Condensed ring compound having GLP-1 receptor agonist activity

Abstract

A compound having GLP-1 receptor agonist activity, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same, which are useful as a therapeutic or prophylactic agent for diseases related to the GLP-1 receptor, particularly a prophylactic and / or therapeutic agent for insulin-independent diabetes (type 2 diabetes) or obesity, are provided. It relates to a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof. TIFF2025084137000064.tif34127 (In the formula, A 1 is C(R 1 ) etc.; R 1 is a hydrogen atom etc.; R 8 is a hydrogen atom etc.; B 1 is CH etc.; R 10 is cyano etc.; R 3 is phenyl etc. which may be substituted with a substituent group F (halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy); Q is a substituted or unsubstituted benzene ring etc.; R 2 is a substituted or unsubstituted alkyl etc.).

Description

Technical Field

[0001] The present invention relates to a compound having GLP-1 receptor agonist activity, a pharmaceutically acceptable salt thereof, which is useful as a therapeutic or prophylactic agent for diseases involving GLP-1 receptor, and a pharmaceutical composition containing them, particularly a prophylactic and / or therapeutic agent for insulin-independent diabetes (type 2 diabetes) or obesity.

Background Art

[0002] Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal L cells in response to food intake. GLP-1 is known to exhibit actions such as promoting glucose-dependent insulin secretion, decreasing glucagon secretion, delaying gastric emptying, and reducing appetite via the GLP-1 receptor. So far, agonists of the GLP-1 receptor have been studied for use in the treatment of diabetes and obesity (Non-Patent Documents 1, 2). Liraglutide, an analog preparation of human GLP-1, is known as a representative agonist, and it has been found to show a strong HbA1c-lowering effect and weight loss. Due to such attractive effects, multiple GLP-1 analog preparations have been put into practical use as therapeutic agents for diabetes and obesity. However, since these GLP-1 analog preparations have poor oral absorbability, most of them are sold as injections. Therefore, the development of an orally administrable GLP-1 receptor agonist is expected. Specifically, a method of orally absorbing semaglutide, a GLP-1 analog, by using an absorption promoter (Patent Document 1) has been put into practical use, but improvement in pharmaceutical properties such as bioavailability is still required. In addition, as non-peptidic GLP-1 receptor agonists, the creation of multiple low-molecular pharmaceuticals has been attempted (Patent Documents 2 to 44), but the compounds substantially disclosed have structures different from those of the compounds of the present invention.

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Patent Document 7

Patent Document 8

Patent Document 9

Patent Document 10

Patent Document 11

Patent Document 12

Patent Document 13

Patent Document 14

Patent Document 15

Patent Document 16

Patent Document 17

Patent Document 18

Patent Document 19

Patent Document 20

[0004] [Non-Patent Document 1] Lancet 374, 1606 - 1616 (2009) [Non-Patent Document 2] Clin. Invest. 2, 59 - 72 (2012) [Summary of the Invention] [Problems to be Solved by the Invention]

[0005] An object of the present invention is to provide a compound having GLP-1 receptor agonist activity, a pharmaceutically acceptable salt thereof, which is useful as a therapeutic or prophylactic agent for diseases related to the GLP-1 receptor, and a pharmaceutical composition containing them, particularly a prophylactic and / or therapeutic agent for insulin-independent diabetes (type 2 diabetes) or obesity. [Means for Solving the Problems]

[0006] The present invention relates to the following. [1] Formula (I): [Chemical Formula] (In the formula, A 1 is C(R 1 ) or N; R 1 is a hydrogen atom or a halogen; R 8 is a hydrogen atom, a halogen, an alkyloxy, or a 5- to 6-membered aromatic heterocyclic group which may be substituted with a halogen or an alkyl; B 1 is CH or N; R 10 is a hydrogen atom, cyano, a fluorine atom, a chlorine atom, methyl, difluoromethyl or trifluoromethyl; R 3 is phenyl which may be substituted with a substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted with a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted with a substituent group F or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted with a substituent group F, Substituent group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy; However, (i) when R 10 is a chlorine atom, B 1 is N, (ii) when R 10 is trifluoromethyl, R 3 is a 5-membered aromatic heterocyclic group which may be substituted with a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted with a substituent group F or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted with a substituent group F, or R 8 is a 5- to 6-membered aromatic heterocyclic group which may be substituted with a halogen or an alkyl, and (iii) excluding the following compounds:

Chemical formula

[10] R 10 is trifluoromethyl, and R 8 is a 5- to 6-membered aromatic heterocyclic group optionally substituted with halogen or alkyl, the compound according to [1] and any one of [3] to [5] or a pharmaceutically acceptable salt thereof.)

[11] Formula (II):

Chemical formula

Chemical formula

Chemical formula

[12] R 3 is the following group, the compound according to

[11] or a pharmaceutically acceptable salt thereof.

Chemical formula

[13] R 3 is a compound according to

[11] or

[12] or a pharmaceutically acceptable salt thereof, wherein R

Chemical formula

[14] R 4 is each independently a fluorine atom, a chlorine atom, cyano, methyl, methyloxy or difluoromethyloxy, a compound according to

[13] or a pharmaceutically acceptable salt thereof.

[15] Q is a compound according to any one of

[11] to

[14] or a pharmaceutically acceptable salt thereof, wherein

Chemical formula

[16] (i) A 2 is C(R 5 ), A 3 is C(R 6 ), and A 4 is C(R 7 ), or (ii) A 2 is N, A 3 is C(R 6 ), and A 4 is C(R 7 ), or (iii) A 2 is C(R 5 ), A 3 is C(R 6 ), and A 4 is N, or (iv) A 2 is N, A 3 is C(R 6 ), and A 4 is N, the compound according to

[15] or a pharmaceutically acceptable salt thereof.

[17] (i) A 2 is C(R 5 ), A 3 is C(R 6 ), and A 4 is C(R 7 ), or (ii) A 2 is N, A 3 is C(R 6 ), and A 4 is C(R 7 ), the compound according to

[16] or a pharmaceutically acceptable salt thereof.

[18] R 5 , R 6 and R 7 are each independently a hydrogen atom, halogen, alkyl or alkyloxy, the compound according to any one of

[15] to

[17] or a pharmaceutically acceptable salt thereof.

[19] R 5 is a hydrogen atom or halogen, R 6is a hydrogen atom, R 7 is a hydrogen atom, halogen, alkyloxy or methylpyrazolyl, a compound according to any one of

[15] to

[17] or a pharmaceutically acceptable salt thereof.

[20] -L- is the following group, a compound according to any one of

[11] to

[19] or a pharmaceutically acceptable salt thereof.

Chemical formula

[21] -L- is the following group, a compound according to

[20] or a pharmaceutically acceptable salt thereof.

Chemical formula

[22] -L- is the following group, a compound according to

[21] or a pharmaceutically acceptable salt thereof.

Chemical formula

[23] R 2 is oxetan-2-ylmethyl, a compound according to any one of

[11] to

[22] or a pharmaceutically acceptable salt thereof.

[24] A pharmaceutical composition comprising a compound according to any one of [1] to

[23] or a pharmaceutically acceptable salt thereof.

[25] A pharmaceutical composition according to

[24] , which is a GLP-1 receptor agonist.

[26] A method for treating and / or preventing a disease involving the GLP-1 receptor, characterized by administering a compound according to any one of [1] to

[23] above, or a pharmaceutically acceptable salt thereof.

[27] Use of a compound according to any one of [1] to

[23] above, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic and / or prophylactic agent for a disease involving the GLP-1 receptor.

[28] A compound according to any one of [1] to

[23] above, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving the GLP-1 receptor.

Advantages of the Invention

[0007] The compound according to the present invention has a GLP-1 receptor agonist action and is useful as a preventive and / or therapeutic agent for diseases involving the GLP-1 receptor, particularly non-insulin-dependent diabetes (type 2 diabetes) or obesity.

Mode for Carrying Out the Invention

[0008] The meanings of the terms used in this specification are explained below. Unless otherwise specified, each term is used with the same meaning whether used alone or in combination with other terms. The term "consisting of" means having only the constituent elements. The term "comprising" means not being limited to the constituent elements and not excluding elements not described. Hereinafter, the present invention will be described while showing embodiments. Throughout this specification, it should be understood that singular expressions include the concepts of their plurals unless otherwise specifically mentioned. Therefore, singular articles (for example, "a", "an", "the" in English, etc.) should be understood to include the concepts of their plurals unless otherwise specifically mentioned. Also, the terms used in this specification should be understood to be used in the meanings usually used in the above technical field unless otherwise specifically mentioned. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meanings as generally understood by those skilled in the art to which the present invention pertains. In case of contradiction, this specification (including the definitions) shall prevail.

[0009] "Halogen" includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Particularly, a fluorine atom and a chlorine atom are preferred.

[0010] "Alkyl" includes a linear or branched hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl, etc. can be mentioned. Preferred embodiments of "alkyl" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Even more preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0011] "Alkenyl" includes a linear or branched hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, with one or more double bonds at any position. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, etc. can be mentioned. Preferred embodiments of "alkenyl" include vinyl, allyl, propenyl, isopropenyl, and butenyl.

[0012] "Alkynyl" includes a linear or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, with one or more triple bonds at any position. It may also have a double bond at any position. For example, it includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc. Preferred embodiments of "alkynyl" include ethynyl, propynyl, butynyl, and pentynyl.

[0013] The "aromatic carbocyclic group" means a monocyclic or polycyclic (two or more rings) cyclic aromatic hydrocarbon group. Examples thereof include phenyl, naphthyl, anthryl, phenanthryl, etc. A preferred embodiment of the "aromatic carbocyclic group" is phenyl.

[0014] The "aromatic carbocycle" means a ring derived from the above "aromatic carbocyclic group". A preferred embodiment of the "aromatic carbocycle" is a benzene ring.

[0015] The "non-aromatic carbocyclic group" means a monocyclic or polycyclic (two or more rings) cyclic saturated hydrocarbon group or cyclic non-aromatic unsaturated hydrocarbon group. The polycyclic (two or more rings) "non-aromatic carbocyclic group" includes those in which a ring in the above "aromatic carbocyclic group" is condensed with a monocyclic or polycyclic (two or more rings) non-aromatic carbocyclic group, and the bond may be in any of the rings. For example, the following rings are shown.

Chemical formula

Chemical formula

[0016] "Non-aromatic carbocyclic ring" means a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0017] "Aromatic heterocyclic" means a monocyclic or polycyclic aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N in the ring. A polycyclic aromatic heterocyclic group includes those in which a ring in the above-mentioned "aromatic carbocyclic group" is condensed with a monocyclic or polycyclic aromatic heterocyclic group, and the bond may be in any of the rings. The monocyclic aromatic heterocyclic group preferably has 5 to 8 members, more preferably 5 or 6 members. Examples of the 5-membered aromatic heterocyclic group include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. Examples of the 6-membered aromatic heterocyclic group include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. The bicyclic aromatic heterocyclic group preferably has 8 to 10 members, more preferably 9 or 10 members. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl, etc. The polycyclic aromatic heterocyclic group having 3 or more rings preferably has 13 to 15 members. For example, carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, dibenzofuryl, etc.

[0018] The term "aromatic heterocyclic ring" means a ring derived from the above-mentioned "aromatic heterocyclic group". As for monocyclic aromatic heterocyclic rings, 5 to 8 members are preferred, and more preferably 5 or 6 members. Examples of 5-member aromatic heterocyclic rings include pyrroline ring, imidazoline ring, pyrazoline ring, triazole ring, tetrazole ring, furan ring, thiophene ring, isoxazole ring, oxazole ring, oxadiazole ring, isothiazole ring, thiazole ring, thiadiazole ring, etc. Examples of 6-member aromatic heterocyclic rings include pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, etc. As for bicyclic aromatic heterocyclic groups, 8 to 10 members are preferred, and more preferably 9 or 10 members. For example, indole ring, isoindole ring, indazole ring, indolizine ring, quinoline ring, isoquinoline ring, cinnoline ring, phthalazine ring, quinazoline ring, naphthyridine ring, quinoxaline ring, purine ring, pteridine ring, benzimidazole ring, benzisoxazole ring, benzoxazole ring, benzoxadiazole ring, benzisothiazole ring, benzothiazole ring, benzothiadiazole ring, benzofuran ring, isobenzofuran ring, benzothiophene ring, benzotriazole ring, imidazopyridine ring, triazolopyridine ring, imidazolothiazole ring, pyrazinopyridazine ring, oxazolopyridine ring, thiazolopyridine ring, etc. As for aromatic heterocyclic rings having 3 or more rings, 13 to 15 members are preferred. For example, carbazole ring, acridine ring, xanthene ring, phenothiazine ring, phenoxathiin ring, phenoxazine ring, dibenzofuran ring, etc.

[0019] The term "non-aromatic heterocyclic group" means a monocyclic or polycyclic non-aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S, and N in the ring. The polycyclic non-aromatic heterocyclic group is a group in which each ring in the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group", and / or "aromatic heterocyclic group" is condensed with a monocyclic or polycyclic non-aromatic heterocyclic group, and further includes a group in which the ring in the above-mentioned "aromatic heterocyclic group" is condensed with a monocyclic or polycyclic non-aromatic carbocyclic group. The bond may be present in any of the rings. Furthermore, the "non-aromatic heterocyclic group" also includes a group having a crosslink as follows, or a group forming a spiro ring.

Chemical formula

[0020] The "non-aromatic heterocycle" means a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0021] The alkyl moieties of "alkyloxy", "haloalkyloxy", "alkylcarbonyloxy", "alkylcarbonyl", "alkyloxycarbonyl", "alkylsulfanyl", "alkylsulfinyl", "alkylsulfonyl", "alkyloxyalkyloxy", and "alkyloxyalkyl" are synonymous with the above-mentioned "alkyl". The alkenyl moieties of "alkenyloxy", "alkenylcarbonyloxy", "alkenylcarbonyl", "alkenyloxycarbonyl", "alkenylsulfanyl", "alkenylsulfinyl" and "alkenylsulfonyl" are synonymous with the above-mentioned "alkenyl". The alkynyl moieties of "alkynyloxy", "alkynylcarbonyloxy", "alkynylcarbonyl", "alkynyloxycarbonyl", "alkynylsulfanyl", "alkynylsulfinyl" and "alkynylsulfonyl" are synonymous with the above-mentioned "alkynyl".

[0022] In this specification, "optionally substituted with substituent group A" means "optionally substituted with one or more groups selected from substituent group A". The same applies to substituent groups B, C, D, E, F, α, β, γ, γ' and the like.

[0023] Examples of substituents such as "substituted alkyl", "substituted alkenyl", "substituted alkynyl", "substituted alkyloxy", "substituted alkenyloxy", "substituted alkynyloxy", "substituted alkylcarbonyloxy", "substituted alkenylcarbonyloxy", "substituted alkynylcarbonyloxy", "substituted alkylcarbonyl", "substituted alkenylcarbonyl", "substituted alkynylcarbonyl", "substituted alkyloxycarbonyl", "substituted alkenyloxycarbonyl", "substituted alkynyloxycarbonyl", "substituted alkylsulfanyl", "substituted alkenylsulfanyl", "substituted alkynylsulfanyl", "substituted alkylsulfinyl", "substituted alkenylsulfinyl", "substituted alkynylsulfinyl", "substituted alkylsulfonyl", "substituted alkenylsulfonyl", "substituted alkynylsulfonyl" include the following substituent group A. Any carbon atom may be bonded to one or more groups selected from the following substituent group A. Substituent group A: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, Alkoxy which may be substituted with substituent group α, alkenyloxy which may be substituted with substituent group α, alkynyloxy which may be substituted with substituent group α, alkylcarbonyloxy which may be substituted with substituent group α, alkenylcarbonyloxy which may be substituted with substituent group α, alkynylcarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkyloxycarbonyl which may be substituted with substituent group α, alkenyloxycarbonyl which may be substituted with substituent group α, alkynyloxycarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α, Amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, sulfamoyl which may be substituted with substituent group β, An aromatic carbocyclic group which may be substituted by a substituent group γ, a non-aromatic carbocyclic group which may be substituted by a substituent group γ', an aromatic heterocyclic group which may be substituted by a substituent group γ, a non-aromatic heterocyclic group which may be substituted by a substituent group γ', an aromatic carbocyclic oxy which may be substituted by a substituent group γ, a non-aromatic carbocyclic oxy which may be substituted by a substituent group γ', an aromatic heterocyclic oxy which may be substituted by a substituent group γ, a non-aromatic heterocyclic oxy which may be substituted by a substituent group γ', an aromatic carbocyclic carbonyloxy which may be substituted by a substituent group γ, a non-aromatic carbocyclic carbonyloxy which may be substituted by a substituent group γ', an aromatic heterocyclic carbonyloxy which may be substituted by a substituent group γ, a non-aromatic heterocyclic carbonyloxy which may be substituted by a substituent group γ', an aromatic carbocyclic carbonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted by a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted by a substituent group γ', an aromatic carbocyclic oxycarbonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted by a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic oxycarbonyl which may be substituted by a substituent group γ', an aromatic carbocyclic alkyloxy which may be substituted by a substituent group γ, a non-aromatic carbocyclic alkyloxy which may be substituted by a substituent group γ', an aromatic heterocyclic alkyloxy which may be substituted by a substituent group γ, a non-aromatic heterocyclic alkyloxy which may be substituted by a substituent group γ', an aromatic carbocyclic alkyloxycarbonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic alkyloxycarbonyl which may be substituted by a substituent group γ', an aromatic heterocyclic alkyloxycarbonyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic alkyloxycarbonyl which may be substituted by a substituent group γ, an aromatic carbocyclic sulfanyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic sulfanyl which may be substituted by a substituent group γ', an aromatic heterocyclic sulfanyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic sulfanyl which may be substituted by a substituent group γ', an aromatic carbocyclic sulfinyl which may be substituted by a substituent group γAn optionally substituted non-aromatic carbocyclic sulfinyl group substituted by a substituent group γ', an optionally substituted aromatic heterocyclic sulfinyl group substituted by a substituent group γ, an optionally substituted non-aromatic heterocyclic sulfinyl group substituted by a substituent group γ', an optionally substituted aromatic carbocyclic sulfonyl group substituted by a substituent group γ, an optionally substituted non-aromatic carbocyclic sulfonyl group substituted by a substituent group γ', an optionally substituted aromatic heterocyclic sulfonyl group substituted by a substituent group γ, and an optionally substituted non-aromatic heterocyclic sulfonyl group substituted by a substituent group γ'.

[0024] Substituent group α: halogen, hydroxy, carboxy, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, sulfanyl, and cyano.

[0025] Substituent group β: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted by substituent group α, alkenyl optionally substituted by substituent group α, alkynyl optionally substituted by substituent group α, alkylcarbonyl optionally substituted by substituent group α, alkenylcarbonyl optionally substituted by substituent group α, alkynylcarbonyl optionally substituted by substituent group α, alkylsulfanyl optionally substituted by substituent group α, alkenylsulfanyl optionally substituted by substituent group α, alkynylsulfanyl optionally substituted by substituent group α, alkylsulfinyl optionally substituted by substituent group α, alkenylsulfinyl optionally substituted by substituent group α, alkynylsulfinyl optionally substituted by substituent group α, alkylsulfonyl optionally substituted by substituent group α, alkenylsulfonyl optionally substituted by substituent group α, alkynylsulfonyl optionally substituted by substituent group α. An aromatic carbocyclic group which may be substituted by a substituent group γ, a non-aromatic carbocyclic group which may be substituted by a substituent group γ', an aromatic heterocyclic group which may be substituted by a substituent group γ, a non-aromatic heterocyclic group which may be substituted by a substituent group γ', an aromatic carbocyclic alkyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic alkyl which may be substituted by a substituent group γ', an aromatic heterocyclic alkyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic alkyl which may be substituted by a substituent group γ', an aromatic carbocyclic carbonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted by a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted by a substituent group γ', an aromatic carbocyclic oxycarbonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted by a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic oxycarbonyl which may be substituted by a substituent group γ, an aromatic carbocyclic sulfanyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic sulfanyl which may be substituted by a substituent group γ', an aromatic heterocyclic sulfanyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic sulfanyl which may be substituted by a substituent group γ, an aromatic carbocyclic sulfinyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic sulfinyl which may be substituted by a substituent group γ', an aromatic heterocyclic sulfinyl which may be substituted by a substituent group γ, a non-aromatic heterocyclic sulfinyl which may be substituted by a substituent group γ, an aromatic carbocyclic sulfonyl which may be substituted by a substituent group γ, a non-aromatic carbocyclic sulfonyl which may be substituted by a substituent group γ', an aromatic heterocyclic sulfonyl which may be substituted by a substituent group γ and a non-aromatic heterocyclic sulfonyl which may be substituted by a substituent group γ'.

[0026] Substituent group γ: Substituent group α, alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, haloalkylcarbonyl, alkenylcarbonyl, and alkynylcarbonyl.

[0027] Substituent group γ': Substituent group γ and oxo.

[0028] Examples of the substituents on the rings of "substituted aromatic carbocyclic groups", "substituted aromatic heterocyclic groups", "substituted aromatic carbocyclic oxy", "substituted aromatic heterocyclic oxy", "substituted aromatic carbocyclic carbonyloxy", "substituted aromatic heterocyclic carbonyloxy", "substituted aromatic carbocyclic carbonyl", "substituted aromatic heterocyclic carbonyl", "substituted aromatic carbocyclic oxycarbonyl", "substituted aromatic heterocyclic oxycarbonyl", "substituted aromatic carbocyclic sulfanyl", "substituted aromatic heterocyclic sulfanyl", "substituted aromatic carbocyclic sulfinyl", "substituted aromatic heterocyclic sulfinyl", "substituted aromatic carbocyclic sulfonyl" and "substituted aromatic heterocyclic sulfonyl", etc., of "aromatic carbocycles" and "aromatic heterocycles" include the following substituent group B. An atom at any position on the ring may be bonded to one or more groups selected from the following substituent group B. Substituent group B: halogen, hydroxy, carboxy, formyl, formyloxy, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso, azide, hydrazino, ureido, amidino, guanidino, pentafluorothio, trialkylsilyl, alkyl which may be substituted with substituent group α, alkenyl which may be substituted with substituent group α, alkynyl which may be substituted with substituent group α, alkyloxy which may be substituted with substituent group α, alkenyloxy which may be substituted with substituent group α, alkynyloxy which may be substituted with substituent group α, alkyloxycarbonyloxy which may be substituted with substituent group α, alkenyloxycarbonyloxy which may be substituted with substituent group α, alkynyloxycarbonyloxy which may be substituted with substituent group α, alkylcarbonyl which may be substituted with substituent group α, alkenylcarbonyl which may be substituted with substituent group α, alkynylcarbonyl which may be substituted with substituent group α, alkyloxycarbonyl which may be substituted with substituent group α, alkenyloxycarbonyl which may be substituted with substituent group α, alkynyloxycarbonyl which may be substituted with substituent group α, alkylsulfanyl which may be substituted with substituent group α, alkenylsulfanyl which may be substituted with substituent group α, alkynylsulfanyl which may be substituted with substituent group α, alkylsulfinyl which may be substituted with substituent group α, alkenylsulfinyl which may be substituted with substituent group α, alkynylsulfinyl which may be substituted with substituent group α, alkylsulfonyl which may be substituted with substituent group α, alkenylsulfonyl which may be substituted with substituent group α, alkynylsulfonyl which may be substituted with substituent group α amino which may be substituted with substituent group β, imino which may be substituted with substituent group β, carbamoyl which may be substituted with substituent group β, sulfamoyl which may be substituted with substituent group β An aromatic carbocyclic group which may be substituted with a substituent group γ, a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ, a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic oxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxy which may be substituted with a substituent group γ', an aromatic heterocyclic oxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxy which may be substituted with a substituent group γ', "an aromatic carbocyclic carbonyloxy which may be substituted with a substituent group γ", "a non-aromatic carbocyclic carbonyloxy which may be substituted with a substituent group γ'", "an aromatic heterocyclic carbonyloxy which may be substituted with a substituent group γ", and "a non-aromatic heterocyclic carbonyloxy which may be substituted with a substituent group γ'", an aromatic carbocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyl which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxy which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyloxy which may be substituted with a substituent group γ', an aromatic heterocyclic alkyloxy which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyloxy which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyloxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyloxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with a substituent group γ'Aromatic carbocyclic alkyloxyalkyl which may be substituted with a substituent group γ, non-aromatic carbocyclic alkyloxyalkyl which may be substituted with a substituent group γ', aromatic heterocyclic alkyloxyalkyl which may be substituted with a substituent group γ, non-aromatic heterocyclic alkyloxyalkyl which may be substituted with a substituent group γ', aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ, non-aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ', aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ, non-aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ, aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ, non-aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ, aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ, non-aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ, aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ, non-aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ, aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ and non-aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ'.

[0029] As the substituents on the rings of "substituted non-aromatic carbocyclic group", "substituted non-aromatic heterocyclic group", "substituted non-aromatic carbocyclic oxy", "substituted non-aromatic heterocyclic oxy", "substituted non-aromatic carbocyclic carbonyloxy", "substituted non-aromatic heterocyclic carbonyloxy", "substituted non-aromatic carbocyclic carbonyl", "substituted non-aromatic heterocyclic carbonyl", "substituted non-aromatic carbocyclic oxycarbonyl", "substituted non-aromatic heterocyclic oxycarbonyl", "substituted non-aromatic carbocyclic sulfanyl", "substituted non-aromatic heterocyclic sulfanyl", "substituted non-aromatic carbocyclic sulfinyl", "substituted non-aromatic heterocyclic sulfinyl", "substituted non-aromatic carbocyclic sulfonyl", and "substituted non-aromatic heterocyclic sulfonyl", the following substituent group C can be mentioned. The atoms at any position on the ring may be bonded to one or more groups selected from the following substituent group C. Substituent group C: Substituent group B and oxo.

[0030] When a "non-aromatic carbocyclic ring", "non-aromatic heterocyclic ring", "non-aromatic carbocyclic group" or "non-aromatic heterocyclic group" is substituted with "oxo", it means a ring in which two hydrogen atoms on a carbon atom are substituted as follows. [Chemical formula]

[0031] Examples of the substituents of "substituted amino", "substituted imino", "substituted carbamoyl" and "substituted sulfamoyl" include the following substituent group D. It may be substituted with one or two groups selected from substituent group D. Substituent group D: halogen, hydroxy, carboxy, cyano, alkyl optionally substituted with substituent group α, alkenyl optionally substituted with substituent group α, alkynyl optionally substituted with substituent group α, alkylcarbonyl optionally substituted with substituent group α, alkenylcarbonyl optionally substituted with substituent group α, alkynylcarbonyl optionally substituted with substituent group α, alkylsulfanyl optionally substituted with substituent group α, alkenylsulfanyl optionally substituted with substituent group α, alkynylsulfanyl optionally substituted with substituent group α, alkylsulfinyl optionally substituted with substituent group α, alkenylsulfinyl optionally substituted with substituent group α, alkynylsulfinyl optionally substituted with substituent group α, alkylsulfonyl optionally substituted with substituent group α, alkenylsulfonyl optionally substituted with substituent group α, alkynylsulfonyl optionally substituted with substituent group α, amino optionally substituted with substituent group β, imino optionally substituted with substituent group β, carbamoyl optionally substituted with substituent group β, sulfamoyl optionally substituted with substituent group β, An aromatic carbocyclic group which may be substituted with a substituent group γ, a non-aromatic carbocyclic group which may be substituted with a substituent group γ', an aromatic heterocyclic group which may be substituted with a substituent group γ, a non-aromatic heterocyclic group which may be substituted with a substituent group γ', an aromatic carbocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic alkyl which may be substituted with a substituent group γ', an aromatic heterocyclic alkyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyl which may be substituted with a substituent group γ', an aromatic carbocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyl which may be substituted with a substituent group γ', an aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxycarbonyl which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxycarbonyl which may be substituted with a substituent group γ, an aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfanyl which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfinyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfinyl which may be substituted with a substituent group γ, an aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfonyl which may be substituted with a substituent group γ', an aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ and a non-aromatic heterocyclic sulfonyl which may be substituted with a substituent group γ'.

[0032] In formula (II), the bond attached with *1 of -L- is bonded to R 3 and the bond attached with *2 of -L- is bonded to the imidazole ring.

[0033] Preferred embodiments of each definition in the compound represented by formula (I) are shown below. As the compound represented by formula (I), embodiments of all combinations of the specific examples shown below are exemplified.

[0034] A 1 is C(R 1 ) or N. A 1 is preferably C(R 1 ).

[0035] R 1 is a hydrogen atom or a halogen. R 1 is preferably a hydrogen atom or a fluorine atom.

[0036] R 8 is a hydrogen atom, a halogen, an alkyloxy, or a 5- to 6-membered aromatic heterocyclic group which may be substituted with a halogen or an alkyl. R 8 is preferably a hydrogen atom, a fluorine atom, a methyloxy, or a methylpyrazolyl, more preferably a hydrogen atom, a fluorine atom, or a methyloxy.

[0037] B 1 is CH or N. B 1 is preferably N. B 1 Another embodiment of B is CH.

[0038] R 10 is a hydrogen atom, cyano, a fluorine atom, a chlorine atom, methyl, difluoromethyl, or trifluoromethyl. R 10 is preferably a chlorine atom, methyl, difluoromethyl, or trifluoromethyl, more preferably trifluoromethyl. R 10 As another embodiment, a hydrogen atom, cyano, a fluorine atom, a chlorine atom, methyl, or difluoromethyl is exemplified. R 10As another aspect, a chlorine atom or difluoromethyl may be mentioned. Here, (i) when R 10 is a chlorine atom, B 1 is N, (ii) when R 10 is trifluoromethyl, R 3 is a 5-membered aromatic heterocyclic group which may be substituted with a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted with a substituent group F or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted with a substituent group F, or R 8 is a 5- to 6-membered aromatic heterocyclic group which may be substituted with a halogen or an alkyl, and (iii) excluding the following compounds:

Chemical formula

[0039] R 3 is phenyl which may be substituted with a substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted with a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted with a substituent group F or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted with a substituent group F. R 3 is preferably the following group.

Chemical formula

Chemical formula

[0040] Preferred embodiments of each definition in the compound represented by formula (II) are shown below. As the compound represented by formula (II), embodiments of all combinations of the specific examples shown below are exemplified.

[0041] Q is a substituted or unsubstituted benzene ring or a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic ring. Q is preferably any of the following groups.

Chemical formula

Chemical formula

[0042] A 2 、A 3 and A 4 are preferably (i) A 2 is C(R 5 ), A 3 is C(R 6 ), and A 4 is C(R 7 ), or (ii) A 2 is N, A 3 is C(R 6 ), and A 4 is C(R 7 ), or (iii) A 2 is C(R 5 ), A 3 is C(R 6 ), and A 4 is N, or (iv) A 2 is N, A 3 is C(R 6 ), and A 4 is N. A 2 、A 3 and A 4 are more preferably (i) A 2 is C(R 5 ), A 3 is C(R 6 ), and A 4 is C(R 7 ), or (ii) A 2 is N, A 3 is C(R 6 ), and A 4 is C(R 7 ).

[0043] R 5 、R 6 and R 7 are preferably each independently a hydrogen atom, a halogen, an alkyl, an alkyloxy, or a 5- to 6-membered aromatic heterocyclic group which may be substituted with a substituent group E. Substituent group E: halogen, alkyl, haloalkyl, alkyloxy and haloalkyloxy. Substituent group E is preferably a group selected from halogen and alkyl. R 5 is preferably a hydrogen atom or a halogen, more preferably a hydrogen atom or a fluorine atom. R 6 is preferably a hydrogen atom. R 7 is preferably a hydrogen atom, a halogen, an alkyloxy or a methylpyrazolyl, more preferably a hydrogen atom, a fluorine atom, a methyloxy or a methylpyrazolyl.

[0044] A 5 is preferably C(R 9 ). R 9 is preferably a hydrogen atom, a halogen, a cyano, an alkyl or an alkyloxy, more preferably a hydrogen atom.

[0045] R 2 is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group. R 2 is preferably an alkyl, an alkyl substituted with a non-aromatic heterocyclic group or an alkyl substituted with an aromatic heterocyclic group, more preferably an oxetanylalkyl or an alkylimidazolylalkyl. R 2 is most preferably oxetanylmethyl.

[0046] -L- is any of the following groups.

Chemical formula

[0047] B 1 is CH or N, preferably N. B 2 is C(R 9 ) or N, preferably N. B 2 Another preferred embodiment of B 9 is C(R B 3 is CH or N, preferably CH.

[0048] R 9 is a hydrogen atom or together with R 13a forms -O- or -CH 2 -O- (the right bond is bonded to the benzene ring), preferably a hydrogen atom. R 9 In another embodiment of R 13a together with R

[0049] R 13a is a hydrogen atom or R 9 together with, -O- or -CH 2 -O- (the right bond is bonded to the benzene ring) is formed, preferably a hydrogen atom. R 13a In another aspect of, R 9 together with, -O- is formed.

[0050] R 13b is a hydrogen atom or a substituted or unsubstituted alkyl (examples of substituents: halogen, etc.), preferably a hydrogen atom or an alkyl.

[0051] R 10a is a hydrogen atom or a substituted or unsubstituted alkyl (examples of substituents: halogen, etc.), preferably methyl. R 10b is a hydrogen atom, cyano, halogen or a substituted or unsubstituted alkyl (examples of substituents: halogen, etc.), preferably a hydrogen atom, cyano, fluorine atom, chlorine atom, methyl, difluoromethyl or trifluoromethyl. More preferably, it is trifluoromethyl.

[0052] -L 1 - is alkylene, preferably C1-C3 alkylene, more preferably ethylene. X is S, NH or CH 2 and is preferably NH.

[0053] R 3 is the same group as in the above formula (I), and the preferred groups are the same.

[0054] The compounds represented by formula (I) or formula (II) are not limited to specific isomers, and include all possible isomers (for example, keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, tautomers as described below, etc.), racemates or mixtures thereof.

[0055] One or more hydrogens, carbons, and / or other atoms of the compound represented by formula (I) or formula (II) may each be substituted with an isotope of hydrogen, carbon, and / or other atoms. Examples of such isotopes include, respectively, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl, including hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine. The compound represented by formula (I) or formula (II) also includes compounds substituted with such isotopes. The compounds substituted with such isotopes are also useful as pharmaceuticals and include all radiolabeled forms of the compound represented by formula (I) or formula (II). Also included in the present invention is a "radiolabeling method" for producing the "radiolabeled compound", and the "radiolabeled compound" is useful as a tool for metabolic pharmacokinetic studies, studies in binding assays, and / or diagnosis.

[0056] The radiolabeled compound of the compound represented by formula (I) or formula (II) can be prepared by methods well known in the art. For example, a tritium-labeled compound represented by formula (I) or formula (II) can be prepared by introducing tritium into a specific compound represented by formula (I) or formula (II) by a catalytic dehalogenation reaction using tritium. This method involves reacting a compound represented by formula (I) or formula (II) with a suitably halogen-substituted precursor and tritium gas in the presence or absence of a base, in the presence of a suitable catalyst such as Pd / C. Other suitable methods for preparing tritium-labeled compounds can be referred to in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds are14 It can be prepared by using a raw material containing C carbon.

[0057] Examples of the pharmaceutically acceptable salts of the compound represented by formula (I) or formula (II) include salts of the compound represented by formula (I) or formula (II) with an alkali metal (e.g., lithium, sodium, potassium, etc.), an alkaline earth metal (e.g., calcium, barium, etc.), magnesium, a transition metal (e.g., zinc, iron, etc.), ammonia, an organic base (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.), and an amino acid, or an inorganic acid (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.), and an organic acid (e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid, etc. are included. These salts can be formed by commonly practiced methods.

[0058] The compounds represented by formula (I) or formula (II) or pharmaceutically acceptable salts thereof may form solvates (e.g., hydrates, etc.), co-crystals and / or crystal polymorphs, and the present invention also encompasses such various solvates, co-crystals and crystal polymorphs. A "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.) with respect to the compound represented by formula (I) or formula (II). When the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere, or a hydrate may be formed. Also, when the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof is recrystallized, crystal polymorphs may be formed. A "co-crystal" means that the compound or salt represented by formula (I) or formula (II) and a counter molecule are present within the same crystal lattice and may contain any number of counter molecules.

[0059] The compounds represented by formula (I) or formula (II) or pharmaceutically acceptable salts thereof may form prodrugs, and the present invention also encompasses such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically decomposed, and is a compound that becomes the pharmaceutically active compound of the present invention by solvolysis or in vivo under physiological conditions. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into the compound represented by formula (I) or formula (II), compounds that are hydrolyzed by gastric acid, etc. to be converted into the compound represented by formula (I) or formula (II), etc. Methods for selecting and producing appropriate prodrug derivatives are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". A prodrug may itself have activity.

[0060] When the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting the compound having a hydroxyl group with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride, and a mixed anhydride or by reacting with a condensing agent are exemplified. For example, CH 3 COO-, C 2 H 5 COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO-, (m-NaOOCPh)COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH(NH 2 )COO-, CH 2 N(CH 3 ) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p-CH 3 O-PhSO 3 -, PhSO 3 -, p-CH 3 PhSO 3 - are mentioned.

[0061] (Method for producing the compound of the present invention) The compound represented by formula (I) or formula (II) can be produced, for example, by the general synthesis methods shown below. All of the starting materials and reaction reagents used in these syntheses are commercially available or can be produced from commercially available compounds according to methods well known in the art. Extraction, purification, etc. may be carried out by the treatments performed in ordinary organic chemistry experiments. The compounds of the present invention can be synthesized with reference to methods known in the art. In the following steps, when there are substituents that hinder the reaction (for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), they can be protected in advance by the methods described in Theodora W Greene (John Wiley & Sons) such as Protective Groups in Organic Synthesis, and the protecting groups can be removed at a desired stage. Also, for all the following steps, the order of the steps to be carried out can be appropriately changed, and each intermediate can be isolated and used in the next step. The reaction time, reaction temperature, solvent, reagent, protecting group, etc. are all merely examples and are not particularly limited as long as there is no hindrance to the reaction.

[0062] A general synthetic method of the compounds of the present invention is shown below. All of the starting materials and reaction reagents used in these syntheses are either commercially available or can be produced according to methods well-known in the art using commercially available compounds.

[0063] The compounds represented by the general formula (I) or formula (II) of the present invention can be produced, for example, by the synthetic routes shown below.

[0064] General Synthetic Method 1

Chemical Formula

[0065] Step 5 Compound a8 can be obtained by reacting compound a6 with compound a7 in the presence of a metal catalyst and a base, and adding tetrabutylammonium bromide, etc. as needed. Examples of the metal catalyst include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, bis(tri-tert-butylphosphine)palladium, etc., and they can be used in an amount of 0.001 to 0.5 molar equivalent based on compound a6. Examples of the base include dicyclohexylamine, potassium tert-butoxide, sodium carbonate, potassium carbonate, etc., and they can be used in an amount of 1 to 10 molar equivalents based on compound a6. Compound a7 can be used in an amount of 1 to 5 molar equivalents based on compound a6. The reaction temperature is carried out at 20°C to the reflux temperature of the solvent, and in some cases, at the temperature under microwave irradiation. The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours. Examples of the reaction solvent include THF, toluene, DMF, dioxane, water, etc., and they can be used alone or in combination. Step 6 Compound a9 can be obtained by reacting compound a8 with hydrogen gas in the presence of a metal catalyst. Examples of the metal catalyst include palladium-carbon, platinum oxide, rhodium-aluminum oxide, chlorotris(triphenylphosphine)rhodium(I), etc., and 0.01 to 100 weight percent can be used with respect to compound a8. The hydrogen pressure can be 1 to 50 atmospheres. In addition, cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, etc. can also be used as the hydrogen source. The reaction temperature is 0°C to the reflux temperature of the solvent, preferably 20°C to 40°C. The reaction time is 0.5 to 72 hours, preferably 1 to 12 hours. Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, toluene, ethyl acetate, acetic acid, water, etc., and they can be used alone or in combination. Step 7 Compound a10 can be obtained by reacting compound a9 with hydrazine monohydrate or the like. Hydrazine monohydrate or the like can be used in an amount of 1 to 20 molar equivalents with respect to compound a9. The reaction temperature is 0°C to 100°C, preferably 20°C to 80°C. The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours. Examples of the reaction solvent include ethanol, etc. Step 8 Compound a11 can be obtained by reacting compound a10 with trifluoroacetic anhydride. Trifluoroacetic anhydride can be used in an amount of 1 to 10 molar equivalents relative to compound a10. The reaction temperature is from -10°C to 80°C, preferably from 0°C to 40°C. The reaction time is from 0.5 hour to 24 hours, preferably from 1 to 12 hours. Examples of the reaction solvent include dichloromethane, THF, dioxane, acetonitrile, etc., and they can be used alone or in combination.

[0066] Step 9 Compound a12 can be obtained by reacting compound a11 with triphenylphosphine and a condensing agent. Examples of the condensing agent include DEAD, DIAD, etc., and they can be used in an amount of 1 to 5 molar equivalents relative to compound a11. Triphenylphosphine can be used in an amount of 1 to 5 molar equivalents relative to compound a11. The reaction temperature is from 0°C to 60°C, preferably from 10°C to 40°C. The reaction time is from 0.1 hour to 12 hours, preferably from 0.2 hour to 6 hours. Examples of the reaction solvent include THF, dioxane, ethyl acetate, toluene, acetonitrile, etc., and they can be used alone or in combination. Step 10 Compound a13 can be obtained by reacting compound a12 with a base. The reaction temperature is from 0°C to 80°C, preferably from 10°C to 60°C. The reaction time is from 0.5 hour to 12 hours, preferably from 1 hour to 10 hours. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., and they can be used in an amount of 1 to 10 molar equivalents relative to compound a12. Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF, etc., and they can be used alone or in combination. Step 11 Compound a15 can be obtained by reacting compound a14 with compound a13 in the presence of a base. Compound a14 can be used in an amount of 0.9 to 3 molar equivalents relative to compound a13. The reaction temperature is from 0 °C to the reflux temperature of the solvent. The reaction time is from 0.5 hour to 12 hours, preferably from 1 hour to 6 hours. Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, etc., and they can be used in an amount of 1 to 10 molar equivalents relative to compound a13. Examples of the reaction solvent include methanol, ethanol, acetonitrile, THF, dimethylformamide, etc., and they can be used alone or in combination.

[0067] General synthesis method 2 [Chemical formula] (In the formula, R' is alkyl or haloalkyl, and other symbols have the same meanings as above) Step 1 Compound d2 can be obtained by reacting compound d1 with an anhydrous sulfonic acid ester or sulfonic acid chloride in the presence of a base. The anhydrous sulfonic acid ester or sulfonic acid chloride can be used in an amount of 1 to 5 molar equivalents relative to compound d1. Examples of the base include triethylamine, diisopropylethylamine, pyridine, etc., and they can be used in an amount of 1 to 10 molar equivalents relative to compound d1. The reaction temperature is from -40 °C to 60 °C, preferably from -20 °C to 40 °C. The reaction time is from 0.1 hour to 48 hours, preferably from 1 hour to 24 hours. Step 2 Compound d3 can be obtained by reacting compound d2 with an amine or alkylboronic acid in the presence of a base, a metal catalyst, and a ligand. Examples of the metal catalyst include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), bis(tri-tert-butylphosphine)palladium, etc., and they can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound d2. Examples of the ligand include BINAP, DPPF, Xantphos, etc., and they can be used in an amount of 0.001 to 1 molar equivalents relative to compound d2. Examples of the base include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, sodium phosphate, disodium hydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, etc., and they can be used in an amount of 1 to 10 molar equivalents relative to compound d2. The amine or alkylboronic acid can be used in an amount of 1 to 10 molar equivalents relative to compound d2. The reaction temperature is from 20 °C to the reflux temperature of the solvent, and in some cases, it is carried out at the temperature under microwave irradiation. The reaction time is from 0.1 to 48 hours, preferably from 0.5 to 12 hours. Examples of the reaction solvent include THF, toluene, DMF, dioxane, water, etc., and they can be used alone or in combination. Step 3 Compound d4 can be obtained by reacting compound d3 with a base. The reaction temperature is from 0 °C to 80 °C, preferably from 10 °C to 60 °C. The reaction time is from 0.5 to 12 hours, preferably from 1 to 10 hours. Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, etc., and they can be used in an amount of 1 to 10 molar equivalents relative to compound d3. Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF, etc., and they can be used alone or in combination. Step 4 Compound d5 can be obtained by reacting compound d4 in the same manner as in Step 11 of General Synthetic Method 1.

[0068] General Synthetic Method 3

Chemical formula

[0069] General Synthesis Method 4

Chemical formula

[0070] General Synthesis Method 5 [Chemical formula] (In the formula, each symbol has the same meaning as above) Step 1 Compound j3 can be obtained by reacting Compound j2 with Compound j1 in the presence of a base. 1 to 5 molar equivalents of Compound j2 can be used with respect to Compound j1. Examples of the base include sodium hydride, sodium methoxide, LHMDS, etc., and 1 to 10 molar equivalents thereof can be used with respect to Compound j1. The reaction temperature is from -40°C to 50°C, preferably from -20°C to 30°C. The reaction time is from 0.1 hour to 24 hours, preferably from 0.5 to 12 hours. Examples of the reaction solvent include THF, dimethoxyethane, etc., and they can be used alone or in combination. Step 2 Compound j4 can be obtained by reacting compound j3 with a reducing agent. Examples of the reducing agent include diisobutylaluminum hydride and lithium borohydride, and 1 to 5 molar equivalents thereof can be used with respect to compound j3. The reaction temperature is from -40°C to 50°C, preferably from -20°C to 30°C. The reaction time is from 0.1 hour to 24 hours, preferably from 0.5 to 12 hours. Examples of the reaction solvent include dichloromethane, THF, toluene, etc., and they can be used alone or in combination. Steps 3 - 4 Compound j6 can be obtained by reacting compound j4 in the same manner as in Steps 2 - 4 of General Synthesis Method 4.

[0071] General Synthesis Method 6

Chemical formula

[0072] General Synthesis Method 7

Chemical Formula

[0073] Step 5 Compound l6 can be obtained by reacting compound l5 with a condensing agent in the presence or absence of a base. Examples of the condensing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, HATU, etc., and 1 to 5 molar equivalents can be used with respect to compound l5. Examples of the base include triethylamine, diisopropylethylamine, para-dimethylaminopyridine, etc., and 1 to 10 molar equivalents can be used with respect to compound l5. The reaction temperature is from -20 °C to 80 °C, preferably from 10 °C to 70 °C. The reaction time is from 0.1 hour to 24 hours, preferably from 1 hour to 12 hours. Examples of the reaction solvent include THF, dichloromethane, DMF, etc., and they can be used alone or in combination. Step 6 Compound l7 can be obtained by reacting compound l6 with a reducing agent. Examples of the reducing agent include lithium aluminum hydride, etc., and 1 to 20 molar equivalents can be used with respect to compound l6. The reaction temperature is from 0 °C to the reflux temperature of the solvent. The reaction time is from 0.5 hour to 24 hours, preferably from 1 hour to 12 hours. As the reaction solvent, THF or the like can be used. Step 7 Compound l7 can be reacted in the same manner as in Step 11 of General Synthesis Method 1 to obtain compound l8.

[0074] General Synthesis Method 8

Chemical formula

[0075] Since the compound according to the present invention has GLP-1 receptor agonist activity, it is useful as a therapeutic agent and / or prophylactic agent for diseases involving the GLP-1 receptor. In the present invention, the term "therapeutic agent and / or prophylactic agent" also includes a symptom-improving agent.

[0076] Diseases involving the GLP-1 receptor include non-insulin-dependent diabetes (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, or dementia, etc.

[0077] In the present invention, "diabetes" means a disease or condition in which the body is unable to maintain an appropriate blood glucose level, resulting in abnormalities in the metabolism of glucose production and utilization, and includes insulin-dependent diabetes (type 1 diabetes) and non-insulin-dependent diabetes (type 2 diabetes).

[0078] "Hyperglycemia" refers to a state in which the plasma glucose level is higher than the normal value (e.g., 80 - 110 mg / dL in fasting humans) either during fasting or after glucose administration, and is also one of the typical symptoms of diabetes.

[0079] "Impaired glucose tolerance" includes insulin-resistant impaired glucose tolerance and insulin secretion deficiency.

[0080] "Diabetes complications" means complications caused by diabetes or hyperglycemia, and may be either acute complications or chronic complications. Examples of "acute complications" include, for example, ketoacidosis, infections (such as skin infections, soft tissue infections, biliary tract infections, respiratory infections, urinary tract infections), and examples of "chronic complications" include, for example, microangiopathy (such as nephropathy, retinopathy), neuropathy (such as sensory neuropathy, motor neuropathy, autonomic neuropathy), and gangrene of the foot. Major diabetes complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. "Coronary heart disease" includes myocardial infarction, angina pectoris, etc.

[0081] Examples of "dementia" include, for example, Alzheimer's disease, vascular dementia, and diabetic dementia. The compound of the present invention not only has GLP-1 receptor agonist activity, but also has utility as a medicament and has any one or all of the following excellent characteristics. a) It has a weak inhibitory effect on CYP enzymes (such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.). b) It exhibits good pharmacokinetics such as high bioavailability and moderate clearance. c) It has high metabolic stability. d) It does not show an irreversible inhibitory effect on CYP enzymes (such as CYP3A4) within the concentration range of the measurement conditions described herein. e) It has no mutagenicity. f) It has a low cardiovascular risk. g) It has a low risk of blood toxicity. h) It shows high solubility.

[0082] The pharmaceutical composition of the present invention can be administered by either oral or parenteral methods. Examples of parenteral administration methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, intranasal, ophthalmic, otic, intravaginal administration, etc.

[0083] In the case of oral administration, it may be prepared into any of the commonly used dosage forms such as internal solid preparations (for example, tablets, powders, granules, capsules, pills, film agents, etc.), internal liquid preparations (for example, suspensions, emulsions, elixirs, syrups, lemonades, spirits, aromatic waters, extracts, decoctions, tinctures, etc.) and administered according to conventional methods. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets. The powders and granules may be dry syrups. The capsules may be soft capsules, microcapsules or sustained-release capsules.

[0084] In the case of parenteral administration, it can be preferably administered in any of the commonly used dosage forms such as injections, drip infusions, external preparations (for example, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellies, creams, patches, poultices, external powders, suppositories, etc.). The injections may be emulsions such as O / W, W / O, O / W / O, W / O / W type, etc.

[0085] An effective amount of the compound of the present invention can be mixed with various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form as needed to form a pharmaceutical composition. Furthermore, the pharmaceutical composition can be made into a pharmaceutical composition for pediatric use, elderly use, critically ill patients or surgical use by appropriately changing the effective amount of the compound of the present invention, dosage form and / or various pharmaceutical additives. The pharmaceutical composition for pediatric use is preferably administered to patients under 12 or 15 years old. Also, the pharmaceutical composition for pediatric use can be administered to patients under 27 days after birth, 28 days to 23 months after birth, 2 to 11 years old, 12 to 17 or 18 years old. The pharmaceutical composition for elderly use is preferably administered to patients 65 years old or older.

[0086] The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, administration route, etc. When administered orally, it is usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, it varies greatly depending on the administration route, but is usually 0.005 to 10 mg / kg / day, preferably in the range of 0.01 to 1 mg / kg / day. It may be administered once to several times a day.

[0087] The compound of the present invention can be used in combination with a concomitant drug for the purpose of enhancing the action of the compound or reducing the dosage of the compound. At this time, the administration time of the compound of the present invention and the concomitant drug is not limited, and they may be administered simultaneously or at different times to the administration subject.

[0088] The concomitant drugs are not limited to commercially available or under - development ones. As commercially available or under - development drugs, there are orlistat, cetilistat, phentermine, mazindol, benzphetamine, amfepramone, methamphetamine, phentermine hydrochloride / topiramate, naltrexone hydrochloride / bupropion hydrochloride, setmelanotide (RM - 493), metreleptin, topiramate, naltrexone, bupropion, acarbose, voglibose, miglitol, ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin, canagliflozin, empagliflozin, ertugliflozin, bexagliflozin, enavogliflozin, henagliflozin, janagliflozin, sotagliflozin, insulin aspart, insulin lispro, insulin glulisine, biosynthetic human neutral insulin, human insulin, biosynthetic human isophane insulin, human isophane insulin, intermediate - acting insulin lispro, insulin detemir, insulin glargine, insulin degludec, glibenclamide, gliclazide, glimepiride, glipizide, gliquidone, nateglinide, mitiglinide calcium hydrate, repaglinide, metformin hydrochloride, buformin hydrochloride, pioglitazone hydrochloride, rosiglitazone, lobeglitazone, sitagliptin phosphate, vildagliptin, alogliptin benzoate, linagliptin, teneligliptin hydrobromide, anagliptin, saxagliptin, treagliptin succinate, omarigliptin, gemigliptin, evogliptin, imeglimin, sitagliptin phosphate / ipragliflozin, pioglitazone hydrochloride / metformin, pioglitazone hydrochloride / glimepiride, teneligliptin hydrobromide / canagliflozin, alogliptin benzoate / pioglitazone hydrochloride, alogliptin benzoate / metformin hydrochloride, vildagliptin / metformin hydrochloride, mitiglinide calcium / boglibose, pravastatin,Simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, lovastatin, clinofibrate, clofibrate, bezafibrate, fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, cholestyramine, colestipol, ezetimibe, probucol, nicomol, tocopherol nicotinate, nisoldipine, ethyl icosapentate, omega-3 fatty acid ethyl, evolocumab, alirocumab, nifedipine, amlodipine, efonidipine, cilnidipine, nicardipine, nisoldipine, nitrendipine, nilvadipine, barnidipine, felodipine, benidipine, manidipine, azelnidipine, aranidipine, diltiazem, trichlormethiazide, bendroflumethiazide, hydrochlorothiazide, meclofenamic acid, indapamide, tripamide, mefruside, furosemide, triamterene, spironolactone, eplerenone, tolvaptan, torsemide, hydrochlorothiazide, bumetanide, chlortalidone, isosorbide, metolazone, losartan, candesartan, valsartan, telmisartan, olmesartan, irbesartan, azilsartan, captopril, enalapril, alacepril, delapril, cilazapril, lisinopril, benazepril, imidapril, temocapril, quinapril,trandolapril, perindopril erbumine, urapidil, terazosin, prazosin, doxazosin, bunazosin, atenolol, bisoprolol, metoprolol, acebutolol, celiprolol, propranolol, nadolol, nipradilol, carteolol, pindolol, nebivolol, carvedilol, labetalol, sotalol, landiolol, arotinolol, amosulalol, arotinolol, carvedilol, labetalol, bevantolol, clonidine, guanabenz, methyldopa, reserpine, hydralazine, nitroprusside, aliskiren, kallidinogenase, alprostadil alpha dextrin, dihydroergotoxine, doxazosin, urapidil,Hydralazine, prazosin, moxonidine, guanfacine, rilmenidine, amlodipine / atorvastatin, losartan / hydrochlorothiazide, valsartan / hydrochlorothiazide, candesartan / hydrochlorothiazide, telmisartan / hydrochlorothiazide, irbesartan / trichlormethiazide, valsartan / amlodipine, olmesartan / azelnidipine, candesartan / amlodipine, telmisartan / amlodipine, irbesartan / amlodipine, valsartan / silnidipine, azilsartan / amlodipine, carbetocin (LV-101), PYY-1562 (NNC0165-1562), PYY-1875 (NNC0165-1875), NGM395, YH34160, SCO-267, SCO-792, diazoxide, tesofensine, namodenoson, ERX1000, ASC41, Xla1, HDV Biotin, EMP16, metoprolol / tesofensine, RZL-012, CB4211, BI1356225, AMG171, NO-13065, bardoxolone methyl, HSG4112, YHC2129, YHC2134, KTX-0200, obeticholic acid, cilofexor (GS-9674), tropifexor (LJN452), EDP-305, EYP-001, resmetirom, VK-2809, cenicriviroc, saroglitazar, lanifibranor, selonsertib, PF-06835919, pegbelfermin, efrugxifermin, aldafermin, aramcol, MK-3655, MSDC-0602K, belapectin, firsocostat (GS-0976), PF-05221304, elbogast, ION-224, AXA-1125, HU-6, MET-409, MET-642, TERN-101, TERN-501, LPCN-1144,Examples include a denifanstat, fulvestrant, relugolix, pegolastim, lenokostat, retoride, tipelcast, S-237648, S-723595, BMS-963272, and the compounds shown below or acceptable salts thereof. [Chemical formula] [Chemical formula] Preferably, the following compounds or their pharmaceutically acceptable salts are included. [Chemical formula]

[0089] The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. Also, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptoms, combination, etc. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

[0090] The pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (pharmaceutical compositions containing compounds having an anti-obesity effect, drugs that can be used for weight management in obesity and the like). For example, by using a pharmaceutical composition containing a compound having an anti-obesity effect in combination with the compound of the present invention, it can be used for the prevention and / or treatment of obesity and weight management in obesity and the like. Also, by using a pharmaceutical composition containing the compound of the present invention in combination with a pharmaceutical composition containing a compound having an anti-obesity effect, it can be used for the prevention and / or treatment of obesity and weight management in obesity and the like. Further, the administration therapy of the pharmaceutical composition of the present invention can also be used in combination with diet therapy, drug therapy, exercise, etc. [Examples]

[0091] The present invention will be described in more detail below with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto.

[0092] In addition, the abbreviations used in this specification have the following meanings. CHCl 3 : Chloroform CDCl 3 : Deuterated chloroform MeOH: Methanol DMSO-d 6 : Deuterated dimethyl sulfoxide DMSO: Dimethyl sulfoxide DMA: Dimethylacetamide DMF: Dimethylformamide THF: Tetrahydrofuran EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide HATU: 2-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate DIAD: Diisopropyl azodicarboxylate DEAD: Diethyl azodicarboxylate TEMPO: 2,2,6,6-Tetramethylpiperidine 1-oxyl TEMPOL: 4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl AZADO: 2-Azaadamantane N-oxyl NCS: N-Chlorosuccinimide BINAP: 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl DPPF: 1,1’-Ferrocenediyl-bis(diphenylphosphine) Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene TLC: Thin layer chromatography SFC: Supercritical fluid chromatography ODS: Octadecylsilyl M: mol / L

[0093] (Method for Identifying Compounds) The NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d 6 or CDCl 3 When showing NMR data, there are cases where not all the measured peaks are described. In the examples, "No." represents the compound number, "Structure" represents the chemical structure, and "MS" represents the mass in LC / MS (Liquid Chromatography / Mass Spectrometry). MS (m / z) can be measured under the following measurement conditions, but is not limited to these conditions.

[0094] (Measurement Condition 1) Column: ACQUITY UPLC BEH C18 (1.7 μm i.d. 2.1x50 mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5% - 100% solvent [B] was performed over 3.5 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (Measurement Condition 2) Column: Shim-pack XR-ODS (2.2 μm, i.d. 3.0x50 mm) (Shimadzu) Flow rate: 1.6 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 10% - 100% solvent [B] was performed over 3 minutes, and then 100% solvent [B] was maintained for 0.5 minutes. (Measurement Condition 3) Column: ACQUITY UPLC BEH C18 (1.7 μm i.d. 2.1x50 mm) (Waters) Flow rate: 0.8 mL / min; UV detection wavelength: 254 nm; Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid Gradient: A linear gradient of 5% - 100% solvent [B] was performed over 3.5 minutes, and 100% solvent [B] was maintained for 0.5 minutes. (Measurement condition 4) Column: ACQUITY UPLC BEH C18 (1.7μm i.d. 2.1x50mm) (Waters) Flow rate: 0.8 mL / min UV detection wavelength: 254 nm Mobile phase: [A] is an aqueous solution containing 10 mM ammonium carbonate, [B] is acetonitrile Gradient: After performing a linear gradient of 5% - 100% solvent [B] over 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes. (Measurement condition 5) Column: L-column2 ODS (3μm i.d. 3x50mm) (National Institute of Advanced Industrial Science and Technology) Flow rate: 1.5 mL / min UV detection wavelength: 220 nm Mobile phase: [A] is an aqueous solution containing 0.05% trifluoroacetic acid, [B] is an acetonitrile solution containing 0.05% trifluoroacetic acid Gradient: A linear gradient of 5% - 95% solvent [B] was performed over 3.5 minutes, and 95% solvent [B] was maintained for 2 minutes.

[0095] Example 1

Chemical formula

[0096] Step 3 To a mixed solution of methanol (25 mL) - THF (50 mL) of compound 3 (3.87 g, 11.9 mmol), 10% palladium - carbon (50% water - containing) (2.54 g, 1.2 mmol) was added, and the mixture was stirred at room temperature for 6.5 hours under a hydrogen (1 atm) atmosphere. The insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain compound 4 (1.55 g, yield 40%). 1 H - NMR(CDCl 3 ) δ: 1.47 (3H, d, J = 6.4Hz), 2.82 - 2.99 (2H, m), 3.84 - 3.89 (2H, m), 3.94 (3H, s), 4.27 (1H, d, J = 8.0Hz), 5.04 - 5.11 (1H, m), 6.62 (1H, d, J = 8.4Hz), 7.50 (1H, d, J = 8.4Hz), 7.71 - 7.75 (2H, m), 7.83 - 7.87 (2H, m). MS(m / z) = 327 [M + H]+ Step 4 Hydrazine monohydrate (1.15 mL, 23.75 mmol) was added to a solution of compound 4 (1.55 g, 4.75 mmol) in ethanol (30 mL), and the mixture was stirred at 80 °C for 35 minutes. The insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. Dichloromethane was added to the obtained residue, and the precipitated insoluble matter was removed by filtration. The solvent was distilled off under reduced pressure to obtain a crude product (1.05 g) of compound 5. 1 H - NMR(CDCl 3) δ: 1.45 (3H, d, J=6.4Hz), 2.62 - 2.78 (2H, m), 2.86 - 3.02 (2H, m), 3.95 (3H, s), 5.01 (1H, q, J=6.4Hz), 6.63 (1H, d, J=8.4Hz), 7.41 (1H, d, J=8.4Hz). MS(m / z) = 197 [M+H]+

[0097] Step 5 To a solution of the crude product of Compound 5 (4.75 mmol) in dichloromethane (10 mL), trifluoroacetic anhydride (2.0 mL, 14.25 mmol) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. After distilling off the solvent under reduced pressure, the obtained residue was dissolved in toluene, and the solvent was distilled off again under reduced pressure. The obtained residue was dissolved in ethyl acetate, slowly poured into an aqueous sodium hydrogen carbonate solution, and stirred at 35 °C for 9 hours. The reaction solution was extracted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 6 (952 mg, yield 69%). 1 H-NMR (CDCl 3 ) δ: 1.48 (3H, d, J = 6.4 Hz), 2.80 - 2.92 (2H, m), 3.50 - 3.64 (2H, m), 3.82 (1H, d, J = 7.0 Hz), 3.95 (3H, s), 4.95 - 5.02 (1H, m), 6.67 (1H, d, J = 8.4 Hz), 6.77 (1H, s), 7.41 (1H, d, J = 8.4 Hz). MS(m / z) = 293 [M+H]+ Step 6 To a solution of compound 6 (952 mg, 3.26 mmol) in THF (30 mL), triphenylphosphine (1.28 g, 4.89 mmol) was added, and DIAD (0.95 mL, 4.89 mmol) was added dropwise under water cooling, followed by stirring at room temperature for 30 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 7 (776 mg, yield 87%). 1 H-NMR(CDCl 3 ) δ: 1.59 (2.1H, d, J=6.9Hz), 1.65 (0.9H, d, J=6.9Hz), 2.64-2.73 (1H, m), 2.87-2.98 (1H, m), 3.14-3.21 (0.3H, m), 3.44-3.51 (0.7H, m), 3.90 (2.1H, s), 3.90 (0.9H, s), 4.09-4.15 (0.7H, m), 4.69 (0.3H, dd, J=13.2, 5.6Hz), 5.01 (0.3H, q, J=6.8Hz), 5.43 (0.7H, q, J=6.8Hz), 6.57-6.61 (1H, m), 7.30-7.34 (1H, m). MS(m / z) = 275 [M+H]+

[0098] Step 7 To a solution of compound 7 (776 mg, 2.83 mmol) in acetonitrile (10 mL), sodium iodide (1.27 g, 8.49 mmol) and trimethylsilyl chloride (1.085 mL, 8.49 mmol) were added, and the mixture was stirred at 45 °C for 6 hours. An aqueous sodium hydrogen carbonate solution and an aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product of compound 8 (747 mg). 1 H-NMR(CDCl 3) δ: 1.65 (2.4H, d, J = 6.8Hz), 1.73 (0.6H, d, J = 6.8Hz), 2.50 - 2.58 (1H, m), 2.73 - 2.84 (1H, m), 3.14 - 3.22 (0.2H, m), 3.44 - 3.52 (0.8H, m), 4.08 - 4.13 (0.8H, m), 4.68 (0.2H, dd, J = 13.4, 5.8Hz), 4.96 (0.2H, q, J = 6.6Hz), 5.43 (0.8H, q, J = 6.8Hz), 6.48 - 6.52 (1H, m), 7.26 - 7.22 (1H, m), 12.82 (1H, s). MS(m / z) = 261 [M + H]+ Step 8 To a solution of compound 8 (800 mg, 3.07 mmol) in DMF (8 mL) was added N-chlorosuccinimide (497 mg, 3.72 mmol) at 45 °C, and the mixture was stirred at the same temperature for 10 h. After the reaction solution was cooled to room temperature, an aqueous sodium thiosulfate solution and an aqueous sodium hydrogen carbonate solution were added, and the resulting solid was collected by filtration to obtain compound 9 (527 mg, yield 58%). MS(m / z) = 295.1 [M + H]+ 1 1H-NMR(DMSO-D 6 ) δ: 1.46 (2.4H, d, J = 6.8Hz), 1.55 (0.6H, d, J = 6.5Hz), 2.58 - 2.67 (2H, m), 3.54 - 3.62 (1H, m), 3.93 (0.8H, d, J = 12.9Hz), 4.39 (0.2H, dd, J = 13.8, 4.5Hz), 4.85 (0.2H, q, J = 6.4Hz), 5.17 (0.8H, dd, J = 6.7, 13.5Hz), 7.62 - 7.65 (1H, m).

[0099] Step 9 To 9 (1.97 g, 6.68 mmol), silver carbonate (2.76 g, 10.01 mmol), and benzyl bromide (1.26 g, 7.34 mmol) was added 1,4-dioxane (20 mL), and the mixture was stirred at 65 °C for 9 h. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration and washed with methanol. The solvent of the filtrate was distilled off under reduced pressure to obtain the crude product of 10 (2.31 g). MS (m / z) = 385.2 [M+H]+ Step 10 To a mixed solution of 10 (2.3 g, 5.98 mmol) in THF (13 mL) - methanol (13 mL) was added 1 M aqueous sodium hydroxide solution (9.0 mL, 9.0 mmol), and the mixture was stirred at room temperature for 1 h. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure to obtain the crude product of 11 (1.77 g). MS (m / z) = 289.2 [M+H]+ 1 1H-NMR (CDCl 3 ) δ: 1.46 (3H, d, J = 6.7 Hz), 2.63 (1H, dt, J = 16.0, 4.1 Hz), 2.75 - 2.83 (1H, m), 2.95 - 3.01 (1H, m), 3.20 - 3.27 (1H, m), 3.97 (1H, dd, J = 6.7, 12.7 Hz), 5.44 (2H, dd, J = 18.4, 12.7 Hz), 7.28 - 7.31 (1H, m), 7.34 - 7.37 (3H, m), 7.48 (2H, d, J = 7.3 Hz).

[0100] Step 11 To 11 (245 mg, 0.85 mmol), 12 (251 mg, 0.85 mmol), and potassium carbonate (235 mg, 1.70 mmol) was added acetonitrile (2.4 mL), and the mixture was stirred at 65 °C for 3.5 h. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain 13 (440 mg, yield 95%). MS (m / z) = 547.4 [M+H]+ 1 H-NMR(CDCl 3 ) δ: 1.44 (3H, d, J=6.7 Hz), 2.36 - 2.42 (1H, m), 2.56 - 2.78 (4H, m), 2.95 - 3.02 (1H, m), 3.80 (1H, dd, J=6.6, 13.5Hz), 3.95 (3H, s), 4.06 - 4.15 (1H, m), 4.30 - 4.39 (2H, m), 4.55 - 4.63 (1H, m), 4.68 (1H, dd, J=15.4, 5.8Hz), 4.75 (1H, dd, J=15.3, 3.0Hz), 5.20 (1H, ddd, J=13.2, 7.2, 2.9Hz), 5.38 - 5.47 (2H, m), 7.28 - 7.31 (1H, m), 7.33 - 7.38 (3H, m), 7.47 (2H, d, J=7.3Hz), 7.77 (1H, d, J=8.5Hz), 7.98 (1H, dd, J=8.5, 1.4Hz), 8.14 (1H, d, J=0.9Hz). Project 12 Compound 13 (439 mg, 0.80 mmol), 10% palladium on carbon (128 mg, 0.12 mmol) were added to methanol (4.5 mL), and the mixture was stirred at room temperature for 2.5 h under a hydrogen atmosphere. The insoluble material was removed by filtration, the solvent of the filtrate was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain Compound 14 (230 mg, yield 63%). MS(m / z) = 457.3 [M + H]+ 1 H-NMR(CDCl 3) δ: 1.50 (3H, d, J=6.8Hz), 2.32 - 2.46 (2H, m), 2.70 - 2.81 (3H, m), 3.02 - 3.10 (1H, m), 3.83 (1H, dd, J=6.6, 13.6Hz), 3.95 (3H, s), 4.18 (1H, d, J=13.6Hz), 4.27 (1H, d, J=13.7 Hz), 4.35 - 4.41 (1H, m), 4.55 - 4.64 (2H, m), 4.77 (1H, dd, J=15.4, 6.6Hz), 5.15 - 5.21 (1H, m), 7.39 (1H, s), 7.69 (1H, d, J=8.4Hz), 7.95 (1H, dd, J=8.5, 1.4Hz), 8.11 (1H, d, J=1.0Hz).

[0101] Step 13 To a solution of Compound 14 (20 mg, 0.044 mmol), 2,6-difluoro-4-chlorobenzyl bromide (13 mg, 0.053 mmol), and silver carbonate (18 mg, 0.066 mmol) in 1,4-dioxane (0.5 mL) was added, and the mixture was stirred at 65 °C for 8 hours. The reaction solution was cooled to room temperature, the insoluble matter was removed by filtration, water was added to the filtrate, and the mixture was extracted with chloroform. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase chromatography to obtain Compound 15 (15 mg, yield 55%). MS (m / z) = 617.2 [M+H]+ Step 14 To a solution of Compound 15 (15 mg, 0.024 mmol) in methanol (0.5 mL)-THF (0.5 mL) was added 1M aqueous sodium hydroxide solution (0.5 mL, 0.50 mmol), and the mixture was stirred at room temperature for 2 hours. Aqueous citric acid solution was added to the reaction solution to adjust the pH to about 7, and the mixture was extracted with chloroform. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase chromatography to obtain Compound I-024 (12 mg, yield 79%). MS (m / z) = 603.1 [M+H]+ 1 H-NMR (DMSO-D 6) δ: 1.37 (3H, d, J=6.7Hz), 2.30-2.39 (1H, m), 2.57-2.79 (4H, m), 2.93-2.99 (1H, m), 3.79 (1H, q, J=6.7Hz), 4.06 (1H, d, J=13.8Hz), 4.18 (1H, d, J=13.9Hz), 4.27-4.32 (1H, m), 4.46 (1H, dd, J=13.4, 7.9Hz), 4.65-4.79 (2H, m), 5.09 (1H, ddd, J=13.8, 6.7, 2.8Hz), 5.35 (1H, d, J=12.3 Hz), 5.44 (1H, d, J=12.2Hz), 7.38-7.43 (2H, m), 7.65-7.68 (2H, m), 7.81 (1H, dd, J=8.5, 1.4Hz), 8.25 (1H, s).

[0102] Example 2

Chemical Structure

[0103] Project 3 To a solution of compound 18 (1.99 g, 4.99 mmol) in DMF (20 mL), methyl difluoro(fluorosulfonyl)acetate (3.15 mL, 24.93 mmol) and copper(I) iodide (1.14 g, 5.98 mmol) were added, and the mixture was stirred at 100 °C for 3 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 19 (1.56 g, yield 94%). MS(m / z) = 342.2 [M+H]+ 1 H-NMR(CDCl 3) δ: 1.56 (2.4H, d, J = 6.9Hz), 1.64 (0.6H, d, J = 6.8Hz), 2.77 - 2.86 (1H, m), 2.92 - 3.02 (1H, m), 3.26 (0.2H, td, J = 12.3, 5.2Hz), 3.52 - 3.60 (0.8H, m), 3.89 (2.4H, s), 3.90 (0.6H, s), 4.02 - 4.13 (0.8H, m), 4.65 (0.2H, dd, J = 13.0, 5.6Hz), 5.14 (0.2H, q, J = 6.8Hz), 5.59 (0.8H, q, J = 6.9Hz), 6.69 (0.2H, s), 6.74 (0.8H, s), 7.33 (0.8H, s), 7.35 (0.2H, s). Project 4 To a solution of compound 19 (1.55 g, 4.41 mmol) in dichloromethane (7.8 mL) was added 1 M boron tribromide dichloromethane solution (13.2 mL, 13.2 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. Methanol (7.8 mL) and water were added to the reaction mixture under ice-cooling, and the mixture was extracted with dichloromethane. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 20 (1.20 g, yield 78%). MS (m / z) = 326.2 [M - H]- 1 H-NMR(CDCl 3 ) δ: 1.53 (2.4H, d, J = 6.9Hz), 1.61 (0.6H, d, J = 6.8 Hz), 2.77 - 2.86 (1H, m), 2.91 - 3.01 (1H, m), 3.24 (0.2H, td, J = 12.6, 4.1Hz), 3.50 - 3.58 (0.8H, m), 4.07 - 4.12 (0.8H, m), 4.64 (0.2H, dd, J = 13.4, 5.8Hz), 5.10 (0.2H, q, J = 6.8Hz), 5.50 - 5.57 (1.6H, m), 6.73 (0.2H, s), 6.76 (0.8H, s), 7.29 (0.8H, s), 7.30 (0.2H, s).

[0104] Project 5 Compound 20 (490.6 mg, 1.50 mmol) was dissolved in trifluoroacetic acid (10 mL), hexamethylenetetramine (315 mg, 2.25 mmol) was added, and the mixture was stirred at 85 °C for 7 hours. Water was added to the reaction solution, and the mixture was stirred at room temperature for 10 minutes and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 21 (411.8 mg, yield 77%). MS (m / z) = 356.0 [M+H]+ 1 H-NMR(CDCl 3 ) δ: 12.70 (0.8H, s), 12.64 (0.2H, s), 10.39 (0.8H, s), 10.32 (0.2H, s), 7.62 (0.2H, s), 7.60 (0.8H, s), 6.31 (1H, q, J=6.8Hz), 4.13 - 4.06 (1H, m), 3.79 - 3.71 (1H, m), 3.11 - 2.86 (2H, m), 1.73 (0.6H, d, J=6.8Hz), 1.64 (2.4H, d, J=6.9Hz). Project 6 A THF (10 mL) solution of 30% aqueous hydrogen peroxide (1.62 mL, 15.8 mmol), boric acid (2.23 g, 36.0 mmol), and 1M sulfuric acid (0.192 mL, 3.60 mmol) was stirred at room temperature for 30 minutes. A THF (15 mL) solution of Compound 21 (2.56 g, 7.20 mmol) was added to the reaction solution, and the mixture was stirred at 60 °C for 8 hours and 30 minutes. Under ice-cooling, a 10% aqueous sodium bisulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 22 (1.53 g, yield 62%). MS (m / z) = 344.2 [M+H]+ 1 H-NMR(CDCl 3) δ: 6.85 (1H, s), 6.22 (1H, br s), 5.99 (0H, br s), 5.84 (0.7H, q, J=6.4Hz), 5.67 (1H, br s), 5.37 (0.3H, q, J=6.6Hz), 4.64-4.60 (0.3H, m), 4.08-4.03 (0.7H, m), 3.66-3.58 (0.7H, m), 3.30-3.27 (0.3H, m), 2.98-2.93 (1H, m), 2.87-2.78 (1H, m), 1.61 (1H, d, J=6.8Hz), 1.54 (2H, d, J=6.8Hz).

[0105] Project 7 Compound 22 (162.1 mg, 0.472 mmol) and a hexane solution of Compound 23 (57 wt%, 128 mg, 0.472 mmol) were dissolved in toluene (2.5 mL), dodecacarbonyltriruthenium (6.04 mg, 9.45 μmol) was added, and the mixture was stirred at 100 °C for 18 hours. The reaction solution was diluted with ethyl acetate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 24 (55.4 mg, yield 24%). MS(m / z) = 498.2 [M+H]+ 1 H-NMR(CDCl 3) δ: 7.50 - 7.47 (1H, m), 7.18 - 7.12 (2H, m), 6.84 (0.3H, s), 6.82 (0.7H, s), 5.68 (0.35H, q, J = 7.2Hz), 5.60 (0.35H, q, J = 6.5Hz), 5.21 - 5.19 (0.15H, m), 4.64 - 4.61 (0.15H, m), 4.10 - 4.07 (1H, m), 3.54 - 3.45 (1H, m), 2.89 - 2.85 (2H, m), 2.15 (1.5H, s), 2.11 (1.5H, s), 1.64 (0.45H, d, J = 6.9Hz), 1.56 (1.05H, d, J = 6.9Hz), 1.52 (0.45H, d, J = 6.8Hz), 1.45 (1.05H, d, J = 6.8Hz). Step 8 To a mixed solution of compound 24 (55.4 mg, 0.111 mmol) in methanol (1 mL) - THF (1 mL), potassium carbonate (30.8 mg, 0.223 mmol) was added, and the mixture was stirred at 50 °C for 7 hours. The reaction solution was returned to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain compound 25 (46.8 mg). MS (m / z) = 402.2 [M + H]+ 1 1H-NMR(CDCl 3 ) δ: 7.51 - 7.48 (1H, m), 7.16 - 7.10 (2H, m), 6.77 (1H, s), 4.22 - 4.15 (1H, m), 3.19 - 3.15 (1H, m), 2.98 - 2.93 (1H, m), 2.74 - 2.62 (2H, m), 2.11 (1.5H, s), 2.10 (1.5H, s), 1.51 (1.5H, d, J = 6.7Hz), 1.42 (1.5H, d, J = 6.8Hz).

[0106] Step 9 By performing the same reaction as in Step 11 of Example 1, a mixture of compound 26 and impurities (58.9 mg) was obtained. MS (m / z) = 660.4 [M + H]+ Project 10 To a mixed solution of methanol (1.5 mL) - THF (1.5 mL) of a mixture of compound 26 and impurities (58.9 mg), 1 M aqueous sodium hydroxide solution (0.382 mL, 0.382 mmol) was added, and the mixture was stirred at 45 °C for 12 hours. The reaction solution was returned to room temperature, 2 M hydrochloric acid was added to adjust the pH to 4, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by reverse-phase column chromatography (acetonitrile - water) to obtain a mixture of diastereomers. The obtained mixture of diastereomers was separated by SFC to obtain compound I-047 (12.2 mg, yield 16%). SFC Conditions Column: P4VP column (manufactured by Daicel) 4.6×250 mm Analysis time: 15 min Mobile phase: A is carbon dioxide, B is a MeOH solution of 0.1% diethylamine Fractionation conditions: Elution was carried out while maintaining a composition ratio of B / (A + B) = 20% Flow rate: 2.0 mL / min Detection wavelength: 220 nm MS (m / z) = 646.4 [M+H]+ 1 H-NMR (CDCl 3 ) δ: 8.20 (1H, s), 8.04 (1H, d, J = 9.0 Hz), 7.81 (1H, d, J = 8.5 Hz), 7.50 (1H, t, J = 8.4 Hz), 7.15 - 7.12 (2H, m), 6.80 (1H, s), 5.24 - 5.17 (1H, m), 4.84 - 4.58 (3H, m), 4.46 - 4.19 (3H, m), 4.15 - 4.03 (1H, m), 3.08 - 2.98 (1H, m), 2.96 - 2.84 (1H, m), 2.83 - 2.55 (3H, m), 2.47 - 2.38 (1H, m), 2.11 (3H, s), 1.35 (3H, d, J = 6.5 Hz).

[0107] Example 3 [Chemistry] Step 1 To a solution of compound 8 (1.17 g, 3.14 mmol) in DMF (12 mL) was added N-iodosuccinimide (2.12 g, 9.42 mmol), and the mixture was stirred at room temperature for 7 hours. An aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent of the organic layer was distilled off under reduced pressure to obtain compound 27 (1.98 g). MS (m / z) = 386.9 [M+H]+ Step 2 By performing the reaction in the same manner as in Step 9 of Example 1, compound 28 (7.59 mg, yield 94%) was obtained. MS (m / z) = 476.9 [M+H]+ 1 1H-NMR (CDCl 3 ) δ: 1.58 - 1.52 (3H, m), 2.71 - 2.63 (1H, m), 2.93 - 2.87 (1H, m), 3.46 - 3.09 (1H, m), 4.70 - 4.05 (1H, m), 5.45 - 4.94 (3H, m), 7.31 - 7.30 (1H, m), 7.39 - 7.36 (2H, m), 7.49 - 7.47 (2H, m), 7.83 - 7.81 (1H, m).

[0108] Step 3 To a solution of compound 28 (5.95 g, 12.3 mmol) in DMF (60 mL) were added palladium acetate (206 mg, 0.92 mmol), 2-(di-tert-butylphosphino)biphenyl (366 mg, 1.23 mmol), sodium carbonate (3.25 g, 30.6 mmol), triethylsilane (5.34 g, 46.0 mmol), and 2-isocyano-2-methylpropane (2.55 g, 30.6 mmol), and the mixture was stirred at 65 °C for 3.5 hours. The reaction mixture was cooled to room temperature, hydrochloric acid was added to adjust the pH to about 4, and then the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 29 (2.37 g, yield 50%). MS (m / z) = 379.0 [M+H]+ 1 H-NMR (CDCl 3 ) δ: 1.65 - 1.57 (3H, m), 2.83 - 2.74 (1H, m), 3.02 - 2.91 (1H, m), 3.51 - 3.14 (1H, m), 4.75 - 4.12 (1H, m), 5.55 - 5.04 (3H, m), 7.39 - 7.34 (3H, m), 7.48 - 7.46 (2H, m), 7.92 - 7.90 (1H, m), 10.39 (1H, s). Step 4 To a solution of compound 29 (2.84 g, 7.28 mmol) in dichloromethane (28 mL), sulfur diethylamino trifluoride (3.95 g, 26.3 mmol) was added under an ice bath, and the mixture was stirred at room temperature for 2.5 h. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 30 (2.55 g, yield 85%). MS (m / z) = 401.0 [M + H]+ 1 H-NMR (CDCl 3 ) δ: 1.62 - 1.54 (3H, m), 2.79 - 2.71 (1H, m), 3.01 - 2.91 (1H, m), 3.51 - 3.13 (1H, m), 4.74 - 4.12 (1H, m), 5.47 - 5.01 (3H, m), 6.86 (1H, t, J = 55.2 Hz), 7.39 - 7.29 (3H, m), 7.44 - 7.42 (2H, m), 7.65 - 7.62 (1H, m).

[0109] Step 5 To a mixed solution of compound 30 (2.0 g, 5.0 mmol) in methanol (12 mL) - THF (12 mL), 1 M aqueous sodium hydroxide solution (12.5 mL, 12.5 mmol) was added, and the mixture was stirred at room temperature for 1 hour. An aqueous citric acid solution was added to the reaction mixture to adjust the pH to about 7, and then the mixture was extracted with chloroform. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 31 (1.49 g, yield 98%). MS(m / z) = 305.1 [M+H]+ 1 H-NMR(CDCl 3 ) δ: 1.49 (3H, d, J=6.8 Hz), 2.68 (1H, dt, J=16.0, 4.1Hz), 2.87-2.79 (1H, m), 3.03-2.97 (1H, m), 3.26 (1H, ddd, J=12.5, 5.3, 4.3Hz), 4.01 (1H, q, J=6.6Hz), 5.40 (1H, d, J=12.5Hz), 5.45 (1H, d, J=12.8Hz), 6.87 (1H, t, J=55.6Hz), 7.32-7.28 (1H, m), 7.36 (2H, t, J=7.4Hz), 7.43 (2H, d, J=7.3Hz), 7.56 (1H, s). Step 6 To a solution of compound 31 (300 mg, 0.936 mmol) in acetonitrile (3 mL), compound 12’ (277 mg, 0.936 mmol) and potassium carbonate (272 mg, 1.97 mmol) were added, and the mixture was stirred at 60 °C for 5 hours. An aqueous citric acid solution was added to the reaction mixture to adjust the pH to about 7, and then the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure to obtain compound 32 (410 mg). MS(m / z) = 564.2 [M+H]+

[0110] Step 7 Compound 32 (410 mg, 0.883 mmol), 10% palladium on carbon (155 mg, 0.088 mmol) were added with THF (5 mL) and methanol (5 mL), and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The insoluble matter was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 33 (320 mg, yield 93%). MS (m / z) = 474.0 [M+H]+ 1 H-NMR(CDCl 3 ) δ: 1.51 (3H, d, J = 6.8 Hz), 2.38 - 2.53 (2H, m), 2.69 - 2.84 (3H, m), 3.05 - 3.12 (1H, m), 3.85 - 3.90 (1H, m), 4.01 (3H, s), 4.25 - 4.39 (3H, m), 4.60 (1H, q, J = 7.2Hz), 4.81 (1H, dd, J = 14.8, 3.0Hz), 4.92 (1H, dd, J = 14.8, 6.5Hz), 5.18 - 5.24 (1H, m), 6.72 (1H, t, J = 55.3Hz), 7.53 (1H, d, J = 9.3Hz), 8.06 (1H, d, J = 8.3Hz), 8.11 (1H, d, J = 8.3Hz). Step 8 To a solution of Compound 33 (20 mg, 0.042 mmol) in dioxane (0.2 mL), silver carbonate (17 mg, 0.063 mmol) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (11 mg, 0.051 mmol) were added, and the mixture was stirred at 65 °C for 3 hours. After cooling to room temperature, the insoluble matter was removed by filtration and washed with ethyl acetate. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by reverse phase chromatography to obtain Compound 34 (11 mg, yield 43%). MS (m / z) = 616.2 [M+H]+

[0111] Step 9 To a solution of compound 34 (11 mg, 0.018 mmol) in methanol (0.25 mL) - THF (0.25 mL), 1 M aqueous sodium hydroxide solution (0.06 mL, 0.06 mmol) was added, and the mixture was stirred at room temperature for 3 hours. An aqueous citric acid solution was added to the reaction mixture to adjust the pH to about 4, and the mixture was extracted with chloroform. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by reverse-phase chromatography to obtain compound I-097 (10.1 mg, yield 93%). MS (m / z) = 602.1 [M+H]+ 1 H-NMR (CDCl 3 ) δ: 1.47 (3H, d, J = 6.8 Hz), 2.39 - 2.44 (1H, m), 2.64 - 2.85 (4H, m), 3.03 - 3.08 (1H, m), 3.82 - 3.87 (1H, m), 4.18 - 4.23 (1H, m), 4.30 - 4.34 (1H, m), 4.42 - 4.46 (1H, m), 4.59 - 4.64 (1H, m), 4.79 - 4.91 (2H, m), 5.20 - 5.25 (1H, m), 5.40 (1H, d, J = 13.1 Hz), 5.47 (1H, d, J = 13.1 Hz), 6.84 (1H, t, J = 55.6 Hz), 7.09 - 7.13 (2H, m), 7.39 (1H, t, J = 8.3 Hz), 7.59 (1H, s), 8.19 - 8.24 (2H, m).

[0112] Example 4

Chemical Structure

[0113] Project 3 To a solution of compound 37 (252 mg, 1.03 mmol) and hexamethylphosphoric triamide (0.197 mL, 1.13 mmol) in 2-methyltetrahydrofuran (4 mL) was added dropwise a THF solution of 1 M lithium bis(trimethylsilyl)amide (1.24 mL, 1.24 mmol) at -15 °C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added t-butyl 2-bromoacetate (0.167 mL, 1.13 mmol), and the mixture was further stirred for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 38 (252 mg, yield 59%). 1 H-NMR(CDCl 3 ) δ: 1.48 (9H, s), 1.97 (1H, ddd, J = 25.8, 12.9, 4.5Hz), 2.22 - 2.28 (1H, m), 2.40 (1H, dd, J = 16.4, 6.7Hz), 2.84 - 3.11 (4H, m), 3.93 (3H, s), 7.47 (1H, s), 7.61 (1H, s). MS(m / z) = 303.0 [M-tBu+H]+ Project 4 To a solution of compound 38 (788 mg, 1.96 mmol) in an aqueous 2-propanol solution (90%, 8 mL) was added sodium borohydride (74.1 mg, 1.96 mmol) at 0 °C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added 0.4 M aqueous hydrochloric acid solution (5 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was solidified from hexane, and the obtained solid was collected by filtration to obtain compound 39 (542 mg, yield 77%). 1 H-NMR (CDCl 3) δ: 1.48 (9H, s), 1.58 - 1.64 (1H, m), 1.95 - 2.00 (1H, m), 2.16 (1H, dt, J = 10.7, 3.9 Hz), 2.36 (1H, dd, J = 15.7, 6.0 Hz), 2.61 (1H, dd, J = 15.7, 7.0 Hz), 2.73 (1H, d, J = 7.5 Hz), 2.76 - 2.83 (1H, m), 3.89 (3H, s), 4.44 (1H, t, J = 8.2 Hz), 7.24 (1H, s), 7.27 (1H, s).

[0114] Steps 5 - 6 To a suspension of compound 39 (540 mg, 1.50 mmol) in toluene (12 mL) were added 1,1’-thiocarbonyldiimidazole (379 mg, 2.13 mmol) and 4-dimethylaminopyridine (18.3 mg, 0.150 mmol), and the mixture was stirred at room temperature for 20.5 h. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 40 (540 mg). To a solution of compound 40 (540 mg) in toluene (10 mL) were added azobisisobutyronitrile (9.4 mg, 0.057 mmol) and tributyltin hydride (423 mg, 1.45 mmol), and the mixture was heated at 100 °C for 3 h under a nitrogen atmosphere. The solvent of the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate). To a solution of the obtained compound (284 mg) in ethyl acetate (10 mL) was added palladium on activated carbon catalyst (NX type, 10% palladium, 50% water content) (88.8 mg, 0.042 mmol), and the mixture was stirred at room temperature for 9 h under a hydrogen stream at 1 atm. The reaction solution was filtered through Celite®, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 41 (racemic mixture, 276 mg, 54% yield over 3 steps). 1 H-NMR(CDCl 3) δ: 1.39 - 1.51 (1H, m), 1.48 (9H, s), 1.96 (1H, t, J = 6.5Hz), 2.26 (3H, tt, J = 15.5, 6.1Hz), 2.51 (1H, dd, J = 16.8, 10.0Hz), 2.78 (2H, d, J = 4.8Hz), 2.91 (1H, dd, J = 16.7, 4.0Hz), 3.85 (3H, s), 6.67 (1H, s), 7.26 (1H, s). Steps 7 - 8 To a solution of compound 41 (273 mg, 0.793 mmol) in dichloromethane (5.5 mL) was added a 1 M boron tribromide dichloromethane solution (2.38 mL, 2.38 mmol) at -15°C, and the mixture was stirred at room temperature for 2 hours. The reaction solution was added to an aqueous solution of sodium bicarbonate (1.33 g) and ice (24 g), and 2 M hydrochloric acid aqueous solution was added to adjust the pH to 4. The resulting reaction solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Methanol (8 mL) was added to the obtained residue, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound 42 (101 mg). To a solution of compound 42 (99 mg) and 1-(bromomethyl)-4-chloro-2-fluorobenzene (85.0 mg, 0.379 mmol) in DMF (2 mL) was added cesium carbonate (168 mg, 0.517 mmol), and the mixture was stirred at room temperature for 11 hours. The reaction solution was diluted with ethyl acetate and washed with water. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 43 (racemic mixture, 101 mg, two-step yield 29%). 1 H-NMR(CDCl 3) δ: 1.39 - 1.52 (1H, m), 1.91 - 2.01 (1H, m), 2.19 - 2.32 (1H, m), 2.37 (2H, dt, J = 16.0, 7.8Hz), 2.50 (1H, dd, J = 16.8, 10.5Hz), 2.80 (2H, d, J = 4.8Hz), 2.91 (1H, dd, J = 16.8, 4.5Hz), 3.71 (3H, s), 5.13 (2H, s), 6.72 (1H, s), 7.11 (1H, dd, J = 9.8, 2.0Hz), 7.18 (1H, dd, J = 8.2, 1.6Hz), 7.29 (1H, s), 7.51 (1H, t, J = 8.2Hz).

[0115] Project 9 To a solution of compound 43 (101 mg, 0.234 mmol) in THF (1.4 mL) - methanol (0.7 mL), 1 M aqueous sodium hydroxide solution (0.702 mL, 0.702 mmol) was added and stirred at room temperature for 1 hour. 2 M aqueous hydrochloric acid solution (0.409 mL, 0.819 mmol) was added to the reaction solution, concentrated, and then diluted with ethyl acetate. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain compound 44 (racemic mixture, 95.6 mg, yield 98%). 1 H-NMR(CDCl 3 ) δ: 1.43 - 1.57 (1H, m), 1.97 - 2.06 (1H, m), 2.28 (1H, dd, J = 7.0, 3.0Hz), 2.44 (2H, dd, J = 7.0, 2.6Hz), 2.53 (1H, dd, J = 16.8, 10.5Hz), 2.81 (2H, d, J = 5.0Hz), 2.96 (1H, dd, J = 16.8, 4.3 Hz), 5.13 (2H, s), 6.73 (1H, s), 7.11 (1H, dd, J = 9.7, 1.6Hz), 7.18 (1H, d, J = 8.3Hz), 7.30 (1H, s), 7.51 (1H, t, J = 8.3Hz). MS(m / z) = 414.9 [M-H]- Project 10 To a pyridine (2 mL) solution of Compound 44 (93.4 mg, 0.224 mmol) and Compound 45 (54.8 mg, 0.232 mmol), an ethyl acetate solution of 50% 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide acetic acid was added, and the mixture was stirred at room temperature for 30 minutes. Toluene was added to the reaction solution, concentrated, and diluted with ethyl acetate. The organic layer was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain Compound 46 (diastereomeric mixture (1:1), 95.6 mg, yield 98%). MS (m / z) = 635.0 [M+H]+

[0116] Project 11 A solution of Compound 46 (36.6 mg, 0.058 mmol) in acetic acid (1.35 mL) was heated and stirred at 60 °C for 3.5 hours and further at 80 °C for 2.5 hours. Toluene was added to the reaction solution and concentrated, then neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the obtained residue was purified by preparative TLC (toluene-ethyl acetate) to obtain Compound 47 (diastereomeric mixture (1:1), 69.1 mg, yield 64%). 1 H-NMR(CDCl 3) δ: 1.52 - 1.67 (1H, m), 2.02 - 2.04 (1H, m), 2.35 - 2.37 (1H, m), 2.60 - 2.83 (5H, m), 2.98 - 3.07 (3H, m). 3.95 (3H, s), 4.31 - 4.48 (3H, m), 4.61 (1H, q, J = 7.3 Hz), 5.10 (2H, s), 5.10 (2H, s), 5.16 - 5.20 (1H, m), 6.71 (1H, d, J = 3.6Hz), 7.10 (1H, dd, J = 9.8, 1.8Hz), 7.17 (1H, d, J = 8.3Hz), 7.30 (1H, s), 7.50 (1H, t, J = 8.3Hz), 7.75 (1H, d, J = 8.5Hz), 7.98 (1H, dd, J = 8.5, 1.3Hz), 8.09 (1H, s). MS(m / z) = 617.0 [M+H]+ Step 12 To a solution of Compound 47 (66.5 mg, 0.108 mmol) in THF (1.4 mL) - methanol (0.7 mL) was added 1 M aqueous sodium hydroxide solution (0.450 mL, 0.450 mmol), and the mixture was stirred at 50 °C for 1.5 hours. 2 M aqueous hydrochloric acid solution (0.225 mL, 0.450 mmol) was added to the reaction mixture, which was then concentrated. Water was added, and the resulting solid was collected by filtration and dried in vacuo at 50 °C to give I-077 (diastereomeric mixture (1:1), 57.0 mg, 88% yield). 1 H-NMR(CDCl 3) δ: 1.58 - 1.68 (1H, m), 2.02 - 2.14 (1H, m), 2.35 - 2.50 (1H, m), 2.54 - 2.88 (5H, m), 2.94 - 3.05 (1H, m), 3.11 (2H, d, J = 5.9Hz), 4.29 - 4.52 (3H, m), 4.62 (1H, q, J = 7.2Hz), 5.09 (2H, s), 5.14 - 5.23 (1H, m), 6.71 (1H, d, J = 3.9Hz), 7.09 (1H, dd, J = 9.8, 1.8Hz), 7.17 (1H, d, J = 8.3Hz), 7.30 (1H, s), 7.49 (1H, t, J = 8.1Hz), 7.83 (1H, d, J = 8.5Hz), 8.06 (1H, d, J = 8.5Hz), 8.17 (1H, s). MS(m / z) = 603.0 [M+H]+

[0117] Example 5

Chemical Structure

[0118] Step 3 To a mixed solution of compound 50 (1.46 g, 6.36 mmol) in THF (15 mL) - water (15 mL) were added di-tert-butyl dicarbonate (2.77 g, 12.7 mmol) and sodium hydrogen carbonate (2.67 g, 31.8 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 51 (1.66 g, yield 79%). 1 1H-NMR (CDCl 3 ) δ: 1.51 - 1.49 (12H, m), 2.55 (3H, s), 2.76 - 2.74 (2H, m), 3.02 (1H, br s), 4.37 (1H, br s), 5.06 (1H, br s). MS (m / z) = 330.0 [M+H]+ Step 4 A solution of compound 51 (400 mg, 1.21 mmol), 10% palladium on carbon (400 mg, 0.38 mmol), and triethylamine (368 mg, 3.64 mmol) in THF (6 mL) was stirred at room temperature for 6 hours under a hydrogen atmosphere. The insoluble matter in the reaction mixture was removed by filtration, and the solvent of the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain compound 52 (360 mg, yield 100%). MS (m / z) = 297.0 [M+H]+ 1 H-NMR (CDCl 3 ) δ: 1.50 - 1.49 (12H, m), 2.55 (3H, s), 2.63 (1H, d, J = 15.6Hz), 2.82 (1H, td, J = 15.2, 5.4Hz), 3.01 (1H, s), 4.34 (1H, br s), 5.06 (1H, br s), 8.28 (1H, s).

[0119] Step 5 Compound 52 (360 mg, 1.21 mmol) was dissolved in dichloromethane (5.4 mL), and 70% meta-chloroperbenzoic acid (600 mg, 2.42 mmol) was added. The mixture was stirred at room temperature for 1 hour. An aqueous sodium bicarbonate solution and an aqueous sodium thiosulfate solution were added to the reaction solution, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure to obtain Compound 53. MS (m / z) = 328.0 [M+H]+ Step 6 (4-Chloro-2-fluorophenyl)methanol (389 mg, 2.42 mmol) in THF (4 mL) solution was added with 60% sodium hydride (58.2 mg, 2.42 mmol) and Compound 53 (397 mg, 1.21 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 54 (410 mg, yield 83%). MS (m / z) = 408.0 [M+H]+ 1 H-NMR (CDCl 3) δ: 1.49 (9H, s), 1.57 (3H, d, J = 5.0Hz), 2.64 (1H, d, J = 15.3Hz), 2.81 (1H, t, J = 11.2Hz), 3.01 (1H, s), 4.34 (1H, br s), 5.06 (1H, br s), 5.46 - 5.41 (2H, m), 7.13 - 7.10 (2H, m), 7.48 (1H, t, J = 7.9Hz), 8.28 (1H, s).

[0120] Step 7 To a solution of Compound 54 (40 mg, 0.098 mmol) in dichloromethane (0.6 mL) was added trifluoroacetic acid (0.2 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 55 (28 mg, yield 93%). MS (m / z) = 308.0 [M + H]+ 1 1H - NMR (CDCl 3 ) δ: 1.50 (3H, d, J = 6.5Hz), 2.69 - 2.65 (1H, m), 2.79 - 2.77 (1H, m), 2.99 - 2.96 (1H, m), 3.29 - 3.27 (1H, m), 3.99 - 3.97 (1H, m), 5.40 (1H, d, J = 13.1Hz), 5.46 (1H, d, J = 12.8Hz), 7.11 (2H, t, J = 8.4Hz), 7.48 (1H, t, J = 7.5Hz), 8.23 (1H, s). Step 8 To a solution of Compound 55 (28 mg, 0.091 mmol) in acetonitrile (0.3 mL) were added Compound 12 (26 mg, 0.086 mmol) and potassium carbonate (25 mg, 0.182 mmol), and the mixture was stirred at 60 °C for 3 hours. Hydrochloric acid was added to the reaction solution to adjust the pH to about 7, and the mixture was extracted with chloroform. The solvent of the organic layer was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane - ethyl acetate) to obtain Compound 56 (36 mg, yield 70%). MS (m / z) = 566.0 [M + H]+ 1 H-NMR (CDCl 3 ) δ: 1.57 - 1.50 (3H, m), 2.48 - 2.35 (1H, m), 2.80 - 2.60 (4H, m), 3.07 - 3.00 (1H, m), 3.87 - 3.77 (1H, m), 3.95 (3H, s), 4.13 - 4.06 (1H, m), 4.38 - 4.34 (2H, m), 4.87 - 4.57 (3H, m), 5.21 - 5.19 (1H, m), 5.40 (1H, d, J = 12.5Hz), 5.46 (1H, d, J = 13.1Hz), 7.13 - 7.10 (2H, m), 7.48 (1H, t, J = 8.0Hz), 7.76 (1H, dd, J = 8.5, 3.3Hz), 7.99 (1H, d, J = 8.5Hz), 8.13 (1H, s), 8.26 (1H, s). Project 9 To a mixed solution of compound 56 (36 mg, 0.064 mmol) in methanol (0.15 mL) - THF (0.15 mL), 1 M aqueous sodium hydroxide solution (0.12 mL, 0.12 mmol) was added, and the mixture was stirred at room temperature for 19 hours. An aqueous citric acid solution was added to the reaction mixture to adjust the pH to about 7, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain I - 078 (a mixture of diastereomers, 28 mg, yield 80%). MS (m / z) = 552.0 [M + H]+ 1 H-NMR (CDCl 3) δ: 1.54 (3H, dd, J=26.2, 6.7Hz), 2.50-2.38 (1H, m), 2.80-2.61 (4H, m), 3.07-3.04 (1H, m), 3.84-3.80 (1H, m), 4.16-4.09 (1H, m), 4.45-4.31 (2H, m), 4.89-4.56 (3H, m), 5.21-5.19 (1H, m), 5.39 (1H, d, J=13.1Hz), 5.46 (1H, d, J=13.1Hz), 7.13-7.10 (2H, m), 7.48 (1H, t, J=7.9Hz), 7.82 (1H, dd, J=8.5, 3.3Hz), 8.05 (1H, d, J=8.5Hz), 8.20 (1H, s), 8.27 (1H, s).

[0121] Example 6

Chem.

[0122] Step 3 By performing the same reaction as in Step 10 of Example 1, Compound 60 (12 mg) was obtained. 1 H-NMR(CDCl 3 ) δ: 1.55 (3H, d, J = 6.8Hz), 2.79 (1H, dt, J = 16.4, 4.0Hz), 2.91 - 2.99 (1H, m), 3.02 - 3.10 (3H, m), 3.13 - 3.24 (2H, m), 3.32 (1H, dt, J = 12.5, 5.0Hz), 4.16 (1H, q, J = 6.4Hz), 7.16 (2H, d, J = 8.3Hz), 7.24 (2H, d, J = 8.3 Hz), 7.58 (1H, s). MS(m / z) = 355 [M + H]+ Step 4 By performing the same reaction as in Step 11 of Example 1, Compound 61 (14 mg, yield 85%) was obtained. 1 H-NMR(CDCl 3 ) δ: 1.53 (3H, br s), 2.36 - 2.45 (1H, m), 2.65 - 2.89 (4H, m), 3.00 - 3.24 (4H, m), 3.95 (3H, s), 4.00 (1H, br s), 4.18 (1H, s), 4.32 - 4.37 (1H, m), 4.41 (1H, br s), 4.60 (1H, dd, J = 13.8, 7.9Hz), 4.72 (2H, br s), 5.17 - 5.23 (1H, m), 7.16 (2H, d, J = 8.4Hz), 7.24 (2H, d, J = 8.4Hz), 7.62 (1H, s), 7.77 (1H, d, J = 8.3Hz), 7.99 (1H, d, J = 8.7Hz), 8.14 (1H, s). MS(m / z) = 613 [M + H]+ Step 5 To a solution of Compound 61 (14 mg, 0.02 mmol) in methanol (0.15 mL) - THF (0.15 mL), 2 M aqueous sodium hydroxide solution (57 μL, 0.11 mmol) was added, and the mixture was stirred at 45 °C for 2 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with water, and dilute sulfuric acid was added until the pH reached about 4, followed by extraction twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform - methanol) to obtain Compound I - 095 (8 mg, yield 59%). 1 H - NMR(CDCl 3 ) δ: 1.52 (3H, br s), 2.35 - 2.45 (1H, m), 2.65 - 3.24 (9H, m), 4.01 (1H, br s), 4.21 (1H, br s), 4.32 - 4.37 (1H, m), 4.40 (1H, br s), 4.61 (1H, dd, J = 14.0, 7.6Hz), 4.74 (2H, br s), 5.18 - 5.23 (1H, br m), 7.15 (2H, d, J = 8.4Hz), 7.23 (2H, d, J = 8.4Hz), 7.62 (1H, s), 7.82 (1H, d, J = 8.5Hz), 8.04 (1H, d, J = 8.5Hz), 8.19 (1H, s). MS(m / z) = 599 [M + H]+

[0123] Using the general synthesis method or the synthesis method described in the examples above, the following compounds were synthesized in the same manner. Note that I - 015 and I - 090 - I - 093 in the table are diastereomer mixtures.

[0124]

Table 1

[0125]

Table 2

[0126]

Table 3

[0127]

Table 4

[0128]

Table 5

[0129]

Table 6

[0130]

Table 7

[0131]

Table 8

[0132]

Table 9

[0133]

Table 10

[0134] Using the general synthesis method described above or the synthesis method described in the examples, the following compounds can also be synthesized in the same manner.

Chemical Formula

[0135] The following describes the biological test examples of the compounds of the present invention. The compounds of the present invention can be tested essentially as described in the following test examples. The compound represented by formula (I) according to the present invention has GLP-1 receptor agonist activity. Specifically, in the evaluation method described below, the EC 50 value is preferably 5000 nM or less, more preferably 1000 nM or less, and even more preferably 100 nM or less.

[0136] Test Example 1: Measurement of GLP-1 Receptor Agonist Activity Cell Culture Human GLP-1 receptor stable expression cells (hGLP-1R / CHO-K1 cells) were cultured in α-MEM medium (Sigma) containing 10% FBS (Hyclone), 2% GlutaMAX (Gibco), 1% G418 (Nacalai Tesque), and 1% Penicillin-Streptomycin Mixed Solution (Sigma) at 37 °C and 5% CO 2 under the conditions, and recovered by treating with a 10-fold diluted 5.0 g / l-trypsin / 5.3 mmol / l-EDTA solution (Nacalai Tesque) and cryopreserved. cAMP Assay A DMSO solution containing the compound of the present invention or human GLP-1 (7-36) (Phoenix Pharmaceuticals) was dispensed into a 384-well microplate (Greiner) at 62.5 nL / well, and 400 μM Forskolin (Nacalai Tesque) was dispensed at 7.5 nL / well. Subsequently, the frozen GLP-1R / CHO-K1 cells were thawed in a 37 °C thermostat and resuspended in HBSS buffer (GIBCO) containing 0.1% BSA (Sigma), 20 mM HEPES, 0.1 mM IBMX (Sigma), and 0.2 mM RO20-1724 (Calbiochem) at 2×10 4Suspend to a concentration of cells / mL and add the cell suspension at 6 μL / well. Incubate at 37 °C for 1 hour, and measure the intracellular cAMP concentration using the cAMP Gs dynamic kit (Cisbio) according to the protocol provided with the product. Specifically, add a total of 6 μL / well of a mixed solution (1:1) of cAMP-d2 and Anti-cAMP-Cryptate, incubate at room temperature for 1 hour, and measure the time-resolved fluorescence using PHERAstar (BMG Labtech). Using the cAMP concentration when dispensing human GLP-1(7-36) to a final concentration of 2 nM as 100% and the cAMP concentration when dispensing only DMSO as 0%, the 50% effective concentration (EC 50 ) and the maximum effect (Emax) of the inventive compound are calculated using TIBCO Spotfire (TIBCO Software). Note that the dilution concentration and dilution solvent can be changed as necessary. The inventive compounds were tested essentially as described above. The EC 50 and Emax of each inventive compound are shown in the following table.

[0137]

Table 11

[0138] Test Example 2: Metabolic Stability Test React the commercially available pooled human liver microsomes with the inventive compound for a certain period of time, calculate the residual rate by comparing the reaction samples and the unreacted samples, and evaluate the degree to which the inventive compound is metabolized in the liver.

[0139] In 0.2 mL of buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL of human liver microsomes, react at 37 °C for 0 or 30 minutes in the presence of 1 mmol / L NADPH (oxidation reaction). After the reaction, add 70 μL of the reaction solution to 140 μL of a methanol / acetonitrile = 1 / 1 (v / v) solution, mix, and centrifuge at 3000 rpm for 15 minutes. Quantify the compound of the present invention in the centrifuged supernatant by LC / MS / MS or solid-phase extraction (SPE) / MS, and show the ratio of the amount of the compound of the present invention after the reaction to the amount at 0 minutes of reaction as the residual rate with the amount of the compound of the present invention at 0 minutes of reaction taken as 100%. The dilution concentration and dilution solvent are changed as necessary. The compound of the present invention can be tested essentially as described above.

[0140] Test Example 3: Solubility Test The solubility of the compound of the present invention is determined under the condition of adding 1% DMSO. Prepare a 10 mmol / L compound solution with DMSO, and add 2 μL of the compound solution of the present invention to 198 μL of the second elution test solution of the 17th revised Japanese Pharmacopoeia. After shaking at room temperature for 3 hours, filter the mixture by suction. Dilute the filtrate 100-fold with methanol / acetonitrile / water = 1 / 1 / 2 (V / V / V), and measure the concentration in the filtrate by LC / MS / MS using the absolute calibration curve method. The compound of the present invention can be tested essentially as described above.

[0141] Test Example 4: CYP Inhibition Test Using commercially available pooled human liver microsomes, as typical substrate metabolic reactions of the five major human CYP molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4), O-demethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) are used as indicators, and the degree to which the production amount of each metabolite is inhibited by the compound of the present invention is evaluated. The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 30 μmol / L or 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 °C; enzyme, pooled human liver microsomes 0.2 mg protein / mL; concentration of the compound of the present invention, 1, 5, 10, 20 μmol / L (4 points). As a reaction solution in a 96-well plate, five kinds of substrates, human liver microsomes, and the compound of the present invention are added in the above composition in 50 mmol / L Hepes buffer, and the coenzyme NADPH is added to initiate the metabolic reaction as an index. After reacting at 37 °C for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifuged supernatant is quantified by a fluorescence multi-label counter or LC / MS / MS, and hydroxylated tolbutamide (CYP2C9 metabolite), mephenytoin 4'-hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS. Using only DMSO, the solvent in which the drug is dissolved, added to the reaction system as a control (100%), the residual activity (%) is calculated, and the IC 50 is calculated by inverse estimation using a logistic model with concentration and inhibition rate. The compound of the present invention can be tested essentially as described above.

[0142] Test Example 5: BA Test Experimental Materials and Methods for Examining Oral Absorbability (1) Animals used: Mice or SD rats are used. (2) Breeding conditions: Mice or SD rats are allowed to freely ingest solid feed and sterilized tap water. (3) Setting of dosage and grouping: Oral administration and intravenous administration are carried out at predetermined dosages. The groups are set as follows. (The dosage is changed for each compound) Oral administration: 2 - 60 μmol / kg or 1 - 30 mg / kg (n = 2 - 3) Intravenous administration: 1 - 20 μmol / kg or 0.5 - 10 mg / kg (n = 2 - 3) (4) Preparation of the administration solution: For oral administration, it is administered as a solution or suspension. For intravenous administration, it is solubilized and then administered. (5) Administration method: For oral administration, it is forcibly administered into the stomach using an oral sonde. For intravenous administration, it is administered from the tail vein or femoral vein using a syringe with a needle. (6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS. (7) Statistical analysis: Regarding the change in the concentration of the compound of the present invention in plasma, the area under the concentration - time curve (AUC) in plasma is calculated by the moment analysis method, and the bioavailability (BA) of the compound of the present invention is calculated from the dose ratio and AUC ratio between the oral administration group and the intravenous administration group. The compound of the present invention can be tested essentially as described above.

[0143] Test Example 6: Clearance Evaluation Test Experimental Materials and Methods (1) Animals used: SD rats are used. (2) Breeding conditions: SD rats are allowed to freely consume solid feed and sterilized tap water. (3) Setting of the dose and grouping: Intravenous administration is performed at a predetermined dose. The groups are set as follows. Intravenous administration: 1 μmol / kg (n = 2) (4) Preparation of the administration solution: It is solubilized using a dimethyl sulfoxide / propylene glycol = 1 / 1 solvent and then administered. (5) Administration method: It is administered from the tail vein using a syringe with a needle. (6) Evaluation items: Blood is collected over time, and the concentration of the compound according to the present invention in plasma is measured using LC / MS / MS. (7) Statistical analysis: Regarding the change in the concentration of the compound according to the present invention in plasma, the total body clearance (CLtot) is calculated by the moment analysis method. Note that the dilution concentration and dilution solvent can be changed as necessary. The compound of the present invention can be essentially tested as described above.

[0144] Test Example 6-2: Clearance Evaluation Test Experimental Materials and Methods (1) Test Animals: Dogs (Marshall Beagles) are used. (2) Breeding Conditions: Dogs are allowed to freely consume solid feed and sterilized tap water. (3) Dosage and Grouping: Intravenous administration is performed at a predetermined dosage. The groups are set as follows. Intravenous administration 0.1 - 1 mg / kg (n = 2) (4) Preparation of Administration Solution: Solubilize and administer using any of the following solvents: dimethylacetamide / ethanol / carbonate buffer = 2 / 3 / 5, ethanol / carbonate buffer = 1 / 1, dimethylacetamide / polyethylene glycol 400 / 20% hydroxypropyl-β-cyclodextrin = 1 / 1 / 2. (5) Administration Method: Administer intravenously using a syringe with a needle. (6) Evaluation Items: Blood is collected over time, and the concentration of the compound according to the present invention in plasma is measured using LC / MS / MS. (7) Statistical Analysis: For the change in the concentration of the compound according to the present invention in plasma, the total body clearance (CLtot) is calculated by the moment analysis method. Note that the dilution concentration and dilution solvent may be changed as necessary. The compound of the present invention can be essentially tested as described above.

[0145] Test Example 7: CYP3A4 (MDZ) MBI Test This is a test to evaluate the mechanism-based inhibition (MBI) ability of the compound of the present invention regarding CYP3A4 inhibition from the enhancement by metabolic reactions. Using pooled human liver microsomes, CYP3A4 inhibition is evaluated with the 1-hydroxylation reaction of midazolam (MDZ) as an index. The reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 °C; pooled human liver microsomes, 0.5 mg / mL during pre-reaction, 0.05 mg / mL during reaction (when diluted 10-fold); concentration of the compound of the present invention during pre-reaction, 0.83, 5, 10, 20 μmol / L (4 points). As a pre-reaction solution in a 96-well plate, pooled human liver microsomes and the compound solution of the present invention were added in the composition of the above pre-reaction in K-Pi buffer (pH 7.4). A part of it was transferred to another 96-well plate so as to be diluted 1 / 10 with substrate and K-Pi buffer, and the reaction using NADPH as a coenzyme as an index was started (without pre-reaction). After reacting for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. Also, NADPH was added to the remaining pre-reaction solution to start the pre-reaction (with pre-reaction). After pre-reacting for a predetermined time, a part of it was transferred to another plate so as to be diluted 1 / 10 with substrate and K-Pi buffer to start the reaction as an index. After reacting for a predetermined time, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. Each plate on which the index reaction was performed was centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the centrifuged supernatant was quantified by LC / MS / MS. Using only DMSO, the solvent in which the compound of the present invention was dissolved, added to the reaction system as a control (100%), the residual activity (%) when the compound of the present invention was added at each concentration was calculated, and the IC was calculated by inverse estimation using the logistic model using the concentration and the inhibition rate. The IC of Preincubataion 0 min / the IC of Preincubataion 30 min was defined as the Shifted IC value. If the Shifted IC is 1.5 or more, it is Positive, and if the Shifted IC is 1.0 or less, it is Negative. The compound of the present invention can be tested essentially as described above.

[0146] Test Example 8: Powder Solubility Test Put an appropriate amount of the compound of the present invention into a suitable container, and add 200 μL each of JP-1 solution (dissolve 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid in water to make 1000 mL), JP-2 solution (dissolve 1.70 g of sodium dihydrogen phosphate and 1.775 g of disodium hydrogen phosphate anhydrous in 1000 mL of water to make a buffer solution with pH 6.8 - 6.9), and 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (add JP-2 solution to 1.08 g of TCA to make 100 mL) to each container. If the whole amount is dissolved after adding the test solution, add the compound of the present invention as appropriate. After sealing and shaking at 37°C for 1 hour, filter, and add 100 μL of methanol to 100 μL of each filtrate for 2-fold dilution. The dilution factor can be changed as necessary. Check for the absence of bubbles and precipitates, and then seal and shake. Quantify the compound of the present invention by HPLC using the absolute calibration curve method. The compound of the present invention can be essentially tested as described above.

[0147] Test Example 9: Fluctuation Ames Test Evaluate the mutagenicity of the compound of the present invention. Inoculate 20 μL of frozen Salmonella typhimurium TA98 strain and TA100 strain into 10 mL of liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and pre-culture with shaking at 37°C for 10 hours. For the TA98 strain, centrifuge 8.0 - 11.0 mL of the bacterial solution (2000×g, 10 minutes) to remove the culture solution. 8.0 - 11.0 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 ·7H 2The bacteria were suspended in 0:0.1 g / L and added to 120 mL of Exposure medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL). For the TA100 strain, the test bacterial solution was prepared by adding it to 120 mL of Exposure medium for 3.1 mL of the bacterial solution. The DMSO solution of the compound of the present invention (serially diluted from the highest dose of 50 mg / mL with a common ratio of 2 - 3 times), DMSO as a negative control, and 4-nitroquinoline-1-oxide DMSO solution at 50 μg / mL for the TA98 strain and 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution at 0.25 μg / mL for the TA100 strain as positive controls under non-metabolic activation conditions, and 2-aminoanthracene DMSO solution at 40 μg / mL for the TA98 strain and 2-aminoanthracene DMSO solution at 20 μg / mL for the TA100 strain under metabolic activation conditions, each 12 μL, were mixed with 588 μL of the test bacterial solution (a mixture of 498 μL of the test bacterial solution and 90 μL of S9 mix under metabolic activation conditions), and cultured with shaking at 37°C for 90 minutes. The bacterial solution exposed to the compound of the present invention and Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL) were mixed at a ratio of 23:115, and a total of 2760 μL of the bacterial solution containing Indicator was dispensed into 48 wells of a microplate at 50 μL per dose and statically cultured at 37°C for 3 days. Wells containing bacteria that have acquired the ability to grow due to mutations in the amino acid (histidine) synthase gene change color from purple to yellow due to pH change. Therefore, the number of bacterial growth wells that have changed color to yellow in 48 wells per dose is counted and evaluated in comparison with the negative control group. Those with negative mutagenicity are indicated as (-), and those with positive mutagenicity are indicated as (+). The compound of the present invention can be tested essentially as described above.

[0148] Test Example 10: hERG Test For the purpose of evaluating the risk of prolonging the QT interval of the electrocardiogram of the compound of the present invention, using CHO cells expressing the human ether-a-go-go related gene (hERG) channel, the delayed rectifier K that plays an important role in the ventricular repolarization process+ Effect of the compound of the present invention on current (I Kr ) is examined. Using an automated patch-clamp system (QPatch; Sophion Bioscience A / S), by the whole-cell patch-clamp method, cells were held at a membrane potential of -80 mV and a leak potential of -50 mV was applied. Then, when a depolarizing stimulus of +20 mV was applied for 2 seconds and a repolarizing stimulus of -50 mV was applied for 2 seconds, the induced I Kr was recorded. An extracellular solution adjusted to 0.1% dimethyl sulfoxide (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol / L, glucose: 10 mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was used as the medium, and the medium and the extracellular solution in which the compound of the present invention was dissolved at the target concentration were each applied to the cells at room temperature for 7 minutes or more. From the obtained I Kr , using analysis software (QPatch Assay software; Sophion Bioscience A / S), the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential. Furthermore, the maximum tail current after application of the compound of the present invention relative to the maximum tail current after application of the medium was calculated as the inhibition rate to evaluate the effect of the compound of the present invention on I Kr . Note that the dilution concentration and dilution solvent can be changed as necessary. The compound of the present invention can be tested essentially as described above.

[0149] Formulation Examples The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, for example orally, in the form of tablets or capsules, or parenterally, for example in the form of injection solutions or suspensions, topically, for example in the form of lotions, gels, ointments or creams, or in nasal form or suppository form. Pharmaceutical compositions comprising the compounds of the present invention in free form or in the form of pharmaceutically acceptable salts, together with at least one pharmaceutically acceptable carrier or diluent, can be prepared by conventional methods, by mixing, granulating or coating methods. For example, oral compositions can be tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and the active ingredient, etc. Further, injection compositions can be solutions or suspensions, may be sterilized, and may contain preservatives, stabilizers, buffering agents, etc.

Industrial Applicability

[0150] The compounds of the present invention are considered to have GLP-1 receptor agonist activity and be useful as therapeutic and / or prophylactic agents for diseases or conditions involving the GLP-1 receptor.

Claims

1. Formula (I): 【Chemical 1】 (wherein A １ is C(R １ ) or N; R １ is a hydrogen atom or a halogen; R ８ is a hydrogen atom, a halogen, an alkyloxy, or a 5- to 6-membered aromatic heterocyclic group which may be substituted with a halogen or an alkyl; B １ is CH or N; R １０ is a hydrogen atom, cyano, fluorine atom, chlorine atom, methyl, difluoromethyl or trifluoromethyl; R ３ is phenyl which may be substituted with substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted with substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted with substituent group F or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted with substituent group F, Substituent group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy; However, (i) when R １０ is a chlorine atom, B １ is N, and (ii) R １０ When R is trifluoromethyl, R ３ is a 5-membered aromatic heterocyclic group which may be substituted with a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted with a substituent group F or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted with a substituent group F, or R ８ is a 5- to 6-membered aromatic heterocyclic group which may be substituted with halogen or alkyl, and (iii) excluding the following compounds: 【Chemical 2】 ) a compound represented by or a pharmaceutically acceptable salt thereof.

2. R １０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom, cyano, fluorine atom, chlorine atom, methyl or difluoromethyl.

3. R ３ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is the following group. 【Chemical Formula 3】 (wherein, W is N or CR １５ ;) R １１ is a hydrogen atom, halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy; R １２ and R １３ are each independently a hydrogen atom or a halogen; R １４ and R １５ are each independently a hydrogen atom, halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy; R １１ and R １２ may together form a 5-membered aromatic heterocyclic ring optionally substituted with a substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring optionally substituted with a substituent group F. R １１ and R １３ may together form a 5-membered aromatic heterocyclic ring optionally substituted with a substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring optionally substituted with a substituent group F. R １３ and R １４ may together form a 5-membered aromatic heterocyclic ring optionally substituted with the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring optionally substituted with the substituent group F).

4. R ３ The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R is any of the following groups. 【Chemical 4】 (wherein each R ４ is independently halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.)

5. R ４ The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein each of R is independently a fluorine atom, a chlorine atom, cyano, methyl, methyloxy or difluoromethyloxy.

6. R １０ The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is a chlorine atom or difluoromethyl.

7. R １０ is trifluoromethyl, R ３ is a 5-membered aromatic heterocyclic group optionally substituted with a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group optionally substituted with a substituent group F, or a bicyclic 8- to 11-membered non-aromatic heterocyclic group optionally substituted with a substituent group F, the compound according to any one of claims 1 and 3 to 5, or a pharmaceutically acceptable salt thereof.

8. R １０ is trifluoromethyl, R ８ is a 5- to 6-membered aromatic heterocyclic group which may be substituted with halogen or alkyl, the compound according to any one of claims 1 and 3 to 5, or a pharmaceutically acceptable salt thereof.

9. Formula (II): [Chemical Formula 5] (wherein Q is a substituted or unsubstituted benzene ring or a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic ring; R ２ is a substituted or unsubstituted alkyl or a substituted or unsubstituted non-aromatic heterocyclic group; -L- is 【Chemical Formula 6】 (wherein B １ is CH or N; B ２ is C(R ９ ) or N; R ９ is a hydrogen atom or R １３ａ which together with -O- or -CH ２ -O- to form; B ３ is CH or N; R １０ａ is a hydrogen atom or a substituted or unsubstituted alkyl; R １０ｂ is a hydrogen atom, cyano, halogen, or substituted or unsubstituted alkyl; -L １ - is alkylene; X is S, NH or CH ２ wherein; R １３ａ is a hydrogen atom or R ９ which, together with, may form -O- or -CH ２ -O-; R １３ｂ is a group represented by a hydrogen atom or a substituted or unsubstituted alkyl; R ３ is phenyl which may be substituted with substituent group F, a 5- or 6-membered aromatic heterocyclic group which may be substituted with substituent group F, a bicyclic 9- or 10-membered aromatic heterocyclic group which may be substituted with substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted with substituent group F, Substituent group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy; provided that (i) when -L- is a group represented by (d), Q is a benzene ring substituted with a substituted or unsubstituted aromatic heterocyclic group, a 6-membered aromatic heterocyclic ring substituted with a substituted or unsubstituted aromatic heterocyclic group or a 5-membered aromatic heterocyclic ring substituted with a substituted or unsubstituted aromatic heterocyclic group, and (ii) excluding the following compounds: 【Chemical Formula 7】 ) a compound represented by or a pharmaceutically acceptable salt thereof.

10. R ３ The compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein R is the following group. [Chemical 8] (wherein, W is N or CR １５ ;) R １１ is a hydrogen atom, halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy; R １２ and R １３ are each independently a hydrogen atom or a halogen; R １４ and R １５ are each independently a hydrogen atom, halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy; R １１ and R １２ may together form a 5-membered aromatic heterocyclic ring optionally substituted with a substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring optionally substituted with a substituent group F, R １１ and R １３ may together form a 5-membered aromatic heterocyclic ring optionally substituted with a substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring optionally substituted with a substituent group F. R １３ and R １４ may together form a 5-membered aromatic heterocyclic ring optionally substituted with the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring optionally substituted with the substituent group F).

11. R ３ The compound according to claim 9 or 10, or a pharmaceutically acceptable salt thereof, wherein R is any one of the following groups. 【Chemical Formula 9】 (wherein R ４ are each independently halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.)

12. R ４ The compound according to claim 11, or a pharmaceutically acceptable salt thereof, wherein each of R is independently a fluorine atom, a chlorine atom, cyano, methyl, methyloxy or difluoromethyloxy.

13. The compound according to any one of Claims 9 to 12, or a pharmaceutically acceptable salt thereof, wherein Q is any one of the following groups. 【Chemical Formula 10】 (wherein A ２ is C(R ５ ) or N; A ３ is C(R ６ ) or N; A ４ is C(R ７ ) or N; R ５ 、 R ６ and R ７ are each independently a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted non-aromatic carbocyclic group; A ５ is C(R ９ ) or N; R ９ is a hydrogen atom, halogen, cyano, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.)

14. (i) A ２ is C(R ５ ), A ３ is C(R ６ ), and A ４ is C(R ７ ), or (ii) A ２ is N, and A ３ is C(R ６ ), and A ４ is C(R ７ ) or (iii) A ２ is C(R ５ ), A ３ is C(R ６ ), and A ４ is N or (iv) A ２ is N, and A ３ is C(R ６ ), and A ４ is N, the compound according to claim 13 or a pharmaceutically acceptable salt thereof.

15. (i) A ２ is C(R ５ ), A ３ is C(R ６ ), and A ４ is C(R ７ ), or (ii) A ２ is N, and A ３ is C(R ６ ), and A ４ is C(R ７ )), the compound according to claim 14 or a pharmaceutically acceptable salt thereof.

16. R ５ , R ６ and R ７ is each independently a hydrogen atom, halogen, alkyl or alkyloxy, a compound according to any one of claims 13 to 15 or a pharmaceutically acceptable salt thereof.

17. The compound according to any one of Claims 9 to 16, or a pharmaceutically acceptable salt thereof, wherein -L- is the following group. 【Chemical 11】

18. R ２ The compound according to any one of claims 9 to 17 or a pharmaceutically acceptable salt thereof, wherein R is oxetanylmethyl.

19. A pharmaceutical composition containing the compound according to any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition according to Claim 19, which is a GLP-1 receptor agonist.

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