1.93, 2.14-2.29, 2.33, 2.58, 2.67-2.78, 3.92, 4.21, 4.32, 6.80-6.91, 7.06, 7.30, 7.42, 7.48, 7.84-7.95, 8.31 .

Example 7-14: 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (1H-pyrazol-1-yl) -3-pyridinyl] -2,3- Dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.60 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.57, 1.63-1.79, 1.89-2.01, 2.08-2.25, 2.50-2.56, 2.60-2.72, 4.03-4.18, 4.27-4.40, 6.59, 6.93, 7.27, 7.40, 7.47-7.60, 7.80-7.91, 7.96, 8.27, 8.63, 8.76, 9.88, 12.10.

Example 7-15: 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (dimethylamino) -3-pyridinyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.58 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.62, 1.63-1.80, 1.84-1.95, 2.06-2.25, 2.51-2.57, 2.60-2.75, 3.18, 4.02-4.17, 4.23-4.39, 6.88, 7.01- 7.21, 7.35-7.47, 7.55, 7.87, 8.10-8.29, 9.92, 12.10.

Example 7-16: 4- [4-cyano-2-({[(2′R, 4S) -6- (6-methyl-3-pyridinyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.63 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.46-1.56, 1.56-1.79, 2.03, 2.16, 2.66, 4.15, 4.22-4.33, 6.86, 7.20, 7.27, 7.33-7.44, 7.44-7.52, 8.08-8.21, 8.70, 11.11.

Example 7-17: 4- [4-cyano-2-({[(2′R, 4S) -6- (6-fluoro-3-pyridinyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.59 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.52-1.60, 1.65-1.79, 1.93, 2.07-2.23, 2.60-2.70, 4.03-4.15, 4.27-4.37, 6.90, 7.19-7.27, 7.40, 7.45, 7.56, 7.87, 8.25, 8.51,
9.87, 12.09.

Example 7-18: 4- {4-cyano-2-[({(2'R, 4S) -6- [6- (methylsulfonyl) -3-pyridinyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.57 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.58, 1.72, 1.92-2.01, 2.09-2.24, 2.60-2.70,
4.06-4.17, 4.30-4.40, 6.96, 7.33-7.45, 7.58, 7.88, 8.06, 8.41, 9.09, 9.90, 12.10.

Example 7-19: 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrrolo [2,3-b] pyridin-5-yl) -2,3- Dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.55 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.61, 1.65-1.80, 1.91, 2.09-2.24, 2.60-2.70, 4.09, 4.25-4.36, 6.47, 6.89, 7.18, 7.38-7.45, 7.45-7.50, 7.56, 7.88, 8.17,
8.47, 9.94, 11.65, 12.06.

Example 7-20: 4- [4-cyano-2-({[(2′R, 4S) -6- (4-methyl-3,4-dihydro-2H-pyrido [3,2-b] [ 1,4] Oxazin-7-yl) -2,3-dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.65 (dichloromethane : Methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.48-1.58, 1.65-1.79, 1.88, 2.06-2.14, 2.19,
2.59-2.70, 3.03, 3.40-3.47, 3.99-4.11, 4.19-4.33, 6.81, 7.03, 7.23, 7.29, 7.40,
7.56, 7.86, 7.95, 9.87, 12.08.

Example 7-21: 4- {4-cyano-2-[({(2'R, 4S) -6- [6- (methylamino) -3-pyridinyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.53 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.52-1.61, 1.72, 1.84-1.94, 2.06-2.23, 2.60-2.70, 2.94, 4.02-4.13, 4.25-4.36, 6.88, 6.99, 7.14, 7.34-7.43, 7.56, 7.86, 8.09-8.21, 9.91, 12.13, 13.60.

Example 7-22: 4- {4-cyano-2-[({(2′R, 4S) -6- [3- (2-hydroxy-2-propanyl) phenyl] -2,3-dihydrospiro [ Chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.56 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.46, 1.54-1.62, 1.72, 1.79-1.88, 2.07-2.24,
2.60-2.70, 4.02-4.15, 4.25-4.36, 5.05, 6.88, 7.09, 7.29-7.46, 7.57, 7.66, 7.87,
9.90, 12.09.

Example 7-23: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-oxo-
1-azetidinyl) -2,3-dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.47 (dichloromethane: methanol = 20: 1 );
¹ H-NMR (DMSO-d ₆ ): δ 1.54-1.79, 2.02-2.11, 2.19, 2.39-2.68, 3.01-3.05, 3.55-3.61, 3.95-4.03, 4.20-4.29, 6.77-6.81, 7.16, 7.41, 7.56, 7.85, 9.90, 12.10.

Example 7-24: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-oxo-1,3-oxazolidin-3-yl) -2,3-dihydrospiro [Chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.47 (dichloromethane: methanol = 20: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.54-1.79, 2.05-2.24, 2.39-2.68, 3.96-4.06, 4.23-4.31, 4.36-4.45, 6.81, 7.01, 7.27, 7.41, 7.56, 7.86, 9.92, 12.10.

Example 7-25: 4- {4-cyano-2-[({(2′R, 4S) -6-[(4R) -4-hydroxy-2-oxo-1-pyrrolidinyl] -2,3- Dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.40 (dichloromethane: methanol = 20: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.80, 2.06-2.13, 2.19, 2.37-2.81, 3.47-3.55, 4.00-4.08, 4.20-4.39, 5.29-5.37, 6.78, 7.14, 7.25, 7.40, 7.55, 7.87, 9.91,
12.10.

Example 7-26: 4- {4-cyano-2-[({(2'R, 4S) -6- [4- (methylsulfonyl) phenyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.49 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.58, 1.72, 1.92, 2.08-2.24, 2.60-2.70, 3.23, 4.05-4.17, 4.27-4.39, 6.93, 7.25, 7.41, 7.50, 7.57, 7.84-7.99, 9.88, 12.09.

Example 7-27: 4- [4-cyano-2-({[(2′R, 4S) -6- (4-cyanophenyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.58 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.56, 1.72, 1.93, 2.08-2.24, 2.59-2.69, 4.04-4.16, 4.27-4.38, 6.92, 7.25, 7.40, 7.51, 7.56, 7.87, 9.86, 12.08.

Example 7-28: 4- [4-cyano-2-({[(2′R, 4S) -6- (1-methyl-1H-pyrazol-5-yl) -2,3-dihydrospiro [chromene] -4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.59 (chloroform: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.61, 1.64-1.88, 2.08-2.28, 2.39-2.46, 2.58-2.71, 3.82, 4.05-4.17, 4.27-4.39, 6.32, 6.90, 7.00, 7.25, 7.37-7.45, 7.55, 7.86, 9.89, 12.10.

Reference Example 16: Ethyl 4- {4-cyano-2-[({(2'R, 4S) -6- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl] -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoate

The same physical properties as in Reference Example 15 were performed using 1- (2-tetrahydropyranyl) -1H-pyrazole-4-boronic acid pinacol ester instead of 4-fluorophenylboronic acid. The title compound was obtained.
TLC: Rf 0.62 (hexane: ethyl acetate = 1: 2);
¹ H-NMR (CDCl ₃ ): δ 0.86, 1.64-1.79, 1.82-1.90, 2.02-2.16, 2.21-2.29, 2.34-2.43, 2.52-2.72, 3.28-3.42, 3.45-3.60, 3.65-3.80, 4.03- 4.16, 4.25-4.40, 5.35-5.45, 6.81, 6.90, 7.13-7.23, 7.28, 7.71, 7.76, 8.74, 9.36.

Example 8: 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-4-yl) -2,3-dihydrospiro [chromene-4,1′- Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

To a 1,4-dioxane (1 mL) solution of the compound prepared in Reference Example 16 (30 mg), a hydrochloric acid-1,4-dioxane (4 mol / L, 0.1 mL) solution was added at room temperature. The reaction mixture was stirred at 60 ° C. for 3 hours. After the reaction mixture was concentrated under reduced pressure, the same operation as in Example 1 was performed to obtain the title compound having the following physical property values.
TLC: Rf 0.40 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.55, 1.64-1.79, 1.81-1.92, 2.04-2.27, 2.35-2.47, 2.52-2.74, 4.02, 4.27, 6.76, 7.09, 7.32, 7.40, 7.56, 7.85, 7.99, 9.89.

Reference Example 17: Ethyl 4- [4-cyano-2-({[(2′R, 4S) -6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl] ) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoate

Under argon substitution, a solution of the compound prepared in Reference Example 10 (4.00 g) in dimethyl sulfoxide (40 mL) was added to potassium acetate (1.44 g), bis (pinacolato) diboron (2.43 g), and [1,1 ′ -Bis (diphenylphosphino) ferrocene] palladium (II) dichloride Dichloromethane complex (300 mg) was added and stirred at 90 ° C. for 4 hours. The reaction mixture was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification device) to obtain the title compound (3.54 g) having the following physical property values.
TLC: Rf 0.37 (hexane: ethyl acetate = 2: 1);
¹ H-NMR (CDCl ₃ ): δ 1.01, 1.20-1.29, 1.31, 1.63-1.77, 1.84, 2.18-2.27, 2.33-2.42, 2.53-2.60, 3.20-3.34, 3.45-3.60, 4.00-4.10, 4.25- 4.37, 6.78, 7.18,
7.28, 7.52, 8.68, 9.37.

Example 9: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane]- 2′-yl] carbonyl} amino) phenyl] butanoic acid

A solution of the compound prepared in Reference Example 17 (100 mg) in 1,2-dimethoxyethane (0.3 mL) and water (0.3 mL) under argon substitution was added to 2-bromopyridine (36 μL) and cesium carbonate (120 mg). And [1,1′-bis (diphenylphosphino) ferrocene] palladium (II) dichloride dichloromethane complex (7.5 mg) were added, and the mixture was stirred at 95 ° C. for 17 hours. The reaction mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyridinyl)] obtained by purifying the obtained residue by silica gel column chromatography (Yamazen automatic purification device) -2,3-Dihydrospiro [chromen-4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoate was used in the same manner as in Example 1, and the following physical properties were obtained. The title compound having
TLC: Rf 0.44 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.54-1.66, 1.68-1.88, 2.07-2.29, 2.54-2.76, 4.04-4.17, 4.26-4.38, 6.89, 7.23-7.33, 7.40, 7.52-7.64, 7.77- 7.99, 8.61, 9.90, 12.10.

Example 10
The same operation as in Example 9 was carried out using the corresponding halogen-containing heterocycle instead of 2-bromopyridine to give the title compound having the following physical data.

Example 10-1: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyrimidinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.45 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.54-1.83, 2.07-2.28, 2.35-2.77, 4.05-4.22, 4.26-4.42, 6.93, 7.29-7.45, 7.56, 7.88, 7.94, 8.15, 8.84, 9.93, 12.10.

Example 10-2: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-thiazol-2-yl) -2,3-dihydrospiro [chromene-4 , 1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.81 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.19-1.32, 1.34-1.85, 2.10-2.25, 2.40-2.79, 3.61, 4.35, 4.48-4.62, 6.88, 7.15-7.30, 7.35, 7.38-7.47, 7.68-7.77, 7.85, 8.88, 10.00.

Example 10-3: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-oxazol-2-yl) -2,3-dihydrospiro [chromene-4 , 1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.81 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.18-1.29, 1.53, 1.68-1.86, 2.09-2.33, 2.43-2.87, 3.60, 4.39, 4.52-4.64, 6.90, 7.15, 7.17, 7.28, 7.67, 7.72, 8.05, 8.92, 9.95.

Example 10-4: 4- [4-cyano-2-({[(2′R, 4S) -6- (1-methyl-1H-1,2,3-triazol-4-yl) -2, 3-Dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.58 (ethyl acetate: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.21-1.32, 1.56, 1.69-1.86, 2.14-2.31, 2.44-2.88, 3.64, 4.15-4.20, 4.34, 4.53, 6.86, 7.13-7.31, 7.63, 7.68, 7.79, 8.92, 10.01.

Example 10-5: 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridazinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane ] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.17-1.31, 1.61, 1.66-1.90, 2.11-2.32, 2.36-2.82, 3.48-3.71, 4.35, 4.54, 6.98, 7.21, 7.28, 7.36, 7.66, 7.83, 7.80- 7.83, 8.87, 9.15, 10.07.

Example 10-6: 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyrazinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane ] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.25, 1.61, 1.68-1.88, 2.08-2.29, 2.40-2.87, 3.49, 4.25-4.41, 4.52, 6.97, 7.21, 7.29, 7.46, 7.61, 8.45, 8.62, 8.85, 8.97, 9.93.

Example 10-7: 4- {4-cyano-2-[({(2′R, 4S) -6- [5- (methylsulfonyl) -2-pyridinyl] -2,3-dihydrospiro [chromene- 4,1'-siku
Lopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.48 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.61, 1.73, 1.80-1.92, 2.07-2.28, 2.38-2.75,
3.34, 4.06-4.20, 4.26-4.44, 6.96, 7.41, 7.57, 7.71, 7.88, 7.97, 8.18-8.36, 9.06, 9.91, 12.08.

Example 10-8: 4- {4-cyano-2-[({(2′R, 4S) -6- [5- (hydroxymethyl) -2-pyridinyl] -2,3-dihydrospiro [chromene- 4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.42 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.62, 1.63-1.87, 2.07-2.30, 2.53-2.75, 4.03-4.19, 4.25-4.39, 4.54, 5.29, 6.88, 7.40, 7.52-7.64, 7.70- 7.94, 8.53, 9.92, 12.07.

Example 10-9: 4- [4-cyano-2-({[(2′R, 4S) -6- (5-fluoro-2-pyridinyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.64 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.64, 1.65-1.88, 2.06-2.32, 2.40-2.80, 4.00-4.19, 4.24-4.40, 6.89, 7.40, 7.51-7.65, 7.71-7.84, 7.88, 8.00-8.05, 8.60, 9.92, 12.08.

Example 10-10: 4- [4-cyano-2-({[(2′R, 4S) -6- (6-methoxy-2-pyridinyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.50 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.64, 1.66-1.79, 1.79-1.91, 2.03-2.30, 2.40-2.79, 3.94, 4.02-4.16, 4.26-4.40, 6.70, 6.89, 7.40, 7.48- 7.62, 7.73, 7.80-7.89, 9.89, 12.07.

Example 10-11: 4- [4-cyano-2-({[(2′R, 4S) -6- (5-methoxy-2-pyridinyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.70 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.16-1.30, 1.57, 1.70-1.83, 2.04-2.27, 2.52, 2.59-2.73, 2.74-2.92, 3.54, 3.92, 4.30, 4.48, 6.89, 7.19, 7.24-7.31, 7.38, 7.49, 7.52, 8.18, 8.83, 10.06.

Example 10-12: 4- [4-cyano-2-({[(2′R, 4S) -6- (5-methyl-1,2,4-oxadiazol-3-yl) -2, 3-dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.69 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.19-1.31, 1.56, 1.70-1.88, 2.12-2.32, 2.42-2.84, 3.54, 4.37, 4.56, 6.92, 7.16-7.31, 7.71-7.82, 8.91, 9.84.

Example 11: 4- (4-cyano-2-{[(2′R, 4S) -2,3-dihydrospiro [1-benzopyran-4,1′-cyclopropane] -2′-carbonyl] amino} Phenyl) butanoic acid Using the compound prepared in Reference Example 9 and the compound prepared in Reference Example 3, the same operation as in Reference Example 10 → Example 1 was performed to obtain the title compound having the following physical property values.
TLC: Rf 0.62 (chloroform: methanol = 9: 1);
¹ H-NMR (CD ₃ OD): δ 1.66, 1.77-1.91, 2.08-2.28, 2.34, 2.48, 2.71, 4.16, 4.28, 6.74, 6.82-6.91, 7.06, 7.42, 7.48, 7.91.

Reference Example 18: (2′R, 4S) -2 ′-{[2- (4-Ethoxy-4-oxobutyl) -5-fluorophenyl] carbamoyl} -2,3-dihydrospiro [1-benzopyran-4, 1′-cyclopropane] -6-carboxylic acid 3-Fluoro-4-iodonitrobenzene instead of 3-nitro-4-bromobenzaldehyde, Reference Example 7 → Reference Example 9 → Reference Example 10 → Example 1 The same operation was performed to obtain the title compound having the following physical property values.
¹ H-NMR (DMSO-d ₆ ): δ 1.12, 1.52-1.77, 2.12, 2.26, 2.51-2.62, 3.87-4.02, 4.12, 4.34, 6.86, 6.92, 7.20, 7.41, 7.47, 7.68, 9.68, 12.68.

Example 12
Using the compound produced in Reference Example 18 instead of the compound produced in Reference Example 11 and using methylamine hydrochloride or the corresponding amine compound, the same operation as in Reference Example 12 → Example 1 was carried out. The title compound having the following physical property values was obtained.

Example 12-1: 4- [4-Fluoro-2-({[(2′R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.69 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (CD ₃ OD): δ 1.62-1.87, 2.12-2.28, 2.32, 2.56-2.78, 2.90, 4.23, 4.34, 6.76-6.89, 7.20, 7.38-7.51, 7.54.

Example 12-2: 4- {4-fluoro-2-[({(2'R, 4S) -6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.67 (ethyl acetate: methanol = 19: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.51-1.79, 2.06-2.22, 2.41-2.61, 3.25, 3.36-3.46, 4.07, 4.31, 6.83, 6.95, 7.19, 7.33, 7.43, 7.63, 8.42, 9.74, 12.06.

Example 12-3: 4- {4-fluoro-2-[({(2'R, 4S) -6-[(1-methyl-1H-pyrazol-4-yl) carbamoyl] -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid TLC: Rf 0.64 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (CD ₃ OD): δ 1.66-1.86, 2.12-2.37, 2.57-2.70, 3.88, 4.25, 4.37, 6.81-6.92, 7.21, 7.45, 7.58, 7.63, 7.68, 8.00.

Reference Example 19: Ethyl 4- (2-{[(1R, 2R) -6 ′-(benzyloxy) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -2-carbonyl] Amino} -4-cyanophenyl) butanoate 4- (benzyloxy) -2,3-dihydro-1H-inden-1-one instead of 4-chromanone, Reference Example 1 → Reference Example 2 → Reference Example 3 → The same operation as in Reference Example 10 was performed to give the title compound having the following physical data.

¹ H-NMR (CDCl ₃ ): δ 1.25, 1.38-1.45, 1.68-1.81, 1.82-1.87, 2.32-2.46, 2.57-2.67, 2.86-3.08, 3.82-3.92, 3.97-4.07, 5.00, 6.46, 6.77, 7.12, 7.17, 7.25-7.31, 7.32-7.43, 8.78, 9.15.

Example 13: 4- [2-({[(1R, 2R) -6 ′-(benzyloxy) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-inden] -2-yl] Carbonyl} amino) -4-cyanophenyl] butanoic acid The same physical properties as in Example 1 were obtained by using the compound prepared in Reference Example 19 instead of the compound prepared in Reference Example 12, and having the following physical properties. The title compound was obtained.
TLC: Rf 0.53 (dichloromethane: methanol = 10: 1);
¹ H-NMR (CDCl ₃ ): δ 1.36-1.43, 1.66-1.77, 1.79-1.85, 2.31, 2.42-2.73, 2.84-3.09, 5.05, 6.49, 6.81, 7.13-7.21, 7.24-7.30, 7.32-7.47, 8.72, 8.92.

Example 14: 4- [4-Cyano-2-({[(1R, 2R) -6′-hydroxy-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -2-yl ] Carbonyl} amino) phenyl] butanoic acid To a solution of the compound prepared in Example 13 (40 mg) in ethyl acetate (3 mL) and 1,4-dioxane (1 mL) was added 10% palladium / carbon (12 mg) and replaced with hydrogen. And stirred for 9 hours at room temperature. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (32 mg) having the following physical data.
TLC: Rf 0.40 (dichloromethane: methanol = 10: 1);
¹ H-NMR (CDCl ₃ ): δ 1.36-1.43, 1.65-1.85, 2.32, 2.47-2.55, 2.58-2.76, 2.83-3.08, 6.37, 6.62, 7.06, 7.22, 7.25-7.37, 8.74, 8.92.

Reference Example 20
: Ethyl 4- (4-cyano-2-{[(1R, 2R) -6′-hydroxy-2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -2-carbonyl] amino} Phenyl) butanoate The same procedure as in Example 14 was carried out using the compound prepared in Reference Example 19 instead of the compound prepared in Example 13, and the title compound having the following physical data was obtained.
¹ H-NMR (CDCl ₃ ): δ 1.24, 1.38-1.43, 1.70-1.87, 2.31-2.49, 2.58-2.67, 2.85-3.07, 3.89-4.01, 4.04-4.16, 4.49, 6.31, 6.58, 7.04, 7.17, 7.26-7.31, 8.78, 9.18.

Reference Example 21: Ethyl 4- [4-cyano-2-({(1R, 2R) -6 ′-[(1-methyl-1H-pyrazol-4-yl) methoxy] -2 ′, 3′-dihydrospiro [Cyclopropane-1,1′-indene] -2-carbonyl} amino) phenyl] butanoate Under nitrogen flow, the compound (30 mg) prepared in Reference Example 20 and (1-methylpyrazol-4-yl) methanol (9. 6 mg) in toluene (0.2 mL) was added dropwise cyanomethylenetributylphosphorane (0.06 mL) and stirred at 100 ° C. overnight. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (7 mg) having the following physical property values.
¹ H-NMR (CDCl ₃ ): δ 1.26, 1.39-1.42, 1.68-1.85, 2.28-2.51, 2.55-2.65, 2.83-3.05, 3.87-4.01, 4.04-4.18, 4.89, 6.40, 6.72-6.79, 7.06- 7.38, 7.41, 7.51,
8.77, 9.13.

Example 15: 4- {4-cyano-2-[({(1R, 2R) -6 '-[(1-methyl-1H-pyrazol-4-yl) methoxy] -2', 3'-dihydrospiro [Cyclopropane-1,1′-indene] -2-yl} carbonyl) amino] phenyl} butanoic acid As in Example 1, using the compound prepared in Reference Example 21 instead of the compound prepared in Reference Example 12. The title compound having the following physical property values was obtained.
TLC: Rf 0.26 (dichloromethane: methanol = 20: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.45-1.57, 1.66-1.79, 2.13-2.25, 2.26-2.75, 2.84-2.92, 3.81, 4.90, 6.51, 6.77, 7.09, 7.39, 7.47, 7.55, 7.77, 7.96.

Reference Example 22: Ethyl 4- [4-cyano-2-({(1R, 2R) -6 ′-[2- (methylamino) -2-oxoethoxy] -2 ′, 3′-dihydrospiro [cyclopropane -1,1′-indene] -2-carbonyl} amino) phenyl] butanoate To a solution of the compound prepared in Reference Example 20 (50 mg) in DMF (0.5 mL), potassium carbonate (33 mg) and tetrabutylammonium iodide ( 4.4 mg) followed by 2-chloro-N-methylacetamide (25.7 mg) at room temperature. The reaction mixture was stirred at 50 ° C. overnight. The reaction mixture was diluted with ethyl acetate, saturated aqueous ammonium chloride solution and water were added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and 20% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification device) to obtain the title compound (51 mg) having the following physical property values.
TLC: Rf 0.26 (hexane: ethyl acetate = 4: 1);
¹ H-NMR (CDCl ₃ ): δ 1.19, 1.39-1.44, 1.68-1.84, 1.86-1.89, 2.27-2.70, 2.84-3.08, 3.79-3.93, 3.95-4.06, 4.07, 4.44, 6.38, 6.55, 6.70, 7.13-7.20, 7.26-7.30, 8.75, 9.07.

Example 16: 4- {4-cyano-2-[({(1R, 2R) -6 '-[2- (methylamino) -2-oxoethoxy] -2', 3'-dihydrospiro [cyclopropane -1,1′-indene] -2-yl} carbonyl) amino] phenyl} butanoic acid The same procedure as in Example 1 was carried out using the compound prepared in Reference Example 22 instead of the compound prepared in Reference Example 12. The title compound having the following physical property values was obtained.
TLC: Rf 0.59 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.44-1.51, 1.56, 2.07-2.34, 2.66, 2.87, 6.54, 6.76, 7.12, 7.41, 7.56, 7.92, 8.01, 9.75, 12.12.

Example 17: 4- {4-cyano-2-[({(1R, 2R) -6 '-[2- (dimethylamino) -2-oxoethoxy] -2', 3'-dihydrospiro [cyclopropane -1,1′-indene] -2-yl} carbonyl) amino] phenyl} butanoic acid 2-chloro-N, N-dimethylacetamide was used instead of 2-chloro-N-methylacetamide, Reference Example 22 → The title compound having the following physical data was obtained by carrying out the same operation as in Example 1.
TLC: Rf 0.54 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.47-1.58, 1.71, 2.08-2.32, 2.33-2.70, 2.82-2.91, 3.00, 4.74, 6.49, 6.70, 7.10, 7.41, 7.57, 7.91, 9.79, 12.16.

Reference Example 23: Ethyl 4- [4-cyano-2-({(1R, 2R) -6 '-[(trifluoro
Olomethanesulfonyl) oxy] -2 ', 3'-dihydrospiro [cyclopropane-1,1'-indene] -2-carbonyl} amino) phenyl] butanoate

Under a nitrogen atmosphere, triethylamine (0.1 mL) and 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) were added to a solution of the compound prepared in Reference Example 20 (100 mg) in dichloromethane (2 mL). Methanesulfonamide (128 mg) was added and stirred at room temperature for 3 hours. Further, 1,1,1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide (128 mg) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was purified by silica gel column chromatography to obtain the title compound (130 mg) having the following physical property values.
¹ H-NMR (CDCl ₃ ): δ 1.22-1.29, 1.39-1.44, 1.70-1.83, 1.86-1.91, 2.34-2.51, 2.60-2.67, 2.95-3.14, 3.90-4.02, 4.05-4.16, 6.67, 7.03, 7.19, 7.21-7.31, 8.78, 9.19.

Reference Example 24: (1R, 2R) -2-{[5-cyano-2- (4-ethoxy-4-oxobutyl) phenyl] carbamoyl} -2 ′, 3′-dihydrospiro [cyclopropane-1,1 ′ -Indene] -6'-carboxylic acid

The compound produced in Reference Example 23 (120 mg) was dissolved in DMSO (3 mL), and degassed with ultrasound under reduced pressure. To the reaction solution, 1,3-bis (diphenylphosphino) propane (dppp) (18 mg), palladium (II) acetate (10 mg), lithium chloride (92 mg), sodium formate (148 mg), diisopropylethylamine (0.34 mL) and Acetic anhydride (0.19 mL) was added, substituted with carbon monoxide, and stirred at 90 ° C. for 4 hours. A 0.1N aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (40 mg) having the following physical data.
¹ H-NMR (CDCl ₃ ): δ 1.18, 1.44-1.51, 1.64-1.79, 1.85-1.90, 2.35-2.48, 2.57-2.78, 2.99-3.17, 3.84-3.91, 4.03-4.11, 7.18, 7.24-7.36, 7.52, 7.89, 8.81,
9.29.

Example 18
Using the compound produced in Reference Example 24 instead of the compound produced in Reference Example 11 and using methylamine hydrochloride or the corresponding amine compound, the same operation as in Reference Example 12 → Example 1 was performed, and the following procedure was performed. The title compound having the following physical property values was obtained.

Example 18-1: 4- [4-cyano-2-({[(1R, 2R) -6 ′-(methylcarbamoyl) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene ] -2-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.29 (dichloromethane: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.26-1.31, 1.66-1.78, 1.82-1.87, 2.23-2.30, 2.34-2.48, 2.52-2.71, 2.91-3.03, 3.04, 3.13-3.27, 6.21-6.29, 7.17, 7.19-7.35, 7.70, 8.82, 9.56.

Example 18-2: 4- {4-cyano-2-[({(1R, 2R) -6 ′-[(2-methoxyethyl) carbamoyl] -2 ′, 3′-dihydrospiro [cyclopropane-1 , 1'-Inden] -2-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.50 (dichloromethane: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.25-1.31, 1.65-1.77, 1.81-1.86, 2.23-2.30, 2.35-2.47, 2.51-2.71, 2.91-3.03, 3.13-3.27, 3.41, 3.54-3.78, 6.62- 6.67, 7.17, 7.19-7.30, 7.34, 7.66, 8.82, 9.51.

Example 18-3: 4- {4-cyano-2-[({(1R, 2R) -6 ′-[(1-methyl-1H-pyrazol-4-yl) carbamoyl] -2 ′, 3′- Dihydrospiro [cyclopropane-1,1′-indene] -2-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.28 (dichloromethane: methanol = 20: 1);
¹ H-NMR (CDCl ₃ ): δ 1.26-1.34, 1.68-1.78, 1.81-1.88, 2.25-2.31, 2.43-2.72, 2.95-3.06, 3.17-3.23, 3.92, 7.16-7.33, 7.42, 7.52, 7.75, 7.86, 7.99, 8.83, 9.54.

Example 19: 4- [4-cyano-2-({[(1R, 2R) -6 ′-(3-pyridinyl) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] 2-yl] carbonyl} amino) phenyl] butanoic acid Using the compound prepared in Reference Example 23 and using pyridine-3-boronic acid instead of 4-fluorophenylboronic acid, Reference Example 15 → Example 1 The title compound having the following physical data was obtained in the same manner as in.
TLC: Rf 0.30 (dichloromethane: methanol = 20: 1);
¹ H-NMR (CD ₃ OD): δ 1.58-1.66, 1.75-1.90, 2.25-2.45, 2.47-2.55, 2.68-2.79, 3.07-3.16, 7.15, 7.34-7.56, 7.98, 8.10, 8.52, 8.78.

Reference Example 25: (2′R, 4S) -2 ′-{[5-cyano-2- (4-ethoxy-4-oxobutyl) phenyl] carbamoyl} -7-fluoro-2,3-dihydrospiro [1- Benzopyran-4,1′-cyclopropane] -6-carboxylic acid

Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 10 → Reference Example 11 using 7-fluorochroman-4-one instead of 4-chromanone The same operation was performed to obtain the title compound having the following physical property values.
¹ H-NMR (CDCl ₃ ): δ 1.13, 1.66-1.78, 1.84-1.90, 2.25-2.35, 2.42-2.47, 2.58-2.67, 3.60-3.73, 3.78-3.90, 4.10-4.22, 4.35-4.44, 6.60, 7.19, 7.26-7.33, 7.50, 8.71, 9.37.

Example 20
Using the compound produced in Reference Example 25 instead of the compound produced in Reference Example 11 and using methylamine hydrochloride or the corresponding amine compound, the same operation as in Reference Example 12 → Example 1 was performed, and the following procedure was performed. The title compound having physical properties was obtained.

Example 20-1: 4- [4-cyano-2-({[(2′R, 4S) -7-fluoro-6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.74 (dichloromethane: methanol = 10: 1);
¹ H-NMR (CDCl ₃ ): δ 1.18-1.29, 1.50-1.62, 1.70-1.80, 2.05-2.15, 2.20-2.27, 2.44-2.76, 3.03, 3.54-3.60, 4.31-4.40, 4.54-4.59, 6.57, 6.82-6.95, 7.20, 7.24-7.33, 8.06, 8.88, 9.94.

Example 20-2: 4- {4-cyano-2-[({(2'R, 4S) -7-fluoro-6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene -4,1'-cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.49 (dichloromethane: methanol = 10: 1);
¹ H-NMR (CDCl ₃ ): δ 1.19-1.26, 1.58-1.64, 1.68-1.84, 2.05-2.29, 2.45-2.77, 3.39, 3.53-3.64, 3.65-3.72, 4.31-4.43, 4.54-4.62, 6.57, 7.17-7.34, 8.05, 8.88, 9.93.

Example 20-3: 4- [4-cyano-2-({[(2′R, 4S) -6- (ethylcarbamoyl) -7-fluoro-2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.62 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (DMSO-d ₆ ): δ 1.09, 1.55, 1.65-1.78, 2.02-2.28, 2.47, 2.60-2.71, 3.17-3.33, 4.12, 4.33, 6.73, 7.19, 7.41, 7.56, 7.88, 8.07, 9.89, 12.11.

Example 20-4: 4- [4-cyano-2-({[(2′R, 4S) -7-fluoro-6- (propylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopro
Pan] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.56 (hexane: ethyl acetate = 1: 2);
¹ H-NMR (DMSO-d ₆ ): δ 0.87, 1.42-1.58, 1.62-1.78, 2.04-2.23, 2.42,
2.60-2.69, 3.11-3.23, 4.12, 4.31, 6.73, 7.18, 7.41, 7.56, 7.88, 8.06, 9.90, 12.11.

Example 20-5: 4- [4-cyano-2-({[(2′R, 4S) -7-fluoro-6- (isopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.68 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (DMSO-d ₆ ): δ 1.13, 1.53, 1.63-1.79, 2.02-2.24, 2.46, 2.61-2.69, 3.96-4.18, 4.33, 6.72, 7.14, 7.41, 7.56, 7.80-7.92, 9.89, 12.11.

Example 21: 4- [4-cyano-2-({[(2′R, 4S) -6-fluoro-2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl ] Carbonyl l} amino) phenyl] butanoic acid 6-fluoro-4-chromanone instead of 4-chromanone, Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 10 → Same operation as Example 1 To give the title compound having the following physical data.
TLC: Rf 0.38 (dichloromethane: methanol = 10: 1);
¹ H-NMR (CDCl ₃ ): δ 1.46-1.80, 2.18-2.24, 2.48-2.75, 4.09-4.32, 6.55, 6.75-6.87, 7.21, 7.25-7.34, 8.66, 9.00.

Reference Example 26: Ethyl 4- (2-{[(2′R, 4S) -6-benzoyl-2,3-dihydrospiro [1-benzopyran-4,1′-cyclopropane] -2′-carbonyl] amino } -4-Cyanophenyl) butanoate To a solution of the compound prepared in Reference Example 10 (30 mg) in anisole (1 mL), phenylboronic acid (10 mg), potassium carbonate (22 mg), [1,1′-bis (diphenylphosphino) Ferrocene] palladium (II) dichloride dichloromethane complex (9 mg) was added, and the mixture was stirred at 80 ° C. for 3 hours in a carbon monoxide atmosphere. Saturated aqueous sodium hydrogen carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification device) to obtain the title compound (18 mg) having the following physical property values.
TLC: Rf 0.38 (hexane: ethyl acetate = 1: 1);
¹ H-NMR (CDCl ₃ ): δ 0.99, 1.61-1.80, 1.87, 2.27-2.36, 2.37-2.44, 2.61, 2.71, 3.43-3.56, 3.66, 3.81, 4.11-4.23, 4.32-4.42, 6.86, 7.19, 7.27, 7.42-7.62, 7.73, 8.73, 9.38.

Example 22: 4- [2-({[(2'R, 4S) -6-benzoyl-2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-yl] carbonyl} amino ) -4-Cyanophenyl] butanoic acid The title compound having the following physical data was obtained by conducting the same operation as in Example 1 using the compound prepared in Reference Example 26 instead of the compound prepared in Reference Example 12. Obtained.
TLC: Rf 0.42 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.64, 1.64-1.78, 2.10-2.30, 2.41-2.75, 3.20-3.49, 4.10-4.23, 4.33-4.45, 6.94, 7.36-7.45, 7.46-7.59, 7.60-7.73, 7.87, 9.89, 12.09.

Example 23
Using the corresponding boronic acid instead of phenylboronic acid, the same operation as in Reference Example 26 → Example 1 was performed to obtain the title compound having the following physical property values.

Example 23-1: 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclopropylcarbonyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.41 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.02-1.38, 1.67-1.83, 2.06-2.38, 2.45-2.78, 4.33-4.45, 4.53-4.67, 6.89, 7.19, 7.25-7.30, 7.87, 7.98, 8.88, 9.85.

Example 23-2: 4- [2-({[(2′R, 4S) -6-acetyl-2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl } Amino) -4-cyanophenyl] butanoic acid TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.20-1.31, 1.70-1.85, 2.05-2.20, 2.23-2.33, 2.44-2.83, 4.33-4.45, 4.53-4.65, 6.85, 7.20, 7.28, 7.70, 8.06, 8.89, 9.83.

Reference Example 27: Ethyl 4- (4-cyano-2-{[(2′R, 4S) -6- (methanesulfonyl) -2,3-dihydrospiro [1-benzopyran-4,1′-cyclopropane] -2'-carbonyl] amino} phenyl) butanoate Under argon atmosphere, sodium hydroxide (2.3 mg) was added to a solution of L-proline (7 mg) in DMSO (2 mL), and the mixture was stirred at room temperature for 30 minutes. To the obtained reaction mixture, the compound produced in Reference Example 10 (40 mg), copper iodide (11 mg) and sodium methanesulfinate (37 mg) were added, and the mixture was heated to 100 ° C. using a microwave reactor (manufactured by Biotage). And stirred for 1 hour. The reaction mixture was purified by silica gel column chromatography (Yamazen automatic purification device) to obtain the title compound (33 mg) having the following physical property values.
TLC: Rf 0.58 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (CDCl ₃ ): δ 1.13, 1.66-1.80, 1.91, 2.20-2.45, 2.53-2.64, 2.67, 3.01, 3.45-3.60, 3.73-3.86, 4.11-4.20, 4.40, 6.96, 7.20, 7.30, 7.40, 7.63, 8.71, 9.44.

Example 24: 4- [4-cyano-2-({[(2′R, 4S) -6- (methylsulfonyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid The same physical properties as in Example 1 were obtained by using the compound prepared in Reference Example 27 instead of the compound prepared in Reference Example 12, and having the following physical properties. The title compound was obtained.
TLC: Rf 0.42 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.53-1.64, 1.72, 1.80-1.87, 2.08-2.29, 2.35-
2.74, 3.18, 4.05-4.20, 4.32-4.44, 7.02, 7.40, 7.42, 7.57, 7.64, 7.87, 9.95, 12.10.

Example 25: 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclopropylsulfonyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane]- 2′-yl] carbonyl} amino) phenyl] butanoic acid Sodium cyclopropanesulfinate is used in place of sodium methanesulfinate, and the same physical properties as in Reference Example 27 → Example 1 are obtained. The title compound was obtained.
TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.00-1.15, 1.20-1.43, 1.60-1.82, 2.09-2.35, 2.38-2.60, 2.63-2.75, 3.39, 4.35, 4.57, 6.95, 7.20, 7.29, 7.59, 7.71, 8.90, 9.64.

Reference Example 28: (2'R, 4S) -7- (benzyloxy) -2,3-dihydrospiro [1-benzopyran-4,1'-cyclopropane] -2'-carboxylic acid

Using 7- (benzyloxy) -2,3-dihydro-4H-chromen-4-one instead of 4-chromanone, the same operation as in Reference Example 1 → Reference Example 2 → Reference Example 3 was performed, and The title compound having the following physical property values was obtained.
TLC: Rf 0.21 (hexane: ethyl acetate = 1: 1);
¹ H-NMR (CDCl ₃ ): δ 1.53-1.70, 2.07, 2.20, 4.20-4.09, 4.23-4.33, 5.01, 6.46, 6.52, 6.60, 7.27-7.44.
HPLC retention time: 12.2 minutes (CHIRALPAK IC 4.6 mm x 250 mm hexane: ethyl acetate: formic acid = 97: 3: 1).

Reference Example 29: Ethyl 4- (2-{[(2′R, 4S) -7- (benzyloxy) -2,3-dihydrospiro [1-benzopyran-4,1′-cyclopropane] -2′- Carbonyl] amino} -4-cyanophenyl) butanoate

Using the compound produced in Reference Example 28 instead of the compound produced in Reference Example 6, the same operation as in Reference Example 10 was performed to obtain the title compound having the following physical property values.
¹ H-NMR (CDCl ₃ ): δ 1.13, 1.54-1.61, 1.64-1.81, 2.22, 2.37-2.45, 2.51-2.66, 3.55-3.68, 3.72-3.86, 4.03, 4.16, 4.22-4.32, 4.99, 6.42- 6.51, 6.73, 7.18
, 7.28, 7.29-7.44, 8.72, 9.28.

Example 26: 4- [2-({[(2′R, 4S) -7- (benzyloxy) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] Carbonyl} amino) -4-cyanophenyl] butanoic acid

The title compound having the following physical data was obtained by conducting the same operation as in Example 1, except that the compound prepared in Reference Example 29 was used instead of the compound prepared in Reference Example 12.
TLC: Rf 0.42 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.58, 1.68-1.84, 2.10-2.20, 2.36, 2.46, 2.50-2.75, 4.03-4.16, 4.20-4.32, 5.02, 6.48, 6.54, 6.71, 7.20, 7.27-7.45, 8.54, 8.82.

Reference Example 30: Ethyl 4- (4-cyano-2-{[(2′R, 4S) -7-hydroxy-2,3-dihydrospiro [1-benzopyran-4,1′-cyclopropane] -2 ′ -Carbonyl] amino} phenyl) butanoate

ASCA-2 (trade name, 50% wet, 300 mg) was added to a mixed solution of the compound produced in Reference Example 29 (650 mg) in ethanol (50 mL) and ethyl acetate (10 mL), and at room temperature for 8 hours under a hydrogen atmosphere. Stir. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification device) and then washed with tert-butyl methyl ether and hexane to obtain the title compound (368 mg) having the following physical property values.
TLC: Rf 0.28 (hexane: ethyl acetate = 1: 1);
¹ H-NMR (CDCl ₃ ): δ 1.16, 1.55-1.62, 1.66-1.80, 2.16-2.25, 2.38-2.47, 2.52-2.66, 3.60-3.73, 3.76-3.87, 4.04-4.15, 4.22-4.32, 4.63, 6.28-6.37, 6.69, 7.18, 7.28, 8.71, 9.28.

Example 27: 4- [4-cyano-2-({[(2′R, 4S) -7- (3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane]- 2′-yl] carbonyl} amino) phenyl] butanoic acid Instead of the compound prepared in Reference Example 20, the compound prepared in Reference Example 30 was used and pyridine-3-boronic acid was used instead of 4-fluorophenylboronic acid. In the same manner as in Reference Example 23 → Reference Example 15 → Example 1, the title compound having the following physical property values was obtained.
TLC: Rf 0.39 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.55-1.63, 1.65-1.80, 2.09-2.18, 2.21, 2.40-2.47, 2.53-2.77, 4.04-4.16, 4.28-4.38, 7.05, 7.15, 7.25, 7.41, 7.43-7.50, 7.57, 7.88, 8.02-8.08, 8.55, 8.85, 9.90, 12.10.

Example 28
Using the compound produced in Reference Example 30 instead of the compound produced in Reference Example 20 and using methylamine hydrochloride or 2-methoxyethylamine, Reference Example 23 → Reference Example 24 → Reference Example 12 → Example 1 The same operation was performed to obtain the title compound having the following physical property values.

Example 28-1: 4- [4-cyano-2-({[(2′R, 4S) -7- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.56, 1.63-1.80, 2.02-2.15, 2.20, 2.42, 2.57-2.69, 2.74, 4.01-4.13, 4.23-4.37, 6.99, 7.24, 7.36, 7.40, 7.56, 7.86, 8.34, 9.89, 12.11.

Example 28-2: 4- {4-cyano-2-[({(2'R, 4S) -7-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.40 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.63-1.89, 2.00-2.13, 2.25-2.47, 2.48-2.73, 2.78-2.93, 3.24-3.39, 3.51, 3.55-3.65, 3.85-4.06, 6.68, 6.79, 7.06, 7.20, 7.29, 7.98, 8.78, 9.84.

Example 29: 4- [2-({[(2'R, 4S) -6- (benzyloxy) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2'-yl] Carbonyl} amino) -4-cyanophenyl] butanoic acid 6- (benzyloxy) -3,4-dihydro-2H-1-benzopyran-4-one instead of 4-chromanone and iodoethane instead of iodomethane In the same manner as in Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 6 → Reference Example 10 → Example 1, the title compound having the following physical property values was obtained.
TLC: Rf 0.47 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.46-1.55, 1.62-1.80, 2.12-2.18, 2.43-2.48, 2.51-2.76, 4.18-4.26, 4.95-5.07, 6.62, 6.75-6.80, 7.18, 7.28, 7.31- 7.45, 8.68, 9.14
.

Reference Example 31: Ethyl 4- (4-cyano-2-{[(2′R, 4S) -6-hydroxy-2,3-dihydrospiro [1-benzopyran-4,1′-cyclopropane] -2 ′ -Carbonyl] amino} phenyl) butanoate 4- (benzyloxy) -3,4-dihydro-2H-1-benzopyran-4-one instead of 4-chromanone, Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 6 → Reference Example 10 → Reference Example 30 The title compound having the following physical properties was obtained in the same manner as in Reference Example 30.
TLC: Rf 0.66 (hexane: ethyl acetate = 1: 2);
¹ H-NMR (CDCl ₃ ): δ 1.16, 1.52-1.58, 1.66-1.83, 2.21, 2.41, 2.55-2.73, 3.65-3.78, 3.84-3.98, 4.02-4.13, 4.17-4.27, 4.54, 6.33, 6.55, 6.68, 7.19, 7.28, 8.74, 9.38.

Example 30: 4- [4-cyano-2-({[(2′R, 4S) -6-hydroxy-2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl ] Carbonyl} amino) phenyl] butanoic acid The title compound having the following physical data was obtained by conducting the same operation as in Example 1 using the compound prepared in Reference Example 31 instead of the compound prepared in Reference Example 12. Obtained.
TLC: Rf 0.38 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CD ₃ OD): δ 1.55-1.70, 1.77-1.90, 2.11-2.20, 2.33, 2.40-2.48, 2.67-2.78, 4.04-4.15, 4.17-4.26, 6.28, 6.53, 6.64, 7.41, 7.48 , 7.90.

Example 31
Using the compound produced in Reference Example 31 instead of the compound produced in Reference Example 20,
The same operation as in Reference Example 21 → Example 1 was carried out using 2-oxazolemethanol or methanol instead of (1-methylpyrazol-4-yl) methanol to obtain the title compound having the following physical property values. .

Example 31-1: 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-oxazol-2-ylmethoxy) -2,3-dihydrospiro [chromene-4 , 1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.45 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CD ₃ OD): δ 1.58-1.76, 1.77-1.90, 2.09-2.21, 2.33, 2.47, 2.72, 4.08-4.17, 4.18-4.29, 5.11, 6.53, 6.70, 6.77, 7.21, 7.42, 7.48 , 7.92, 7.96.

Example 31-2: 4- (4-cyano-2-{[(2′R, 4S) -6-methoxy-2,3-dihydrospiro [1-benzopyran-4,1′-cyclopropane] -2 '-Carbonyl] amino} phenyl) butanoic acid TLC: Rf 0.35 (ethyl acetate);
¹ H-NMR (DMSO-d ₆ ) δ 1.50-1.56, 1.65-1.80, 2.00-2.09, 2.20, 2.35-2.47, 2.55-2.60, 2.61-2.69, 2.70-2.75, 3.69-4.04, 4.15-4.26 , 6.43, 6.71, 7.40, 7.56, 7.85, 9.86, 12.11.

Example 32: 4- [4-cyano-2-({[(2′R, 4S) -7- (1,3-oxazo
2-ylmethoxy) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid Reference instead of the compound prepared in Reference Example 20 Using the compound prepared in Example 30,
The same operation as in Reference Example 21 → Example 1 was carried out using 2-oxazolemethanol instead of (1-methylpyrazol-4-yl) methanol to obtain the title compound having the following physical property values.
TLC: Rf 0.47 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.58-1.68, 1.68-1.80, 2.03-2.15, 2.18-2.46, 2.41-2.50, 2.50-2.63, 2.64-2.83, 4.00-4.13, 4.20-4.31, 5.05, 5.17, 6.33, 6.48, 6.63,
7.10, 7.20, 7.28, 7.73, 8.62, 8.91.

Reference Example 32: Ethyl (2'R, 4S) -7-methoxy-2,3-dihydrospiro [1-benzopyran-4,1'-cyclopropane] -2'-carboxylate

The same operation as in Reference Example 4 was performed using the compound prepared in Reference Example 28 instead of the compound prepared in Reference Example 3 and using iodoethane instead of iodomethane. To a solution of the obtained compound (2.1 g) in ethyl acetate (5 mL) was added palladium hydroxide / carbon (10% wet, 0.2 g), and the mixture was stirred at room temperature for 30 minutes in a hydrogen atmosphere. The reaction mixture was filtered through Celite (trade name), and the filtrate was concentrated under reduced pressure. Potassium carbonate (1.46 g) was added to a DMF (5 mL) solution of the obtained residue (1.31 g), iodomethane (1.5 g) was added dropwise, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with a hexane-ethyl acetate mixed solution. The obtained organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (1.38 g) having the following physical data.
TLC: Rf 0.69 (hexane: ethyl acetate = 1: 1);
¹ H-NMR (CDCl ₃ ): δ 1.25, 1.55-1.60, 2.05, 2.13-2.20, 3.75, 4.05-4.20, 4.23-4.31, 6.38, 6.45, 6.59.

Example 33
Using the compound produced in Reference Example 32 instead of the compound produced in Reference Example 4 and using methylamine hydrochloride or the corresponding amine compound, Reference Example 5 → Reference Example 6 → Reference Example 10 → Reference Example 11 → Reference Example 12 → The same operation as in Example 1 was performed to give the title compound having the following physical data.

Example 33-1: 4- [4-cyano-2-({[(2′R, 4S) -7-methoxy-6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.39 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.42-1.60, 1.65-1.79, 2.00-2.29, 2.32-2.74, 2.77, 3.83, 4.05-4.17, 4.24-4.38, 6.54, 7.35-7.45, 7.55, 7.89, 7.98, 9.88, 12.12.

Example 33-2: 4- {4-cyano-2-[({(2'R, 4S) -7-methoxy-6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene -4,1'-cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.39 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.46-1.60, 1.64-1.81, 2.00-2.29, 2.36-2.76, 3.27, 3.38-3.48, 3.85, 4.06-4.18, 4.25-4.36, 6.56, 7.40, 7.41, 7.55, 7.89, 8.09,
9.87, 12.10.

Example 33-3: 4- [4-cyano-2-({[(2′R, 4S) -6- (ethylcarbamoyl) -7-methoxy-2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.54 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (DMSO-d ₆ ): δ 1.09, 1.47-1.58, 1.65-1.78, 2.04-2.23, 2.47,
2.60-2.69, 3.21-3.30, 3.84, 4.11, 4.30, 6.54, 7.35-7.44, 7.56, 7.89, 8.04, 9.88, 12.11.

Example 33-4: 4- [4-cyano-2-({[(2′R, 4S) -7-methoxy-6- (propylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.70 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (DMSO-d ₆ ): δ 0.87, 1.41-1.58, 1.63-1.76, 2.00-2.23, 2.43,
2.59-2.70, 3.13-3.28, 3.84, 4.11, 4.29, 6.55, 7.32-7.42, 7.56, 7.90, 8.02, 9.88, 12.11.

Example 33-5: 4- [4-cyano-2-({[(2′R, 4S) -6- (isopropylcarbamoyl) -7-methoxy-2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid TLC: Rf 0.68 (hexane: ethyl acetate = 1: 3);
¹ H-NMR (DMSO-d ₆ ): δ 1.14, 1.46-1.58, 1.63-1.78, 2.01-2.22, 2.46,
2.58-2.69, 3.84, 3.97-4.16, 4.31, 6.55, 7.34-7.43, 7.56, 7.74, 7.89, 9.87, 12.09.

Example 34: 4- [4-cyano-2-({[(2′R, 4S) -7-methoxy-6- (5-methyl-1,3,4-oxadiazol-2-yl)- 2,3-dihydrospiro [chromen-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid The compound prepared in Reference Example 32 was used instead of the compound prepared in Reference Example 4. In the same manner as in Reference Example 5 → Reference Example 6 → Reference Example 10 → Reference Example 11 → Reference Example 13 → Example 1, the title compound having the following physical property values was obtained.
TLC: Rf 0.38 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.16-1.27, 1.50-1.58, 1.66-1.85, 2.09-2.30, 2.42-2.83, 3.46, 3.85, 4.35, 4.55, 6.48, 7.19, 7.27, 7.68, 8.88, 9.90.

Example 35: 4- [4-cyano-2-({[(2′R, 4S) -6- (4-morpholinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane]- 2′-yl] carbonyl} amino) phenyl] butanoic acid To a solution of the compound prepared in Reference Example 10 (72 mg) in DMF (1 mL) was added cesium carbonate (129 mg), [(2-dicyclohexylphosphino-2 ′, 4 ′, 6'-Triisopropyl-
1,1′-biphenyl) [2- (2-aminoethyl) phenyl] palladium (II) chloride (9 mg) and morpholine (34 mg) were added, and the mixture was heated to 110 ° C. using a microwave reactor (Biotage). And stirred for 1 hour. An aqueous potassium carbonate solution was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Yamazen automatic purification apparatus) to obtain an ethyl ester form (46 mg). The title compound was obtained by carrying out the same reaction as in Example 1 using the ethyl ester obtained instead of the compound produced in Reference Example 12.
TLC: Rf 0.36 (dichloromethane: methanol = 9: 1);
¹ H-NMR (DMSO-d ₆ ): δ 1.45-1.55, 1.62-1.80, 2.00-2.10, 2.16-2.26, 2.32-2.77, 2.89-3.06, 3.65-3.78, 3.90-4.05, 4.13-4.26, 6.39, 6.67, 6.74, 7.40, 7.56, 7.84, 9.87, 12.08.

Reference Example 33: Ethyl 4- (4-cyano-2-{[(2′R, 3S) -5-iodo-2H-spiro [1-benzofuran-3,1′-cyclopropane] -2′-carbonyl] Amino} phenyl) butanoate

Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 4 → Reference Example 5 → Reference Example 6 → Reference Example 10 using 3-coumaran instead of 4-chromanone and using iodoethane instead of iodomethane The same operation was performed to obtain the title compound having the following physical property values.
¹ H-NMR (CDCl ₃ ): δ 1.32, 1.57, 1.66-1.82, 2.36-2.70, 2.79, 3.95-4.22, 4.70, 6.60, 7.02, 7.20, 7.24-7.32, 7.38, 8.74, 9.40.

Example 36: 4- [4-cyano-2-({[(2′R, 3S) -5- (3-pyridinyl) -2H-spiro [1-benzofuran-3,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid

In the same manner as in Reference Example 15 → Example 1 using the compound prepared in Reference Example 33 instead of the compound prepared in Reference Example 10 and using pyridine-3-boronic acid instead of 4-fluorophenylboronic acid The title compound having the following physical property values was obtained by the operation.
TLC: Rf 0.42 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.06, 1.62-1.92, 2.58, 2.78, 2.94, 4.85, 6.47, 6.87, 7.01-7.40, 8.41, 8.61, 8.79, 9.75.

Example 37
Using the compound produced in Reference Example 33 instead of the compound produced in Reference Example 10 and using methylamine hydrochloride or 2-methoxyethylamine, the same procedure as in Reference Example 11 → Reference Example 12 → Example 1 was performed. The title compound having the following physical property values was obtained.

Example 37-1: 4- [4-cyano-2-({[(2′R, 3S) -5- (methylcarbamoyl) -2H-spiro [1-benzofuran-3,1′-cyclopropane]- 2′-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.47 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.57, 1.61-1.86, 2.30-2.73, 3.02, 3.22, 4.59, 4.
73, 6.18, 6.76, 7.18, 7.20-7.32, 7.59, 8.70, 9.51.

Example 37-2: 4- {4-cyano-2-[({(2'R, 3S) -5-[(2-methoxyethyl) carbamoyl] -2H-spiro [1-benzofuran-3,1 ' -Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid

TLC: Rf 0.57 (dichloromethane: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.58, 1.60-1.85, 2.30-2.75, 3.19, 3.41, 3.50-3.73, 4.61, 4.74, 6.47-6.62, 6.77, 7.19, 7.21-7.40, 7.56, 8.72, 9.47.

Reference Example 34: 6-iodo-3,3-dimethyl-2,3-dihydro-1H-inden-1-one

An aqueous solution of sodium nitrite (4.5 mol / L, 4 mL) was added to an aqueous solution of 6-amino-3,3-dimethyl-indan-1-one (2.1 g) in hydrochloric acid (5 mol / L, 15 mL) under ice-cooling. After dropping, the mixture was stirred for 30 minutes. After confirming disappearance of the raw materials, an aqueous solution of potassium iodide (4 mol / L, 6 mL) was added dropwise under ice-cooling, acetonitrile (20 mL) was added, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with a saturated aqueous sodium thiosulfate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (2.66 g) having the following physical property values.
TLC: Rf 0.86 (hexane: ethyl acetate = 1: 1);
¹ H-NMR (CDCl ₃ ): δ 1.38-1.44, 2.59, 7.25-7.30, 7.90, 8.03.

Reference Example 35: Ethyl 4- (4-cyano-2-{[(1S, 2R) -6′-iodo-3 ′, 3′-dimethyl-2 ′, 3′-dihydrospiro [cyclopropane-1,1 '-Indene] -2-carbonyl] amino} phenyl) butanoate

Using the compound prepared in Reference Example 34 instead of 4-chromanone, the same operation as Reference Example 1 → Reference Example 2 → Reference Example 3 → Reference Example 10 was performed to obtain the title compound having the following physical property values. It was.
¹ H-NMR (CDCl ₃ ): δ 1.14-1.35, 1.44, 1.64-1.79, 1.79-1.88, 2.17, 2.28-2.50, 2.50-2.71, 3.83, 4.05, 6.91, 7.11, 7.19, 7.22-7.31, 7.45- 7.53, 8.79, 9.28.

Example 38
Using the compound produced in Reference Example 35 instead of the compound produced in Reference Example 10 and using methylamine hydrochloride or 2-methoxyethylamine, the same procedure as in Reference Example 11 → Reference Example 12 → Example 1 was performed. The title compound having the following physical property values was obtained.

Example 38-1: 4- [4-cyano-2-({[(1S, 2R) -6 ′-[(2-methoxyethyl) carbamoyl] -3 ′, 3′-dimethyl-2 ′, 3 ′ -Dihydrospiro [cyclopropane-1,1'-indene] -2-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.64 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.28-1.40, 1.72, 1.86, 2.01-2.10, 2.14-2.23, 2.63, 3.16, 3.40, 3.53-3.81, 6.64, 7.17, 7.22-7.31, 7.33-7.44, 7.70, 8.82, 9.51.

Example 38-2: 4- [4-cyano-2-({[(1S, 2R) -3 ′, 3′-dimethyl-6 ′-(methylcarbamoyl) -2 ′, 3′-dihydrospiro [cyclo Propane-1,1'-indene] -2-yl] carbonyl} amino) phenyl] butanoic acid

TLC: Rf 0.55 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 1.29-1.42, 1.63-1.80 1.83-1.90, 1.98-2.11, 2.11-2.24, 2.32-2.56, 2.57-2.69, 3.04, 3.19, 6.24, 7.11-7.19, 7.21-7.34 , 7.72, 8.82, 9.57.

Example 39: 4- [4-cyano-2-({[(1S, 2R) -3 ′, 3′-dimethyl-6 ′-(3-pyridinyl) -2 ′, 3′-dihydrospiro [cyclopropane -1,1'-indene] -2-yl] carbonyl} amino) phenyl] butanoic acid

Similar to Reference Example 15 → Example 1 except that the compound prepared in Reference Example 35 was used instead of the compound prepared in Reference Example 10 and pyridine-3-boronic acid was used instead of 4-fluorophenylboronic acid. The title compound having the following physical property values was obtained by the operation.
TLC: Rf 0.62 (ethyl acetate: methanol = 9: 1);
¹ H-NMR (CDCl ₃ ): δ 0.59, 1.27-1.43, 1.55-1.69, 1.79, 2.18-2.38, 2.52-2.64, 2.64-2.91, 6.53, 7.16-7.35, 7.54, 8.39-8.50, 8.75-8.84, 9.35.

Pharmacological examples:
Pharmacological Example 1: prostanoid receptor subtype expressing according cells EP ₄ antagonistic activity measurement experiment Nishigaki (Nishigaki) et al method using a (non-patent document 4), CHO cells expressing rat EP ₄ receptor subtype, respectively Were prepared and subjected to experiments. Cells cultured until subconfluent were detached and suspended in assay medium (MEM containing 1 mmol / L IBMX, 1% HSA) to 1 × 10 ⁶ cells / mL. The cell suspension (25 μL) was added with a final concentration of 10 nmol / L of PGE ₂ alone, or a solution containing this and a test compound (25 μL) to start the reaction. After reacting at room temperature for 30 minutes, cAMP assay kit According to the method described in (assay kit) (manufactured by CISBIO), the amount of intracellular cAMP was quantified.

The antagonistic action (IC ₅₀ value) of the test compound was calculated as the inhibition rate against 10 nM reaction, which is a concentration showing submaximal cAMP production action with PGE ₂ alone, and the IC ₅₀ value was obtained.

As a result, it was found that the compound used in the present invention has a strong EP ₄ receptor antagonistic activity. For example, the IC ₅₀ values of some of the compounds used in the present invention were as shown in Table 1 below. On the other hand, the EP ₄ receptor antagonistic activity of Examples 8-128 described in Patent Document 2 was very weak and was 2800 nM.

Pharmacology Example 2: Pharmacokinetic study (liver microsome stability study)
(1) Preparation of test substance solution A DMSO solution (10 mmol / L; 5 μL) of a test substance (compound used in the present invention and a comparative compound) is diluted with a 50% acetonitrile aqueous solution (195 μL) to obtain a test substance of 250 μmol / L. A solution was prepared.

(2) Preparation of standard sample (sample immediately after the start of reaction) In a reaction container preheated to 37 ° C. in a water bath, NADPH-Co-Factor (BD-Bioscience) and 1 mg / mL human liver microsomes were added. 245 μL of 1 mol / L phosphate buffer (pH 7.4) was added and preincubated for 5 minutes. The previous test substance solution 5 μL was added thereto to start the reaction (final concentration 1 μmol / L). Immediately after the start of the reaction, 20 μL of the reaction solution was collected, and this solution was added to 180 μL of acetonitrile (containing the internal standard substance candesartan) to stop the reaction. A solution (20 μL; sample solution immediately after the start of the reaction) in which the reaction was stopped was stirred with 50% acetonitrile (180 μL) on the filter plate for protein removal, and then suction filtered to obtain a filtrate as a standard sample.

(3) Preparation of reaction sample (sample after 60 minutes of reaction) After incubating the previous reaction solution at 37 ° C. for 60 minutes, 20 μL of this reaction solution was sampled and added to 180 μL of acetonitrile (containing internal standard substance candesartan). The reaction was stopped. A solution (20 μL; sample solution reacted for 60 minutes) in which the reaction was stopped was stirred with 50% acetonitrile (180 μL) on a filter plate for protein removal, and then suction filtered, and the filtrate was used as a reaction sample.

(4) Evaluation method Using the peak area obtained by LC-MS / MS, from the test substance amount (X) of the standard sample and the test substance amount (Y) of the reaction sample, according to the following formula, the residual rate of the test substance (%) Was calculated.
Residual rate (%) = (Y / X) × 100
X: amount of test substance in standard sample (Ratio = peak area of test substance / peak area of internal standard substance)
Y: amount of test substance in reaction sample (Ratio = peak area of test substance / peak area of internal standard substance)

(5) Results The compound used in the present invention was found to have high stability against human liver microsomes (high residual ratio (%)). For example, the residual ratio values of some of the compounds used in the present invention are as shown in Table 2 below. On the other hand, the residual rate of Example 6-117 described in Patent Document 2 was 35%.

Pharmacological Example 3: Anti-tumor effect in the allograft model of mouse colon cancer cell line CT26 The anti-tumor effect of the compound used in the present invention was evaluated in the allograft model of CT26, a mouse colon cancer cell line. CT26 was cultured in a RPMI-1640 medium containing 10 vol% inactivated fetal bovine serum (FBS), 100 units / mL Penicillin and 100 μg / mL Streptomycin in a CO ₂ incubator. On the day of transplantation, the culture supernatant was removed, and CT26 was washed with a phosphate buffer (hereinafter abbreviated as PBS) and then collected. The recovered CT26 was suspended in Hank's buffer to obtain cells for transplantation. Under anesthesia, 300,000 cells for transplantation were subcutaneously transplanted into the right back of female Balb / C mice (Nippon Charles River Co., Ltd.). 10 mg / kg of the compound used in the present invention was orally administered once on the day of transplantation, and orally administered twice a day after the date of transplantation. In the control group, distilled water was administered for the same period as the compound administration group used in the present invention. For the tumor volume (mm ³ ), the short axis and long axis of the tumor were measured using an electronic caliper, and the relative tumor volume was calculated using the following formulas 1 and 2.

  As a result, the compound used in the present invention had an inhibitory effect on tumor growth. For example, the relative tumor volumes of Example 2-2 and Example 2-13 were as shown in FIG.

[Formulation example]
Formulation Example 1
The following components are mixed by a conventional method and then tableted to obtain 10,000 tablets each containing 10 mg of the active ingredient.
4- [4-cyano-2-({[(2′R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl ] Carbonyl} amino) phenyl] butanoic acid 100 g
・ Carboxymethylcellulose calcium (disintegrant) 20g
・ Magnesium stearate (lubricant) 10g
・ Microcrystalline cellulose ... 870g

Formulation Example 2
Each of the following components is mixed by a conventional method, then filtered through a dust filter, filled into ampoules in 5 ml increments, and heat sterilized in an autoclave to obtain 10,000 ampoules containing 20 mg of active ingredient in one ampule. it can.
4- [4-cyano-2-({[(2′R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl ] Carbonyl} amino) phenyl] butanoic acid 200 g
・ Mannitol …… 20g
・ Distilled water: 50L

Since the compound used in the present invention has antagonistic activity against the EP ₄ receptor, the pharmaceutical composition containing the compound used in the present invention can prevent diseases caused by the activation of the EP ₄ receptor. And / or effective for treatment.

Claims (17)

Formula (I)

(Where
R ¹ represents COOR ⁸ , tetrazole, SO ₃ H, SO ₂ NH ₂ , SO ₂ NHR ^8-1 , CONHSO ₂ R ^8-1 , SO ₂ NHCOR ^8-1 , or hydroxamic acid,
R ⁸ represents a hydrogen atom, C 1-4 alkyl, or benzyl,
R ^8-1 represents C 1-4 alkyl, C 1-4 haloalkyl, a C 3-10 carbocycle, or a 3-10 membered heterocyclic ring, each of the C 3-10 carbocycle and 3-10 membered heterocyclic ring being C 1 -4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, -O (C1-4 haloalkyl), C1-4 alkylthio, -S (C1-4 haloalkyl), halogen, or nitrile ("-CN" is shown below; The same)),
L ¹ represents C 1-5 alkylene, C 2-5 alkenylene, or C 2-5 alkynylene,
R ² is halogen, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, C ^2-4 alkenyl, C ^2-4 alkynyl, —O (C 1-4 haloalkyl), —S (C 1-4 haloalkyl), — C (O) (C1-4 alkyl), —SO ₂ (C1-4 alkyl), —CONH (C1-4 alkyl), —CON (C1-4 alkyl) ₂ , —NHC (O) (C1-4 alkyl) ), - N (C1-4 alkyl) C (O) (C1-4 alkyl), _- NHSO 2 (C1-4 alkyl), - N (C1-4 _alkyl) SO 2 (C1-4 alkyl), - SO ₂ NH (C1-4 alkyl), —SO ₂ N (C1-4 alkyl) ₂ , —NR ¹⁷ R ¹⁷ , nitro, nitrile, hydroxyl group, aldehyde (indicating formyl; the same shall apply hereinafter) or carboxyl Each C1-4 alkyl may be substituted with halogen,
The in ^{R 2} and (C1-4 _{alkyl) 2,} independently represents a two C1-4 alkyl, each of C1-4 alkyl may be the same or different,
X ¹ represents CR ⁶ or a nitrogen atom, R ⁶ represents a hydrogen atom or R ² ,
X ² represents CR ⁷ or a nitrogen atom, R ⁷ represents a hydrogen atom, R ² , or —L ³ —R ⁹ , and L ³ represents a methylene, oxygen atom, or an optionally oxidized sulfur atom. R ⁹ represents a 4-10 membered heterocyclic ring optionally substituted with a substituent selected from the group consisting of halogen, C 1-4 alkyl, and C 1-4 haloalkyl;
L ² _{is, -CH 2 CH 2 -, -} CH = CH -, - CH 2 O -, - OCH 2 -, - CH 2 S -, - SCH 2 -, - CH 2 S (O) -, - S _{(O) CH 2 -, -} CH 2 SO 2 -, - SO 2 CH 2 -, - CH 2 NH -, - NHCH 2 -, - NHCO -, - CONH -, - NHSO 2 -, or _-SO 2 NH -
R ³ represents C 1-4 alkyl or halogen,
R ⁴ represents halogen, C ^1-4 alkyl, or C ^1-4 haloalkyl,
X ³ represents methylene, an oxygen atom, an optionally oxidized sulfur atom, or NR ¹⁰ ;
R ¹⁰ represents C 1-4 alkyl, —C (O) (C 1-4 alkyl), —C (O) O (C 1-4 alkyl), or —SO ₂ (C 1-4 alkyl), C1-4 alkyl may be substituted with halogen,
ring represents a benzene ring or a 5-6 membered monocyclic aromatic heterocycle;

Represents a single bond or a double bond,
R ⁵ is (1) halogen, (2) C1-4 alkyl, (3) carboxyl, (4) nitrile, (5) -CONHR ¹¹ , (6) -C (O) R ¹² , (7) -OR ¹⁴ , (8) -S (O) _t R ¹⁵ , (9) —CH ₂ R ¹⁶ , (10) —NR ¹⁷ R ¹⁷ , (11) —NHCOR ¹¹ , (12) C 4-10 carbocyclic ring, or ( 13) Represents a 4-10 membered heterocyclic ring, and the C4-10 carbocyclic ring or 4-10 membered heterocyclic ring may be substituted with 1 to 3 R ^{18 s} , and when R ¹⁸ is plural, ¹⁸ may be independently the same or different,
R ¹¹ is, C1-6 alkyl, represents C3-6 cycloalkyl, phenyl, or a 4-6 membered heterocyclic ^{ring, R 11} may be optionally substituted with 1-3 ^{R 13,} wherein ^{R 13} is more Each R ¹³ may independently be the same or different,
R ¹³ represents halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, hydroxyl group, —NR ²⁰ R ²¹ , benzene, or a 4-6 membered heterocyclic ring;
R ²⁰ and R ²¹ each independently represents a hydrogen atom or C 1-4 alkyl;
R ¹² represents C 1-6 alkyl, C 3-6 cycloalkyl, benzene, or a 4-6 membered heterocyclic ring, and the C 3-6 cycloalkyl, benzene, or 4-6 membered heterocyclic ring each independently represents: Optionally substituted with halogen, C1-4 alkyl, or C1-4 alkoxy;
R ¹⁴ is a hydrogen atom, C1-6 alkyl, C3-6 cycloalkyl, benzene or a benzyl, wherein the C1-6 alkyl may be optionally substituted with 1-3 ^{R 19,} wherein ^{R 19} is When there are a plurality of R ^{19 s} , each R ¹⁹ may be independently the same or different;
R ¹⁹ is substituted with a substituent selected from the group consisting of C 1-4 alkoxy, —CONH (C 1-4 alkyl), —CON (C 1-4 alkyl) ₂ , or C 1-4 alkyl and C 1-4 haloalkyl. Represents a 5-6 membered monocyclic aromatic heterocycle which may have
(C1-4 alkyl) ₂ in R ¹⁹ represents two independent C1-4 alkyl, and each C1-4 alkyl may be the same or different;
R ¹⁵ represents C 1-6 alkyl, C 3-6 cycloalkyl, benzene, or benzyl,
R ¹⁶ represents a hydroxyl group or C 1-4 alkoxy;
R ¹⁷ each independently represents a hydrogen atom, C 1-6 alkyl, or C 3-6 cycloalkyl;
R ¹⁸ is halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-4 alkoxy, oxo, nitrile, hydroxyl group, hydroxymethyl, 1-methyl-1-hydroxyethyl, (C 1-4 alkyl) SO ₂ —, 4-6 membered heterocyclic ring, (C1-4 alkyl) NH-, or (C1-4 _alkyl) 2 N-a represents,
(C1-4 alkyl) ₂ in R ¹⁸ represents two independent C1-4 alkyl, and each C1-4 alkyl may be the same or different;
m represents an integer of 1 to 4, n represents an integer of 0 to 4, p represents an integer of 0 to 2, q represents an integer of 0 to 6, r represents an integer of 0 to 6, s represents an integer of 0 to 4, t represents an integer of 0 to 2,
However, when p, q, r, and s each represent an integer of 2 or more, R ² , R ³ , R ⁴ , and R ⁵ may be independently the same or different. ), A salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof. The compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is represented by the general formula (I-1)

(In the formula, na represents an integer of 0 to 1, qa represents an integer of 0 to 3, ra represents an integer of 0 to 4, X ^3a represents a methylene or oxygen atom, and other symbols are claimed. The pharmaceutical composition of Claim 1 which is the same meaning as the symbol of Claim 1.), its salt, its N-oxide body, its solvate, or those prodrugs. The pharmaceutical composition according to claim 1 or 2, wherein at least one R ⁵ is -CONHR ¹¹ . The pharmaceutical composition according to any one of claims 1 to 3, wherein L ² is -NHCO- or -CONH-. A compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is represented by the general formula (I-2)

Wherein R ^2a represents halogen, R ^6a represents a hydrogen atom or halogen, and other symbols have the same meanings as those in claim 1 or claim 2, and salts thereof, The pharmaceutical composition according to claim 1, which is an N-oxide thereof, a solvate thereof, or a prodrug thereof. (1) 4- [4-Cyano-2-({[(2′R, 4S) -6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(2) 4- {4-cyano-2-[({(2′R, 4S) -6-[(cyclopropylmethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(3) 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(4) 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-methyl-2-propanyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(5) 4- [4-cyano-2-({[(2′R, 4S) -6-{[(2S) -1-methoxy-2-propanyl] carbamoyl} -2,3-dihydrospiro [chromene] -4,1'-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(6) 4- {4-cyano-2-[({(2′R, 4S) -6-[(1-methyl-1H-pyrazol-3-yl) carbamoyl] -2,3-dihydrospiro [chromene -4,1'-cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(7) 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(8) 4- [4-cyano-2-({[(2′R, 4S) -6- (isopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(9) 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclopentylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(10) 4- {2-[({(2′R, 4S) -6-[(2S) -2-butanylcarbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl} carbonyl) amino] -4-cyanophenyl} butanoic acid,
(11) 4- {4-cyano-2-[({(2′R, 4S) -6-[(trans-4-hydroxycyclohexyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(12) 4- {4-cyano-2-[({(2′R, 4S) -6-[(cis-4-hydroxycyclohexyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(13) 4- [4-Cyano-2-({[(2′R, 4S) -6- (2-pyridinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(14) 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridazinylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(15) 4- [4-cyano-2-({[(2′R, 4S) -6- (cyclobutylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(16) 4- [4-cyano-2-({[(2′R, 4S) -6-{[1- (2-methyl-2-propanyl) -1H-pyrazol-4-yl] carbamoyl}- 2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(17) 4- [4-cyano-2-({[(2′R, 4S) -6- (tetrahydro-2H-pyran-4-ylcarbamoyl) -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(18) 4- [4-cyano-2-({[(2'R, 4S) -6- (propylcarbamoyl) -2,3-dihydrospiro [chromene-4,1'-cyclopropane] -2 ' -Il]
Carbonyl} amino) phenyl] butanoic acid,
(19) 4- {4-cyano-2-[({(2′R, 4S) -6-[(2-ethoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2′-yl} carbonyl) amino] phenyl} butanoic acid, or (20) 4- [4-cyano-2-({[(2′R, 4S) -6- (ethylcarbamoyl) -2, 3-dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(21) 4- [4-Cyano-2-({[(1R, 2R) -6 ′-(methylcarbamoyl) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -2 -Yl] carbonyl} amino) phenyl] butanoic acid,
(22) 4- {4-cyano-2-[({(1R, 2R) -6 ′-[(2-methoxyethyl) carbamoyl] -2 ′, 3′-dihydrospiro [cyclopropane-1,1 ′ -Indene] -2-yl} carbonyl) amino] phenyl} butanoic acid,
(23) 4- {4-cyano-2-[({(1R, 2R) -6 ′-[(1-methyl-1H-pyrazol-4-yl) carbamoyl] -2 ′, 3′-dihydrospiro [ Cyclopropane-1,1′-indene] -2-yl} carbonyl) amino] phenyl} butanoic acid,
(24) 4- [4-cyano-2-({[(2′R, 4S) -7-fluoro-6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(25) 4- {4-cyano-2-[({(2′R, 4S) -7-fluoro-6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4, 1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid,
(26) 4- [4-cyano-2-({[(2′R, 4S) -7-fluoro-6- (isopropylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(27) 4- [4-cyano-2-({[(2′R, 4S) -7- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid,
(28) 4- {4-cyano-2-[({(2′R, 4S) -7-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(29) 4- [4-cyano-2-({[(2′R, 4S) -7-methoxy-6- (methylcarbamoyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane ] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(30) 4- {4-cyano-2-[({(2'R, 4S) -7-methoxy-6-[(2-methoxyethyl) carbamoyl] -2,3-dihydrospiro [chromene-4, 1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid,
(31) 4- [4-cyano-2-({[(2′R, 3S) -5- (methylcarbamoyl) -2H-spiro [1-benzofuran-3,1′-cyclopropane] -2′- Yl] carbonyl} amino) phenyl] butanoic acid,
(32) 4- {4-cyano-2-[({(2′R, 3S) -5-[(2-methoxyethyl) carbamoyl] -2H-spiro [1-benzofuran-3,1′-cyclopropane] ] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(33) 4- [4-cyano-2-({[(1S, 2R) -6 ′-[(2-methoxyethyl) carbamoyl] -3 ′, 3′-dimethyl-2 ′, 3′-dihydrospiro [Cyclopropane-1,1′-indene] -2-yl] carbonyl} amino) phenyl] butanoic acid, or (34) 4- [4-cyano-2-({[(1S, 2R) -3 ′, 3′-dimethyl-6 ′-(methylcarbamoyl) -2 ′, 3′-dihydrospiro [cyclopropane-1,1′-indene] -2-yl] carbonyl} amino) phenyl] butanoic acid, its salt, its The pharmaceutical composition according to claim 1, comprising an N-oxide, a solvate thereof, or a prodrug thereof. At least one of ^{R 5} may be substituted with 1-3 ^{R 18,} a C4-10 carbocyclic or 4-10 membered heterocyclic ring, if the ^{R 18} is ^{plural, R 18} are each The pharmaceutical composition according to claim 1 or 2, which may be the same or different independently. The pharmaceutical composition according to claim 7, wherein L ² is -NHCO- or -CONH-. The compound represented by the general formula (I), a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof is represented by the general formula (I-3)

^{(Wherein, R 5a} is optionally substituted with 1-3 ^{R 18,} a C4-10 carbocyclic or 4-10 membered heterocyclic ring, if the ^{R 18} is ^{plural, R 18} is Each independently may be the same or different, and the other symbols have the same meanings as those in claim 1, claim 2, or claim 5), a salt thereof, an N-oxide thereof The pharmaceutical composition according to claim 1, which is a body, a solvate thereof, or a prodrug thereof. (1) 4- [4-Cyano-2-({[(2′R, 4S) -6- (5-methyl-1,3,4-oxadiazol-2-yl) -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(2) 4- [4-cyano-2-({[(2′R, 4S) -6- (5-cyclopropyl-1,3,4-oxadiazol-2-yl) -2,3- Dihydrospiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(3) 4- [4-cyano-2-({[(2′R, 4S) -6- (3-methyl-1,2,4-oxadiazol-5-yl) -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(4) 4- [4-Cyano-2-({[(2′R, 4S) -6- (3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(5) 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-1-yl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(6) 4- [4-cyano-2-({[(2′R, 4S) -6- (1H-pyrazol-5-yl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(7) 4- [4-cyano-2-({[(2′R, 4S) -6- (4-pyridazinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(8) 4- [4-cyano-2-({[(2′R, 4S) -6- (2-oxo-1-pyrrolidinyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(9) 4- [4-Cyano-2-({[(2′R, 4S) -6- (6-methoxy-3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(10) 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (1H-pyrazol-1-yl) -3-pyridinyl] -2,3-dihydrospiro [ Chromene-4,1′-cyclopropane] -2′-yl} carbonyl) amino] phenyl} butanoic acid,
(11) 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (dimethylamino) -3-pyridinyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(12) 4- [4-cyano-2-({[(2′R, 4S) -6- (6-methyl-3-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclo Propane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(13) 4- {4-cyano-2-[({(2′R, 4S) -6- [6- (methylamino) -3-pyridinyl] -2,3-dihydrospiro [chromene-4,1 '-Cyclopropane] -2'-yl} carbonyl) amino] phenyl} butanoic acid,
(14) 4- [4-cyano-2-({[(2′R, 4S) -6- (2-pyridinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(15) 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-thiazol-2-yl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(16) 4- [4-cyano-2-({[(2′R, 4S) -6- (1,3-oxazol-2-yl) -2,3-dihydrospiro [chromene-4,1 ′ -Cyclopropane] -2'-yl] carbonyl} amino) phenyl] butanoic acid,
(17) 4- [4-cyano-2-({[(2′R, 4S) -6- (1-methyl-1H-1,2,3-triazol-4-yl) -2,3-dihydro Spiro [chromene-4,1′-cyclopropane] -2′-yl] carbonyl} amino) phenyl] butanoic acid,
(18) 4- [4-cyano-2-({[(2′R, 4S) -6- (3-pyridazinyl) -2,3-dihydrospiro [chromene-4,1′-cyclopropane] -2 '-Yl] carbonyl} amino) phenyl] butanoic acid,
(19) 4- [4-Cyano-2-({[(2′R, 3S) -5- (3-pyridinyl) -2H-spiro [1-benzofuran-3,1′-cyclopropane] -2 ′ -Yl] carbonyl} amino) phenyl] butanoic acid or (20) 4- [4-cyano-2-({[(1S, 2R) -3 ′, 3′-dimethyl-6 ′-(3-pyridinyl)] -2 ', 3'-dihydrospiro [cyclopropane-1,1'-inden] -2-yl] carbonyl} amino) phenyl] butanoic acid, its salt, its N-oxide, its solvate, or they The pharmaceutical composition according to claim 1, comprising a prodrug of The pharmaceutical composition according to claim 1, which is an EP ₄ receptor antagonist. Containing a compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, and further containing a pharmaceutically acceptable carrier. An agent for preventing and / or treating a disease caused by activation of EP ₄ receptor. Diseases resulting from the activation of EP ₄ receptor are bone disease, cancer, systemic granuloma, immune disease, alveolar pyorrhea, gingivitis, periodontal disease, Kawasaki disease, multiple organ failure, chronic headache, pain, The agent according to claim 12, which is vasculitis, venous insufficiency, varicose vein, aneurysm, aortic aneurysm, hemorrhoids, diabetes insipidus, neonatal patent ductus arteriosus, or cholelithiasis. Cancer is breast cancer, ovarian cancer, colon cancer, lung cancer, prostate cancer, head and neck cancer, malignant lymphoma, uveal malignant melanoma, thymoma, mesothelioma, esophageal cancer, stomach cancer, duodenal cancer , Hepatocellular carcinoma, bile duct cancer, gallbladder cancer, pancreatic cancer, renal cell cancer, renal pelvis / ureter cancer, bladder cancer, penile cancer, testicular cancer, uterine cancer, vagina cancer, The agent according to claim 13, which is vulvar cancer, skin cancer, malignant bone tumor, soft tissue sarcoma, chondrosarcoma, leukemia, myelodysplastic syndrome, or multiple myeloma. A compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, an alkylating agent, an antimetabolite, an anticancer antibiotic, From the group consisting of botanical preparations, hormone agents, platinum compounds, topoisomerase inhibitors, kinase inhibitors, anti-CD20 antibodies, anti-HER2 antibodies, anti-EGFR antibodies, anti-VEGF antibodies, proteasome inhibitors, HDAC inhibitors, and immunomodulators A pharmaceutical comprising a combination of at least one selected from the above. A compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, an HMG-CoA reductase inhibitor, an antihypertensive agent, and a tetracycline system A pharmaceutical comprising a combination of at least one selected from the group consisting of antibiotics. A compound represented by the general formula (I) according to claim 1, a salt thereof, an N-oxide thereof, a solvate thereof, or a prodrug thereof, an N-type calcium channel inhibitor, nitric oxide synthase (NOS) ) A pharmaceutical comprising a combination of at least one selected from the group consisting of an inhibitor and a cannabinoid-2 receptor stimulator.

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