Condensed ring compound with GLP-1 receptor agonist effect

Abstract

The present invention relates to a compound represented by formula (I) or (II) or a pharmaceutically acceptable salt thereof. Formula (I): In the formula, A1 is C (R1) or the like; r1 is a hydrogen atom or the like; r8 represents a hydrogen atom or the like; b1 is CH or the like; r10 represents a cyano group or the like; r3 is phenyl which may be substituted by substituent group F, or the like; a substituent group F: halogen, a cyano group, an alkyl group, a halogenated alkyl group, an alkyloxy group and a halogenated alkyloxy group; q is a substituted or unsubstituted benzene ring or the like; r2 represents a substituted or unsubstituted alkyl group or the like; and-L represents a group represented by the following or the like. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds having GLP-1 receptor agonist activity and useful as therapeutic or preventive agents for GLP-1 receptor-related diseases or their pharmaceutically acceptable salts, and pharmaceutical compositions containing them, in particular, preventive and / or therapeutic agents for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity. Background Art

[0002] Glucagon-like peptide-1 (GLP-1: glucagon-like peptide-1) is an incretin hormone secreted by intestinal L cells in response to food intake. It is known that GLP-1 exhibits effects such as promoting glucose-dependent insulin secretion, reducing glucagon secretion, delaying gastric emptying, and reducing appetite through the GLP-1 receptor. So far, the use of GLP-1 receptor agonists in the treatment of diabetes or obesity has been studied (non-patent literature 1, 2). As a representative agonist, liraglutide, an analog of human GLP-1, is known, but it is known to show a strong HbA1c-lowering effect and weight loss. Due to such attractive effects, a variety of GLP-1 analog preparations are actually used as diabetes therapeutics or obesity therapeutics. However, most of these GLP-1 analog preparations are sold as injections due to lack of oral absorbability. Therefore, the development of orally administrable GLP-1 receptor agonists is expected. Specifically, a method of orally absorbing semaglutide as a GLP-1 analog by using an absorption enhancer (Patent Document 1) has been put into practical use, but it is necessary to improve drug properties such as bioavailability. In addition, as non-peptide GLP-1 receptor agonists, the development of various small molecule drugs has been attempted (Patent Documents 2 to 58). The compounds substantially disclosed in Patent Documents 2 to 42, 44 to 55 and 57 have structures different from those of the compounds of the present invention. On the other hand, the compounds disclosed in Patent Documents 43, 56 and 58 are compounds that are structurally close to the compounds of the present invention.

[0003] Prior art literature

[0004] Patent Literature

[0005] Patent Document 1: International Publication No. 2012 / 080471,

[0006] Patent document 2: International Publication No. 2009 / 111700,

[0007] Patent document 3: International Publication No. 2010 / 114824,

[0008] Patent Document 4: International Publication No. 2018 / 056453,

[0009] Patent Document 5: International Publication No. 2018 / 109607,

[0010] Patent Document 6: International Publication No. 2019 / 239319,

[0011] Patent Document 7: International Publication No. 2019 / 239371,

[0012] Patent Document 8: International Publication No. 2020 / 103815,

[0013] Patent Document 9: International Publication No. 2020 / 207474,

[0014] Patent Document 10: International Publication No. 2020 / 263695,

[0015] Patent Document 11: International Publication No. 2021 / 018023,

[0016] Patent Document 12: International Publication No. 2021 / 081207,

[0017] Patent Document 13: International Publication No. 2021 / 096284,

[0018] Patent Document 14: International Publication No. 2021 / 096304,

[0019] Patent document 15: International Publication No. 2021 / 112538,

[0020] Patent document 16: International Publication No. 2021 / 155841,

[0021] Patent document 17: International Publication No. 2021 / 160127,

[0022] Patent Document 18: International Publication No. 2021 / 187886,

[0023] Patent Document 19: Chinese Patent Application Publication No. 113493447,

[0024] Patent document 20: International Publication No. 2021 / 197464,

[0025] Patent document 21: International Publication No. 2021 / 219019,

[0026] Patent document 22: Chinese patent application publication No. 113480534,

[0027] Patent document 23: International Publication No. 2021 / 244645,

[0028] Patent document 24: International Publication No. 2021 / 249492,

[0029] Patent document 25: International Publication No. 2021 / 242817,

[0030] Patent document 26: Chinese patent application publication No. 113773310,

[0031] Patent document 27: Chinese patent application publication No. 113816948,

[0032] Patent document 28: Chinese patent application publication No. 113801136,

[0033] Patent Document 29: International Publication No. 2021 / 254470,

[0034] Patent document 30: International Publication No. 2021 / 259309,

[0035] Patent document 31: International Publication No. 2022 / 028572,

[0036] Patent document 32: International Publication No. 2022 / 031994,

[0037] Patent document 33: International Publication No. 2022 / 040600,

[0038] Patent document 34: International Publication No. 2022 / 042691,

[0039] Patent document 35: International Publication No. 2022 / 078380,

[0040] Patent document 36: International Publication No. 2022 / 078152,

[0041] Patent document 37: International Publication No. 2022 / 078407,

[0042] Patent document 38: International Publication No. 2022 / 109182,

[0043] Patent document 39: International Publication No. 2022 / 111624,

[0044] Patent document 40: International Publication No. 2022 / 116693,

[0045] Patent document 41: Chinese patent application publication No. 114478497,

[0046] Patent document 42: Chinese patent application publication No. 114716423,

[0047] Patent document 43: International patent application No. JP2022 / 13362,

[0048] Patent document 44: International Publication No. 2022 / 068772,

[0049] Patent document 45: International Publication No. 2022 / 184849,

[0050] Patent document 46: International Publication No. 2022 / 192428,

[0051] Patent document 47: International Publication No. 2022 / 192430,

[0052] Patent document 48: International Publication No. 2022 / 199458,

[0053] Patent Document 49: International Publication No. 2022 / 199661,

[0054] Patent document 50: International Publication No. 2022 / 219495,

[0055] Patent document 51: International Publication No. 2022 / 225914,

[0056] Patent document 52: International Publication No. 2022 / 225941,

[0057] Patent document 53: International Publication No. 2022 / 228490,

[0058] Patent document 54: International Publication No. 2022 / 246019,

[0059] Patent document 55: International Publication No. 2022 / 268152,

[0060] Patent document 56: Chinese patent application publication No. 115594669,

[0061] Patent document 57: U.S. Patent Application Publication No. 20220396569,

[0062] Patent document 58: International Publication No. 2023 / 138684.

[0063] Non-patent literature

[0064] Non-patent document 1: Lancet 374, 1606-1616 (2009),

[0065] Non-patent document 2: Clin. Invest. 2, 59-72 (2012). Summary of the invention

[0066] Problems to be solved by the invention

[0067] The object of the present invention is to provide a compound or a pharmaceutically acceptable salt thereof having GLP-1 receptor agonist activity and useful as a therapeutic or preventive agent for GLP-1 receptor-related diseases, and a pharmaceutical composition containing them, in particular, a preventive and / or therapeutic agent for non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity.

[0068] Means of solving problems

[0069] The present invention relates to the following contents.

[0070] [1] A compound represented by formula (I) or a pharmaceutically acceptable salt thereof:

[0071] [Chemical formula 1]

[0072]

[0073] In the formula,

[0074] A 1 C(R 1 ) or N;

[0075] R 1 is a hydrogen atom or a halogen;

[0076] R 8 is a hydrogen atom, a halogen, an alkyloxy group, or a 5- to 6-membered aromatic heterocyclic group which may be substituted by a halogen or an alkyl group;

[0077] B 1 is CH or N;

[0078] R 10 is a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group;

[0079] R 3 is a phenyl group which may be substituted by a substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted by a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by a substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by a substituent group F,

[0080] Substituent Group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy;

[0081] However, (i) in R 10 In the case of chlorine atoms, B 1 For N,

[0082] (ii) In R 10 In the case of trifluoromethyl, R 3is a 5-membered aromatic heterocyclic group which may be substituted by a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by a substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by 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

[0083] (iii) Except for the following compounds:

[0084] [Chemical formula 2]

[0085] and

[0086] [2] The compound according to [1] or a pharmaceutically acceptable salt thereof, wherein R 10 It is a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group or a difluoromethyl group.

[0087] [3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R 3 For the following groups:

[0088] [Chemical formula 3]

[0089]

[0090] Where W is N or CR 15 ;

[0091] R 11 is a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0092] R 12 and R 13 are each independently a hydrogen atom or a halogen;

[0093] R 14 and R 15 are each independently a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0094] R 11 and R 12 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0095] R 11 and R 13 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0096] R 13 and R14 They may form together a 5-membered aromatic heterocyclic ring which may be substituted by the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by the substituent group F.

[0097] [4] The compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein R 3 Any of the following groups:

[0098] [Chemical formula 4]

[0099]

[0100] In the formula, R 4 Each is independently halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.

[0101] [5] The compound according to [4] or a pharmaceutically acceptable salt thereof, wherein R 4 Each is independently a fluorine atom, a chlorine atom, a cyano group, a methyl group, a methoxy group or a difluoromethoxy group.

[0102] [6] The compound according to any one of [1] to [5] or a pharmaceutically acceptable salt thereof, wherein R 10 is a chlorine atom or a difluoromethyl group.

[0103] [7] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein R 10 It is difluoromethyl.

[0104] [8] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein R 10 is a chlorine atom, B 1 is N.

[0105] [9] The compound or pharmaceutically acceptable salt thereof according to any one of [1] and [3] to [5], wherein R 10 is trifluoromethyl,

[0106] R 3 It is a 5-membered aromatic heterocyclic group which may be substituted by the substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by the substituent group F, or a bicyclic 8- to 11-membered non-aromatic heterocyclic group which may be substituted by the substituent group F.

[0107]

[10] The compound according to any one of [1] and [3] to [5], or a pharmaceutically acceptable salt thereof, wherein R 10 is trifluoromethyl,

[0108] R 8 It is a 5- to 6-membered aromatic heterocyclic group which may be substituted with halogen or alkyl.

[0109]

[11] A compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0110] [Chemical formula 5]

[0111]

[0112] In the formula,

[0113] Q is a substituted or unsubstituted benzene ring or a substituted or unsubstituted 5- to 6-membered aromatic heterocycle;

[0114] R 2 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group;

[0115] -L- is a group represented by the following formula:

[0116] [Chemical formula 6]

[0117]

[0118] In the formula,

[0119] B 1 is CH or N,

[0120] B 2 C(R 9 ) or N,

[0121] R 9 A hydrogen atom or 13a Together they form -O- or -CH 2 -O-,

[0122] B 3 is CH or N,

[0123] R 10a is a hydrogen atom or a substituted or unsubstituted alkyl group,

[0124] R 10b is a hydrogen atom, a cyano group, a halogen group or a substituted or unsubstituted alkyl group,

[0125] -L 1 - is an alkylene group,

[0126] X is S, NH or CH 2 ,

[0127] R 13a It can be a hydrogen atom or 9 Together they form -O- or -CH 2 -O-,

[0128] R 13bis a hydrogen atom or a substituted or unsubstituted alkyl group;

[0129] R 3 is a phenyl group which may be substituted by a substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted by a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by a substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by a substituent group F,

[0130] Substituent Group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy;

[0131] However, (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 substituted or unsubstituted 5-membered aromatic heterocyclic ring, and

[0132] (ii) Except for the following compounds:

[0133] [Chemical formula 7]

[0134]

[0135]

[12] The compound according to

[11] or a pharmaceutically acceptable salt thereof, wherein R 3 For the following groups:

[0136] [Chemical formula 8]

[0137]

[0138] Where W is N or CR 15 ;

[0139] R 11 is a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0140] R 12 and R 13 are each independently a hydrogen atom or a halogen;

[0141] R 14 and R 15 are each independently a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0142] R 11 and R 12 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0143] R 11 and R13 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0144] R 13 and R 14 They may form together a 5-membered aromatic heterocyclic ring which may be substituted by the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by the substituent group F.

[0145]

[13] The compound according to

[11] or

[12] or a pharmaceutically acceptable salt thereof, wherein R 3 Any of the following groups:

[0146] [Chemical formula 9]

[0147]

[0148] In the formula, R 4 Each is independently halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.

[0149]

[14] The compound according to

[13] or a pharmaceutically acceptable salt thereof, wherein R 4 Each is independently a fluorine atom, a chlorine atom, a cyano group, a methyl group, a methoxy group or a difluoromethoxy group.

[0150]

[15] The compound or pharmaceutically acceptable salt thereof according to any one of

[11] to

[14] , wherein Q is any of the following groups:

[0151] [Chemical formula 10]

[0152]

[0153] In the formula,

[0154] A 2 C(R 5 ) or N;

[0155] A 3 C(R 6 ) or N;

[0156] A 4 C(R 7 ) or N;

[0157] R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group;

[0158] A 5 C(R 9 ) or N;

[0159] R 9 is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group.

[0160]

[16] The compound according to

[15] or a pharmaceutically acceptable salt thereof, wherein (i) A 2 C(R 5 ), A 3 C(R 6 ) and A 4 C(R 7 ),or

[0161] (ii)A 2 N, A 3 C(R 6 ) and A 4 C(R 7 ),or

[0162] (iii)A 2 C(R 5 ), A 3 C(R 6 ) and A 4 is N, or

[0163] (iv)A 2 N, A 3 C(R 6 ) and A 4 is N.

[0164]

[17] The compound according to

[16] or a pharmaceutically acceptable salt thereof, wherein (i) A 2 C(R 5 ), A 3 C(R 6 ) and A 4 C(R 7 ),or

[0165] (ii)A 2 N, A 3 C(R 6 ) and A 4 C(R 7 ).

[0166]

[18] The compound or pharmaceutically acceptable salt thereof according to any one of

[15] to

[17] , wherein R 5 , R 6 and R 7 Each is independently a hydrogen atom, a halogen, an alkyl group or an alkyloxy group.

[0167]

[19] The compound according to any one of

[15] to

[17] or a pharmaceutically acceptable salt thereof, wherein R 5 is a hydrogen atom or a halogen, R 6 is a hydrogen atom, R 7 is a hydrogen atom, a halogen, an alkyloxy group or a methylpyrazolyl group.

[0168]

[20] The compound or pharmaceutically acceptable salt thereof according to any one of

[11] to

[19] , wherein -L- is the following group:

[0169] [Chemical formula 11]

[0170]

[0171]

[21] The compound according to

[20] or a pharmaceutically acceptable salt thereof, wherein -L- is the following group:

[0172] [Chemical formula 12]

[0173]

[0174] [21-1] The compound according to

[20] or a pharmaceutically acceptable salt thereof, wherein -L- is the following group:

[0175] [Chemical formula 13]

[0176]

[0177]

[22] The compound according to

[21] or a pharmaceutically acceptable salt thereof, wherein -L- is the following group:

[0178] [Chemical formula 14]

[0179]

[0180]

[23] The compound according to any one of

[11] to

[21] , [21-1] and

[22] , or a pharmaceutically acceptable salt thereof, wherein R 2 It is an oxetanylmethyl group.

[0181]

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

[21] , [21-1],

[22] and

[23] or a pharmaceutically acceptable salt thereof.

[0182]

[25] The pharmaceutical composition according to

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

[0183]

[26] A method for treating and / or preventing a GLP-1 receptor-related disease, characterized by administering a compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[21] , [21-1],

[22] and

[23] above.

[0184]

[27] Use of the compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[21] , [21-1],

[22] and

[23] above for the manufacture of a therapeutic and / or preventive agent for a GLP-1 receptor-related disease.

[0185]

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

[21] , [21-1],

[22] and

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

[0186] Effects of the Invention

[0187] The compound of the present invention has a GLP-1 receptor agonist action and is useful as a preventive and / or therapeutic agent for GLP-1 receptor-related diseases, particularly non-insulin-dependent diabetes mellitus (type 2 diabetes) or obesity. DETAILED DESCRIPTION

[0188] The meaning of each term used in this specification is explained below. Unless otherwise specified, each term has the same meaning whether used alone or in combination with other terms.

[0189] The term "consisting of" means having only the constituent elements.

[0190] The term "comprising" is intended to mean not to be limited to the constituent elements, and not to exclude unrecited elements.

[0191] Hereinafter, the present invention will be described while showing the embodiments. Throughout the specification, unless otherwise specifically mentioned, expressions in the singular should be understood as also including the concept of its plural form. Therefore, unless otherwise specifically mentioned, articles in the singular (for example, "a", "an", "the", etc. in English) should be understood as also including the concept of its plural form. In addition, unless otherwise specifically mentioned, the terms used in this specification should be understood to be used with the meaning commonly used in the art. Therefore, unless otherwise defined, all technical terms and scientific and technical terms used in this specification have the same meaning as those commonly understood by technicians in the field to which the present invention belongs. In the event of a conflict, this specification (including definitions) takes precedence.

[0192] The "halogen" includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, and a fluorine atom and a chlorine atom are particularly preferred.

[0193] The "alkyl group" 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 still more preferably 1 to 4 carbon atoms. Examples thereof include 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, and n-decyl.

[0194] Preferred embodiments of the "alkyl group" include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Further preferred embodiments include methyl, ethyl, n-propyl, isopropyl, and tert-butyl.

[0195] The "alkenyl group" 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 still more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, isoprenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, and the like can be cited.

[0196] Preferred embodiments of the "alkenyl group" include vinyl, allyl, propenyl, isopropenyl and butenyl.

[0197] The "alkynyl group" includes a straight-chain or branched hydrocarbon group having 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. In addition, it may have a double bond at any position. For example, it includes ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, etc.

[0198] Preferred embodiments of the "alkynyl group" include an ethynyl group, a propynyl group, a butynyl group, and a pentynyl group.

[0199] The "aromatic carbocyclic group" means a monocyclic or bicyclic or higher-ring cyclic aromatic hydrocarbon group, and examples thereof include phenyl, naphthyl, anthracenyl, and phenanthryl.

[0200] As a preferred embodiment of the "aromatic carbocyclic group", a phenyl group can be mentioned.

[0201] The "aromatic carbocyclic ring" means a ring derived from the above-mentioned "aromatic carbocyclic group".

[0202] As a preferred embodiment of the "aromatic carbocyclic ring", a benzene ring can be mentioned.

[0203] "Non-aromatic carbocyclic group" means a monocyclic or bicyclic or more cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group. "Non-aromatic carbocyclic group" having two or more rings also includes a group in which a ring in the above "aromatic carbocyclic group" is fused with a monocyclic or bicyclic or more non-aromatic carbocyclic group, and the bond may be present on any ring.

[0204] For example, the following ring can be shown.

[0205] [Chemical formula 15]

[0206]

[0207] Furthermore, the "non-aromatic carbocyclic group" also includes the following cross-linked groups or groups forming a spiro ring.

[0208] [Chemical formula 16]

[0209]

[0210] The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like.

[0211] The non-aromatic carbocyclic group having two or more rings preferably has 8 to 20 carbon atoms, and more preferably has 8 to 16 carbon atoms. Examples thereof include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, and fluorenyl.

[0212] The "non-aromatic carbocyclic ring" means a ring derived from the above-mentioned "non-aromatic carbocyclic group".

[0213] The "aromatic heterocyclic group" means a monocyclic or bicyclic or higher aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N which are the same or different in the ring.

[0214] The aromatic heterocyclic group having two or more rings also includes a group in which a ring in the above-mentioned "aromatic carbocyclic group" is condensed with a monocyclic or bicyclic or more aromatic heterocyclic group, and the bond may be present on any ring.

[0215] As a monocyclic aromatic heterocyclic group, 5- to 8-membered is preferred, and 5- or 6-membered is more preferred. As a 5-membered aromatic heterocyclic group, for example, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc. can be cited. As a 6-membered aromatic heterocyclic group, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. can be cited. As a bicyclic aromatic heterocyclic group, 8- to 10-membered is preferred, and 9- or 10-membered is more preferred. For example, indolyl, isoindolyl, indazolyl, indolizinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuranyl, isobenzofuranyl, benzothiophene ring, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolylpyridyl and the like can be cited.

[0216] The aromatic heterocyclic group having three or more rings is preferably a 13- to 15-membered group and examples thereof include a carbazolyl group, an acridinyl group, a xanthenyl group, a phenothiazinyl group, a phenoxathiyl group, a phenoxazinyl group, and a dibenzofuranyl group.

[0217] The "aromatic heterocyclic ring" means a ring derived from the above-mentioned "aromatic heterocyclic group".

[0218] As a monocyclic aromatic heterocyclic ring, 5- to 8-membered is preferred, and 5- or 6-membered is more preferred. Examples of the 5-membered aromatic heterocyclic ring 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 the 6-membered aromatic heterocyclic ring include pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, etc.

[0219] The bicyclic aromatic heterocyclic group is preferably 8-10-membered, more preferably 9-membered or 10-membered. Examples thereof include an indole ring, an isoindole ring, an indazole ring, an indolizine ring, a quinoline ring, an isoquinoline ring, a cinnoline ring, a phthalazine ring, a quinazoline ring, a naphthyridine ring, a quinoxaline ring, a purine ring, a pteridine ring, a benzimidazole ring, a benzisoxazole ring, a benzoxazole ring, a benzoxadiazole ring, a benzisothiazole ring, a benzothiazole ring, a benzothiadiazole ring, a benzofuran ring, an isobenzofuran ring, a benzothiophene ring, a benzotriazole ring, an imidazopyridine ring, a triazolopyridine ring, an imidazothiazole ring, a pyrazinopyridazine ring, an oxazolopyridine ring, and a thiazolopyridine ring.

[0220] The aromatic heterocyclic ring having three or more rings is preferably 13-15-membered, and examples thereof include a carbazole ring, an acridine ring, a xanthene ring, a phenothiazine ring, a phenoxathiol ring, a phenoxazine ring, and a dibenzofuran ring.

[0221] The "non-aromatic heterocyclic group" means a monocyclic or bicyclic or higher non-aromatic cyclic group having one or more identical or different heteroatoms arbitrarily selected from O, S and N in the ring. Bicyclic or higher non-aromatic heterocyclic groups also include groups in which the respective rings in the above-mentioned "aromatic carbocyclic group", "non-aromatic carbocyclic group" and / or "aromatic heterocyclic group" are fused with a monocyclic or bicyclic or higher non-aromatic heterocyclic group, and further include groups in which the ring in the above-mentioned "aromatic heterocyclic group" is fused with a monocyclic or bicyclic or higher non-aromatic carbocyclic group, and the bond may be present on any ring.

[0222] Furthermore, the "non-aromatic heterocyclic group" also includes the following cross-linked groups or groups forming a spiro ring.

[0223] [Chemical formula 17]

[0224]

[0225] The monocyclic non-aromatic heterocyclic group preferably has 3 to 8 members, and more preferably has 4 to 6 members.

[0226] As the 3-membered non-aromatic heterocyclic group, for example, thiirane, oxirane, and aziridine groups can be listed. As the 4-membered non-aromatic heterocyclic group, for example, oxetanyl and azetidinyl groups can be listed. As the 5-membered non-aromatic heterocyclic group, for example, oxathiolanyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, tetrahydrofuranyl, dihydrothiazolyl, tetrahydroisothiazolyl, dioxolanyl, dioxolenyl, thiolanyl, etc. can be listed. Examples of the 6-membered non-aromatic heterocyclic group include dioxanyl, thiohexyl, piperidinyl, piperazinyl, morpholinyl, morpholino, thiomorpholino, thiomorpholino, dihydropyridinyl, tetrahydropyridinyl, tetrahydropyranyl, dihydrooxazinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxazinyl, thienyl, thiazinyl, etc. Examples of the 7-membered non-aromatic heterocyclic group include hexahydroazepinyl, tetrahydrodiazepinyl, and oxepinyl.

[0227] The non-aromatic heterocyclic group having two or more rings is preferably 8-20-membered, and more preferably 8-10-membered. Examples thereof include indolinyl, isoindolinyl, chromanyl, and isochromanyl.

[0228] The "non-aromatic heterocyclic ring" means a ring derived from the above-mentioned "non-aromatic heterocyclic group".

[0229] The alkyl part of “alkyloxy”, “haloalkyloxy”, “alkylcarbonyloxy”, “alkylcarbonyl”, “alkyloxycarbonyl”, “alkylmercapto”, “alkylsulfinyl”, “alkylsulfonyl”, “alkyloxyalkyloxy” and “alkyloxyalkyl” is synonymous with the above-mentioned “alkyl”.

[0230] The alkenyl part of “alkenyloxy”, “alkenylcarbonyloxy”, “alkenylcarbonyl”, “alkenyloxycarbonyl”, “alkenylmercapto”, “alkenylsulfinyl” and “alkenylsulfonyl” is synonymous with the above-mentioned “alkenyl”.

[0231] The alkynyl part of “alkynyloxy”, “alkynylcarbonyloxy”, “alkynylcarbonyl”, “alkynyloxycarbonyl”, “alkynylmercapto”, “alkynylsulfinyl” and “alkynylsulfonyl” is synonymous with the above-mentioned “alkynyl”.

[0232] In the present specification, “may be substituted by substituent group A” means “may be substituted by one or more groups selected from substituent group A”. The same applies to substituent groups B, C, D, E, F, α, β, γ, γ′, etc.

[0233] Examples of substituents such as “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylcarbonyloxy”, “substituted alkynylcarbonyloxy”, “substituted alkynylcarbonyloxy”, “substituted alkylcarbonyl”, “substituted alkenylcarbonyl”, “substituted alkynylcarbonyl”, “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl”, “substituted alkynyloxycarbonyl”, “substituted alkylthio”, “substituted alkenylthio”, “substituted alkynylthio”, “substituted alkylsulfinyl”, “substituted alkenylsulfinyl”, “substituted alkynylsulfinyl”, “substituted alkylsulfonyl”, “substituted alkenylsulfonyl”, and “substituted alkynylsulfonyl” include the following substituent group A. Carbon atoms at any position may be bonded to one or more groups selected from the following substituent group A.

[0234] Substituent Group A: halogen, hydroxyl, carboxyl, formyl, formyloxy, mercapto, sulfinyl, sulfo, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, ureide, amidino, guanidino, pentafluorosulfenyl, trialkylsilyl,

[0235] Alkyloxy group which may be substituted by substituent group α, alkenyloxy group which may be substituted by substituent group α, alkynyloxy group which may be substituted by substituent group α, alkylcarbonyloxy group which may be substituted by substituent group α, alkenylcarbonyloxy group which may be substituted by substituent group α, alkynylcarbonyloxy group which may be substituted by substituent group α, alkylcarbonyl group which may be substituted by substituent group α, alkenylcarbonyl group which may be substituted by substituent group α, alkynylcarbonyl group which may be substituted by substituent group α, alkyloxycarbonyl group which may be substituted by substituent group α alkenyloxycarbonyl, alkynyloxycarbonyl which may be substituted by substituent group α, alkylthio which may be substituted by substituent group α, alkenylthio which may be substituted by substituent group α, alkynylthio which may be substituted by substituent group α, alkylsulfinyl which may be substituted by substituent group α, alkenylsulfinyl which may be substituted by substituent group α, alkynylsulfinyl which may be substituted by substituent group α, alkylsulfonyl which may be substituted by substituent group α, alkenylsulfonyl which may be substituted by substituent group α, alkynylsulfonyl which may be substituted by substituent group α,

[0236] an amino group which may be substituted by a substituent group β, an imino group which may be substituted by a substituent group β, a carbamoyl group which may be substituted by a substituent group β, a sulfamoyl group which may be substituted by a substituent group β,

[0237] an aromatic carbocyclic group which may be substituted with the substituent group γ, a non-aromatic carbocyclic group which may be substituted with the substituent group γ', an aromatic heterocyclic group which may be substituted with the substituent group γ, a non-aromatic heterocyclic group which may be substituted with the substituent group γ', an aromatic carbocyclic oxy group which may be substituted with the substituent group γ, a non-aromatic carbocyclic oxy group which may be substituted with the substituent group γ', an aromatic heterocyclic oxy group which may be substituted with the substituent group γ, a non-aromatic heterocyclic oxy group which may be substituted with the substituent group γ', an aromatic carbocyclic carbonyloxy group which may be substituted with the substituent group γ, a non-aromatic carbocyclic carbonyloxy group which may be substituted with the substituent group γ', a substituent group an aromatic heterocyclic carbonyloxy group which may be substituted with the γ' substituent group, an aromatic carbocyclic carbonyl group which may be substituted with the γ' substituent group, a non-aromatic carbocyclic carbonyl group which may be substituted with the γ' substituent group, an aromatic heterocyclic carbonyl group which may be substituted with the γ substituent group, a non-aromatic heterocyclic carbonyl group which may be substituted with the γ' substituent group, an aromatic heterocyclic carbonyl group which may be substituted with the γ substituent group, a non-aromatic heterocyclic carbonyl group which may be substituted with the γ' substituent group, an aromatic carbocyclic oxycarbonyl group which may be substituted with the γ substituent group, a non-aromatic carbocyclic oxycarbonyl group which may be substituted with the γ' substituent group, an aromatic heterocyclic oxycarbonyl group which may be substituted with the γ substituent group, a non-aromatic heterocyclic oxycarbonyl group which may be substituted with the γ' substituent group, a substituted aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy which may be substituted with substituent group γ', aromatic heterocyclic alkyloxy which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxy which may be substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic carbocyclic mercapto which may be substituted with substituent group γ, non-aromatic carbocyclic mercapto which may be substituted with substituent group γ' The invention also includes an aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ, an aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfinyl group which may be substituted with a substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ, a non-aromatic heterocyclic sulfinyl group which may be substituted with a substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ, a non-aromatic carbocyclic sulfonyl group which may be substituted with a substituent group γ', an aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted with a substituent group γ'.

[0238] Substituent Group α: halogen, hydroxy, carboxyl, alkyloxy, haloalkyloxy, alkenyloxy, alkynyloxy, mercapto, and cyano.

[0239] Substituent group β: halogen, hydroxyl, carboxyl, cyano, alkyl which may be substituted by substituent group α, alkenyl which may be substituted by substituent group α, alkynyl which may be substituted by substituent group α, alkylcarbonyl which may be substituted by substituent group α, alkenylcarbonyl which may be substituted by substituent group α, alkynylcarbonyl which may be substituted by substituent group α, alkylthio which may be substituted by substituent group α, alkenylthio which may be substituted by substituent group α, alkynylthio which may be substituted by substituent group α, alkylsulfinyl which may be substituted by substituent group α, alkenylsulfinyl which may be substituted by substituent group α, alkynylsulfinyl which may be substituted by substituent group α, alkylsulfonyl which may be substituted by substituent group α, alkenylsulfonyl which may be substituted by substituent group α, alkynylsulfonyl which may be substituted by substituent group α,

[0240] an aromatic carbocyclic group which may be substituted with the substituent group γ, a non-aromatic carbocyclic group which may be substituted with the substituent group γ', an aromatic heterocyclic group which may be substituted with the substituent group γ, a non-aromatic heterocyclic group which may be substituted with the substituent group γ', an aromatic carbocyclic alkyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclic alkyl group which may be substituted with the substituent group γ', an aromatic heterocyclic alkyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclic alkyl group which may be substituted with the substituent group γ', an aromatic carbocyclic carbonyl group which may be substituted with the substituent group γ', an aromatic heterocyclic carbonyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclic carbonyl group which may be substituted with the substituent group γ', an aromatic carbocyclic oxycarbonyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclic oxycarbonyl group which may be substituted with the substituent group γ', an aromatic heterocyclic oxycarbonyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic oxycarbonyl group which may be substituted by the substituent group γ', an aromatic carbocyclic thiol group which may be substituted by the substituent group γ, a non-aromatic carbocyclic thiol group which may be substituted by the substituent group γ', an aromatic heterocyclic thiol group which may be substituted by the substituent group γ, a non-aromatic heterocyclic thiol group which may be substituted by the substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic sulfinyl group which may be substituted by the substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic sulfinyl group which may be substituted by the substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic sulfonyl group which may be substituted by the substituent group γ', an aromatic heterocyclic sulfonyl group which may be substituted by the substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted by the substituent group γ'.

[0241] Substituent Group γ: Substituent Group α, alkyl, halogenated alkyl, cyanoalkyl, hydroxyalkyl, alkenyl, alkynyl, alkylcarbonyl, halogenated alkylcarbonyl, alkenylcarbonyl and alkynylcarbonyl.

[0242] Substituent group γ': substituent group γ and oxo.

[0243] Examples of the substituents on the rings of the “aromatic carbocyclic ring” and “aromatic heterocyclic ring” such as “substituted aromatic carbocyclic group”, “substituted aromatic heterocyclic group”, “substituted aromatic carbocyclic oxy group”, “substituted aromatic heterocyclic oxy group”, “substituted aromatic carbocyclic carbonyloxy group”, “substituted aromatic heterocyclic carbonyloxy group”, “substituted aromatic carbocyclic carbonyl group”, “substituted aromatic heterocyclic carbonyl group”, “substituted aromatic carbocyclic oxycarbonyl group”, “substituted aromatic heterocyclic oxycarbonyl group”, “substituted aromatic carbocyclic mercapto group”, “substituted aromatic heterocyclic mercapto group”, “substituted aromatic carbocyclic sulfinyl group”, “substituted aromatic heterocyclic sulfinyl group”, “substituted aromatic carbocyclic sulfonyl group” and “substituted aromatic heterocyclic sulfonyl group” include the following Substituent Group B. The atoms at any positions on the ring may be bonded to one or more groups selected from the following Substituent Group B.

[0244] Substituent Group B: halogen, hydroxyl, carboxyl, formyl, methoxyl, mercapto, sulfinyl, sulfo, thioformyl, thiocarboxyl, dithiocarboxyl, thiocarbamoyl, cyano, nitro, nitroso, azido, hydrazine, ureide, amidino, guanidino, pentafluorosulfenyl, trialkylsilyl,

[0245] Alkyl which may be substituted by substituent group α, alkenyl which may be substituted by substituent group α, alkynyl which may be substituted by substituent group α, alkyloxy which may be substituted by substituent group α, alkenyloxy which may be substituted by substituent group α, alkynyloxy which may be substituted by substituent group α, alkylcarbonyloxy which may be substituted by substituent group α, alkenylcarbonyloxy which may be substituted by substituent group α, alkynylcarbonyloxy which may be substituted by substituent group α, alkylcarbonyl which may be substituted by substituent group α, alkenylcarbonyl which may be substituted by substituent group α, alkynylcarbonyl which may be substituted by substituent group α, substituted alkyloxycarbonyl, alkenyloxycarbonyl which may be substituted by substituent group α, alkynyloxycarbonyl which may be substituted by substituent group α, alkylthio which may be substituted by substituent group α, alkenylthio which may be substituted by substituent group α, alkynylthio which may be substituted by substituent group α, alkylsulfinyl which may be substituted by substituent group α, alkenylsulfinyl which may be substituted by substituent group α, alkynylsulfinyl which may be substituted by substituent group α, alkylsulfonyl which may be substituted by substituent group α, alkenylsulfonyl which may be substituted by substituent group α, alkynylsulfonyl which may be substituted by substituent group α,

[0246] an amino group which may be substituted by a substituent group β, an imino group which may be substituted by a substituent group β, a carbamoyl group which may be substituted by a substituent group β, a sulfamoyl group which may be substituted by a substituent group β,

[0247] 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 group which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxy group which may be substituted with a substituent group γ', an aromatic heterocyclic oxy group which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxy group which may be substituted with a substituent group γ', an "aromatic carbocyclic carbonyloxy group which may be substituted with a substituent group γ", a "non-aromatic carbocyclic carbonyloxy group which may be substituted with a substituent group γ'", an "aromatic heterocyclic carbonyloxy group which may be substituted with a substituent group γ", and a "non-aromatic heterocyclic carbonyloxy group which may be substituted with a substituent group γ'", an aromatic carbocyclic carbonyl group which may be substituted with a substituent group γ, a non-aromatic carbocyclic carbonyl group which may be substituted with a substituent group γ', an aromatic heterocyclic carbonyl group which may be substituted with a substituent group γ, a non-aromatic heterocyclic carbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclic oxycarbonyl group which may be substituted with a substituent group γ, a non-aromatic carbocyclic oxycarbonyl group which may be substituted with a substituent group γ', an aromatic heterocyclic oxycarbonyl group which may be substituted with a substituent group γ, a non-aromatic heterocyclic oxycarbonyl group which may be substituted with a substituent group γ', an aromatic carbocyclic alkyl group which may be substituted with a substituent group γ', an aromatic heterocyclic alkyl group which may be substituted with a substituent group γ, a non-aromatic heterocyclic alkyl group which may be substituted with a substituent group γ', an aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy which may be substituted with substituent group γ', aromatic heterocyclic alkyloxy which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxy which may be substituted with substituent group γ', aromatic carbocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic carbocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxycarbonyl which may be substituted with substituent group γ', aromatic carbocyclic alkyloxyalkyl which may be substituted with substituent group γ, non-aromatic carbocyclic alkyloxyalkyl which may be substituted with substituent group γ', aromatic heterocyclic alkyloxyalkyl which may be substituted with substituent group γ, non-aromatic heterocyclic alkyloxyalkyl which may be substituted with substituent group γ' Cycloalkyloxyalkyl, an aromatic carbocyclic thiol group which may be substituted by substituent group γ, a non-aromatic carbocyclic thiol group which may be substituted by substituent group γ', an aromatic heterocyclic thiol group which may be substituted by substituent group γ, a non-aromatic heterocyclic thiol group which may be substituted by substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted by substituent group γ, a non-aromatic carbocyclic sulfinyl group which may be substituted by substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted by substituent group γ, a non-aromatic heterocyclic sulfinyl group which may be substituted by substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted by substituent group γ, a non-aromatic carbocyclic sulfonyl group which may be substituted by substituent group γ', an aromatic heterocyclic sulfonyl group which may be substituted by substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted by substituent group γ'.

[0248] Examples of the substituents on the rings of the “non-aromatic carbocyclic group”, “substituted non-aromatic heterocyclic group”, “substituted non-aromatic carbocyclic oxy group”, “substituted non-aromatic heterocyclic oxy group”, “substituted non-aromatic carbocyclic carbonyloxy group”, “substituted non-aromatic heterocyclic carbonyloxy group”, “substituted non-aromatic carbocyclic carbonyl group”, “substituted non-aromatic heterocyclic carbonyl group”, “substituted non-aromatic carbocyclic carbonyl group”, “substituted non-aromatic heterocyclic carbonyl group”, “substituted non-aromatic carbocyclic oxycarbonyl group”, “substituted non-aromatic heterocyclic oxycarbonyl group”, “substituted non-aromatic carbocyclic mercapto group”, “substituted non-aromatic heterocyclic mercapto group”, “substituted non-aromatic carbocyclic sulfinyl group”, “substituted non-aromatic heterocyclic sulfinyl group”, “substituted non-aromatic carbocyclic sulfonyl group” and “substituted non-aromatic heterocyclic sulfonyl group” include the following Substituent Group C. The atom at any position on the ring may be bonded to one or more groups selected from the following Substituent Group C.

[0249] Substituent Group C: Substituent Group B and oxo.

[0250] When a "non-aromatic carbocycle", "non-aromatic heterocycle", "non-aromatic carbocyclic group" and "non-aromatic heterocyclic group" are substituted with oxo, it means a ring in which two hydrogen atoms on the following carbon atom are substituted.

[0251] [Chemical formula 18]

[0252]

[0253] Examples of the substituents of the "substituted amino group", "substituted imino group", "substituted carbamoyl group" and "substituted sulfamoyl group" include the following substituent group D. The substituent group may be substituted by one or two groups selected from the substituent group D.

[0254] Substituent Group D: halogen, hydroxyl, carboxyl, cyano, alkyl which may be substituted by Substituent Group α, alkenyl which may be substituted by Substituent Group α, alkynyl which may be substituted by Substituent Group α, alkylcarbonyl which may be substituted by Substituent Group α, alkenylcarbonyl which may be substituted by Substituent Group α, alkynylcarbonyl which may be substituted by Substituent Group α, alkylthio which may be substituted by Substituent Group α, alkenylthio which may be substituted by Substituent Group α, alkynylthio which may be substituted by Substituent Group α, alkylsulfinyl which may be substituted by Substituent Group α, alkenylsulfinyl which may be substituted by Substituent Group α, alkynylsulfinyl which may be substituted by Substituent Group α, alkylsulfonyl which may be substituted by Substituent Group α, alkenylsulfonyl which may be substituted by Substituent Group α, alkynylsulfonyl which may be substituted by Substituent Group α,

[0255] an amino group which may be substituted by a substituent group β, an imino group which may be substituted by a substituent group β, a carbamoyl group which may be substituted by a substituent group β, a sulfamoyl group which may be substituted by a substituent group β,

[0256] an aromatic carbocyclic group which may be substituted with the substituent group γ, a non-aromatic carbocyclic group which may be substituted with the substituent group γ', an aromatic heterocyclic group which may be substituted with the substituent group γ, a non-aromatic heterocyclic group which may be substituted with the substituent group γ', an aromatic carbocyclic alkyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclic alkyl group which may be substituted with the substituent group γ', an aromatic heterocyclic alkyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclic alkyl group which may be substituted with the substituent group γ', an aromatic carbocyclic carbonyl group which may be substituted with the substituent group γ', an aromatic heterocyclic carbonyl group which may be substituted with the substituent group γ, a non-aromatic heterocyclic carbonyl group which may be substituted with the substituent group γ', an aromatic carbocyclic oxycarbonyl group which may be substituted with the substituent group γ, a non-aromatic carbocyclic oxycarbonyl group which may be substituted with the substituent group γ', an aromatic heterocyclic oxycarbonyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic oxycarbonyl group which may be substituted by the substituent group γ', an aromatic carbocyclic thiol group which may be substituted by the substituent group γ, a non-aromatic carbocyclic thiol group which may be substituted by the substituent group γ', an aromatic heterocyclic thiol group which may be substituted by the substituent group γ, a non-aromatic heterocyclic thiol group which may be substituted by the substituent group γ', an aromatic carbocyclic sulfinyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic sulfinyl group which may be substituted by the substituent group γ', an aromatic heterocyclic sulfinyl group which may be substituted by the substituent group γ, a non-aromatic heterocyclic sulfinyl group which may be substituted by the substituent group γ', an aromatic carbocyclic sulfonyl group which may be substituted by the substituent group γ, a non-aromatic carbocyclic sulfonyl group which may be substituted by the substituent group γ', an aromatic heterocyclic sulfonyl group which may be substituted by the substituent group γ, and a non-aromatic heterocyclic sulfonyl group which may be substituted by the substituent group γ'.

[0257] In formula (II), the bond marked with *1 of -L- and R 3 The bond marked with *2 of -L- is bonded to the imidazole ring.

[0258] Preferred embodiments of the respective definitions of the compound represented by the formula (I) are shown below. As the compound represented by the formula (I), all combinations of the specific examples shown below can be exemplified.

[0259] A 1 C(R 1 ) or N.

[0260] A 1 Preferably C(R 1 ).

[0261] R 1 A hydrogen atom or a halogen.

[0262] R 1 Preferred is a hydrogen atom or a fluorine atom.

[0263] R 8 It is a hydrogen atom, a halogen, an alkyloxy group or a 5- to 6-membered aromatic heterocyclic group which may be substituted with a halogen or an alkyl group.

[0264] R 8 It is preferably a hydrogen atom, a fluorine atom, a methyloxy group or a methylpyrazolyl group, and more preferably a hydrogen atom, a fluorine atom or a methyloxy group.

[0265] B 1 It is CH or N.

[0266] B 1 Preferably N.

[0267] B 1 Another way is CH.

[0268] R 10 It is a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group.

[0269] R 10 A chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group is preferred, and a trifluoromethyl group is more preferred.

[0270] As another way, R 10 Examples thereof include a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group, and a difluoromethyl group.

[0271] As another way, R 10 A chlorine atom or a difluoromethyl group can be mentioned.

[0272] Here, (i) in R 10 In the case of chlorine atoms, B 1 For N,

[0273] (ii) In R 10 In the case of trifluoromethyl, R 3 is a 5-membered aromatic heterocyclic group which may be substituted by a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by a substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by 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

[0274] (iii) Except for the following compounds:

[0275] [Chemical formula 19]

[0276]

[0277] Substituent Group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy.

[0278] Preferred embodiments of the substituent group F are a fluorine atom, a chlorine atom, a cyano group, a methyl group, a methyloxy group or a difluoromethyloxy group.

[0279] R 3 It is a phenyl group which may be substituted by substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted by substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by substituent group F.

[0280] R 3 The following groups are preferred.

[0281] [Chemical formula 20]

[0282]

[0283] (W is N or CR 15 ;

[0284] R 11 is a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0285] R 12 and R 13 are each independently a hydrogen atom or a halogen;

[0286] R 14 and R 15 are each independently a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0287] R 11 and R 12 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0288] R 11 and R 13 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0289] R 13 and R 14 They may form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F.

[0290] R 3 More preferably, it is any of the following groups.

[0291] [Chemical formula 21]

[0292]

[0293] (Where R 4are each independently halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.

[0294] R 4 Preferably, each independently is a fluorine atom, a chlorine atom, a cyano group, a methyl group, a methyloxy group or a difluoromethyloxy group.

[0295] In R 10 When it is trifluoromethyl, as another embodiment, R 3 Examples thereof include a 5-membered aromatic heterocyclic group which may be substituted with the substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted with the substituent group F, and a bicyclic 8- to 11-membered non-aromatic heterocyclic group which may be substituted with the substituent group F.

[0296] Preferred embodiments of the respective definitions of the compound represented by formula (II) are shown below. As the compound represented by formula (II), all combinations of the specific examples shown below can be exemplified.

[0297] Q is a substituted or unsubstituted benzene ring or a substituted or unsubstituted 5- to 6-membered aromatic heterocyclic ring.

[0298] Q is preferably any of the following groups.

[0299] [Chemical formula 22]

[0300]

[0301] (Where,

[0302] A 2 C(R 5 ) or N;

[0303] A 3 C(R 6 ) or N;

[0304] A 4 C(R 7 ) or N;

[0305] R 5 , R 6 and R 7 each independently represents a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group (examples of the substituent: halogen, etc.), a substituted or unsubstituted alkyloxy group (examples of the substituent: halogen, etc.), a substituted or unsubstituted aromatic heterocyclic group (examples of the substituent: halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, etc.), or a substituted or unsubstituted non-aromatic carbocyclic group (examples of the substituent: halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, etc.);

[0306] A 5 C(R9 ) or N;

[0307] R 9 is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group (examples of the substituent: halogen, etc.) or a substituted or unsubstituted alkyloxy group (examples of the substituent: halogen, etc.)

[0308] Q is more preferably the following groups.

[0309] [Chemical formula 23]

[0310]

[0311] (In the formula, each symbol has the same meaning as above)

[0312] A 2 , A 3 and A 4 Preferably: (i) A 2 C(R 5 ), A 3 C(R 6 ) and A 4 C(R 7 ),or

[0313] (ii)A 2 N, A 3 C(R 6 ) and A 4 C(R 7 ),or

[0314] (iii)A 2 C(R 5 ), A 3 C(R 6 ) and A 4 is N, or

[0315] (iv)A 2 N, A 3 C(R 6 ) and A 4 is N.

[0316] A 2 , A 3 and A 4 More preferably: (i) A 2 C(R 5 ), A 3 C(R 6 ) and A 4 C(R 7 ),or

[0317] (ii)A 2 N, A 3C(R 6 ) and A 4 C(R 7 ).

[0318] R 5 , R 6 and R 7 Preferably, each independently represents a hydrogen atom, a halogen, an alkyl group, an alkyloxy group or a 5- to 6-membered aromatic heterocyclic group which may be substituted with the substituent group E.

[0319] Substituent Group E: halogen, alkyl, haloalkyl, alkyloxy and haloalkyloxy.

[0320] The substituent group E is preferably a group selected from halogen and alkyl.

[0321] R 5 A hydrogen atom or a halogen is preferred, and a hydrogen atom or a fluorine atom is more preferred.

[0322] R 6 Preferred is a hydrogen atom.

[0323] R 7 It is preferably a hydrogen atom, a halogen, an alkyloxy group or a methylpyrazolyl group, and more preferably a hydrogen atom, a fluorine atom, a methyloxy group or a methylpyrazolyl group.

[0324] A 5 Preferably C(R 9 ).

[0325] R 9 A hydrogen atom, a halogen, a cyano group, an alkyl group or an alkyloxy group is preferred, and a hydrogen atom is more preferred.

[0326] R 2 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group.

[0327] R 2 An alkyl group, an alkyl group substituted by a non-aromatic heterocyclic group, or an alkyl group substituted by an aromatic heterocyclic group is preferred, and an oxetanylalkyl group or an alkylimidazolylalkyl group is more preferred.

[0328] R 2 Most preferred is oxetanylmethyl.

[0329] -L- is any of the following groups.

[0330] [Chemical formula 24]

[0331]

[0332] -L- is preferably a group represented by (a), (c), (d), (e), (f), (g), (h) or (j) above, more preferably (a), (c), (d), (g), (h) or (j) above. Further preferably (a), (c) or (d) above.

[0333] Another preferred embodiment of -L- is the above-mentioned (c) or (h).

[0334] Here, (i) when -L- is a group represented by (d), Q is a benzene ring substituted with a substituted or unsubstituted aromatic heterocyclic group (examples of substituents: halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, etc.), a 6-membered aromatic heterocyclic ring substituted with a substituted or unsubstituted aromatic heterocyclic group (examples of substituents: halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, etc.), or a substituted or unsubstituted 5-membered aromatic heterocyclic ring (examples of substituents: halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, etc.), preferably a benzene ring substituted with a substituted or unsubstituted aromatic heterocyclic group (examples of substituents: halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, etc.) or a substituted or unsubstituted 5-membered aromatic heterocyclic ring (examples of substituents: halogen, alkyl, haloalkyl, alkyloxy, haloalkyloxy, etc.).

[0335] B 1 It is CH or N, preferably N.

[0336] B 2 C(R 9 ) or N, preferably N.

[0337] B 2 Another preferred embodiment is C(R 9 ).

[0338] B 3 It is CH or N, preferably CH.

[0339] R 9 A hydrogen atom or 13a Together they form -O- or -CH 2 -O- (the bond on the right side is bonded to the benzene ring), and is preferably a hydrogen atom.

[0340] As R 9 Another way, with R 13a Together they form -O-.

[0341] R 13a A hydrogen atom or 9 Together they form -O- or -CH 2 -O- (the bond on the right side is bonded to the benzene ring), and is preferably a hydrogen atom.

[0342] As R 13a Another way, with R 9 Together they form -O-.

[0343] R 13b It is a hydrogen atom or a substituted or unsubstituted alkyl group (examples of the substituent: halogen, etc.), and preferably a hydrogen atom or an alkyl group.

[0344] R 10a It is a hydrogen atom or a substituted or unsubstituted alkyl group (examples of the substituent: halogen, etc.), and preferably a methyl group.

[0345] R 10b It is a hydrogen atom, a cyano group, a halogen or a substituted or unsubstituted alkyl group (examples of the substituent: halogen, etc.), preferably a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group, and more preferably a trifluoromethyl group.

[0346] -L 1 - is an alkylene group, preferably a C1-C3 alkylene group, more preferably an ethylene group.

[0347] X is S, NH or CH 2 , preferably NH.

[0348] R 3 Examples of the group include the same groups as those in the above formula (I), and preferred groups are also the same.

[0349] (Implementation Method 1)

[0350] A compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof:

[0351] [Chemical formula 25]

[0352]

[0353] (Where,

[0354] A 2 C(R 5 ) or N;

[0355] R 5 is a hydrogen atom or a halogen;

[0356] R 7 is a hydrogen atom, a halogen, an alkyloxy group, or a 5- to 6-membered aromatic heterocyclic group which may be substituted by a halogen or an alkyl group;

[0357] R 10b is a cyano group, a fluorine atom, a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group;

[0358] W is N or CR 15 ;

[0359] R 11 is a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0360] R 12 and R 13 are each independently a hydrogen atom or a halogen;

[0361] R 14 and R 15 are each independently a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0362] R 11 and R 12 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0363] R 11 and R 13 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0364] R 13 and R 14 They may form together a 5-membered aromatic heterocyclic ring which may be substituted by the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by the substituent group F.

[0365] (Implementation Method 2)

[0366] A compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof:

[0367] [Chemical formula 26]

[0368]

[0369] (Where,

[0370] A 2 C(R 5 ) or N;

[0371] R 5 is a hydrogen atom or a halogen;

[0372] R 7 is a hydrogen atom, a halogen, an alkyloxy group, or a 5- to 6-membered aromatic heterocyclic group which may be substituted by a halogen or an alkyl group;

[0373] R 10b is a cyano group, a fluorine atom, a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group;

[0374] W is N or CR 15 ;

[0375] R 11 is a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0376] R 12 and R 13 are each independently a hydrogen atom or a halogen;

[0377] R 14 and R 15 are each independently a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group;

[0378] R 11 and R 12 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0379] R 11 and R 13 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F,

[0380] R 13 and R 14 They may form together a 5-membered aromatic heterocyclic ring which may be substituted by the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by the substituent group F.

[0381] (Implementation 3)

[0382] The compound or pharmaceutically acceptable salt thereof of embodiment 1 or 2, wherein R 10b It is trifluoromethyl.

[0383] (Implementation 4)

[0384] The compound or pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 3, wherein R 7 It is an alkyloxy group or a 5- to 6-membered aromatic heterocyclic group which may be substituted with halogen or alkyl.

[0385] The compounds represented by formula (I), formula (II) or formula (II-1) to formula (II-2) are not limited to specific isomers, and include all possible isomers (for example, keto-enol tautomers, imine-enamine tautomers, diastereomers, optical isomers, rotational isomers, tautomers as described below, etc.), racemates or mixtures thereof.

[0386] One or more hydrogen, carbon and / or other atoms in the compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) may be replaced by isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are: 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 compounds represented by formula (I), formula (II) or formula (II-1) to formula (II-2) also include compounds substituted with such isotopes. The compounds substituted with the isotopes are also useful as pharmaceuticals, including all isotopes and radioactive labels of the compounds represented by formula (I), formula (II) or formula (II-1) to formula (II-2). In addition, the "radioactive labeling method" for producing the "radioactive label" is also included in the present invention, and the "radioactive label" is useful as a tool for research and / or diagnosis in metabolic pharmacokinetics research and binding analysis.

[0387] The radioactive label of the compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) can be prepared by methods well known in the art. For example, the tritium-labeled compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) can be prepared by introducing tritium into a specific compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) based on a catalytic dehalogenation reaction using tritium. The method comprises reacting a precursor in which a compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) is appropriately substituted with a halogen with tritium gas in the presence of a suitable catalyst (e.g., Pd / C) in the presence or absence of a base. Other suitable methods for preparing tritium-labeled compounds can be found in "Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)". 14 C-labeled compounds can be prepared by using 14 C carbon raw materials to prepare.

[0388] Examples of pharmaceutically acceptable salts of the compounds represented by formula (I), (II) or (II-1) to (II-2) include compounds represented by formula (I), (II) or (II-1) to (II-2) with alkali metals (e.g., lithium, sodium, potassium, etc.), alkaline earth metals (e.g., calcium, barium, etc.), magnesium, transition metals (e.g., zinc, iron, etc.), ammonia, organic bases (e.g., trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, The invention also provides salts with amino acids (e.g., triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.), or salts with inorganic acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (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.). In particular, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, and methanesulfonic acid can be cited. These salts can be formed by commonly used methods.

[0389] The compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) or its pharmaceutically acceptable salt may form a solvate (e.g., hydrate, etc.), cocrystal and / or crystal polymorph, and the present invention also includes such various solvates, cocrystals and crystal polymorphs. For the compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2), "solvate" may be coordinated with any number of solvent molecules (e.g., water molecules, etc.). By placing the compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) or its pharmaceutically acceptable salt in the air, it may absorb moisture and adhere to adsorbed water, or it may form a hydrate. In addition, by recrystallizing the compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) or its pharmaceutically acceptable salt, a crystal polymorph may be formed. "Co-crystal" means that the compound or salt represented by formula (I), formula (II) or formula (II-1) to formula (II-2) and the counter molecule exist in the same crystal lattice, and may contain any number of counter molecules.

[0390] The compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) or its pharmaceutically acceptable salt sometimes forms a prodrug, and the present invention also includes such various prodrugs. A prodrug is a derivative of the compound of the present invention having a group that can be decomposed chemically or metabolically, and is a compound that becomes a pharmaceutically active compound of the present invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are converted into compounds represented by formula (I), formula (II) or formula (II-1) to formula (II-2) by enzymatic oxidation, reduction, hydrolysis, etc. under physiological conditions in the body, and compounds that are converted into compounds represented by formula (I), formula (II) or formula (II-1) to formula (II-2) by hydrolysis with gastric acid, etc. Methods for selecting appropriate prodrug derivatives and methods for producing them are described, for example, in "Design of Prodrugs, Elsevier, Amsterdam, 1985". Prodrugs sometimes have activity themselves.

[0391] When the compound represented by formula (I), formula (II) or formula (II-1) to formula (II-2) or its pharmaceutically acceptable salt has a hydroxyl group, for example, a prodrug such as an acyloxy derivative or a sulfonyloxy derivative prepared by reacting the compound having a hydroxyl group with a suitable acid halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonic acid anhydride and a mixed acid anhydride, or by using a fusing agent. 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 -.

[0392] (Method for producing the compound of the present invention)

[0393] The compounds represented by formula (I), formula (II) or formula (II-1) to formula (II-2) can be prepared, for example, by the general synthesis method shown below. The starting materials and reaction reagents used in these syntheses are all commercially available or can be prepared using commercially available compounds according to methods well known in the art. Extraction, purification, etc. can be carried out by the treatments performed in ordinary organic chemistry experiments.

[0394] The compounds of the present invention can be synthesized by referring to methods known in the art.

[0395] In the following steps, when there is a substituent that hinders the reaction (for example, a hydroxyl group, a thiol group, an amino group, a formyl group, a carbonyl group, a carboxyl group, etc.), it can be protected in advance by the method described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons) and the like, and the protecting group can be removed at the desired stage.

[0396] In addition, for all the following steps, the order of the steps can be appropriately changed, and each intermediate can be isolated and used in the next step. Reaction time, reaction temperature, solvent, reagent, protecting group, etc. are all just examples and are not particularly limited as long as they do not affect the reaction.

[0397] The following is a general method for synthesizing the compounds of the present invention. The starting materials and reagents used in these syntheses are commercially available or can be prepared using commercially available compounds according to methods well known in the art.

[0398] The compound represented by the general formula (I), formula (II) or formula (II-1) to formula (II-2) of the present invention can be produced, for example, by the synthetic route shown below.

[0399] General Synthesis Method 1

[0400] [Chemical formula 27]

[0401]

[0402] (wherein R is an alkyl group, X 2 and X 3 is a leaving group such as a halogen, M is Li, MgCl or MgBr, and other symbols are synonymous with the above)

[0403] Although the case where X is O is described as an example, synthesis can be performed using S in the same manner.

[0404] Process 1

[0405] By reacting a basic water-soluble compound with compound a1, compound a2 can be obtained.

[0406] The reaction temperature is 0°C to 70°C, preferably 0°C to 50°C.

[0407] The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.

[0408] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and the base can be used in an amount of 1 to 10 molar equivalents based on compound a1.

[0409] Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF, and the like, which can be used alone or in combination.

[0410] Process 2

[0411] Compound a4 can be obtained by reacting compound a3 with compound a2 in the presence of a fusing agent.

[0412] Examples of the fusing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, and HATU, and the fusing agent can be used in an amount of 1 to 5 molar equivalents based on compound a2.

[0413] Examples of the base include triethylamine, diisopropylethylamine, and p-dimethylaminopyridine, and the base can be used in an amount of 1 to 10 molar equivalents based on compound a2.

[0414] The compound a3 can be used in an amount of 1 to 5 molar equivalents based on the compound a2.

[0415] The reaction temperature is -20°C to 80°C, preferably 10°C to 70°C.

[0416] The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours.

[0417] Examples of the reaction solvent include THF, dichloromethane, and DMF, which can be used alone or in combination.

[0418] Process 3

[0419] By making the organometallic reagent R 10a -M reacts with compound a4 to obtain compound a5.

[0420] Examples of the organometallic reagent include Grignard reagents and organolithium reagents, and the organometallic reagent can be used in an amount of 1 to 10 molar equivalents based on compound a4.

[0421] The reaction temperature is -40°C to 60°C, preferably -20°C to 40°C.

[0422] The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.

[0423] Examples of the reaction solvent include THF, diethyl ether, and dioxane, which can be used alone or in combination.

[0424] Process 4

[0425] By reacting formic acid and amine with compound a5 in the presence of a ruthenium catalyst, compound a6 can be obtained.

[0426] Examples of ruthenium catalysts include [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-isopropyltoluene)ruthenium, [(S,S)-N-(2-amino-1,2-diphenylethyl)-p-toluenesulfonamide]chloro(p-isopropyltoluene)ruthenium, and the like, which can be used in an amount of 0.05 to 1 molar equivalent relative to compound a5.

[0427] Examples of the amine include triethylamine, and 1 to 5 molar equivalents of the amine can be used based on compound a5.

[0428] The reaction temperature is -10°C to 80°C, preferably 10°C to 60°C.

[0429] The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.

[0430] As the reaction solvent, acetonitrile or the like can be used.

[0431] Process 5

[0432] Compound a8 can be obtained by reacting compound a6 with compound a7 in the presence of a metal catalyst and a base, with the addition of tetrabutylammonium bromide or the like as necessary.

[0433] Examples of the metal catalyst include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium. The metal catalyst can be used in an amount of 0.001 to 0.5 molar equivalents based on compound a6.

[0434] Examples of the base include dicyclohexylamine, potassium tert-butoxide, sodium carbonate, potassium carbonate, and the like, and the base can be used in an amount of 1 to 10 molar equivalents based on compound a6.

[0435] Compound a7 can be used in an amount of 1 to 5 molar equivalents based on compound a6.

[0436] The reaction temperature is from 20°C to the reflux temperature of the solvent, and in some cases, the reaction is carried out under microwave irradiation.

[0437] The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.

[0438] Examples of the reaction solvent include THF, toluene, DMF, dioxane, and water, and these solvents can be used alone or in combination.

[0439] Process 6

[0440] Compound a9 can be obtained by reacting compound a8 with hydrogen in the presence of a metal catalyst.

[0441] Examples of the metal catalyst include palladium-carbon, platinum oxide, rhodium-alumina, and tris(triphenylphosphine)rhodium (I) chloride, and the metal catalyst can be used in an amount of 0.01 to 100% by weight based on compound a8.

[0442] The hydrogen pressure may be 1 to 50 atmospheres. As the hydrogen source, cyclohexene, 1,4-cyclohexadiene, formic acid, ammonium formate, etc. may also be used.

[0443] The reaction temperature is 0°C to the reflux temperature of the solvent, preferably 20°C to 40°C.

[0444] The reaction time is 0.5 to 72 hours, preferably 1 to 12 hours.

[0445] Examples of the reaction solvent include methanol, ethanol, propanol, isopropanol, butanol, THF, diethyl ether, toluene, ethyl acetate, acetic acid, and water, and these solvents can be used alone or in combination.

[0446] Process 7

[0447] Compound a10 can be obtained by reacting compound a9 with hydrazine monohydrate or the like.

[0448] Hydrazine monohydrate or the like can be used in an amount of 1 to 20 molar equivalents based on compound a9.

[0449] The reaction temperature is 0°C to 100°C, preferably 20°C to 80°C.

[0450] The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.

[0451] Examples of the reaction solvent include ethanol and the like.

[0452] Process 8

[0453] Compound a11 can be obtained by reacting compound a10 with trifluoroacetic anhydride.

[0454] Trifluoroacetic anhydride can be used in an amount of 1 to 10 molar equivalents based on compound a10.

[0455] The reaction temperature is -10°C to 80°C, preferably 0°C to 40°C.

[0456] The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.

[0457] Examples of the reaction solvent include dichloromethane, THF, dioxane, and acetonitrile, which can be used alone or in combination.

[0458] Process 9

[0459] Compound a1 can be obtained by reacting compound a11 with triphenylphosphine and a condensing agent.

[0460] Examples of the fusing agent include DEAD and DIAD, and the fusing agent can be used in an amount of 1 to 5 molar equivalents based on compound a11.

[0461] Triphenylphosphine can be used in an amount of 1 to 5 molar equivalents based on compound a11.

[0462] The reaction temperature is 0°C to 60°C, preferably 10°C to 40°C.

[0463] The reaction time is 0.1 to 12 hours, preferably 0.2 to 6 hours.

[0464] Examples of the reaction solvent include THF, dioxane, ethyl acetate, toluene, and acetonitrile, which can be used alone or in combination.

[0465] Process 10

[0466] Compound a13 can be obtained by reacting compound a12 with a base.

[0467] The reaction temperature is 0°C to 80°C, preferably 10°C to 60°C.

[0468] The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.

[0469] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and the base can be used in an amount of 1 to 10 molar equivalents based on compound a12.

[0470] Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF, and the like, which can be used alone or in combination.

[0471] Process 11

[0472] Compound a15 can be obtained by allowing compound a14 to act on compound a13 in the presence of a base.

[0473] The compound a14 can be used in an amount of 0.9 to 3 molar equivalents based on the compound a13.

[0474] The reaction temperature is from 0°C to the reflux temperature of the solvent.

[0475] The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.

[0476] Examples of the base include potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, and cesium carbonate, and the base can be used in an amount of 1 to 10 molar equivalents based on compound a13.

[0477] Examples of the reaction solvent include methanol, ethanol, acetonitrile, THF, and dimethylformamide, which can be used alone or in combination.

[0478] General Synthesis 2

[0479] [Chemical formula 28]

[0480]

[0481] (wherein, R' is an alkyl group or a halogenated alkyl group, and other symbols have the same meanings as above)

[0482] Process 1

[0483] Compound d2 can be obtained by allowing anhydrous sulfonate or sulfonyl chloride to act on compound d1 in the presence of a base.

[0484] The anhydrous sulfonate or sulfonyl chloride can be used in an amount of 1 to 5 molar equivalents based on compound d1.

[0485] Examples of the base include triethylamine, diisopropylethylamine, and pyridine, and the base can be used in an amount of 1 to 10 molar equivalents based on compound d1.

[0486] The reaction temperature is -40°C to 60°C, preferably -20°C to 40°C.

[0487] The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.

[0488] Process 2

[0489] Compound d3 can be obtained by allowing compound d2 to react with amine or alkylboronic acid in the presence of a base, a metal catalyst or a ligand.

[0490] 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), and bis(tri-tert-butylphosphine)palladium, and the like can be used in an amount of 0.001 to 0.5 molar equivalents relative to compound d2.

[0491] Examples of the ligand include BINAP, DPPF, and Xantphos, and the ligand can be used in an amount of 0.001 to 1 molar equivalent relative to compound d2.

[0492] 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, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and the like, and 1 to 10 molar equivalents can be used based on compound d2.

[0493] The amine or alkylboronic acid can be used in an amount of 1 to 10 molar equivalents based on compound d2.

[0494] The reaction temperature is from 20°C to the reflux temperature of the solvent, and is carried out under microwave irradiation in some cases.

[0495] The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.

[0496] Examples of the reaction solvent include THF, toluene, DMF, dioxane, and water, and these solvents can be used alone or in combination.

[0497] Process 3

[0498] Compound d4 can be obtained by reacting compound d3 with a base.

[0499] The reaction temperature is 0°C to 80°C, preferably 10°C to 60°C.

[0500] The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.

[0501] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and the base can be used in an amount of 1 to 10 molar equivalents based on compound d3.

[0502] Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF, and the like, which can be used alone or in combination.

[0503] Process 4

[0504] By reacting compound d4 in the same manner as in step 11 of general synthesis method 1, compound d5 can be obtained.

[0505] General Synthesis 3

[0506] [Chemical formula 29]

[0507]

[0508] (In the formula, each symbol has the same meaning as above)

[0509] Process 1

[0510] Compound g3 can be obtained by reacting compound g1 with compound g2 in the presence of a metal catalyst and a base.

[0511] Examples of the metal catalyst include palladium acetate, bis(dibenzylideneacetone)palladium, tetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladium(II) dichloride, and bis(tri-tert-butylphosphine)palladium. The metal catalyst can be used in an amount of 0.001 to 0.5 molar equivalents based on compound g1.

[0512] 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, sodium hydrogen phosphate, potassium phosphate, potassium hydrogen phosphate, and the like, and 1 to 10 molar equivalents can be used based on compound g1.

[0513] The compound g2 can be used in an amount of 1 to 10 molar equivalents relative to the compound g1.

[0514] The reaction temperature is from 20°C to the reflux temperature of the solvent, and is carried out under microwave irradiation in some cases.

[0515] The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.

[0516] Examples of the reaction solvent include THF, toluene, DMF, dioxane, and water, and these solvents can be used alone or in combination.

[0517] Process 2

[0518] Compound g4 can be obtained by reacting compound g3 with a base.

[0519] The reaction temperature is 0°C to 80°C, preferably 10°C to 60°C.

[0520] The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.

[0521] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and the base can be used in an amount of 1 to 10 molar equivalents relative to compound g3.

[0522] Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF, and the like, which can be used alone or in combination.

[0523] Process 3

[0524] By reacting compound g4 in the same manner as in step 11 of general synthesis method 1, compound g5 can be obtained.

[0525] General Synthesis Method 4

[0526] [Chemical formula 30]

[0527]

[0528] (In the formula, each symbol has the same meaning as above)

[0529] Process 1

[0530] By reacting compound i1 with a reducing agent, compound i2 can be obtained.

[0531] Examples of the reducing agent include diisobutylaluminum hydride and lithium borohydride, and the reducing agent can be used in an amount of 1 to 5 molar equivalents based on compound i1.

[0532] The reaction temperature is -40°C to 50°C, preferably -20°C to 30°C.

[0533] The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.

[0534] Examples of the reaction solvent include dichloromethane, THF, and toluene, which can be used alone or in combination.

[0535] Process 2

[0536] Compound i3 can be obtained by reacting compound i2 with diiodomethane in the presence of diethylzinc and a Lewis acid.

[0537] Diethylzinc can be used in an amount of 1 to 10 molar equivalents based on compound i2.

[0538] Diiodomethane can be used in an amount of 1 to 10 molar equivalents based on compound i2.

[0539] Examples of the Lewis acid include boron trifluoride ethyl ether, and the Lewis acid can be used in an amount of 1 to 5 molar equivalents based on compound i2.

[0540] The reaction temperature is -10°C to 50°C, preferably 0°C to 30°C.

[0541] The reaction time is 1 to 48 hours, preferably 3 to 24 hours.

[0542] Examples of the reaction solvent include dichloromethane, THF, and dioxane, which can be used alone or in combination.

[0543] Process 3

[0544] Compound i4 can be obtained by reacting compound i3 with a radical initiator and an oxidizing agent in the presence of a base.

[0545] Examples of the base include sodium hydrogen carbonate, sodium carbonate, sodium hydroxide, potassium carbonate, and calcium carbonate, and the base can be used in an amount of 1 to 2 molar equivalents relative to compound i3.

[0546] Examples of the radical initiator include TEMPO, AZADO, and TEMPOL, and the radical initiator can be used in an amount of 0.01 to 1 molar equivalent relative to compound i3.

[0547] Examples of the oxidizing agent include sodium chlorite, sodium hypochlorite, tert-butoxychloride, NCS, and meta-chloroperbenzoic acid. The oxidizing agent can be used in an amount of 2 to 5 molar equivalents relative to compound i3.

[0548] The reaction temperature is -20°C to 50°C, preferably 0°C to 30°C.

[0549] The reaction time is 0.1 to 24 hours, preferably 0.5 to 6 hours.

[0550] Examples of the reaction solvent include acetonitrile, water, dichloromethane, THF, DMF, and DMA, and these can be used alone or in combination.

[0551] Process 4

[0552] Compound i6 can be obtained by reacting a fusing agent and compound i5 with compound i4 in the presence or absence of a base and then reacting in an acid solution.

[0553] Compound i5 can be used in an amount of 1 to 5 molar equivalents relative to compound i4.

[0554] Examples of the fusing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride, and HATU, and 1 to 5 molar equivalents can be used relative to compound i4.

[0555] Examples of the base include triethylamine, diisopropylethylamine, and p-dimethylaminopyridine, and the base can be used in an amount of 1 to 10 molar equivalents based on compound i4.

[0556] Examples of the acid include hydrochloric acid and acetic acid, and the acid can be used in an amount of 1 to 20 molar equivalents based on compound i4.

[0557] The reaction temperature is -20°C to 60°C, preferably 0°C to 30°C, and the subsequent reaction in the acid solution is 10°C to 80°C.

[0558] The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours, for the condensation reaction, and the reaction in the acid solution thereafter is 0.5 to 10 hours.

[0559] General Synthesis 5

[0560] [Chemical formula 31]

[0561]

[0562] (In the formula, each symbol has the same meaning as above)

[0563] Process 1

[0564] Compound j3 can be obtained by reacting compound j2 with compound j1 in the presence of a base.

[0565] Compound j2 can be used in an amount of 1 to 5 molar equivalents relative to compound j1.

[0566] Examples of the base include sodium hydride, sodium methoxide, and LHMDS, and the base can be used in an amount of 1 to 10 molar equivalents based on compound j1.

[0567] The reaction temperature is -40°C to 50°C, preferably -20°C to 30°C.

[0568] The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.

[0569] Examples of the reaction solvent include THF and dimethoxyethane, which can be used alone or in combination.

[0570] Process 2

[0571] By reacting compound j3 with a reducing agent, compound j4 can be obtained.

[0572] Examples of the reducing agent include diisobutylaluminum hydride and lithium borohydride, and the reducing agent can be used in an amount of 1 to 5 molar equivalents based on compound j3.

[0573] The reaction temperature is -40°C to 50°C, preferably -20°C to 30°C.

[0574] The reaction time is 0.1 to 24 hours, preferably 0.5 to 12 hours.

[0575] Examples of the reaction solvent include dichloromethane, THF, and toluene, which can be used alone or in combination.

[0576] Process 3-4

[0577] By reacting compound j4 in the same manner as steps 2 to 4 of general synthesis method 4, compound j6 can be obtained.

[0578] General Synthesis Method 6

[0579] [Chemical formula 32]

[0580]

[0581] Process 1

[0582] By reacting the compound k1 with an acyl chloride, the organometallic reagent R 10 -M(R 10a is other than a hydrogen atom) or a hydride (R 10a is a hydrogen atom) to react with it to obtain compound k2.

[0583] Examples of the acid chloride include acetyl chloride and benzoyl chloride, and the acid chloride can be used in an amount of 1 to 10 molar equivalents based on compound k1.

[0584] Examples of the organometallic reagent include Grignard reagents and organolithium reagents, and the organometallic reagent can be used in an amount of 1 to 10 molar equivalents based on compound k1.

[0585] As the hydride, sodium borohydride and the like are mentioned, and 1 to 10 molar equivalents can be used based on compound k1.

[0586] The reaction temperature is 0°C to 80°C, preferably 10°C to 60°C.

[0587] The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.

[0588] Examples of the reaction solvent include THF and dichloromethane, which can be used alone or in combination.

[0589] Process 2

[0590] By reacting compound k2 in the same manner as in step 2 of general synthesis method 4, compound k3 can be obtained.

[0591] Process 3

[0592] Compound k4 can be obtained by reacting compound k3 with a base.

[0593] The reaction temperature is 0°C to 80°C, preferably 10°C to 60°C.

[0594] The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.

[0595] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like, and the base can be used in an amount of 1 to 10 molar equivalents based on compound k3.

[0596] Examples of the reaction solvent include methanol, ethanol, water, acetone, acetonitrile, THF, and the like, which can be used alone or in combination.

[0597] Process 4

[0598] By reacting compound k4 in the same manner as in step 11 of general synthesis method 1, compound k5 can be obtained.

[0599] General Synthesis 7

[0600] [Chemical formula 33]

[0601]

[0602] (In the formula, each symbol has the same meaning as above)

[0603] Process 1

[0604] By making the organometallic reagent R 10a -M(R 10a is other than a hydrogen atom) or a hydride (R 10a is a hydrogen atom) and react with compound 11 to obtain compound 12.

[0605] Examples of the organometallic reagent include Grignard reagents and organolithium reagents, and the organometallic reagent can be used in an amount of 1 to 5 molar equivalents based on compound 11.

[0606] As the hydride, sodium borohydride and the like are exemplified, and 1 to 10 molar equivalents can be used based on compound 11.

[0607] The reaction temperature is -40°C to 60°C, preferably -20°C to 50°C.

[0608] The reaction time is 0.5 to 12 hours, preferably 1 to 6 hours.

[0609] Examples of the reaction solvent include THF, dioxane, and dimethoxyethane, which can be used alone or in combination.

[0610] Process 2

[0611] Compound 13 can be obtained by reacting anhydrous sulfonate or sulfonyl chloride with Compound 12 in the presence of a base.

[0612] The anhydrous sulfonate or sulfonyl chloride can be used in an amount of 1 to 10 molar equivalents based on compound 12.

[0613] Examples of the base include triethylamine, diisopropylethylamine, and pyridine, and the base can be used in an amount of 1 to 10 molar equivalents relative to compound 12.

[0614] The reaction temperature is -40°C to 60°C, preferably -20°C to 40°C.

[0615] The reaction time is 0.1 to 48 hours, preferably 1 to 24 hours.

[0616] Examples of the reaction solvent include dichloromethane, THF, DMF, and acetonitrile, which can be used alone or in combination.

[0617] Process 3

[0618] Compound 14 can be obtained by reacting compound 13 with sodium azide and then reacting triphenylphosphine and water.

[0619] Sodium azide can be used in an amount of 1 to 10 molar equivalents based on compound 13.

[0620] The reaction temperature in the first stage is 0°C to 80°C, preferably 10°C to 60°C.

[0621] The reaction time of the first stage is 0.5 to 24 hours, preferably 1 to 12 hours.

[0622] Examples of the reaction solvent in the first step include THF, dichloromethane, DMF, and acetonitrile, which can be used alone or in combination.

[0623] Triphenylphosphine can be used in an amount of 1 to 10 molar equivalents based on compound 13.

[0624] The reaction temperature in the second stage is 0°C to 80°C, preferably 10°C to 60°C.

[0625] The reaction time of the second stage is 0.5 to 48 hours, preferably 1 to 24 hours.

[0626] Examples of the reaction solvent in the second step include THF and the like.

[0627] Process 4

[0628] Compound 15 can be obtained by reacting compound 14 with a base.

[0629] The reaction temperature is 0°C to 80°C, preferably 10°C to 60°C.

[0630] The reaction time is 0.5 to 12 hours, preferably 1 to 10 hours.

[0631] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, and the base can be used in an amount of 1 to 10 molar equivalents based on compound 14.

[0632] Examples of the reaction solvent include methanol, ethanol, water, and THF, which can be used alone or in combination.

[0633] Process 5

[0634] Compound 16 can be obtained by reacting a fusing agent with compound 15 in the presence / absence of a base.

[0635] Examples of the fusing agent include dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, EDC, and HATU, and the fusing agent can be used in an amount of 1 to 5 molar equivalents relative to compound 15.

[0636] Examples of the base include triethylamine, diisopropylethylamine, and p-dimethylaminopyridine, and the base can be used in an amount of 1 to 10 molar equivalents relative to compound 15.

[0637] The reaction temperature is -20°C to 80°C, preferably 10°C to 70°C.

[0638] The reaction time is 0.1 to 24 hours, preferably 1 to 12 hours.

[0639] Examples of the reaction solvent include THF, dichloromethane, and DMF, which can be used alone or in combination.

[0640] Process 6

[0641] Compound 17 can be obtained by reacting compound 16 with a reducing agent.

[0642] Examples of the reducing agent include lithium aluminum hydride, which can be used in an amount of 1 to 20 molar equivalents relative to compound 16.

[0643] The reaction temperature is from 0°C to the reflux temperature of the solvent.

[0644] The reaction time is 0.5 to 24 hours, preferably 1 to 12 hours.

[0645] As the reaction solvent, THF or the like can be used.

[0646] Process 7

[0647] By reacting compound 17 in the same manner as in step 11 of general synthesis method 1, compound 18 can be obtained.

[0648] General Synthesis 8

[0649] [Chemical formula 34]

[0650]

[0651] (In the formula, each symbol has the same meaning as above)

[0652] Process 1

[0653] Compound m2 can be obtained by reacting diphenylphosphoryl azide with compound m1 in the presence of a base and then reacting water therewith.

[0654] Diphenyl phosphoryl azide can be used in an amount of 1 to 10 molar equivalents based on compound m1.

[0655] Examples of the base include triethylamine, diisopropylethylamine, and pyridine, and the base can be used in an amount of 1 to 10 molar equivalents based on compound m1.

[0656] The reaction temperature is -10°C to the reflux temperature of the solvent, preferably 20°C to the reflux temperature of the solvent, for the transfer reaction, and -20°C to 60°C, preferably 0°C to 40°C for the hydrolysis reaction.

[0657] The reaction time is 0.5 to 48 hours, preferably 1 to 24 hours, for the transfer reaction, and 0.1 to 24 hours, preferably 0.1 to 6 hours, for the hydrolysis reaction.

[0658] Examples of the reaction solvent include toluene and THF, which can be used alone or in combination.

[0659] Process 2

[0660] By reacting compound m2 in the same manner as in step 8 of general synthesis method 1, compound m3 can be obtained.

[0661] Process 3

[0662] By reacting compound m3 in the same manner as in step 1 of general synthesis method 7, compound m4 can be obtained.

[0663] Process 4

[0664] By reacting compound m4 in the same manner as in step 9 of general synthesis method 1, compound m5 can be obtained.

[0665] Process 5

[0666] By reacting compound m5 in the same manner as in step 10 of general synthesis method 1, compound m6 can be obtained.

[0667] Process 6

[0668] By reacting compound m6 in the same manner as in step 11 of general synthesis method 1, compound m7 can be obtained.

[0669] Since the compound of the present invention has GLP-1 receptor agonist activity, it is useful as a therapeutic agent and / or preventive agent for GLP-1 receptor-related diseases.

[0670] In the present invention, when referring to a "therapeutic agent and / or preventive agent", a symptom-alleviating agent is also included.

[0671] Examples of GLP-1 receptor-related diseases include non-insulin-dependent diabetes mellitus (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin-dependent diabetes mellitus (type 1 diabetes), diabetic complications, obesity, hypertension, dyslipidemia, arteriosclerosis, myocardial infarction, coronary heart disease, cerebral infarction, non-alcoholic steatohepatitis, Parkinson's disease, and dementia.

[0672] In the present invention, "diabetes" refers to a disease or condition in which metabolic abnormalities occur in the production and utilization of glucose due to failure to maintain an appropriate blood sugar level in the body, and includes insulin-dependent diabetes mellitus (type 1 diabetes) and non-insulin-dependent diabetes mellitus (type 2 diabetes).

[0673] "Hyperglycemia" refers to a state in which the plasma glucose level when fasting or after administration of glucose is higher than the normal value (for example, 80 to 110 mg / dL in humans when fasting), and is one of the representative symptoms of diabetes.

[0674] "Improper glucose tolerance" includes impaired glucose tolerance due to insulin resistance and defective insulin secretion.

[0675] "Diabetic complications" refer to complications caused by diabetes or hyperglycemia, and may be either acute or chronic. Examples of "acute complications" include ketoacidosis, infections (e.g., skin infections, soft tissue infections, biliary system infections, respiratory system infections, and urinary tract infections); examples of "chronic complications" include microangiopathy (e.g., nephropathy, retinopathy), neurological disorders (e.g., sensory nerve disorders, motor nerve disorders, and autonomic nerve disorders), and foot gangrene. Major diabetic complications include diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. "Coronary heart disease" includes myocardial infarction, angina pectoris, and the like.

[0676] Examples of "dementia" include Alzheimer's disease, vascular dementia, and diabetic dementia.

[0677] The compound of the present invention not only has GLP-1 receptor agonist activity but also has usefulness as a medicine and has any or all of the following excellent characteristics.

[0678] a) The inhibitory effect on CYP enzymes (such as CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.

[0679] b) It exhibits good pharmacokinetics such as high bioavailability and moderate clearance.

[0680] c) High metabolic stability.

[0681] d) It does not show irreversible inhibitory action on CYP enzymes (such as CYP3A4) within the concentration range of the assay conditions described in the present specification.

[0682] e) Not mutagenic.

[0683] f) Low risk to the cardiovascular system.

[0684] g) Low risk of hematologic toxicity.

[0685] h) Shows high solubility.

[0686] The pharmaceutical composition of the present invention can be administered by any method, either orally or parenterally. Examples of parenterally administered methods include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drops, ear drops, and vaginal administration.

[0687] In the case of oral administration, the drug may be prepared according to conventional methods into any commonly used dosage forms such as solid preparations for internal use (e.g., tablets, powders, granules, capsules, pills, films, etc.), liquid preparations for internal use (e.g., suspensions, emulsions, elixirs, syrups, lemonades, alcohols, aromatic waters, extracts, decoctions, tinctures, etc.). Tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, lozenges, sublingual tablets, buccal tablets, chewable tablets, or orally disintegrating tablets; powders and granules may be dry syrups; and capsules may be soft capsules, microcapsules, or sustained-release capsules.

[0688] In the case of parenteral administration, it can be appropriately administered in any commonly used dosage form such as injection, drip, external preparation (e.g., eye drops, nose drops, ear drops, aerosol, inhalation, lotion, injection, coating, gargle, enema, ointment, plaster, gel, cream, patch, paste, external powder, suppository, etc.). Injection can be an emulsion such as O / W, W / O, O / W / O, W / O / W type.

[0689] Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants, etc. suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as needed to prepare a pharmaceutical composition. Furthermore, by appropriately changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention, the pharmaceutical composition can also be prepared as a pharmaceutical composition for children, the elderly, critically ill patients or surgery. The pharmaceutical composition for children is preferably administered to patients less than 12 years old or less than 15 years old. In addition, the pharmaceutical composition for children can be administered to patients less than 27 days after birth, 28 days to 23 months after birth, 2 years to 11 years old or 12 years to 17 years old or 18 years old. The pharmaceutical composition for the elderly is preferably administered to patients over 65 years old.

[0690] The dosage of the pharmaceutical composition of the present invention is preferably set after considering the patient's age, weight, type or degree of disease, route of administration, etc. In the case of oral administration, 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 route of administration, but is usually 0.005 to 10 mg / kg / day, preferably in the range of 0.01 to 1 mg / kg / day. It can be divided into 1 to several times a day for administration.

[0691] The compound of the present invention may be used in combination with a concomitant drug for the purpose of enhancing the effect of the compound or reducing the dosage of the compound. In this case, the administration period of the compound of the present invention and the concomitant drug is not limited, and they may be administered to the subject at the same time or at a time interval.

[0692] The concomitant drug is not limited to the drugs on the market or under development. Examples of the drugs on the market or under development include orlistat, synalistat, phentermine, mazindol, benzphetamine, amphetamine, methamphetamine, phentermine hydrochloride / topiramate, naltrexone hydrochloride / bupropion hydrochloride, setmelanotide (RM-493), metreleptin, topiramate, naltrexone, bupropion, acarbose, voglibose, miglitol, ipragliflozin, dapagliflozin, rupagliflozin, togliflozin, canagliflozin, empagliflozin, erpagliflozin, bexagliflozin, enavogliflozin, henagliflozin, and semagliflozin. zin), janagliflozin, soglipizin, aspart insulin, lispro insulin, glulisine insulin, biosynthetic human neutral insulin, human insulin, biosynthetic human low-protamine zinc insulin, human low-protamine zinc insulin, intermediate lispro insulin, detemir insulin, glargine insulin, degludec insulin, 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, alagliptin, saxagliptin, trelagliptin succinate, ogliptin, gemagliptin, evogliptin, imeglitin, sitagliptin phosphate / evogliptin, pioglitazone hydrochloride / metformin, pioglitazone hydrochloride / glimepiride, teneligliptin hydrobromide / canagliflozin, alogliptin benzoate / pioglitazone hydrochloride, alogliptin benzoate / metformin hydrochloride, vildagliptin / metformin hydrochloride, mitiglinide calcium / voglibose, pravastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, lovastatin, clinofibrate, clofibrate, bezafibrate, fenofibrate, Ciprofibrate, Pemafibrate, Gemfibrozil, Costin, Cholestyramine, Colesevelam hydrochloride, Colestipol, Ezetimibe, Probucol, Nicomol, Tocopherol Nicotinate, Pentylenetetrazolyl, Eicosapentaenoic Acid Ethyl, Omega-3 fatty acid ethyl esters, Elocumab, Alisumeb, Nifedipine, Amlodipine, Efonidipine, Cilnidipine, Nicardipine, Nisoldipine, Nitrendipine, Nilvadipine, Barnidipine, Felodipine, Benidipine, Manidipine, Azelnidipine, Aranidipine, Diltiazem, Trichlorothiazide, Benzyl hydrochlorothiazide, Hydrochlorothiazide, Meikuran, Indapamide, Tripamide, Mefuse, 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 tert-butylamine, 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 α-cyclodextrin inclusion complex, dihydroergot alkaloids, doxazosin, urapidil, hydralazine, prazosin, moxonidine, guanfacine, rilmenidine, amlodipine / atorvastatin, losartan / hydrochlorothiazide, valsartan / hydrochlorothiazide, candesartan / Hydrochlorothiazide, Telmisartan / Hydrochlorothiazide, Irbesartan / Trichlorothiazide, Valsartan / Amlodipine, Olmesartan / Azelnidipine, Candesartan / Amlodipine, Telmisartan / Amlodipine, Irbesartan / Amlodipine, Valsartan / Cilnidipine, 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, cilofisol (GS-9674), tropifexor (LJN452), EDP-305, EYP-001, resmetirom, VK-2809, cenicriviroc, saroglitazar,lanifranor, selosertin, PF-06835919, pegbelfermin, efrugxifermin, aldafermin, aramcol, MK-3655, MSDC-0602K, belapectin, firsocostat (GS-0976), PF-05221304, ervogastat, ION-224, AXA-1125, HU-6, MET-409, MET-642, TERN-101, TERN-501, LPCN-1144, denivasostat, iluxifrmin, lelizumab, pegozafermin, rencofilstat, retaglutide, talukast, S-237648, S-723595, BMS-963272, and the compounds shown below or their acceptable salts, etc. ,

[0693] [Chemical formula 35]

[0694]

[0695] [Chemical formula 36]

[0696]

[0697] Preferred examples include the following compounds or pharmaceutically acceptable salts thereof.

[0698] [Chemical formula 37]

[0699]

[0700] The dosage of the combined drug can be appropriately selected based on the dosage used clinically. In addition, the ratio of the compound of the present invention to the combined drug can be appropriately selected according to the subject of administration, route of administration, target disease, symptoms, combination, etc. For example, in the case of a human subject, 0.01 to 100 parts by weight of the combined drug can be used relative to 1 part by weight of the compound of the present invention.

[0701] The pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (pharmaceutical compositions containing compounds with anti-obesity effects, agents that can be used for obesity or weight management of obesity, etc.). For example, by using a pharmaceutical composition containing a compound with anti-obesity effects in combination with the compound of the present invention, it can be used for the prevention and / or treatment of obesity or weight management of obesity, etc. In addition, by using a pharmaceutical composition containing the compound of the present invention in combination with a pharmaceutical composition containing a compound with anti-obesity effects, it can be used for the prevention and / or treatment of obesity or weight management of obesity, etc. In addition, the administration therapy of the pharmaceutical composition of the present invention can also be used in combination with diet therapy, drug therapy, exercise, etc.

[0702] Example

[0703] 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 to these Examples.

[0704] In addition, the abbreviations used in this specification have the following meanings.

[0705] CHCl 3 :Chloroform

[0706] CDCl 3 : Deuterated chloroform

[0707] MeOH: Methanol

[0708] DMSO-d 6 : Deuterated dimethyl sulfoxide

[0709] DMSO: dimethyl sulfoxide

[0710] DMA: dimethylacetamide

[0711] DMF: dimethylformamide

[0712] THF: Tetrahydrofuran

[0713] EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0714] HATU: 2-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0715] DIAD: diisopropyl azodicarboxylate

[0716] DEAD: Diethyl azodicarboxylate

[0717] TBDPS: tert-butyldiphenylsilyl

[0718] TEMPO: 2,2,6,6-tetramethylpiperidin-1-oxyl

[0719] TEMPOL: 4-Hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl

[0720] AZADO: 2-Azaadamantane-N-oxyl

[0721] NCS: N-chlorosuccinimide

[0722] BINAP: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0723] DPPF: 1,1'-bis(diphenylphosphino)ferrocene

[0724] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0725] TLC: Thin layer chromatography

[0726] SFC: Supercritical Fluid Chromatography

[0727] ODS: Octadecylsilyl

[0728] M: mol / L

[0729] (Method for identification of compounds)

[0730] The NMR analysis obtained in each example was performed at 400 MHz using DMSO-d 6 or CDCl 3 When NMR data are shown, all the peaks measured may not be described.

[0731] In the examples, "No." indicates the compound number, "Structure" indicates the chemical structure, and "MS" indicates 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.

[0732] (Measurement Condition 1)

[0733] Column: ACQUITY UPLC BEH C18 (1.7μm id2.1×50mm) (Waters)

[0734] Flow rate: 0.8 mL / min

[0735] UV detection wavelength: 254nm

[0736] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0737] Gradient: After a linear gradient of 5%-100% solvent [B] in 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.

[0738] (Measurement Condition 2)

[0739] Column: Shim-pack XR-ODS (2.2μm, id3.0×50mm) (Shimadzu)

[0740] Flow rate: 1.6 mL / min; UV detection wavelength: 254 nm;

[0741] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0742] Gradient: After a linear gradient of 10%-100% solvent [B] in 3 minutes, 100% solvent [B] was maintained for 0.5 minutes.

[0743] (Measurement Condition 3)

[0744] Column: ACQUITY UPLC BEH C18 (1.7μm id2.1×50mm) (Waters)

[0745] Flow rate: 0.8 mL / min; UV detection wavelength: 254 nm;

[0746] Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid

[0747] Gradient: After a linear gradient of 5%-100% solvent [B] in 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.

[0748] (Measurement Condition 4)

[0749] Column: ACQUITY UPLC BEH C18 (1.7μm id2.1×50mm) (Waters)

[0750] Flow rate: 0.8 mL / min

[0751] UV detection wavelength: 254nm

[0752] Mobile phase: [A] aqueous solution containing 10 mM ammonium carbonate, [B] acetonitrile

[0753] Gradient: After a linear gradient of 5%-100% solvent [B] in 3.5 minutes, 100% solvent [B] was maintained for 0.5 minutes.

[0754] (Measurement Condition 5)

[0755] Column: L-column2 ODS (3μm i.d. 3×50mm) (National Institute for the Evaluation of Chemical Substances)

[0756] Flow rate: 1.5mL / min

[0757] UV detection wavelength: 220nm

[0758] Mobile phase: [A] is an aqueous solution containing 0.05% trifluoroacetic acid, [B] is an acetonitrile solution containing 0.05% trifluoroacetic acid

[0759] Gradient: After a linear gradient of 5%-95% solvent [B] in 3.5 minutes, 95% solvent [B] was maintained for 2 minutes.

[0760] Example 1

[0761] [Chemical formula 38]

[0762]

[0763] Process 1

[0764] To a solution of compound 1 (3.42 g, 14.85 mmol) in acetonitrile (35 mL) were added formic acid (2.45 mL, 63.8 mmol), triethylamine (5.15 mL, 37.1 mmol), [(R,R)-N-(2-amino-1,2-diphenylethyl)-p-methylbenzenesulfonamide]chloro(p-isopropyltoluene)ruthenium (II) (0.19 g, 0.30 mmol), and stirred at room temperature for 6 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was washed with an aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 2 (3.44 g, yield 100%).

[0765] 1 H-NMR (CDCl 3 )δ: 1.45 (3H, d, J = 6.4Hz), 3.96 (3H, s), 4.03 (1H, d, J = 8.3Hz), 5.01-5.08 (1H, m), 6.59 (1H, d, J = 8.7Hz), 7.67 (1H, d, J = 8.7Hz).

[0766] MS (m / z) = 232 [M + H] +

[0767] Process 2

[0768] To a DMF (27.5 mL) solution of compound 2 (3.44 g, 14.82 mmol), tetrabutylammonium bromide (4.78 g, 14.82 mmol), palladium acetate (0.33 g, 1.48 mmol), N,N-dicyclohexyl-N-methylamine (4.72 mL, 22.23 mmol) were added. The reaction vessel was degassed under reduced pressure and replaced with nitrogen, and the reaction solution was stirred at 110°C for 1 hour. Water was added to the reaction solution, and the generated solid was filtered out. The obtained solid was washed with diisopropyl ether to obtain compound 3 (3.87 g, yield 81%).

[0769] 1 H-NMR (CDCl 3 )δ:1.45(3H,d,J=6.4Hz),3.99(3H,s),4.54(1H,d,J=7.7Hz),5.09-5.16(1H,m),6.71(1H,d,J =8.5Hz),7.17(1H,d,J=14.9Hz),7.72(1H,d,J=14.9Hz),7.77-7.81(3H,m),7.90-7.93(2H,m).

[0770] MS (m / z) = 325 [M + H] +

[0771] Process 3

[0772] 10% palladium-carbon (water 50%) (2.54 g, 1.2 mmol) was added to a mixed solution of compound 3 (3.87 g, 11.9 mmol) in methanol (25 mL)-THF (50 mL), and stirred at room temperature for 6 and a half hours under a hydrogen (1 atmosphere). Insoluble matter was removed by filtration, and the solvent was removed by distillation under reduced pressure to obtain compound 4 (1.55 g, 40% yield).

[0773] 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).

[0774] MS (m / z) = 327 [M + H] +

[0775] Process 4

[0776] To a solution of compound 4 (1.55 g, 4.75 mmol) in ethanol (30 mL) was added hydrazine monohydrate (1.15 mL, 23.75 mmol), and the mixture was stirred at 80° C. for 35 minutes. Insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure. Dichloromethane was added to the resulting residue, the precipitated insoluble matter was removed by filtration, and the solvent was distilled off under reduced pressure to obtain a crude product of compound 5 (1.05 g).

[0777] 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).

[0778] MS (m / z) = 197 [M + H] +

[0779] Process 5

[0780] Trifluoroacetic anhydride (2.0 mL, 14.25 mmol) was added dropwise to a solution of the crude product (4.75 mmol) of compound 5 in dichloromethane (10 mL) under ice cooling, and stirred at room temperature for 45 minutes. After the solvent was distilled off under reduced pressure, the obtained residue was dissolved in toluene, and the solvent was distilled off under reduced pressure again. The obtained residue was dissolved in ethyl acetate, slowly injected into an aqueous sodium bicarbonate solution, and stirred at 35 ° C for 9 hours. The reaction solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining compound 6 (952 mg, yield 69%).

[0781] 1 H-NMR (CDCl 3 )δ:1.48(3H,d,J=6.4Hz),2.80-2.92(2H,m),3.50-3.64(2H,m),3.82(1H,d,J=7.0Hz),3 .95(3H,s),4.95-5.02(1H,m),6.67(1H,d,J=8.4Hz),6.77(1H,s),7.41(1H,d,J=8.4Hz).

[0782] MS (m / z) = 293 [M + H] +

[0783] Process 6

[0784] Triphenylphosphine (1.28 g, 4.89 mmol) was added to a solution of compound 6 (952 mg, 3.26 mmol) in THF (30 mL), DIAD (0.95 mL, 4.89 mmol) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 7 (776 mg, yield 87%).

[0785] 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),2.8 7-2.98(1H,m),3.14-3.21(0.3H,m),3.44-3.51(0.7H,m),3.90(2.1H,s),3.9 0(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).

[0786] MS (m / z) = 275 [M + H] +

[0787] Process 7

[0788] Sodium iodide (1.27 g, 8.49 mmol) and trimethylsilyl chloride (1.085 mL, 8.49 mmol) were added to a solution of compound 7 (776 mg, 2.83 mmol) in acetonitrile (10 mL), and the mixture was stirred at 45 ° C for 6 hours. Sodium bicarbonate aqueous solution and sodium thiosulfate aqueous solution were added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product of compound 8 (747 mg).

[0789] 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).

[0790] MS (m / z) = 261 [M + H] +

[0791] Process 8

[0792] N-chlorosuccinimide (497 mg, 3.72 mmol) was added to a DMF (8 mL) solution of compound 8 (800 mg, 3.07 mmol) at 45°C, and the mixture was stirred at the same temperature for 10 hours. After the reaction solution was cooled to room temperature, an aqueous sodium thiosulfate solution and an aqueous sodium bicarbonate solution were added, and the resulting solid was filtered to obtain compound 9 (527 mg, yield 58%).

[0793] MS (m / z) = 295.1 [M+H] +

[0794] 1 H-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=12.9 Hz), 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).

[0795] Process 9

[0796] 1,4-dioxane (20 mL) was added to compound 9 (1.97 g, 6.68 mmol), silver carbonate (2.76, 10.01 mmol), and benzyl bromide (1.26 g, 7.34 mmol), and stirred at 65°C for 9 hours. The reaction solution was cooled to room temperature, insoluble matter was removed by filtration, and washed with methanol. The solvent of the filtrate was removed by distillation under reduced pressure to obtain a crude product of compound 10 (2.31 g).

[0797] MS (m / z) = 385.2 [M + H] +

[0798] Process 10

[0799] To a mixed solution of compound 10 (2.3 g, 5.98 mmol) in THF (13 mL)-methanol (13 mL) was added 1 M sodium hydroxide aqueous solution (9.0 mL, 9.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extraction was performed with ethyl acetate. The solvent was distilled off under reduced pressure to obtain a crude product of compound 11 (1.77 g).

[0800] MS (m / z) = 289.2 [M+H] +

[0801] 1 H-NMR (CDCl 3 )δ:1.46(3H,d,J=6.7Hz),2.63(1H,dt,J=16.0,4.1Hz),2.75-2.83(1H,m),2.95-3.01(1H,m),3.20-3.27(1H,m),3.9 7(1H,dd,J=6.7,12.7Hz),5.44(2H,dd,J=18.4,12.7Hz),7.28-7.31(1H,m),7.34-7.37(3H,m),7.48(2H,d,J=7.3Hz).

[0802] Process 11

[0803] Acetonitrile (2.4 mL) was added to compound 11 (245 mg, 0.85 mmol), compound 12 (251 mg, 0.85 mmol), and potassium carbonate (235 mg, 1.70 mmol), and the mixture was stirred at 65° C. for 3.5 hours. The reaction solution was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 13 (440 mg, yield 95%).

[0804] MS (m / z) = 547.4 [M+H] +

[0805] 1 H-NMR (CDCl 3)δ:1.44(3H,d,J=6.7Hz),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).

[0806] Process 12

[0807] Methanol (4.5 mL) was added to compound 13 (439 mg, 0.80 mmol) and 10% palladium on carbon (128 mg, 0.12 mmol), and stirred at room temperature for 2.5 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration, the solvent of the filtrate was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 14 (230 mg, yield 63%).

[0808] MS (m / z) = 457.3 [M + H] +

[0809] 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),3.8 3(1H,dd,J=6.6,13.6Hz),3.95(3H,s),4.18(1H,d,J=13.6Hz),4.27(1H,d,J=13.7Hz), 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).

[0810] Process 13

[0811] 1,4-dioxane (0.5 mL) was added to 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), 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 extraction was performed with chloroform. The solvent of the organic layer was removed by distillation under reduced pressure, and the obtained residue was purified by reverse phase chromatography to obtain compound 15 (15 mg, yield 55%).

[0812] MS (m / z) = 617.2 [M + H] +

[0813] Process 14

[0814] A 1M sodium hydroxide aqueous solution (0.5 mL, 0.50 mmol) was added to a solution of compound 15 (15 mg, 0.024 mmol) in methanol (0.5 mL)-THF (0.5 mL), and the mixture was stirred at room temperature for 2 hours. A citric acid aqueous solution was added to the reaction solution, the pH was adjusted to about 7, and the mixture was extracted with chloroform. The solvent of the organic layer was removed by distillation under reduced pressure, and the residue was purified by reverse phase chromatography to obtain compound I-024 (12 mg, yield 79%).

[0815] MS (m / z) = 603.1 [M+H] +

[0816] 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=12.3Hz),5.44(1 H,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).

[0817] Example 2

[0818] [Chemical formula 39]

[0819]

[0820] Process 1

[0821] Trifluoroacetic anhydride (2.5 mL, 16.7 mmol) was added to a solution of compound 16 (WO2019200120A) (1.90 g, 10.7 mmol) in dichloromethane (19 mL), and stirred at room temperature for 4.5 hours. Water was added to the reaction solution and extracted with dichloromethane. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 17 (2.25 g, yield 74%).

[0822] MS (m / z) = 274.2 [M + H] +

[0823] 1 H-NMR (CDCl 3 )δ:1.53(2.4H,d,J=6.8Hz),1.61(0.6H,d,J=6.7Hz),2.74-2.82(1H,m),2.91-3.00(1H,m),3.2 6(0.2H,td,J=12.5,4.4Hz),3.56(0.8H,td,J=12.5,4.3Hz),3.79(2.4H,s),3.80(0.6H,s),4.04 (0.8H,d,J=12.8Hz),4.59(0.2H,dd,J=12.8,5.6Hz),5.10(0.2H,q,J=6.8Hz),5.53(0.8H,q,J= 6.8Hz), 6.62 (0.2H, d, J = 2.5Hz), 6.66 (0.8H, d, J = 2.5Hz), 6.75-6.80 (1H, m), 7.03-7.07 (1H, m).

[0824] Process 2

[0825] Silver trifluoroacetate (1.74 g, 7.87 mmol) and iodine (1.99 g, 7.84 mmol) were added to a solution of compound 17 (1.95 g, 7.13 mmol) in dichloromethane (19 mL), and stirred at room temperature for 1 hour. The insoluble matter of the reaction solution was removed by filtration, and an aqueous sodium thiosulfate solution was added to the filtrate, and extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining compound 18 (2.00 g, yield 70%).

[0826] MS (m / z) = 400.2 [M + H] +

[0827] 1H-NMR (CDCl 3 )δ:1.53(2.4H,d,J=6.8Hz),1.61(0.6H,d,J=6.8Hz),2.71-2.79(1H,m),2.89-2.97( 1H,m),3.23(0.2H,td,J=12.7,4.5Hz),3.50-3.57(0.8H,m),3.86(2.4H,s),3.88(0.6 H,s),4.01-4.05(0.8H,m),4.59(0.2H,dd,J=13.3,5.3Hz),5.08(0.2H,q,J=6.5Hz),5 .52(0.8H,q,J=6.8Hz),6.51(0.2H,s),6.55(0.8H,s),7.55(0.8H,s),7.57(0.2H,s).

[0828] Process 3

[0829] To a DMF (20 mL) solution of compound 18 (1.99 g, 4.99 mmol) was added difluoro (fluorosulfonyl) methyl acetate (3.15 mL, 24.93 mmol) and copper iodide (1.14 g, 5.98 mmol), and stirred at 100 ° C for 3 hours under a nitrogen atmosphere. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 19 (1.56 g, yield 94%).

[0830] MS (m / z) = 342.2 [M + H] +

[0831] 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(0.6 H,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).

[0832] Process 4

[0833] To a dichloromethane (7.8 mL) solution of compound 19 (1.55 g, 4.41 mmol) was added 1 M boron tribromide dichloromethane solution (13.2 mL, 13.2 mmol) under ice cooling, and stirred at room temperature for 2.5 hours. Methanol (7.8 mL) and water were added to the reaction solution under ice cooling, and extracted with dichloromethane. The solvent of the organic layer was removed by reduced pressure distillation, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 20 (1.20 g, yield 78%).

[0834] MS (m / z) = 326.2 [MH] -

[0835] 1 H-NMR (CDCl 3 )δ:1.53(2.4H,d,J=6.9Hz),1.61(0.6H,d,J=6.8Hz),2.77-2.86(1H,m),2.9 1-3.01(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).

[0836] Process 5

[0837] 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, stirred at room temperature for 10 minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 21 (411.8 mg, yield 77%).

[0838] MS (m / z) = 356.0 [M+H] +

[0839] 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).

[0840] Process 6

[0841] A solution of 30% hydrogen peroxide solution (1.62 mL, 15.8 mmol), boric acid (2.23 g, 36.0 mmol), and 1 M sulfuric acid (0.192 mL, 3.60 mmol) in THF (10 mL) was stirred at room temperature for 30 minutes. A solution of compound 21 (2.56 g, 7.20 mmol) in THF (15 mL) was added to the reaction solution and stirred at 60°C for 8 hours and 30 minutes. A 10% sodium bisulfite aqueous solution was added to the reaction solution under ice cooling, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 22 (1.53 g, yield 62%).

[0842] MS (m / z) = 344.2 [M + H] +

[0843] 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).

[0844] Process 7

[0845] Compound 22 (162.1 mg, 0.472 mmol) and a hexane solution of compound 23 (57% by weight, 128 mg, 0.472 mmol) were dissolved in toluene (2.5 mL), triruthenium dodecacarbonyl (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 removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 24 (55.4 mg, yield 24%).

[0846] MS (m / z) = 498.2 [M + H] +

[0847] 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).

[0848] Process 8

[0849] Potassium carbonate (30.8 mg, 0.223 mmol) was added to a mixed solution of compound 24 (55.4 mg, 0.111 mmol) in methanol (1 mL)-THF (1 mL), and stirred at 50°C for 7 hours. The reaction solution was returned to room temperature, water was added, and extraction was performed with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain compound 25 (46.8 mg).

[0850] MS (m / z) = 402.2 [M + H] +

[0851] 1 H-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(1 H,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).

[0852] Process 9

[0853] By conducting the same reaction as in step 11 of Example 1, a mixture of compound 26 and impurities (58.9 mg) was obtained.

[0854] MS (m / z) = 660.4 [M+H] +

[0855] Process 10

[0856] To a mixed solution of a mixture of compound 26 and impurities (58.9 mg) in methanol (1.5 mL)-THF (1.5 mL) was added 1 M aqueous sodium hydroxide solution (0.382 mL, 0.382 mmol), and stirred at 45 ° C for 12 hours. The reaction solution was returned to room temperature, 2 M hydrochloric acid was added, the pH was adjusted to 4, and extracted with ethyl acetate. After drying the organic layer with anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The obtained residue was purified by reverse phase chromatography (acetonitrile-water) to obtain a diastereomeric mixture.

[0857] The resulting diastereomeric mixture was separated by SFC to afford compound I-047 (12.2 mg, yield 16%).

[0858] SFC conditions

[0859] Column: P4VP column (Daicel) 4.6×250 mm

[0860] Analysis time: 15min

[0861] Mobile phase: A is carbon dioxide, B is 0.1% diethylamine in MeOH solution

[0862] Fractionation conditions: Keep the composition ratio of B / (A+B) = 20% to send liquid

[0863] Flow rate: 2.0mL / min

[0864] Detection wavelength: 220nm

[0865] MS (m / z) = 646.4 [M + H] +

[0866] 1 H-NMR (CDCl 3 )δ:8.20(1H,s),8.04(1H,d,J=9.0Hz),7.81(1H,d,J=8.5Hz),7.50(1H,t,J= 8.4Hz),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=6.5Hz).

[0867] Example 3

[0868] [Chemical formula 40]

[0869]

[0870] Process 1

[0871] N-iodosuccinimide (2.12 g, 9.42 mmol) was added to a DMF (12 mL) solution of compound 8 (1.17 g, 3.14 mmol), and the mixture was stirred at room temperature for 7 hours. Aqueous sodium thiosulfate solution was added to the reaction solution, and extraction was performed with ethyl acetate. The solvent of the organic layer was removed by distillation under reduced pressure to obtain compound 27 (1.98 g).

[0872] MS (m / z) = 386.9 [M + H] +

[0873] Process 2

[0874] The reaction was carried out in the same manner as in Step 9 of Example 1 to obtain Compound 28 (7.59 mg, yield 94%).

[0875] MS (m / z) = 476.9 [M + H] +

[0876] 1 H-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).

[0877] Process 3

[0878] To a DMF (60 mL) solution of compound 28 (5.95 g, 12.3 mmol) was 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), 2-isocyano-2-methylpropane (2.55 g, 30.6 mmol), and stirred at 65° C. for 3.5 hours. The reaction solution was cooled to room temperature, hydrochloric acid was added, the pH was adjusted to about 4, and then extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 29 (2.37 g, yield 50%).

[0879] MS (m / z) = 379.0 [M+H] +

[0880] 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).

[0881] Process 4

[0882] N,N-diethylaminosulfur trifluoride (3.95 g, 26.3 mmol) was added to a solution of compound 29 (2.84 g, 7.28 mmol) in dichloromethane (28 mL) under an ice bath, and stirred at room temperature for 2.5 hours. Sodium bicarbonate aqueous solution was added to the reaction solution, and extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 30 (2.55 g, yield 85%).

[0883] MS (m / z) = 401.0 [M+H] +

[0884] 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=55.2Hz),7.39-7.29(3H,m),7.44-7.42(2H,m),7.65-7.62(1H,m).

[0885] Process 5

[0886] A 1M sodium hydroxide aqueous solution (12.5 mL, 12.5 mmol) was added to a mixed solution of compound 30 (2.0 g, 5.0 mmol) in methanol (12 mL)-THF (12 mL), and the mixture was stirred at room temperature for 1 hour. A citric acid aqueous solution was added to the reaction solution, the pH was adjusted to about 7, and chloroform was used for extraction. The solvent of the organic layer was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 31 (1.49 g, yield 98%).

[0887] MS (m / z) = 305.1 [M+H] +

[0888] 1 H-NMR (CDCl 3 )δ:1.49(3H,d,J=6.8Hz),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).

[0889] Process 6

[0890] Compound 12' (277 mg, 0.936 mmol) and potassium carbonate (272 mg, 1.97 mmol) were added to a solution of compound 31 (300 mg, 0.936 mmol) in acetonitrile (3 mL), and the mixture was stirred at 60°C for 5 hours. A citric acid aqueous solution was added to the reaction solution to adjust the pH to about 7, and then extraction was performed with chloroform. The solvent was distilled off under reduced pressure to obtain compound 32 (410 mg).

[0891] MS (m / z) = 564.2 [M + H] +

[0892] Process 7

[0893] THF (5 mL) and methanol (5 mL) were added to compound 32 (410 mg, 0.883 mmol) and 10% palladium on carbon (155 mg, 0.088 mmol), and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration, and the solvent of the filtrate was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 33 (320 mg, yield 93%).

[0894] MS (m / z) = 474.0 [M + H] +

[0895] 1 H-NMR (CDCl 3 )δ:1.51(3H,d,J=6.8Hz),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).

[0896] Process 8

[0897] Silver carbonate (17 mg, 0.063 mmol) and 1-bromomethyl-4-chloro-2-fluorobenzene (11 mg, 0.051 mmol) were added to a solution of compound 33 (20 mg, 0.042 mmol) in dioxane (0.2 mL), and the mixture was stirred at 65° C. for 3 hours. The mixture was cooled to room temperature, insoluble matter was removed by filtration, and washed with ethyl acetate. The solvent of the organic layer was removed by distillation under reduced pressure, and the resulting residue was purified by reverse phase chromatography to obtain compound 34 (11 mg, yield 43%).

[0898] MS (m / z) = 616.2 [M+H] +

[0899] Process 9

[0900] To a solution of compound 34 (11 mg, 0.018 mmol) in methanol (0.25 mL)-THF (0.25 mL) was added 1 M sodium hydroxide aqueous solution (0.06 mL, 0.06 mmol), and the mixture was stirred at room temperature for 3 hours. A citric acid aqueous solution was added to the reaction solution, the pH was adjusted to about 4, and extraction was performed with chloroform. The solvent of the organic layer was removed by distillation under reduced pressure, and the obtained residue was purified by reverse phase chromatography to obtain compound I-097 (10.1 mg, yield 93%).

[0901] MS (m / z) = 602.1 [M+H] +

[0902] 1 H-NMR (CDCl 3 )δ:1.47(3H,d,J=6.8Hz),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=13.1Hz),5.47(1H,d,J=13.1Hz),6.84(1 H,t,J=55.6Hz),7.09-7.13(2H,m),7.39(1H,t,J=8.3Hz),7.59(1H,s),8.19-8.24(2H,m).

[0903] Example 4

[0904] [Chemical formula 41]

[0905]

[0906] Process 1

[0907] Copper iodide (0.659 g, 3.46 mmol) and sodium iodide (5.20 g, 34.7 mmol) were added to a solution of compound 35 (4.42 g, 17.3 mmol) and (±)-trans-N,N'-dimethylaminocyclohexane (0.999 g, 7.02 mmol) in dioxane (66 mL) under a nitrogen atmosphere, and the mixture was heated and stirred at 100°C for 9 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate and filtered through Celite (registered trademark). The filtrate was washed with 3% aqueous ammonia solution and water, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 36 (4.79 g, yield 86.4%).

[0908] 1 H-NMR (CDCl 3 )δ:2.08-2.14(2H,m),2.63(2H,t,J=6.3Hz),2.87(2H,t,J=6.3Hz),3.92(3H,s),7.40(1H,s),7.75(1H,s).

[0909] MS (m / z) = 302.8 [M+H] +

[0910] Process 2

[0911] To a DMF (56 mL) solution of compound 36 (3.76 g, 11.7 mmol) was added copper iodide (2.68 g, 14.1 mmol) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (7.42 mL, 58.7 mmol) under a nitrogen atmosphere, and the mixture was heated and stirred at 100 ° C for 2 hours. After the reaction solution was cooled to room temperature, it was diluted with ethyl acetate and filtered through Celite (registered trademark). The filtrate was washed with sodium bicarbonate aqueous solution and water, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 37 (2.79 g, yield 92%).

[0912] 1 H-NMR (CDCl 3 )δ:2.12-2.18(2H,m),2.68(2H,t,J=6.4Hz),2.94(2H,t,J=6.4Hz),3.94(3H,s),7.49(1H,s),7.62(1H,s).

[0913] MS (m / z) = 244.8 [M+H] +

[0914] Process 3

[0915] 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 1 M THF solution of lithium bis(trimethylsilyl)amide (1.24 mL, 1.24 mmol) at -15 ° C, and stirred at the same temperature for 30 minutes. 2-tert-butyl bromoacetate (0.167 mL, 1.13 mmol) was added to the reaction solution and further stirred for 1 hour. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and the solvent was removed by distillation under reduced pressure. The residue obtained was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 38 (252 mg, yield 59%).

[0916] 1H-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(1 H,dd,J=16.4,6.7Hz),2.84-3.11(4H,m),3.93(3H,s),7.47(1H,s),7.61(1H,s).

[0917] MS (m / z) = 303.0 [M-tBu+H]+

[0918] Process 4

[0919] Sodium borohydride (74.1 mg, 1.96 mmol) was added to a 2-propanol aqueous solution (90%, 8 mL) of compound 38 at 0°C and stirred at the same temperature for 30 minutes. A 0.4 M aqueous hydrochloric acid solution (5 mL) was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and the solvent was removed by distillation under reduced pressure. The obtained residue was solidified by cyclohexane and the obtained solid was filtered to obtain compound 39 (542 mg, yield 77%).

[0920] 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=10.7,3.9Hz),2.36(1H,dd,J=15.7,6.0Hz),2.61(1H, dd,J=15.7,7.0Hz),2.73(1H,d,J=7.5Hz),2.76-2.83(1H,m),3.89(3H,s),4.44(1H,t,J=8.2Hz),7.24(1H,s),7.27(1H,s).

[0921] Steps 5-6

[0922] 1,1'-Thiocarbonyldiimidazole (379 mg, 2.13 mmol) and 4-dimethylaminopyridine (18.3 mg, 0.150 mmol) were added to a suspension of compound 39 (540 mg, 1.50 mmol) in toluene (12 mL), and the mixture was stirred at room temperature for 20.5 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 40 (540 mg).

[0923] Azobisisobutyronitrile (9.4 mg, 0.057 mmol) and tributyltin hydride (423 mg, 1.45 mmol) were added to a toluene (10 mL) solution of compound 40 (540 mg), and the mixture was heated at 100° C. for 3 hours under a nitrogen atmosphere. The solvent of the reaction solution was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate).

[0924] To the obtained compound (284 mg) in ethyl acetate (10 mL) solution was added activated carbon supported palladium catalyst (NX type, 10% palladium, 50% water) (88.8 mg, 0.042 mmol), and stirred at room temperature for 9 hours under a hydrogen stream of 1 atmosphere. The reaction solution was filtered through Celite (registered trademark) and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 41 (racemic mixture, 276 mg, 3 steps yield 54%).

[0925] 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=1 6.8,10.0Hz),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).

[0926] Steps 7-8

[0927] To a dichloromethane (5.5 mL) solution of compound 41 (273 mg, 0.793 mmol) was added 1 M dichloromethane solution (2.38 mL, 2.38 mmol) at -15°C, and 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 a 2 M aqueous hydrochloric acid solution was added to adjust the pH to 4. The obtained reaction solution was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. Methanol (8 mL) was added to the obtained residue, and the solvent was removed by distillation under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 42 (101 mg).

[0928] Cesium carbonate (168 mg, 0.517 mmol) was added to a DMF (2 mL) solution of compound 42 (99 mg) and 1-bromomethyl-4-chloro-2-fluorobenzene (85.0 mg, 0.379 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 removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 43 (racemic mixture, 101 mg, 2-step yield 29%).

[0929] 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).

[0930] Process 9

[0931] To a solution of compound 43 (101 mg, 0.234 mmol) in THF (1.4 mL)-methanol (0.7 mL) was added 1 M sodium hydroxide aqueous solution (0.702 mL, 0.702 mmol), and the mixture was stirred at room temperature for 1 hour. A 2 M hydrochloric acid aqueous solution (0.409 mL, 0.819 mmol) was added to the reaction solution and concentrated, and then diluted with ethyl acetate. The organic layer was washed with water, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 44 (racemic mixture, 95.6 mg, yield 98%).

[0932] 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),2.4 4(2H,dd,J=7.0,2.6Hz),2.53(1H,dd,J=16.8,10.5Hz),2.81(2H,d,J=5.0 Hz),2.96(1H,dd,J=16.8,4.3Hz),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).

[0933] MS (m / z) = 414.9 [MH] -

[0934] Process 10

[0935] To a pyridine (2 mL) solution of compound 44 (93.4 mg, 0.224 mmol) and compound 45 (54.8 mg, 0.232 mmol) was added 50% 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide ethyl acetate solution and stirred at room temperature for 30 minutes. Toluene was added to the reaction solution and concentrated, and diluted with ethyl acetate. The organic layer was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound 46 (diastereomeric mixture (1:1), 95.6 mg, yield 98%).

[0936] MS (m / z) = 635.0 [M+H] +

[0937] Process 11

[0938] 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 heated and stirred at 80° C. for 2.5 hours. Toluene was added to the reaction solution and concentrated, then neutralized with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with water, the solvent was distilled off under reduced pressure, and the residue was purified by preparative TLC (toluene-ethyl acetate) to obtain compound 47 (diastereomeric mixture (1:1), 69.1 mg, yield 64%).

[0939] 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(3 H,m).3.95(3H,s),4.31-4.48(3H,m),4.61(1H,q,J=7.3Hz),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).

[0940] MS (m / z) = 617.0 [M+H] +

[0941] Process 12

[0942] 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 sodium hydroxide aqueous solution (0.450 mL, 0.450 mmol), and the mixture was stirred at 50° C. for 1.5 hours. To the reaction solution was added 2 M hydrochloric acid aqueous solution (0.225 mL, 0.450 mmol), and after concentration, water was added, and the resulting solid was filtered out and dried in vacuo at 50° C. to obtain I-077 (diastereomer mixture (1:1), 57.0 mg, yield 88%).

[0943] 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).

[0944] MS (m / z) = 603.0 [M+H] +

[0945] Example 5

[0946] [Chemical formula 42]

[0947]

[0948] Process 1

[0949] Thiourea (1.07 g, 14.0 mmol) and 20% sodium ethanol ethanol solution were added to compound 48 (800 mg, 3.07 mmol) and stirred at 90 ° C for 2 hours. The reaction solution was cooled to room temperature, iodomethane (1.49 g, 10.5 mmol) was added, and stirred at room temperature for 1 hour. DOWEX 50Wx8 100-200 mesh (H) cation exchange resin was added to the reaction solution, and the solid was removed by filtration. The solvent of the filtrate was removed by reduced pressure distillation, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 49 (1.98 g, yield 91%).

[0950] MS (m / z) = 312.0 [M+H] +

[0951] 1 H-NMR (CDCl 3 )δ: 1.43(3H,d,J=6.8Hz),1.49(9H,s),2.58-2.50(5H,m),2.92-2.90(1H,m),4.31-4.18(1H,m),4.94-4.76(1H,m),10.86(1H,s).

[0952] Process 2

[0953] To a solution of compound 49 (1.98 g, 6.36 mmol) in acetonitrile (20 mL) was added phosphorus oxychloride (1.95 g, 12.7 mmol), and the mixture was stirred at 90° C. for 1 hour. The solvent was evaporated under reduced pressure to obtain compound 50.

[0954] MS (m / z) = 229.9 [M + H] +

[0955] Process 3

[0956] To a THF (15 mL)-water (15 mL) mixed solution of compound 50 (1.46 g, 6.36 mmol), di-tert-butyl dicarbonate (2.77 g, 12.7 mmol) and sodium bicarbonate (2.67 g, 31.8 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate), thereby obtaining compound 51 (1.66 g, yield 79%).

[0957] 1 H-NMR (CDCl 3 )δ:1.51-1.49(12H,m),2.55(3H,s),2.76-2.74(2H,m),3.02(1H,brs),4.37(1H,br s),5.06(1H,br s).

[0958] MS (m / z) = 330.0 [M+H] +

[0959] Process 4

[0960] 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 of the reaction solution was removed by filtration, and the solvent of the filtrate was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 52 (360 mg, yield 100%).

[0961] MS (m / z) = 297.0 [M+H] +

[0962] 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).

[0963] Process 5

[0964] Compound 52 (360 mg, 1.21 mmol) was dissolved in dichloromethane (5.4 mL), and 70% m-chloroperbenzoic acid (600 mg, 2.42 mmol) was added, and stirred at room temperature for 1 hour. Sodium bicarbonate aqueous solution and sodium thiosulfate aqueous solution were added to the reaction solution, and extracted with chloroform. The solvent was distilled off under reduced pressure to obtain Compound 53.

[0965] MS (m / z) = 328.0 [M+H] +

[0966] Process 6

[0967] To a solution of (4-chloro-2-fluorophenyl)methanol (389 mg, 2.42 mmol) in THF (4 mL) were added 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 extracted with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 54 (410 mg, yield 83%).

[0968] MS (m / z) = 408.0 [M+H] +

[0969] 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).

[0970] Process 7

[0971] Trifluoroacetic acid (0.2 mL) was added to a solution of compound 54 (40 mg, 0.098 mmol) in dichloromethane (0.6 mL), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 55 (28 mg, yield 93%).

[0972] MS (m / z) = 308.0 [M+H] +

[0973] 1 H-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).

[0974] Process 8

[0975] Compound 12 (26 mg, 0.086 mmol) and potassium carbonate (25 mg, 0.182 mmol) were added to a solution of compound 55 (28 mg, 0.091 mmol) in acetonitrile (0.3 mL), 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 removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 56 (36 mg, yield 70%).

[0976] MS (m / z) = 566.0 [M + H] +

[0977] 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).

[0978] Process 9

[0979] To a mixed solution of compound 56 (36 mg, 0.064 mmol) in methanol (0.15 mL)-THF (0.15 mL) was added 1 M sodium hydroxide aqueous solution (0.12 mL, 0.12 mmol), and the mixture was stirred at room temperature for 19 hours. Aqueous citric acid solution was added to the reaction solution, the pH was adjusted to about 7, and extraction was performed with chloroform. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain I-078 (diastereomeric mixture, 28 mg, yield 80%).

[0980] MS (m / z) = 552.0 [M+H] +

[0981] 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),5.21-5.1 9(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).

[0982] Example 6

[0983] [Chemical formula 43]

[0984]

[0985] Process 1

[0986] Trifluoromethanesulfonic anhydride (386 μL, 2.29 mmol) and triethylamine (422 μL, 3.05 mmol) were added to a solution of compound 57 (500 mg, 1.52 mmol) in dichloromethane (7.5 mL) under ice cooling, and the mixture was stirred for 1 hour under ice cooling. Sodium bicarbonate aqueous solution was added to the reaction solution, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 58 (717 mg, yield 97%).

[0987] 1 H-NMR (CDCl 3)δ:1.62(2.25H,d,J=6.9Hz),1.69(0.75H,d,J=6.8Hz),2.90-2.99(1H,m),3.04-3.24(1.25H,m),3.47-3.55(0.75H,m),4.24(0.75H,dd ,J=14.2,4.4Hz),4.81(0.25H,dd,J=13.2,5.3Hz),5.16(0.25H,q,J=6.6Hz),5.60(0.75H,q,J=6.9Hz),7.92(0.75H,s),7.94(0.25H,s).

[0988] MS (m / z) = 461 [M + H] +

[0989] Process 2

[0990] 2-(4-chlorophenyl)ethylboronic acid pinacol ester (127 mg, 0.48 mmol), palladium (19.5 mg, 0.02 mmol), cesium carbonate (156 mg, 0.48 mmol), water (100 μL) were added to a solution of compound 58 (110 mg, 0.24 mmol) in 1,4-dioxane (1 mL), and stirred at 100 ° C for 2 hours under a nitrogen atmosphere. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 59 (12 mg, yield 11%).

[0991] 1 H-NMR (CDCl 3 )δ:1.60(2.1H,d,J=6.9Hz),1.66(0.9H,d,J=6.8Hz),2.81-2.89(1H,m),2 .98-3.10(3H,m),3.13-3.25(2.3H,m),3.48-3.55(0.7H,m),4.18(0.7H,dd ,J=14.2,4.1Hz),4.75(0.3H,dd,J=13.4,5.8Hz),5.18(0.3H,q,J=6.8Hz), 5.60(0.7H,q,J=6.9Hz),7.13-7.24(4H,m),7.66(0.7H,s),7.69(0.3H,s).

[0992] MS (m / z) = 451 [M + H] +

[0993] Process 3

[0994] By carrying out the same reaction as in Step 10 of Example 1, Compound 60 (12 mg) was obtained.

[0995] 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=8.3Hz), 7.58(1H,s).

[0996] MS (m / z) = 355 [M + H] +

[0997] Process 4

[0998] By carrying out the same reaction as in Step 11 of Example 1, Compound 61 (14 mg, yield 85%) was obtained.

[0999] 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).

[1000] MS (m / z) = 613 [M + H] +

[1001] Process 5

[1002] To a solution of compound 61 (14 mg, 0.02 mmol) in methanol (0.15 mL)-THF (0.15 mL) was added 2M sodium hydroxide aqueous solution (57 μL, 0.11 mmol), 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, dilute sulfuric acid was added to pH = 4, and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound I-095 (8 mg, yield 59%).

[1003] 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).

[1004] MS (m / z) = 599 [M + H] +

[1005] Example 7

[1006] [Chemical formula 44]

[1007]

[1008] Process 1

[1009] To a solution of compound 62 (5.00 g, 22.5 mmol) in THF (30 mL) was added a THF solution of isopropylmagnesium chloride lithium chloride (20.8 mL, 27.0 mmol) at -20°C, and the mixture was stirred at -10°C for 1 hour. 4-pentenoyl chloride (3.7 mL, 33.7 mmol) was added to the reaction solution and stirred at 0°C for 5 hours. Aqueous hydrochloric acid solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with water and brine, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give compound 63 (4.81 g, yield 94%).

[1010] MS (m / z) = 225.9 [M + H] +

[1011] Process 2

[1012] To compound 63 (4.81 g, 17.0 mmol) was added palladium (II) acetate (762 mg, 3.39 mmol), BINAP (4.23 g, 6.79 mmol) and acetonitrile (80 mL), and the mixture was stirred at 85°C for 17.5 hours. The reaction solution was cooled to room temperature, water was added and extracted twice with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 64 (3.12 g, yield 97%).

[1013] 1 H-NMR (CDCl 3 )δ:2.70-2.74(2H,m),2.88-2.92(2H,m),4.04(3H,s),5.43(1H,q,J=1.6Hz),6.35(1H,s),6.73(1H,d,J=8.7Hz),8.16(1H,d,J=8.7Hz).

[1014] MS (m / z) = 189.9 [M + H] +

[1015] Process 3

[1016] THF (62 mL) and ethanol (6 mL) were added to compound 64 (3.12 g, 16.5 mmol) and the mixture was cooled with ice. p-Toluenesulfonylmethyl isocyanide (4.83 g, 24.7 mmol) and potassium tert-butoxide (2.78 g, 24.7 mmol) were added and stirred at room temperature for 6 hours. During the stirring process, p-Toluenesulfonylmethyl isocyanide (4.83 g, 24.7 mmol) and potassium tert-butoxide (2.78 g, 24.7 mmol) were added at 2.5 hours and 4.5 hours respectively. An aqueous solution of ammonium chloride was added to the reaction solution and extracted with ethyl acetate twice. The solvent of the organic layer was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 65 (1.41 g, yield 43%).

[1017] MS (m / z) = 201.0 [M+H] +

[1018] Process 4

[1019] Methanol (35 mL) and trimethylsilyl chloride (27.0 mL, 211 mmol) were added to compound 65 (1.41 g, 7.0 mmol) and stirred at 50° C. for 5 hours. Sodium bicarbonate aqueous solution was added to the reaction solution and extracted twice with ethyl acetate. The solvent of the organic layer was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 66 (563 mg, yield 34%).

[1020] MS (m / z) = 234.0 [M + H] +

[1021] Process 5

[1022] Methanol (11 mL) and dichloromethane (11 mL) were added to compound 66 (563 mg, 2.42 mmol) and stirred at room temperature to perform ozonolysis reaction. After the reaction, triphenylphosphine (1266 mg, 4.83 mmol) was added to the reaction solution and stirred at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 67 (482 mg, 85%).

[1023] MS (m / z) = 236.0 [M+H] +

[1024] Process 6

[1025] To compound 67 (482 mg, 2.05 mmol) was added ethanol (17 mL), water (1 mL), hydroxylamine hydrochloride (185 mg, 2.66 mmol), triethylamine (0.43 mL, 3.07 mmol) and stirred at room temperature for 30 minutes. Water was added to the reaction solution and extracted twice with ethyl acetate. The organic layer was washed with aqueous hydrochloric acid, water, and saline, and the organic layer was concentrated to obtain a crude product of compound 68 (424 mg, 83%) as an extraction residue.

[1026] MS (m / z) = 251.0 [M + H] +

[1027] Process 7

[1028] Methanol (12 mL), acetic acid (1.5 mL), and 10% palladium-carbon (361 mg, 0.34 mmol) were added to the entire amount of the crude product of compound 68 (1.69 mmol), and stirred for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through Celite, washed with methanol, and the solvent of the filtrate was removed by distillation under reduced pressure to obtain a crude product of compound 69.

[1029] MS (m / z) = 237.0 [M+H] +

[1030] Process 8

[1031] Methanol (25 mL) was added to the crude product of the entire amount of compound 69 (1.69 mmol), and the mixture was stirred under ice cooling. 55% sodium hydride (163 mg, 3.73 mmol) was added to the mixture, and the mixture was stirred at 50° C. for 8.5 hours. The solvent of the reaction solution was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol), thereby obtaining compound 70 (200.4 mg, yield 58%).

[1032] 1 H-NMR (CDCl 3 )δ:1.61-1.69(1H,m),1.71-1.79(1H,m),2.09-2.16(1H,m),2.19-2.27(1H,m),3.78(1H,q,J=2. 5Hz),3.92(3H,s),4.63-4.66(1H,m),6.21(1H,s),6.61(1H,d,J=8.1Hz),7.46(1H,d,J=8.1Hz).

[1033] MS (m / z) = 205.0 [M+H] +

[1034] Process 9

[1035] Borane dimethyl sulfide complex (1.86 mL, 19.6 mmol) was added to a THF (8 mL) solution of compound 70 (200 mg, 0.98 mmol) and stirred at 65° C. for 14 hours. Methanol (10 mL) was added to the reaction solution, and after 1 hour at 65° C., a 2 mol / L hydrochloric acid aqueous solution (2 mL) was added and stirred at 70° C. for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure to obtain a crude product of compound 71.

[1036] Process 10

[1037] By carrying out the same reaction as in Step 1 of Example 2, Compound 72 (338.7 mg) was obtained.

[1038] MS (m / z) = 287.0 [M+H] +

[1039] Process 11

[1040] Sodium iodide (0.28 g, 1.89 mmol), trimethylsilyl chloride (0.24 mL, 1.89 mmol), acetonitrile (5 mL) were added to compound 72 (180 mg, 0.63 mmol) and stirred at 50 ° C for 16 hours. During the reaction, sodium iodide and trimethylsilyl chloride were appropriately added to allow the reaction to proceed. Sodium bicarbonate and sodium thiosulfate aqueous solution were added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product of compound 73.

[1041] MS (m / z) = 273.1 [M+H] +

[1042] Process 12

[1043] N, N-formamide (5 mL) and N-iodosuccinimide (212 mg, 0.94 mmol) were added to the crude product of compound 73 (0.63 mmol) and stirred at room temperature for 20 minutes. Ice water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product of compound 74.

[1044] Process 13

[1045] 1,4-dioxane (5 mL), silver (I) carbonate (346 mg, 1.26 mmol), and 4-chloro-2-fluorobenzyl bromide (154 mg, 0.69 mmol) were added to the entire amount of the crude product of compound 74 (0.63 mmol), and the mixture was stirred at 65° C. for 2 hours. Insoluble matter was removed by filtration, the solvent of the reaction solution was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 75 (103 mg, yield 30%) and a mixture of compound 75 and 4-chloro-2-fluorobenzyl bromide (244 mg, purity 43%, yield 31%).

[1046] MS (m / z) = 541.1 [M+H] +

[1047] Process 14

[1048] To a mixture of compound 75 and 4-chloro-2-fluorobenzyl bromide (244 mg, purity 43%, 0.19 mmol), N,N-dimethylformamide (3.7 mL), copper iodide (185 mg, 0.97 mmol), difluoro(fluorosulfonyl)acetic acid methyl ester (123 μL, 0.97 mmol) were added, and then degassed under reduced pressure and replaced with nitrogen. The reaction solution was stirred at 100° C. for 1 hour under a nitrogen atmosphere. The reaction solution was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain compound 76 (80 mg, yield 85%).

[1049] MS (m / z) = 483.2 [M + H] +

[1050] Process 15

[1051] By carrying out the same reaction as in Step 10 of Example 1, a crude product of Compound 77 was obtained.

[1052] Process 16

[1053] To the crude product of compound 77 (0.17 mmol) of the whole amount, acetonitrile (0.64 mL), compound 12 (49 mg, 0.17 mmol), and potassium carbonate (46 mg, 0.33 mmol) were added, and the mixture was stirred at 65° C. for 2 hours and allowed to stand overnight at room temperature. Water was added to the reaction solution, and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product of compound 78.

[1054] Process 17

[1055] To a solution of the crude product of compound 78 (0.17 mmol) in methanol (0.5 mL) and THF (0.5 mL) was added 1 M sodium hydroxide aqueous solution (0.5 mL, 0.50 mmol), and the mixture was stirred at 45°C for 5.5 hours. Aqueous hydrochloric acid was added to the reaction solution, the pH was adjusted to about 4, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a residue of a mixture of diastereomers. The obtained mixture of diastereomers was separated by SFC to obtain compound I-200 (21.2 mg, yield 20%) and compound I-201 (26.6 mg, yield 26%).

[1056] SFC conditions

[1057] Column: ID column (Daicel) 4.6×250 mm

[1058] Analysis time: 15min

[1059] Mobile phase: A is carbon dioxide, B is 0.1% diethylamine in 2-propanol solution

[1060] Fractionation conditions: Keep the composition ratio of B / (A+B) = 50% to send liquid

[1061] Flow rate: 2.0mL / min

[1062] Detection wavelength: 220nm

[1063] Compound I-200

[1064] 1 H-NMR (CDCl 3 )δ:1.32-1.41(1H,m),1.57(1H,t,J=12.6Hz),1.82(1H,t,J=11.7Hz),2.27-2.43(3H,m),2.65-2.75( 1H,m),3.07-3.14(2H,m),3.47(1H,d,J=13.6Hz),3.93(1H,s),4.09-4.17(1H,m),4.26-4.32(1H,m), 4.54-4.64(2H,m),4.85(1H,dd,J=15.4,2.9Hz),5.20-5.26(1H,m),5.55(2H,q,J=13.4Hz),7.08-7.1 6(2H,m),7.52(1H,t,J=8.1Hz),7.72-7.77(2H,m,J=8.1Hz),8.02(1H,dd,J=8.5,1.4Hz),8.20(1H,s).

[1065] MS (m / z) = 631.3 [M + H] +

[1066] Compound I-201

[1067] 1 H-NMR (CDCl 3)δ:1.36-1.43(1H,m),1.61(1H,t,J=12.6Hz),1.84(1H,t,J=11.5Hz),2.29-2.37(2H,m),2.43-2.53(1H,m),2.7 4-2.82(1H,m),3.07-3.14(2H,m),3.42(1H,d,J=13.6Hz),3.97(1H,s),4.08-4.15(1H,m),4.43-4.53(2H,m),4.6 6(1H,dd,J=14.1,7.8Hz),4.91(1H,dd,J=15.2,7.3Hz),5.19(1H,ddd,J=14.3,7.2,2.5Hz),5.56(2H,dd,J=29.3 ,13.4Hz),7.08-7.16(2H,m),7.52(1H,t,J=8.1Hz),7.72-7.74(2H,m),8.00(1H,dd,J=8.5,1.3Hz),8.20(1H,s).

[1068] MS (m / z) = 631.3 [M + H] +

[1069] The compounds shown below were synthesized in the same manner using the above general synthesis method or the synthesis method described in the Examples. It should be noted that I-015 and I-090 to I-093 in the table are diastereomeric mixtures.

[1070] [Table 1]

[1071]

[1072] [Table 2]

[1073]

[1074] [Table 3]

[1075]

[1076] [Table 4]

[1077]

[1078] [Table 5]

[1079]

[1080] [Table 6]

[1081]

[1082] [Table 7]

[1083]

[1084] [Table 8]

[1085]

[1086] [Table 9]

[1087]

[1088] [Table 10]

[1089]

[1090] [Table 11]

[1091]

[1092] [Table 12]

[1093]

[1094] [Table 13]

[1095]

[1096] [Table 14]

[1097]

[1098] [Table 15]

[1099]

[1100] [Table 16]

[1101]

[1102] The compounds shown below can also be synthesized in the same manner using the above-mentioned general synthesis method or the synthesis method described in the Examples.

[1103] [Chemical formula 45]

[1104]

[1105] The following describes biological test examples of the compounds of the present invention. The compounds of the present invention can be tested basically according to the following test examples.

[1106] The compound represented by formula (I) of the present invention has GLP-1 receptor agonist activity.

[1107] Specifically, in the evaluation method described below, EC 50 The value is preferably 5000 nM or less, more preferably 1000 nM or less, and further preferably 100 nM or less.

[1108] Test Example 1: Determination of GLP-1 receptor agonist activity

[1109] Cell culture

[1110] The human GLP-1 receptor stably expressing cells (hGLP-1R / CHO-K1 cells) were cultured at 37°C and 5% CO 2 The 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), and then recovered by treating with 10-fold diluted 5.0 g / l-trypsin / 5.3 mmol / l-EDTA solution (NACALAI TESQUE), and then cryopreserved.

[1111] cAMP analysis

[1112] 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. Then, the frozen GLP-1R / CHO-K1 cells were thawed in a 37°C thermostat and suspended to 2×10 cells in HBSS buffer (GIBCO) containing 0.1% BSA (Sigma), 20 mM HEPES, 0.1 mM IBMX (Sigma), and 0.2 mM RO20-1724 (Calbiochem). 4 Cells / mL, 6 μL / well of cell suspension were added. Incubated at 37°C for 1 hour, and the intracellular cAMP concentration was measured using the cAMP Gs dynamic kit (Cisbio) according to the instructions provided with the product. Specifically, a total of 6 μL / well of a mixture of cAMP-d2 and Anti-cAMP-Cryptate (1:1) was added, incubated at room temperature for 1 hour, and time-resolved fluorescence was measured using PHERAstar (BMG Labtech).

[1113] The cAMP concentration when human GLP-1 (7-36) was injected to a final concentration of 2 nM was set as 100%, and the cAMP concentration when only DMSO was injected was set as 0%. TIBCO Spotfire (TIBCO Software) was used to calculate the 50% effective concentration (EC) of the invention compound using the increase in cAMP concentration as an index. 50) and maximum effect (Emax). It should be noted that the dilution concentration or dilution solvent may be changed as needed.

[1114] The compounds of the invention were tested essentially as described above. The EC 50 , Emax are shown in the following table.

[1115] [Table 17]

[1116]

[1117] [Table 18]

[1118]

[1119] From the above results, since the compound of the present invention exhibits GLP-1 receptor agonist activity, it can be expected to be effective as a therapeutic or preventive agent for GLP-1 receptor-related diseases.

[1120] Test Example 2: Metabolic stability test

[1121] Commercially available mixed human liver microsomes were reacted with the compound of the present invention for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of liver metabolism of the compound of the present invention.

[1122] In 0.2 mL of a buffer solution (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes, react at 37°C in the presence of 1 mmol / L NADPH for 0 minutes or 30 minutes (oxidation reaction). After the reaction, 70 μL of the reaction solution was added and mixed to 140 μL of a methanol / acetonitrile = 1 / 1 (v / v) solution, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / MS, and the amount of the compound of the present invention at 0 minutes of reaction was set to 100%, and the residual rate was expressed as a ratio to the amount of the compound after the reaction. The dilution concentration or dilution solvent was changed as needed.

[1123] The compounds of the invention were tested essentially as described above.

[1124] Test Example 3: Solubility Test

[1125] The solubility of the compound of the present invention is determined under the condition of adding 1% DMSO. A 10mmol / L compound solution is prepared with DMSO, and 2μL of the compound of the present invention solution is added to 198μL of the 17th edition Japanese Pharmacopoeia Dissolution Test No. 2 Liquid. After shaking at room temperature for 3 hours, the mixed solution is filtered. The filtrate is diluted 100 times with methanol / acetonitrile / water = 1 / 1 / 2 (V / V / V), and the concentration in the filtrate is determined using LC / MS / MS by the absolute calibration curve method.

[1126] The compounds of the invention were tested essentially as described above.

[1127] Test Example 4: CYP inhibition test

[1128] Commercially available mixed human liver microsomes were used as typical substrate metabolic reactions of the major human CYP5 molecular types (CYP1A2, 2C9, 2C19, 2D6, 3A4), with O-deethylation of 7-ethoxyresorufin (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4'-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) as indicators to evaluate the degree to which the production of each metabolite was inhibited by the compounds of the present invention.

[1129] 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, 0.2 mg protein / mL mixed human liver microsomes; concentration of the compound of the present invention, 1, 5, 10, 20 μmol / L (4 points).

[1130] In a 96-well plate, as a reaction solution, 5 substrates, human liver microsomes, and the compound of the present invention were added to 50 mmol / L Hepes buffer in the above composition, and NADPH was added as a coenzyme to start the metabolic reaction as an index. After reacting at 37°C for 15 minutes, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified by a fluorescent multi-label counter or LC / MS / MS, and tolbutamide hydroxylate (CYP2C9 metabolite), mephenytoin 4'hydroxylate (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcoholate (CYP3A4 metabolite) were quantified by LC / MS / MS.

[1131] The sample obtained by adding only DMSO as a solvent for dissolving the drug to the reaction system was used as a control (100%), and the residual activity (%) was calculated. The IC was calculated by the reverse method using the logistic model using the concentration and inhibition rate. 50 .

[1132] The compounds of the invention were tested essentially as described above.

[1133] Test Example 5: BA Test

[1134] Experimental Materials and Methods for Oral Absorbability Studies

[1135] (1) Animals used: Mice or SD rats were used.

[1136] (2) Feeding conditions: Mice or SD rats were allowed to freely consume solid feed and sterilized tap water.

[1137] (3) Dosage and group setting: Oral administration and intravenous administration are administered according to the prescribed dosage. The groups are set as follows. (The dosage of each compound may be changed)

[1138] Oral administration: 2-60 μmol / kg or 1-30 mg / kg (n=2-3)

[1139] Intravenous administration 1-20 μmol / kg or 0.5-10 mg / kg (n=2-3)

[1140] (4) Preparation of dosing solution: Oral administration is by solution or suspension. Intravenous administration is by dissolution.

[1141] (5) Administration method: Oral administration is forced into the stomach through an oral probe. Intravenous administration is administered through the tail vein or femoral vein using a syringe with an injection needle.

[1142] (6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.

[1143] (7) Statistical analysis: The area under the plasma concentration-time curve (AUC) was calculated by moment analysis for the concentration changes of the compound of the present invention in plasma. The bioavailability (BA) of the compound of the present invention was calculated based on the dosage ratio and AUC ratio of the oral administration group and the intravenous administration group.

[1144] The compounds of the invention may be tested essentially as described above.

[1145] Test Example 6: Clearance Evaluation Test

[1146] Experimental Materials and Methods

[1147] (1) Animals used: SD rats were used.

[1148] (2) Feeding conditions: SD rats were allowed to freely consume solid feed and sterile tap water.

[1149] (3) Dosage and group setting: Intravenous administration was performed according to the prescribed dosage. Groups were set as follows.

[1150] Intravenous administration of 1 μmol / kg (n=2)

[1151] (4) Preparation of dosing solution: Dissolve the solution in a 1 / 1 dimethyl sulfoxide / propylene glycol solvent and administer the solution.

[1152] (5) Administration method: The drug is administered via the tail vein using a syringe with an injection needle.

[1153] (6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.

[1154] (7) Statistical analysis: The total body clearance (CLtot) was calculated by moment analysis of the concentration changes of the compound of the present invention in plasma. It should be noted that the dilution concentration or dilution solvent may be changed as needed.

[1155] The compounds of the invention were tested essentially as described above.

[1156] Test Example 6-2: Clearance Evaluation Test

[1157] Experimental Materials and Methods

[1158] (1) Animals used: Dogs (Marshall Beagle) were used.

[1159] (2) Feeding conditions: Dogs were allowed to freely consume solid feed and sterile tap water.

[1160] (3) Dosage and group setting: Intravenous administration was based on the prescribed dose. Groups were set as follows.

[1161] Intravenous administration 0.1-1 mg / kg (n=2)

[1162] (4) Preparation of dosing solution: Use any one 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, dissolve and administer.

[1163] (5) Administration method: Administer intravenously via a syringe with an injection needle.

[1164] (6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.

[1165] (7) Statistical analysis: The total body clearance (CLtot) was calculated by moment analysis of the concentration changes of the compound of the present invention in plasma. It should be noted that the dilution concentration or dilution solvent may be changed as needed.

[1166] The compounds of the invention were tested essentially as described above.

[1167] Test Example 7: CYP3A4 (MDZ) MBI Test

[1168] This test is to evaluate the mechanism-based inhibition (MBI) ability of the compounds of the present invention regarding the CYP3A4 inhibitory effect based on the enhancement caused by metabolic reactions. The CYP3A4 inhibitory effect is evaluated using the 1-hydroxylation reaction of midazolam (MDZ) as an indicator using pooled human liver microsomes.

[1169] 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; mixed human liver microsomes, 0.5 mg / mL in pre-reaction, 0.05 mg / mL in reaction (at 10-fold dilution); concentration of the compound of the present invention in pre-reaction, 0.83, 5, 10, 20 μmol / L (4 points).

[1170] In a 96-well plate, as a pre-reaction solution, a mixture of human liver microsomes and the compound of the present invention was added to K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and a portion thereof was transferred to another 96-well plate, diluted 1 / 10 with substrate and K-Pi buffer, and NADPH as a coenzyme was added to start a reaction as an index (without pre-reaction). After a predetermined reaction time, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. In addition, NADPH was also added to the remaining pre-reaction solution to start a pre-reaction (with pre-reaction). After a predetermined pre-reaction time, a portion was transferred to another plate, diluted 1 / 10 with substrate and K-Pi buffer, and a reaction as an index was started. After a predetermined reaction time, the reaction was stopped by adding a methanol / acetonitrile = 1 / 1 (V / V) solution. After the plate on which each index reaction was performed was centrifuged at 3000 rpm for 15 minutes, 1-hydroxylated midazolam in the supernatant of the centrifugation was quantified by LC / MS / MS.

[1171] The sample obtained by adding only DMSO as a solvent for dissolving the compound of the present invention to the reaction system was used as a control (100%), and the residual activity (%) when various concentrations of the compound of the present invention were added was calculated. The concentration and inhibition rate were used to calculate the IC by the reverse method using the logistic model. The IC of pre-incubation 0 min / IC of pre-incubation 30 min was used as the shift IC value. If the shift IC was 1.5 or more, it was judged as positive, and if the shift IC was 1.0 or less, it was judged as negative.

[1172] The compounds of the invention were tested essentially as described above.

[1173] Test Example 8: Powder Solubility Test

[1174] Add an appropriate amount of the compound of the present invention to an appropriate container, add 200 μL of JP-1 solution (add water to 2.0 g of sodium chloride and 7.0 mL of hydrochloric acid to make 1000 mL), JP-2 solution (dissolve 1.70 g of sodium dihydrogen phosphate and 1.775 g of anhydrous disodium hydrogen phosphate in 1000 mL of water to make a buffer solution of pH 6.8 to 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. When all dissolved after adding the test solution, add the compound of the present invention appropriately. Seal, shake at 37°C for 1 hour and filter, add 100 μL of methanol to each 100 μL filtrate to dilute it 2 times. The dilution ratio is changed as needed. Confirm whether there are bubbles and precipitates, seal and shake. Quantify the compound of the present invention using HPLC by the absolute calibration curve method.

[1175] The compounds of the invention may be tested essentially as described above.

[1176] Test Example 9: Fluctuating Ames Test

[1177] The compounds of the invention were evaluated for their mutagenicity.

[1178] 20 μL of frozen Salmonella typhimurium (Salmonella typhimurium TA98 strain, TA100 strain) was inoculated into 10 mL of liquid nutrient medium (2.5% Oxoid No. 2 nutrient broth) and pre-cultured at 37°C for 10 hours with shaking. For TA98 strain, 8.0-11.0 mL of bacterial solution was centrifuged (2000×g, 10 minutes) to remove the culture medium. The bacteria were suspended in 8.0-11.0 mL of Micro F buffer (K 2 HPO 4 :3.5g / L,KH 2 PO 4 :1g / L,(NH 4 )2 SO 4 : 1g / L, trisodium citrate dihydrate: 0.25g / L, MgSO 4 7H 2 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, 3.1 mL of the bacterial solution was added to 120 mL of Exposure medium to prepare the test bacterial solution. 12 μL of each DMSO solution of the compound of the present invention (diluted in 2- to 3-fold steps from the highest dose of 50 mg / mL), DMSO as a negative control, 50 μg / mL 4-nitroquinoline-1-oxide DMSO solution for TA98 strain under non-metabolic activation conditions as a positive control, 0.25 μg / mL 2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for TA100 strain, 40 μg / mL 2-aminoanthracene DMSO solution for TA98 strain under metabolic activation conditions, and 20 μg / mL 2-aminoanthracene DMSO solution for TA100 strain 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 the 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 the indicator was dispensed into 48 wells of a microplate at 50 μL per dosage, and statically cultured at 37°C for 3 days. Since the wells containing bacteria that have acquired the ability to proliferate due to the mutation of the amino acid (histidine) synthetase gene change color from purple to yellow due to pH changes, the number of bacterial proliferation wells that changed color to yellow in each of the 48 wells per dosage was counted and compared with the negative control group for evaluation. Mutagenicity is indicated as negative (-) and positive (+).

[1179] The compounds of the invention were tested essentially as described above.

[1180] Test Example 10: hERG Test

[1181] In order to evaluate the risk of the compounds of the present invention to prolong the QT interval of the electrocardiogram, CHO cells expressing human ether-a-go-go related gene (hERG) channels were used to study the effects of the compounds of the present invention on the delayed rectifier K, which plays an important role in the process of ventricular repolarization. + Current (I Kr)’s role.

[1182] The cells were maintained at a membrane potential of -80 mV by whole-cell patch clamping using a fully automated patch clamp system (Qpatch, Sophion Bioscience A / S). After applying a leak potential of -50 mV, a depolarizing stimulus of +20 mV was applied for 2 seconds, and a repolarizing stimulus of -50 mV was further applied for 2 seconds. The I induced at this time was recorded. Kr The extracellular solution (NaCl: 145mmol / L, KCl: 4mmol / L, CaCl) was adjusted to 0.1% dimethyl sulfoxide. 2 :2mmol / L,MgCl 2 :1mmol / L, glucose: 10mmol / L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10mmol / L, pH=7.4) as the medium, the medium and the extracellular fluid in which the compound of the present invention is dissolved at the target concentration are respectively applied to the cells at room temperature for more than 7 minutes. According to 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 membrane potential. Further, the maximum tail current after the administration of the compound of the present invention was calculated relative to the maximum tail current after the administration of the medium as the inhibition rate to evaluate the effect of the compound of the present invention on I Kr It should be noted that the dilution concentration or dilution solvent may be changed as required.

[1183] The compounds of the invention may be tested essentially as described above.

[1184] Preparation Examples

[1185] The compounds of the present invention can be administered as a pharmaceutical composition by any conventional route, in particular enteral, such as oral, such as in the form of tablets or capsules, or parenteral, such as in the form of injection liquids or suspensions, topically, such as in the form of lotions, gels, ointments or creams, or in the form of nasal or suppositories. Pharmaceutical compositions comprising the compounds of the present invention in free form or in the form of pharmaceutically acceptable salts and at least one pharmaceutically acceptable carrier or diluent can be prepared by conventional methods by mixing, granulating or coating. For example, as an oral composition, tablets, granules, capsules containing excipients, disintegrants, binders, lubricants, etc. and active ingredients can be prepared. In addition, as an injectable composition, a solution or suspension can be prepared, which can be sterilized, and can also contain preservatives, stabilizers, buffers, etc.

[1186] Industrial Applicability

[1187] The compounds of the present invention have GLP-1 receptor agonist activity and are considered to be useful as therapeutic and / or preventive agents for GLP-1 receptor-related diseases or conditions.

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof: [Chemical formula 1] In the formula, A1 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 group, or a 5- to 6-membered aromatic heterocyclic group which may be substituted by a halogen or an alkyl group; B1 is CH or N; R 10 is a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group, a difluoromethyl group or a trifluoromethyl group; R 3 is a phenyl group which may be substituted by a substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted by a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by a substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by a substituent group F, Substituent Group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy; However, (i) in R 10 When B1 is a chlorine atom, B1 is N. (ii) In R 10 In the case of trifluoromethyl, R 3 is a 5-membered aromatic heterocyclic group which may be substituted by a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by a substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by 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) Except for the following compounds: [Chemical formula 2] 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 10 It is a hydrogen atom, a cyano group, a fluorine atom, a chlorine atom, a methyl group or a difluoromethyl group.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 3 For the following groups: [Chemical formula 3] Where W is N or CR 15 ; R 11 is a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group; 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, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group; R 11 and R 12 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F, R 11 and R 13 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F, R 13 and R 14 They may form together a 5-membered aromatic heterocyclic ring which may be substituted by the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by the substituent group F.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 3 Any of the following groups: [Chemical formula 4] In the formula, R 4 Each is independently halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein R 4 Each is independently a fluorine atom, a chlorine atom, a cyano group, a methyl group, a methoxy group or a difluoromethoxy group.

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

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

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

9. A compound represented by formula (II) or a pharmaceutically acceptable salt thereof: [Chemical formula 5] In the formula, Q is a substituted or unsubstituted benzene ring or a substituted or unsubstituted 5- to 6-membered aromatic heterocycle; R 2 is a substituted or unsubstituted alkyl group or a substituted or unsubstituted non-aromatic heterocyclic group; -L- is a group represented by the following formula: [Chemical formula 6] In the formula, B1 is CH or N, B2 is C(R 9 ) or N, R 9 A hydrogen atom or 13a Together they form -O- or -CH2-O-, B3 is CH or N, R 10a is a hydrogen atom or a substituted or unsubstituted alkyl group, R 10b is a hydrogen atom, a cyano group, a halogen group or a substituted or unsubstituted alkyl group, -L1- is an alkylene group, X is S, NH or CH2, R 13a It can be a hydrogen atom or 9 Together they form -O- or -CH2-O-, R 13b is a hydrogen atom or a substituted or unsubstituted alkyl group; R 3 is a phenyl group which may be substituted by a substituent group F, a 5- to 6-membered aromatic heterocyclic group which may be substituted by a substituent group F, a bicyclic 9- to 10-membered aromatic heterocyclic group which may be substituted by a substituent group F, or a 5- to 12-membered non-aromatic heterocyclic group which may be substituted by a substituent group F, Substituent Group F: halogen, cyano, alkyl, haloalkyl, alkyloxy and haloalkyloxy; However, (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 substituted or unsubstituted 5-membered aromatic heterocyclic ring, and (ii) Except for the following compounds: [Chemical formula 7] 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 3 For the following groups: [Chemical formula 8] Where W is N or CR 15 ; R 11 is a hydrogen atom, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group; 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, a halogen, a cyano group, an alkyl group, a haloalkyl group, an alkyloxy group or a haloalkyloxy group; R 11 and R 12 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F, R 11 and R 13 can form together a 5-membered aromatic heterocyclic ring which may be substituted by substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by substituent group F, R 13 and R 14 They may form together a 5-membered aromatic heterocyclic ring which may be substituted by the substituent group F or a 5- to 7-membered non-aromatic heterocyclic ring which may be substituted by the substituent group F.

11. The compound according to claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein R 3 Any of the following groups: [Chemical formula 9] In the formula, R 4 Each is independently halogen, cyano, alkyl, haloalkyl, alkyloxy or haloalkyloxy.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 4 Each is independently a fluorine atom, a chlorine atom, a cyano group, a methyl group, a methoxy group or a difluoromethoxy group.

13. The compound or pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, wherein Q is any of the following groups: [Chemical formula 10] In the formula, A2 is C(R 5 ) or N; A3 is C(R 6 ) or N; A4 is C(R 7 ) or N; R 5 , R 6 and R 7 are each independently a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkyloxy group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted non-aromatic carbocyclic group; A5 is C(R 9 ) or N; R 9 is a hydrogen atom, a halogen, a cyano group, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted alkyloxy group.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein (i) A2 is C(R 5 )、A3 is C(R 6 ) and A4 is C(R 7 ),or (ii) A2 is N, A3 is C (R 6 ) and A4 is C(R 7 ),or (iii) A2 is C(R 5 )、A3 is C(R 6 ) and A4 is N, or (iv) A2 is N, A3 is C (R 6 ) and A4 is N.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein (i) A2 is C(R 5 )、A3 is C(R 6 ) and A4 is C(R 7 ),or (ii) A2 is N, A3 is C (R 6 ) and A4 is C(R 7 ).

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

17. The compound or pharmaceutically acceptable salt thereof according to any one of claims 9 to 16, wherein -L- is the following group: [Chemical formula 11] 18. The compound or pharmaceutically acceptable salt thereof according to any one of claims 9 to 17, wherein R 2 It is an oxetanylmethyl group.

19. A pharmaceutical composition comprising 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.

Images