PYRAZOLO[1,5-a]PYRIMIDINE COMPOUND AND THE USE THEREOF, PHARMACEUTICAL COMPOSITION, AGENT AND TOPICAL TRANSDERMAL FORMULATION

Abstract

This invention provides a pyrazolo[1,5-a]pyrimidine compound or a salt thereof, represented by general formula [I], with PAR2 inhibitory activity: The symbols are as defined in this specification; and the pharmaceutical compositions containing them.

Description

[Technical Field]

[0001] This invention relates to a pyrazolo[1,5-a]pyrimidine compound having PAR2 inhibitory activity or a pharmaceutically acceptable salt thereof. [Previous Technology]

[0002] PAR2 is one of the G protein-coupled 7-transmembrane receptors encoded by the F2RL1 gene, and it transmits signals into the cell via proteases. PAR2 is known as a tether receptor, and when the N-terminus of PAR2 is digested by proteases (mainly serine proteases), the newly exposed N-terminal sequence acts as a ligand to activate the receptor. Synthetic peptides resulting from the digestion of the N-terminal sequence can also activate the receptor (NPL 1, 2).

[0003] PAR2 is present in a wide range of areas of the body and is known to be involved in itching, allergies, inflammation, pain, and cancer. Therefore, PAR2 inhibitors are suitable as treatments for these conditions (NPL 3).

[0004] PAR2 is known to be involved in pruritus, especially dermatitis. Exogenous proteases from plants or ticks, proteases secreted by keratinocytes due to skin irritation, and proteases secreted by immune cells (such as mast cells) activate PAR2 expressed in peripheral nerve endings and induce pruritus by transmitting signals to the brain (NPL 4). Several diseases are known to be associated with pruritus, some with skin lesions and others without. In the former type of pruritus accompanied by inflammation and swelling, proteases from immune cells or keratinocytes activate PAR2 as an pruritus substance. On the other hand, in the latter type of pruritus that does not accompany skin lesions but leads to permanent dry skin, the threshold for pruritus is lowered due to intraepidermal invasion or peripheral nerve sprouting, and the skin barrier is reduced due to scratching, thus creating an environment conducive to PAR2 activation (NPL 5). For this reason, PAR2 inhibitors are applicable not only to atopic dermatitis and urticaria, but also to itching caused by dry skin without skin lesions (such as xerosis in the elderly) or underlying diseases (such as kidney or liver failure).

[0005] It has also been reported that activation of PAR2 in keratinocytes increases the expression of matrix metalloproteinases, and mice that overexpress PAR2 in their skin are prone to itching and skin inflammation, which are exacerbated by sensitization to mite antigens (NPL 6, 7). These findings suggest that PAR2 is involved not only in itching but also in skin barrier function and inflammation, and that PAR2 inhibitors are suitable for restoring the skin barrier and reducing inflammation.

[0006] PAR2 is involved in pain signaling and itch signaling, and is a target of hyperalgesia or tactile pain (NPL 8). Therefore, PAR2 inhibitors are suitable as treatments for these conditions.

[0007] PAR2 inhibitory activity of compounds having a pyrazolo[1,5-a]pyrimidine framework is described in PTLs 1 to 5. [List of Citations] [Patent Literature]

[0008] [PTL 1] JP 2003-286171 A [PTL 2] JP 2004-170323 A [PTL 3] WO 2018 / 043461 [PTL 4] WO 2019 / 163956 [PTL 5] JP 2020-007262 A [Non-Patent Literature]

[0009] [NPL 1] Dery O et al., Am J Physiol, 274, C1429-1452, 1998 [NPL 2] Macfarlane SR et al., Pharmacol Rev, 53, 245-282, 2001 [NPL 3] Yau MK et al., Expert Opinion Ther Pat., 26, 471-483, 2016 [NPL 4] Akiyama T et al., Handb Exp Pharmacol., 226, 219-223, 2015 [NPL 5] Sato et al., Clinical Practice Guidelines for Generalized Pruritus 2012 [NPL 6] Yamada Y et al., Int Arch Allergy Immunol., 173, 84-92, 2017 [NPL 7] Smith L et al., Exp Dermatol., 28, 1298-1308, 2019 [NPL 8] Dale C et al., NJ Recept Signal Transduct Res., 28, 29-37, 2008 [Summary of the Invention]

[0010] [Technical Issues]

[0011] One object of the present invention is to provide a pyrazolo[1,5-a]pyrimidine compound or a salt thereof having PAR2 inhibitory activity, and pharmaceutical compositions containing the same. Another object of the present invention is to provide a pyrazolo[1,5-a]pyrimidine compound or a salt thereof suitable as an active ingredient in a topical transdermal formulation, such as an ointment, cream, lotion, or the like. [Problem Solving]

[0012] As a result of extensive research to solve the problems mentioned above, the inventors of the present invention discovered that pyrazolo[1,5-a]pyrimidine compounds represented by the following formula [I] have PAR2 inhibitory activity, thereby completing the present invention.

[0013] That is, the present invention includes the following embodiments. [1-1] A compound represented by general formula [I]: wherein R1 is a C1-6 alkyl, C3-8 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-8 cycloalkoxy, C1-6 alkylthio or mono- or di-C1-6 alkylamino; R2 is, as appropriate, a C3-8 cycloalkyl substituted with halogen or C1-6 alkyl; a C4-10 bicycloalkyl substituted with halogen or C1-6 alkyl; a C5-13 spiroalkyl; a C6-12 tricycloalkyl; a C3-8 cycloalkyl-C1-6 alkyl substituted with halogen, C1-6 alkyl or C1-6 haloalkyl; a C3-8 cycloalkoxy-C1-6 alkyl; a C4-10 bicycloalkyl-C1-6 alkyl substituted with halogen or C1-6 alkyl; a C6-12 tricycloalkyl-C1-6 alkyl; a C6-12 tricycloalkyl-amino; or piperidinyl; R3 is hydrogen, halogen, or C1-6 alkyl; a 5 to 9 saturated or partially unsaturated heterocycle or its side oxygen group containing a nitrogen atom as a cyclizing atom, which may have a halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, hydroxyl, or methylene as a substituent, wherein the heterocycle may further have a nitrogen atom, an oxygen atom, and / or a sulfur atom as a cyclizing atom; or a salt thereof.

[0014] [1-2] The compound of [1-1] wherein, in the general formula [I], is piperidinyl, aziridine, aziridine octyl, aziridine nonyl, aziridine, 2,3,4,7-tetrahydroaziridine, 2,3,6,7-tetrahydroaziridine, diaziridine, piperidyl, aziridine, thioaziridine, oxaziridine or its side oxygen group, wherein the heterocycle may have halogen, C1-6 alkyl, C1-6 alkoxy or hydroxy as substituent, or a salt thereof.

[0015] [1-3] The compound of [1-1], wherein in the general formula [I], R1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tributyl, 2-methyl-1-propyl, 2-methyl-1-butyl, 1-pentyl, 3-pentyl, 1-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, trifluoromethyl, 1,1-difluoroethyl, propoxy, cyclohexyloxy, ethylthio, methylpropylamino or dipropylamino; R2 is cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4-butylcyclohexyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptylmethyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, decahydronaphthyl, adamantyl (tricyclo[3.3.1).[1] Decyl), spiro[2,5]octyl, spiro[3,3]heptylmethyl, 1-cyclohexylcyclopropyl, 1-methylcyclohexylmethyl, 2-methylcyclohexylmethyl, 3-methylcyclohexylmethyl, 3,5-dimethylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-butylcyclohexylmethyl, 4-fluorocyclohexylmethyl, 4-methoxycyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, 1-cyclohexylethyl, adamantylmethyl, 4-methylcyclohexylmethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, adamantylamino or piperidinyl; R3 represents hydrogen; and is an aziridine heptyl group, an aziridine octyl group, an aziridine nonyl group, 2,3,4,7-tetrahydroaziridine, 2,3,6,7-tetrahydroaziridine, 1,4-diazacycloheptyl, oxaziridine heptyl, 2,2-dimethylaziridine heptyl, 3-hydroxyaziridine heptyl, 4-hydroxyaziridine heptyl, 4-methylaziridine heptyl, 4,4-difluoroaziridine heptyl, 4-methylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-methylene-piperidinyl, 2,2-dimethyl-4-hydroxypiperidinyl, 2,2-dimethyl-3-methoxypiperidinyl, 2,2-dimethyl-4-methoxy Piperidinyl, 2,2,4,4-tetramethylpiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-4-methoxypiperidinyl, 2,2-dimethyl-4-methoxyethylpiperidinyl, 2,2-dimethyl-3-methylenepiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-4-hydroxypiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2-dimethyl-4-thiopiperidinyl, 3,3-dimethyl-4-thiopiperidinyl or oxazineheptanyl; or salts thereof.

[0016] [1-4] The compound of [1-1] wherein, in the general formula [I], R1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 3-pentyl, cyclohexyl or trifluoromethyl; R2 is cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyloxymethyl, 1-cyclohexylethyl, 4-methylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, bicyclo[2.2.1]heptylmethyl, spiro[3.3]heptylmethyl or adamantylamino; R3 is hydrogen; or is piperidinyl, azircycloheptyl, azircyclooctyl, 2,3,4,7-tetrahydroaziryl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-sideoxypiperidinyl, 2,2,4,4-tetramethyl-3-sideoxypiperidinyl or 3,3-dimethyl-4-thiopyrinyl; or a salt thereof.

[0017] [1-5] The compounds of [1-1] are selected from the group consisting of the following compounds: or their salts.

[0018] [2] A pharmaceutical composition comprising a compound or salt thereof, such as any one of [1-1] to [1-5], as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0019] [3-1] A therapeutic, preventive and / or diagnostic agent for symptoms and / or diseases caused by PAR2 activation, comprising a compound or a salt thereof as described in any one of [1-1] to [1-5].

[0020] [3-2] The therapeutic, preventive and / or diagnostic agents as in [3-1], wherein the symptom caused by PAR2 activation is pruritus.

[0021] [3-3] The therapeutic, preventive and / or diagnostic agents as described in [3-2], wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous agenesis, sebaceous agenesis eczema, senile pruritus, xeroderma, xerosis senile, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis and / or pruritus associated with chronic liver disease.

[0022] [3-4] The therapeutic, preventive and / or diagnostic agents as in [3-1], wherein the disease caused by PAR2 activation is a skin disease.

[0023] [3-5] Therapeutic, preventive and / or diagnostic agents as described in [3-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0024] [4-1] A therapeutic, preventive and / or diagnostic pharmaceutical composition for symptoms and / or diseases caused by PAR2 activation, comprising a compound or a salt thereof as an active ingredient, such as any one of [1-1] to [1-5].

[0025] [4-2] The therapeutic, preventive and / or diagnostic pharmaceutical composition of [4-1] wherein the symptom caused by PAR2 activation is pruritus.

[0026] [4-3] The therapeutic, preventive and / or diagnostic pharmaceutical composition of [4-2], wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous agenesis, sebaceous agenesis eczema, senile pruritus, xeroderma, xerosis senile, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis and / or pruritus associated with chronic liver disease.

[0027] [4-4] The therapeutic, preventive and / or diagnostic pharmaceutical composition of [4-1], wherein the disease caused by PAR2 activation is a skin disease.

[0028] [4-5] The therapeutic, preventive and / or diagnostic pharmaceutical composition of [4-4] wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0029] [5-1] A method for treating, preventing and / or diagnosing symptoms and / or diseases caused by PAR2 activation, comprising administering to a human in need an effective amount of a compound or a salt thereof, such as any one of [1-1] to [1-5].

[0030] [5-2] As in [5-1], wherein the symptom caused by PAR2 activation is skin itching.

[0031] [5-3] The method of [5-2] wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous agenesis, sebaceous agenesis eczema, senile pruritus, xeroderma, xerosis senile, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis and / or pruritus related to chronic liver disease.

[0032] [5-4] As in [5-1], wherein the disease caused by PAR2 activation is a skin disease.

[0033] [5-5] The method of [5-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0034] [6-1] A compound or a salt thereof as described in any one of [1-1] to [1-5], which is suitable for the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

[0035] [6-2] The compound or salt thereof as in [6-1], wherein the symptom caused by PAR2 activation is skin itching.

[0036] [6-3] The compound or salt thereof as described in [6-2], wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous abscess, sebaceous abscess eczema, senile pruritus, xeroderma, xerosis senile, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis and / or pruritus associated with chronic liver disease.

[0037] [6-4] The compound or salt thereof as in [6-1], wherein the disease caused by PAR2 activation is a skin disease.

[0038] [6-5] The compound or salt thereof as described in [6-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0039] [7-1] Use of a compound or a salt thereof as described in any one of [1-1] to [1-5] for the manufacture of a medicament for the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

[0040] [7-2] As used in [7-1], wherein the symptom caused by PAR2 activation is skin itching.

[0041] [7-3] As used in [7-2], wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous agenesis, sebaceous agenesis eczema, senile pruritus, xeroderma, xerosis senile, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitivity dermatitis, pruritus caused by kidney dialysis and / or pruritus related to chronic liver disease.

[0042] [7-4] As used in [7-1], wherein the disease caused by PAR2 activation is a skin disease.

[0043] [7-5] As used in [7-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0044] [8-1] A topical transdermal formulation comprising a compound or salt thereof, such as any one of [1-1] to [1-5], as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0045] [8-2] The topical transdermal formulation of [8-1] is in the form of ointment, cream, lotion, and foam. [Advantages of the Invention]

[0046] The compounds of the present invention or their salts have excellent PAR2 inhibitory activity. Furthermore, the compounds of the present invention or their salts have minimal or no skin irritation and excellent skin absorption.

Implementation Method

[0047] The terms and phrases used in this specification will be described in detail below.

[0048] In this specification, "halogen" means fluorine, chlorine, bromine or iodine. It is preferred to be fluorine, chlorine or bromine, and even more preferably fluorine or chlorine.

[0049] In this specification, "C1-6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (C1-6), and specific examples include methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, n-butyl, isobutyl, secondary butyl, tertiary butyl, 3-methylbutyl, n-pentyl, isopentyl, neopentyl, 3-pentyl, n-hexyl, isohexyl, 3-methylpentyl, 1,1-dimethylethyl, 1,2-dimethylethyl, 2,2-dimethylethyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and similar groups. Furthermore, "C1-6 alkyl" includes C1-6 alkyl groups in which 1 to 7 hydrogen atoms are substituted with deuterium atoms.

[0050] In this specification, "C1-6 haloalkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (C1-6) that has been substituted with 1 to 4 halogens, and specific examples include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, 2-fluoroethyl, 2-chloroethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl, 3-chloropropyl, 2,3-dichloropropyl, 4,4,4-trichlorobutyl, 4-fluorobutyl, 5-chloropentyl, 3-chloro-2-methylpropyl, 5-bromohexyl, 5,6-dibromohexyl and similar groups.

[0051] In this specification, "C3-8 cycloalkyl" refers to a cycloalkyl group having 3 to 8 carbon atoms (C3-8), and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and similar groups.

[0052] In this specification, "C4-10 bicycloalkyl" refers to a bicycloalkyl group having 4 to 10 carbon atoms (C4-10), and specific examples include bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl and similar groups.

[0053] In this specification, "C6-12 tricycloalkyl" refers to a tricycloalkyl group having 6 to 12 carbon atoms (C6-12), and specific examples include adamantyl and similar groups.

[0054] In this specification, “C5-13spiroalkyl” includes spiro[2,2]pentyl, spiro[2,3]hexyl, spiro[2,4]heptyl, spiro[2,5]octyl, spiro[2,6]nonyl, spiro[2,7]decyl, spiro[3,3]heptyl, spiro[3,4]octyl, spiro[3,5]nonyl, spiro[3,6]decyl and similar groups.

[0055] In this specification, "C1-6 alkoxy" refers to a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms (C1-6), and specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, 2-methylpropoxy, n-butoxy, isobutoxy, secondary butoxy, tertiary butoxy, 3-methylbutoxy, n-pentoxy, isopentoxy, neopentoxy, 3-pentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, 1,1-dimethylethoxy, 1,2-dimethylethoxy, 2,2-dimethylethoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy and similar groups.

[0056] In this specification, "C3-8 cycloalkoxy" is a cycloalkyloxy group having 3 to 8 carbon atoms (C3-8), and specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy and similar groups.

[0057] In this specification, "C1-6 alkylthio" refers to a straight-chain or branched-chain alkylthio group having 1 to 6 carbon atoms (C1-6), and specific examples include methylthio, ethylthio, n-propylthio, isopropylthio, 1-methylpropylthio, 2-methylpropylthio, n-butylthio, isobutylthio, secondary butylthio, tertiary butylthio, 3-methylbutylthio, n-pentylthio, isopentylthio, neopentylthio, 3-pentylthio, n-hexylthio, isohexylthio, 3-methylpentylthio, 1,1-dimethylethyl, 1,2-dimethylethylthio, 2,2-dimethylethylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio and similar groups.

[0058] In this specification, "mono or diC1-6 alkylamino" refers to an amino group containing one or two straight-chain or branched-chain alkyl groups having 1 to 6 carbon atoms (C1-6), and specific examples include methylamino, ethylamino, n-propylamino, isopropylamino, 1-methylpropylamino, 2-methylpropylamino, n-butylamino, isobutylamino, secondary butylamino, tertiary butylamino, 3-methylbutylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino, and similar groups.

[0059] In this specification, "C3-8 cycloalkyl-C1-6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (C1-6) that has been substituted with a cycloalkyl group having 3 to 8 carbon atoms (C3-8), and specific examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclohexyl-2-propyl and similar groups.

[0060] In this specification, "C4-10 bicycloalkyl-C1-6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (C1-6) substituted with a bicycloalkyl group having 4 to 10 carbon atoms (C4-10), and specific examples include bicyclo[2.2.1]heptylmethyl, bicyclo[2.2.2]octylmethyl, bicyclo[2.2.1]heptylethyl, bicyclo[2.2.2]octylethyl and similar groups.

[0061] In this specification, "C6-12 tricycloalkyl-C1-6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (C1-6) substituted with a tricycloalkyl group having 6 to 12 carbon atoms (C6-12), and specific examples include adamantylmethyl, adamantylethyl, adamantylpropyl and similar groups.

[0062] In this specification, "C6-12 tricycloalkyl-amine" is an amine substituted with a tricycloalkyl group having 6 to 12 carbon atoms (C6-12), and specific examples include adamantylamine and similar groups.

[0063] In this specification, "C3-8 cycloalkoxy-C1-6 alkyl" refers to a straight-chain or branched alkyl group having 1 to 6 carbon atoms (C1-6) substituted with a cycloalkoxy group having 3 to 8 carbon atoms (C3-8), and specific examples include cyclopropyloxymethyl, cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, cyclooctyloxymethyl, cyclopropyloxyethyl, cyclobutyloxyethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, cycloheptyloxyethyl, cyclooctyloxyethyl and similar groups.

[0064] In this specification, "a 5 to 9 saturated or partially unsaturated heterocycle or its side oxygen atom containing a nitrogen atom as a cyclizing atom" includes pyrrolidinyl, piperidinyl, azirrocycloheptyl, azirrocyclooctyl, azirrocyclononyl, azirrocyclopyranyl, 2,3,4,7-tetrahydroazirrocyclopyranyl, 2,3,6,7-tetrahydroazirrocyclopyranyl, 1,4-diazacycloheptyl, imidazoridinyl, pyrazolidinyl, piperidinyl, diazacycloheptyl, azirroridinyl, isozazolidinyl, thiazoridinyl, thiazoridinyl, isothiazolidinyl, thio-thiazoridinyl, and similar groups.

[0065] In this specification, the term "condensing agent" is not particularly limited, and specific examples include 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC·HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N,N'-carbonyldiimidazole (CDI), and 4-(4,6-dimethoxy-1,3,5-tris(2-yl)-4-methylpyrrolidone) chloride (DMT-MM). Benzotriazol-1-yloxys(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyridinephosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate (HATU), (1-cyano-2-ethoxy-2-sideoxyethyleneaminooxy)dimethylamino(N-hydroxylinyl)hexafluorophosphate (COMU) and their analogues, preferably WSC·HCl, HATU and COMU.

[0066] In this specification, "magnesium halide" includes magnesium fluoride, magnesium chloride, magnesium bromide, magnesium iodide and the like.

[0067] In this specification, "additive" is not particularly limited, and specific examples include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxybutyridine (HOSu), ethyl (hydroxyimino)cyanoacetate (Oxyma), 4-dimethylaminopyridine (DMAP), triethylamine (TEA), diisopropylethylamine (DIPEA), N-methyl sulfophylline and analogues thereof, preferably HOBt, TEA and DIPEA.

[0068] In this specification, the “catalyst” used in the reduction reaction is not particularly limited, but specific examples include carbon-supported palladium (Pd / C), carbon-supported platinum (Pt / C) and the like.

[0069] In this specification, "halogenating agent" is not particularly limited, but specific examples include fluorinating agents, chlorinating agents, brominating agents and iodizing agents, such as potassium fluoride, tetrabutylammonium fluoride, trifluoride (diethylamino)sulfur, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalic acid chloride, trichlorophosphoric acid, bromine, phosphorus oxybromide, phosphorus tribromide, iodine, sodium iodide and the like.

[0070] In this specification, "copper compound" is not particularly limited, but specific examples include copper iodide, copper bromide, copper chloride and the like.

[0071] In this specification, the term "acid" is not particularly limited, but includes inorganic acids, organic acids, and the like. Examples of "inorganic acids" include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, and the like. Examples of "organic acids" include acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, and the like. These acids may be used alone or in mixtures of two or more thereof.

[0072] In this specification, the term "base" is not particularly limited, but includes inorganic bases, organic bases, and the like. Examples of "inorganic bases" include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, and potassium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, and barium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, and cesium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, and barium carbonate), alkali metal bicarbonates (e.g., sodium bicarbonate and potassium bicarbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate, and cerium phosphate), alkaline earth metal phosphates (e.g., magnesium phosphate and calcium phosphate), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tributoxide, and potassium tributoxide), alkali metal hydrides (e.g., sodium hydride and potassium hydride), and the like. Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine, and N,N-diisopropylethylamine (DIPEA)), dialkylamines (e.g., diethylamine and diisopropylamine), 4-dimethylaminopyridine (DMAP), N-methylpyridine, methylpyridine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the like. These bases may be used alone or in mixtures of two or more thereof. DMAP or TEA is preferred.

[0073] In this specification, "amine" is not particularly limited, but examples include trialkylamines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA)), dialkylamines (e.g., diethylamine, diisopropylamine), dialkylanilines (e.g., N,N-diethylaniline, N,N-dimethylaniline) and the like.

[0074] The term "palladium compound" as used in this specification is not particularly limited, and examples include tetravalent palladium catalysts such as sodium hexachloropalladium(IV) tetrahydrate and potassium hexachloropalladium(IV); divalent palladium catalysts such as [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (Pd(dppf)Cl2·CH2Cl2), methanesulfonic acid (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (XPhos Pd G3), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium(II) acetylacetonate, palladium(II) dichlorobis(benzonitrile)palladium(II), palladium(II) dichlorobis(acetonitrile)palladium(II), palladium(II) dichlorobis(triphenylphosphine)palladium(II), palladium(II) dichlorotetramine, palladium(II) dichloro(cyclooctyl-1,5-diene)palladium(II) and palladium(II) trifluoroacetate, and 1,1'-bis(diphenylphosphine)ferrocene dichloropalladium(II) dichloromethane complex; and zero-valent palladium catalysts, such as triphenylmethylene acetone dipalladium(O) (Pd2(dba)3), triphenylmethylene acetone dipalladium(O)-chloroform complex and tetra(triphenylphosphine)palladium(O) (Pd(PPh3)4). These palladium compounds are used alone or in mixtures of two or more thereof.

[0075] Specific examples of the "de-radical" used in this specification include halogens, C1-18 alkylsulfonyl groups, low-carbon alkylsulfonyloxy groups, arylsulfonyloxy groups, aralkylsulfonyloxy groups, perhaloalkylsulfonyloxy groups, dihydrothio groups, toluenethiooxy groups, and similar groups. Halogens are preferred as the de-radical.

[0076] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0077] Examples of "C1-18 alkylsulfonyl" include straight-chain or branched alkylsulfonyl groups having 1 to 18 carbon atoms (C1-18), and specific examples include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl and similar groups.

[0078] Examples of "low carbon number alkylsulfonyloxy group" include straight-chain or branched alkylsulfonyloxy groups having 1 to 6 carbon atoms (C1-6), and specific examples include methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy and similar groups.

[0079] Examples of "arylsulfonyloxy" include phenylsulfonyloxy, which, as appropriate, has 1 to 3 groups selected from the group consisting of the following as substituents on the phenyl ring: straight-chain or branched alkyl having 1 to 6 carbon atoms (C1-6), straight-chain or branched alkoxy having 1 to 6 carbon atoms (C1-6), nitro and halogen; naphthylsulfonyloxy; and similar groups. Specific examples of "phenylsulfonyloxy having one or more substituents as appropriate" include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, and similar groups. Specific examples of "naphthylsulfonylutrioxy" include α-naphthylsulfonylutrioxy, β-naphthylsulfonylutrioxy, and similar groups.

[0080] Examples of "aralkylsulfonyloxy" include phenyl-substituted straight-chain or branched alkylsulfonyloxy having 1 to 6 carbon atoms (C1-6), which, as appropriate, have 1 to 3 groups selected from the group consisting of: straight-chain or branched alkyl having 1 to 6 carbon atoms (C1-6), straight-chain or branched alkoxy having 1 to 6 carbon atoms (C1-6), nitro and halogen; and naphthyl-substituted straight-chain or branched alkylsulfonyloxy having 1 to 6 carbon atoms (C1-6); and similar groups. Specific examples of "phenyl-substituted alkylsulfonyloxy groups" include benzylmethylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylmethylsulfonyloxy, 2-methylbenzylmethylsulfonyloxy, 4-nitrobenzylmethylsulfonyloxy, 4-methoxybenzylmethylsulfonyloxy, 3-chlorobenzylmethylsulfonyloxy, and similar groups. Specific examples of "naphthyl-substituted alkylsulfonyloxy groups" include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy, and similar groups.

[0081] Specific examples of "perhaloalkylsulfonyloxy" include trifluoromethanesulfonyloxy and similar groups.

[0082] Specific examples of "dihydrosulfide" include dimethyl dihydrosulfide, diethyl dihydrosulfide, dipropyl dihydrosulfide, di(2-cyanoethyl) dihydrosulfide, di(2-nitroethyl) dihydrosulfide, di(aminoethyl) dihydrosulfide, di(2-methylaminoethyl) dihydrosulfide, di(2-dimethylaminoethyl) dihydrosulfide, di(2-hydroxyethyl) dihydrosulfide, di(3-hydroxypropyl) dihydrosulfide, di(2-methoxyethyl) dihydrosulfide, di(2-aminomethoxyethyl) dihydrosulfide, di(2-aminomethoxyethyl) dihydrosulfide, di(2-carboxyethyl) dihydrosulfide, di(2-methoxycarbonylethyl) dihydrosulfide, diphenyl dihydrosulfide and similar groups.

[0083] The "solvent" used in the reactions described in this specification may be an inert solvent in the reaction, and examples include water, ethers (e.g., diethane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, and ethylene glycol dimethyl ether), halogenated hydrocarbons (e.g., dichloromethane, chloroform, 1,2-dichloroethane, and carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, and xylene), lower alcohols (e.g., methanol, ethanol, and isopropanol), and polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphonic triamine, and acetonitrile). These solvents may be used alone or in mixtures of two or more of them.

[0084] The various substituents in the compounds represented by the general formula [I] of the present invention (hereinafter referred to as "compound [I]") are explained below.

[0085] R1 in compound [I] is a C1-6 alkyl, C3-8 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-8 cycloalkoxy, C1-6 alkylthio or mono- or di-C1-6 alkylamino, preferably ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tributyl, 2-methyl-1-propyl, 2-methyl-1-butyl, 1-pentyl, 3-pentyl, 1-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, trifluoromethyl, 1,1-difluoroethyl, propoxy, cyclohexyloxy, ethylthio, methylpropylamino or dipropylamino, more preferably ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 3-pentyl, cyclohexyl or trifluoromethyl.

[0086] R2 in compound [I] is, as appropriate, a C3-8 cycloalkyl substituted with a halogen or C1-6 alkyl; a C4-10 bicycloalkyl substituted with a halogen or C1-6 alkyl; a C5-13 spiroalkyl; a C6-12 tricycloalkyl; a C3-8 cycloalkyl-C1-6 alkyl substituted with a halogen, C1-6 alkyl, or C1-6 haloalkyl; a C3-8 cycloalkoxy-C1-6 alkyl; a C4-10 bicycloalkyl-C1-6 alkyl substituted with a halogen or C1-6 alkyl; a C6-12 tricycloalkyl-C1-6 alkyl; a C3-8 cycloalkoxy-C1-6 alkyl; a C4-10 bicycloalkyl-C1-6 alkyl substituted with a halogen or C1-6 alkyl; a C6-12 tricycloalkyl-C1-6 alkyl; a C3-8 cycloalkoxy-C1-6 alkyl; a C4-10 bicycloalkyl-C1-6 alkyl substituted with a halogen or C1-6 alkyl; a C6-12 tricycloalkyl-C1-6 alkyl; a C3-8 cycloalkoxy-C1-6 alkyl; a C4-10 bicycloalkyl-C1-6 alkyl; a C6-12 tricycloalkyl-C1-6 alkyl; a C4-10 bi ... C1-6 alkyl; C6-12 tricycloalkyl-amino; or piperidinyl, preferably cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4-butylcyclohexyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptylmethyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, decahydronaphthyl, adamantyl (tricyclo[3.3.1.1]decyl), spiro[2,5]octyl, spiro[3,3]heptylmethyl, 1-cyclohexylcyclopropyl, 1-methylcyclohexylmethyl, 2-methylcyclohexylmethyl 3-methylcyclohexylmethyl, 4-methylcyclohexylmethyl, 3,5-dimethylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-butylcyclohexylmethyl, 4-fluorocyclohexylmethyl, 4-methoxycyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, 1-cyclohexylethyl, adamantylmethyl, 4-methyl Cyclohexylmethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, adamantylamino or piperidinyl, preferably cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclopentyloxymethyl, 1-cyclohexylethyl, 4-methylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, bicyclo[2.2.1]heptylmethyl, spiro[3.3]heptylmethyl or adamantylamino.

[0087] R3 in compound [I] is hydrogen, halogen or C1-6 alkyl, preferably hydrogen, fluorine, chlorine, bromine or iodine, more preferably hydrogen or fluorine, and even more preferably hydrogen.

[0088] Compound [I] comprises 5 to 9 saturated or partially unsaturated heterocycles or their side oxygen groups containing a nitrogen atom as a cyclizing atom, and may have halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, hydroxyl or methylene as substituents, wherein the heterocycle may further have a nitrogen atom, an oxygen atom and / or a sulfur atom as cyclizing atoms; preferably piperidinyl, aziridine, aziridine octyl, aziridine nonyl, aziridine, 2,3,4,7-tetrahydroaziridine, 2,3,6,7-tetrahydroaziridine, diaziridine heptyl, piperidinyl The heterocycle may contain α-phylinyl, thio-α-phylinyl, oxazolidinyl heptyl, or its side oxygen group, wherein the heterocycle may have halogen, C1-6 alkyl, C1-6 alkoxy, or hydroxyl as a substituent; more preferably, it is azeolidinyl, azeolidinyl octyl, azeolidinyl nonyl, 2,3,4,7-tetrahydroazeolidinyl, 2,3,6,7-tetrahydroazeolidinyl, 1,4-diazacycloheptyl, oxazolidinyl heptyl, 2,2-dimethylazeolidinyl heptyl, 3-hydroxyazeolidinyl heptyl, 4-hydroxyazeolidinyl heptyl, 4-methylazeolidinyl heptyl, 4,4-difluoroazeolidinyl heptyl, 4-methylpiperidinyl, or 2,2-dimethylpiperidinyl. 2,2-Dimethyl-3-hydroxypiperidinyl, 2,2-Dimethyl-3-methylene-piperidinyl, 2,2-Dimethyl-4-hydroxypiperidinyl, 2,2-Dimethyl-3-methoxypiperidinyl, 2,2-Dimethyl-4-methoxypiperidinyl, 2,2,4,4-Tetramethylpiperidinyl, 2,2,4,4-Tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-Tetramethyl-4-methoxypiperidinyl, 2,2-Dimethyl-4-methoxyethylpiperidinyl, 2,2-Dimethyl-3-methylenepiperidinyl, 2,2-Dimethylpiperidinyl, 2,2-Dimethylpiperidinyl, 2,2-Dimethylpiperidinyl, 2,2-Dimethylpiperidinyl, 2,2-Dimethylpiperidinyl -3-Side-oxypiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-3-side-oxypiperidinyl, 2,2-dimethyl-4-thiopyridine, 3,3-dimethyl-4-thiopyridine, or oxazyrazine-heptyl; more preferably piperidinyl, aziridine-heptyl, aziridine-octyl, 2,3,4,7-tetrahydroaziridine, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-side-oxypiperidinyl, 2,2,4,4-tetramethyl-3-side-oxypiperidinyl, or 3,3-dimethyl-4-thiopyridine.

[0089] Specific examples of compound [I] include,

[0090] One embodiment of the present invention relates to a pharmaceutical composition comprising a compound [I] or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0091] One embodiment of the present invention relates to a therapeutic, preventive and / or diagnostic agent for symptoms and / or diseases caused by PAR2 activation, comprising compound [I] or a salt thereof.

[0092] One embodiment of the present invention relates to a therapeutic, preventive and / or diagnostic pharmaceutical composition for symptoms and / or diseases caused by PAR2 activation, comprising a compound [I] or a salt thereof as an active ingredient.

[0093] One embodiment of the present invention relates to a method for treating, preventing and / or diagnosing symptoms and / or diseases caused by PAR2 activation, comprising administering an effective amount of the compound [I] or a salt thereof to a human in need.

[0094] One embodiment of the present invention relates to compound [I] or a salt thereof, which is used for the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

[0095] One embodiment of the present invention relates to the use of compound [I] or salt for the manufacture of a medicament for the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

[0096] One embodiment of the present invention relates to a topical transdermal formulation comprising a compound [I] or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0097] In this specification, preferred embodiments and alternatives to the different features of the compound [I] of the present invention or its salts, uses, methods and compositions may be combined, and combinations of preferred embodiments and alternatives to the different features are also included unless such combinations are incompatible with their properties.

[0098] A method for manufacturing compound [I] will be described below. Compound [I] can be manufactured according to the manufacturing method described below. These manufacturing methods are examples and the methods for manufacturing compound [I] are not limited thereto.

[0099] In the following reaction formulas, alkylation, hydrolysis, amination, esterification, acetylation, etherification, nucleophilic substitution, addition, oxidation, reduction and similar reactions are carried out according to methods known per se. Examples of such methods include those described in the following literature: Experimental Chemistry (5th edition, published by The Chemical Society of Japan, Maruzen Co., Ltd.); Organic Functional Group Preparations, 2nd edition, Academic Press, Inc. (1989); Comprehensive Organic Transformations, VCH Publishers Inc. (1989); Greene's Protective Groups in Organic Synthesis, 4th edition, (2006) by PGM Wuts and TW Greene; and similar methods.

[0100] General Synthetic Route of Compound [I] (1)

[0101] Step 1, where each symbol is defined as above.

[0102] The intermediate [4] of compound [I] can be produced by the reaction indicated by the synthetic route described above. Specifically, intermediate [4] can be produced by reacting compound [2] and compound [3] in the presence of a condensing agent and magnesium halide in an inert solvent used for the reaction.

[0103] Step 2, where each symbol is defined as above.

[0104] The intermediate [6] of compound [I] can be produced by the reaction indicated by the synthetic route described above. Specifically, intermediate [6] can be produced by reacting compound [4] and compound [5] in ethanol in the presence of an acid to form a closed ring. The solvent used in the reaction is not limited to ethanol, but also includes alcohols such as methanol and propanol. In such cases, an ethyl ester of intermediate [6] is not formed, but an alkyl ester of intermediate [6] is formed depending on the solvent used.

[0105] Step 3, where each symbol is defined as above.

[0106] The intermediate [7a] of compound [I] can be produced by the reaction indicated by the synthetic route described above. Specifically, the intermediate [7a] can be produced by reacting compound [6] with a halogenating agent in the presence of an amine in an inert solvent used for the reaction.

[0107] Step 4-1 where Y is the detachment base, R1' is R1 as defined above or its partially unsaturated form, and other symbols are as defined above.

[0108] The intermediate [9] of compound [I] can be produced by the reaction indicated by the synthetic route described above. Specifically, the intermediate [9] can be produced by carrying out a Suzuki coupling reaction between a compound [7] having a detachable group and a boric acid compound [8] in the presence of a base and a palladium compound in an inert solvent used for the reaction.

[0109] The “boronic acid compound” used in this reaction may be a borate ester compound or a boric acid compound.

[0110] Step 4-2 where X and Y are detachment bases, R1' is R1 as defined above or its partially unsaturated form, and other symbols are as defined above.

[0111] The intermediate [9] of compound [I] can also be produced by the reaction indicated by the synthetic route described above. Specifically, intermediate [9] can be produced by reacting a compound [7] with an organozinc compound

[10] in the presence of a copper compound and an additive in an inert solvent used for the reaction.

[0112] Step 5, where each symbol is defined as above.

[0113] The intermediate

[12] of compound [I] can be produced by the reaction indicated by the synthetic route described above. Specifically, intermediate

[12] can be produced by adding hydrogen to compound

[11] in an inert solvent used for the reaction in the presence of a catalyst.

[0114] Step 6, where each symbol is defined as above.

[0115] The intermediate

[14] of compound [I] can be produced by the reaction indicated by the synthetic route described above. Specifically, the intermediate

[14] can be produced by deesterifying compound

[13] in an inert solvent used for the reaction in the presence of a base.

[0116] Step 7, where each symbol is defined as above.

[0117] Compound [I] can be prepared by the reaction indicated by the synthetic route described above. Specifically, compound [I] can be prepared by acetylation of compound

[14] with cyclic amine compound

[15] in the presence of a condensing agent and an additive in an inert solvent used for the reaction.

[0118] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on each known reaction.

[0119] The reactions shown in the above synthetic pathway are general reactions in this invention, and the reaction order can be backward or forward, as long as the target compound is obtained.

[0120] In the reactions mentioned above, the products may be used in the next reaction in the form of a reaction solution or as crude products. However, the products can be separated from the reaction mixture by known methods or easily purified by common separation techniques. Examples of common separation techniques include recrystallization, distillation, and chromatography.

[0121] The starting compound, intermediate compound, and target compound mentioned in the above steps, as well as the compounds or salts thereof of the present invention, include geometric isomers, stereoisomers, optical isomers, and tautomers. Various isomers can be separated by conventional optical analysis methods. They can also be manufactured using suitable optically active raw material compounds.

[0122] The compounds or salts thereof of the present invention may be manufactured according to the synthesis method indicated by the equations described above or similar methods.

[0123] When no specific method for preparing the raw material compound used in the manufacture of the compound of the present invention or its salt is described, the raw material compound may be a commercially available product or a product manufactured according to a method known by itself or a similar method.

[0124] The starting material compounds and target compounds mentioned in the steps above may be used in appropriate salt form. Examples of salts include salts similar to those of the salts of the compounds [I] illustrated below as the present invention.

[0125] The compounds of the present invention include their salt forms, including acid addition salt forms, or salts formed with bases depending on the type of substituent. Examples of "acids" include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.); organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, etc.); and the like. Examples of "bases" include inorganic bases (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.); organic bases (e.g., methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, hydroxymethyl methylamine, dicyclohexylamine, N,N'-diphenylmethylethylenediamine, guanidine, pyridine, methylpyridine, choline, etc.); ammonium salts; and the like. In addition, it can form salts with amino acids, such as lysine, arginine, aspartic acid, glutamic acid and their analogues.

[0126] The compounds of the present invention include compounds in which one or more atoms are substituted with one or more isotopes. Examples of isotopes include deuterium (2H), tritium (3H), 13C, 15N, 18O and the like.

[0127] The compounds of the present invention [I] include pharmaceutically acceptable prodrugs. Examples of substituents that can be modified to prepare prodrugs include reactive functional groups, such as -OH, -COOH, amine groups and similar groups. The modifying groups of such functional groups are suitably selected from the term "substituents" in this specification.

[0128] Compounds represented by general formula [I] or their pharmaceutically acceptable salts are suitable as therapeutic agents, preventative agents, exacerbation preventative agents, or diagnostic agents for symptoms and / or diseases involving PAR2 hyperfunction. In addition, compounds represented by general formula [I] or their salts have PAR2 inhibitory activity and are therefore suitable as research tools for studying the physiological effects of PAR2.

[0129] Examples of symptoms and / or diseases involving PAR2 hyperfunction include itching, skin diseases, allergic diseases, inflammatory diseases, autoimmune diseases and cancer.

[0130] Compounds represented by general formula [I] or their salts exhibit excellent in vivo antipruritic activity and are therefore suitable as antipruritic agents and as therapeutic or preventative agents for various diseases accompanied by pruritus. Examples of diseases accompanied by pruritus include atopic dermatitis, urticaria, eczema, sebaceous agenesis, sebaceous agenesis eczema, senile pruritus, xeroderma, xerosis senile, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, insect bites, caterpillar dermatitis, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis, pruritus associated with chronic liver disease, lichenification of the leg, tinea cruris, cutaneous candidiasis, scabies, pruritus caused by lice, lice, drug eruptions or administration of opioid analgesics, atopic keratoconjunctivitis, allergic keratoconjunctivitis, infectious keratoconjunctivitis, spring catarrh and similar conditions. Other examples of diseases accompanied by itching include those caused by: internal medical conditions (malignant tumors, diabetes, liver disease, kidney failure, gout, thyroid disease, blood disorders); infections by parasites, fungi, viruses or similar pathogens; psychological stress; drug allergies; or pregnancy.

[0131] Specific examples of diseases include skin diseases (e.g., atopic dermatitis, psoriasis, eczema, scleroderma, and dermatitis), asthma, bronchitis, allergic reactions, allergic contact allergies, allergic keratoconjunctivitis, arthritis (including osteoarthritis, spondyloarthritis, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, and chronic rheumatoid arthritis), autoimmune diseases, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, sarcoidosis, Behcet's syndrome, inflammatory bowel disease, Crohn's disease, Alzheimer's disease, organ transplant toxicity, cancer (e.g., solid tumor cancers, including colorectal cancer, breast cancer, lung cancer, and prostate cancer; hematopoietic malignancies, including leukemia and lymphoma; Hodgkin's disease). (diseases); aplastic anemia, skin cancer and familial adenomatous polyposis), hemophilia, cachexia, tumor invasion, tumor growth, tumor metastasis and similar conditions.

[0132] The following is a description of the dosage and dosage form of a pharmaceutical preparation containing the compound of the present invention as an active ingredient, such as a therapeutic agent, preventive agent or diagnostic agent for the above-mentioned diseases.

[0133] The compounds of the present invention can be administered orally or in the non-enteral form, and can be in the form of pharmaceutical compositions having appropriate additives, matrices and carriers to be used in various formulations suitable for oral or non-enteral administration to humans or non-human animals. For example, when administered orally, they can be administered in commonly used dosage forms such as tablets, capsules, syrups, suspensions, etc. When administered in the non-enteral form, they can be administered in liquid form (such as solutions, emulsions, suspensions, etc.) as injections or eye drops; in the form of suppositories administered rectally; or in the form of topical transdermal formulations (such as ointments, creams, lotions, sprays, etc.).

[0134] Such dosage forms can be produced by conventional methods by blending the active ingredient with adjuvants such as carriers, excipients, binders, and stabilizers. When used in injectable form, it is dissolved or suspended in a physiologically acceptable carrier, such as water, saline solution, oil, glucose solution, and the like. If necessary, adjuvants such as emulsifiers, stabilizers, osmotic pressure adjusting salts, solubilizers, or buffers may be added.

[0135] When administered topically as a transdermal formulation, stabilizers, preservatives, emulsifiers, suspension stabilizers, antioxidants, fragrances, fillers, or other transdermal absorption enhancers and bases may be added as needed. Examples of bases in ointments include fatty oils, lanolin, vaseline, paraffin, resin bases, glycols, higher fatty acids, and higher alcohols. Examples of bases in emulsions include ethanol, glycerin, and glycols. Examples of bases in liquid formulations include ethanol, water, and glycols.

[0136] Dosage and frequency of administration may vary depending on the target disease, patient symptoms, age, weight, dosage form, and similar factors. When administered orally, the active ingredient is usually administered to adults in a single or multiple doses at a dose ranging from about 1 to 1000 mg daily, preferably from about 10 to 500 mg daily. When administered by injection, the active ingredient is administered in a single or multiple doses at a dose ranging from about 0.1 to about 500 mg, preferably from about 3 to about 100 mg. When administered as a transdermal formulation, an appropriate amount of the active ingredient may be applied to the infected area once or several times daily.

[0137] The compounds of the present invention have excellent transdermal absorption and are therefore preferred for use as topical transdermal formulations, such as ointments, creams and lotions.

[0138] The compounds of the present invention can be used in combination with the following: steroids (e.g., clobetasol propionate, diflucortolone valerate, betamethasone valerate ester, hydrocortisone butyrate). Butyrate), calcineurin inhibitors (e.g., cyclosporin, tacrolimus), JAK inhibitors (e.g., delgocitinib, baricitinib), PDE4 inhibitors (e.g., crisaborole, apremilast), vitamin D and its derivatives (e.g., maxacalcitol), vitamin A derivatives (e.g., adapalene), disease-modifying antirheumatic agents (DMARDs, e.g., methotrexate), κ-opioid agonists (e.g., nalfurafine hydrochloride), antihistamines, antihistamines (e.g., sodium cromoglycate, tranist, suplatast tosylate, chlorpheniramine maleate, fexofenadine hydrochloride). hydrochloride, olopatadine hydrochloride, bilastine, rupatadine fumarate fumarate), humectants (e.g., heparin analogs, urea, zinc oxide), TNFα antibodies (e.g., infliximab, adalimumab), IL-4 / 13R antibodies (e.g., dupilumab), IL-12 / 23p40 antibodies (e.g., ustekinumab), IL-13 antibodies (e.g., lebrikizumab), IL-17 antibodies (e.g., secukinumab, ixekizumab), IL-17R antibodies (e.g., brodalumab), IL-23 antibodies (e.g., guselkumab), and IL-31R antibodies (e.g., nemolizumab).

[0139] When the compounds of the present invention are used in combination with concomitant drugs, the compounds may be administered simultaneously, separately at approximately the same time, or separately at different times. The compounds and concomitant drugs may also be mixed and administered in a single formulation.

[0140] All PTL and NPL disclosures referenced in this specification are incorporated herein by reference in their entirety.

[0141] [Examples] The invention is explained in detail below with reference to test examples, reference examples, and examples. These examples should not be construed as limiting and may be used to modify the invention within its scope. The following abbreviations may be used in this specification.

[0142] abbreviation words REX Reference Example Number EX Instance number STR structural RProp Manufacturing method (the numbers indicate the method of manufacturing the compound using the corresponding raw materials in the same manner as the reference example compound having the same number as the reference example compound numbered as the reference example compound). Prop Manufacturing method (numerical indications indicate the method of manufacturing the compound using the corresponding raw materials in the same manner as the example compound having that number as the example number). material Physical property data (NMR 1: DMSO-d6) 1 δ (ppm) of H-NMR; NMR2: CDCl3 1 δ (ppm) of H-NMR; MS (mass spectrometry) AcOEt Ethyl acetate AcOH Acetic acid AcOK Potassium acetate AcONa Sodium acetate BBr3 Boron tribromide n-BuLi n-Butyllithium tBu3P･HBF4 Tetraphenylboronic acid triterpenoid butylphosphonium (BPin)2 bis(pinacolyl)diboron CDI 1,1'-Carbonyldiimidazole COMU Hexafluorophosphate (1-cyano-2-ethoxy-2-sideoxyethyleneaminooxy)dimethylamino(N-hydroxylinyl) m-CPBA m-chloroperoxybenzoic acid CPME Cyclopentyl methyl ether Cs2CO3 cesium carbonate DBU 1,8-diazabicyclo[5.4.0]-7-undecene DCC Dicyclohexylcarbodiimide DCE 1,2-Dichloroethane DCM dichloromethane DEAD diethyl azodicarboxylate DHP 3,4-Dihydro-2H-piperanan DIBAL diisobutylaluminum hydride DIBOC Dibutyl dicarbonate (di-tertiary butyl ester) abbreviation words DIPEA Diisopropylethylamine DMA N,N-Dimethylacetamide DMAP 4-(Dimethylamino)pyridine DME Dimethoxyethane DMF N,N-Dimethylformamide DMSO Dimethicone DPPA Diphenylphosphine azide Et2O Diethyl ether EtOH ethanol HATU o-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate HCl hydrochloric acid hexane n-Hexane HOBt 1-Hydroxybenzotriazole IPA 2-Propanol IPE diisopropyl ether K2CO3 Potassium carbonate K3PO4 Tripotassium phosphate KHCO3 Potassium bicarbonate KOH potassium hydroxide KOtBu Potassium butoxide (tertiary grade) LAH Lithium aluminum hydride LDA Lithium diisopropylamine LHMDS Bis(trimethylsilane)amine lithium LiOH Lithium hydroxide MeCN Acetonitrile MEK 2-Butanone MeOH methanol NaBH4 Sodium borohydride Na2CO3 Sodium carbonate NaH Sodium hydride NaHCO3 Sodium bicarbonate NaOH Sodium hydroxide NaOtBu Sodium butanol NBS N-bromosuccinimide NCS N-Chloroprene diimide NHS N-hydroxybutyric acid NMP N-methylpyrrolidone abbreviation words Pd / C carbon-supported palladium Pd2(dba)3 Tris(diphenylmethyleneacetone)dipalladium(0) Pd(tBu3P)2 Bis(tri-tert-butylphosphine)palladium PdCl2(dppf)DCM [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) chloride Pd(OAc)2 Palladium(II) acetate Pd(PPh3)4 4-(triphenylphosphine)palladium(0) Pt / C carbon-supported platinum PEG polyethylene glycol PPTS p-Pyridonium p-toluenesulfonate TBAF Tetrabutylammonium fluoride TCDI 1,1'-Thiocarbonyldiimidazole TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TosMIC Toluenesulfonylmethylisocyanate TPP Triphenylphosphine p-TsOH･H2O p-Toluenesulfonic acid monohydrate WSC 3-Ethyl-1-(3-dimethylaminopropyl)carbodiimide ZCl Benzyl chloroformate

[0143] In the following examples, "room temperature" generally means from about 10°C to about 35°C. Unless otherwise specified, the ratios indicated for mixed solvents are volume mixing ratios. Unless otherwise specified, % means wt%. 1H NMR (proton nuclear magnetic resonance spectrum) is measured by Fourier-transform type NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz). Mass spectrometry (MS) is measured by LC / MS (ACQUITY UPLC H category). ESI method is used as the ionization method. Data indicate actual measured values ​​(experimental values). Generally, molecular ion peaks ([M+H]+, [MH]-, etc.) are observed. In the case of salts, molecular ion peaks or fragment ion peaks in their free form are generally observed. In silicone column chromatography, when the indication is basic, silicone bonded with aminopropyl silane is used. The absolute configuration of the compound is determined by known X-ray crystal structure analysis methods (e.g., "Basic Course for Chemists 12, X-ray Crystal Structure Analysis", Shigeru Ohba and Shigenobu Yano, 1st edition, 1999) or estimated according to the empirical rules of Shi asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401; Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0144] [Reference Example] Reference Example 1: Synthesis of 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid Ethyl 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (170 mg) was added to a solution of ethyl 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (170 mg) in THF (1.7 ml)-MeOH (1.7 ml) at 0 °C, and the mixture was stirred overnight at room temperature. The reaction mixture was acidified by adding 1N HCl, followed by extraction with AcOEt. The organic layer was concentrated to give the target compound (157 mg).

[0145] Reference Example 2: Synthesis of Ethyl 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylate K₂CO₃ (1383 mg) and trans-dichlorobis(triphenylphosphine)palladium(II) (176 mg) were added to a solution of ethyl 5-(1-adamantyl)-7-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate (900 mg) and n-propylboronic acid (770 mg) in 1,4-dimethylbenzane (18 ml), and the mixture was stirred overnight at 80 °C. Water was added to the reaction mixture, and the insoluble substances were filtered off. The filtrate was extracted with AcEt, and the organic layer was concentrated. The residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give the target compound (615 mg).

[0146] Reference Example 3: Synthesis of 5-(1-adamantyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid Ethyl 5-(1-adamantyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (98 mg) in EtOH (3 ml) was added to a solution of 1N NaOH (0.533 ml), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was acidified by adding water and 1N HCl. The resulting mixture was stirred for 30 minutes, and the precipitate was collected by filtration to give the target compound (81 mg).

[0147] Reference Example 4: Synthesis of Ethyl 5-(1-adamantyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate Pd / C (25 mg) was added to a solution of ethyl 5-(1-adamantyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate (100 mg) in AcOEt (5 ml), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the target compound (99 mg).

[0148] Reference Example 5: Synthesis of Ethyl 5-(1-adamantyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate PdCl2(dppf)DCM (187 mg) and 2N Na2CO3 aqueous solution (3.44 ml) were added to a solution of ethyl 5-(1-adamantyl)-7-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate (825 mg) and 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (0.517 ml) in 1,4-dioxane (10 ml), and the mixture was stirred at 90°C for 5 hours under an argon atmosphere. The reaction mixture was concentrated. Water and AcOEt were added to the residue, and the mixture was then filtered through diatomaceous earth. The filtrate was extracted with AcOEt, and the organic layer was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the target compound (747 mg).

[0149] Reference Example 6: Synthesis of Ethyl 5-(1-adamantyl)-7-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 5-(1-adamantyl)-7-sideoxy-4H-pyrazolo[1,5-a]pyrimidine-2-carboxylate (1.1 g), phosphorus oxychloride (11 ml), and N,N-dimethylaniline (0.408 ml) were mixed and stirred at 90 °C for 8 hours. The reaction mixture was concentrated, and the residue was poured into ice water. Na2CO3 aqueous solution was added and neutralized. The resulting mixture was extracted with AcOEt, and the extract was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the target compound (825 mg).

[0150] Reference Example 7: Synthesis of Ethyl 5-(1-adamantyl)-7-sideoxy-4H-pyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 3-(1-adamantyl)-3-sideoxypropionate (7.2 g), ethyl 5-amino-1H-pyrazol-3-carboxylate (4.46 g), and p-TsOH·H2O (0.547 g) were added to EtOH (80 ml), and the mixture was heated to reflux and kept overnight. The reaction mixture was concentrated, water was added, and the precipitate was collected by filtration to give the target compound (7.59 g).

[0151] Reference Example 8: Synthesis of 5-(cyclohexylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid. A solution of ethyl 5-(cyclohexylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (138 mg) in THF (10 ml) was cooled to -2°C. An aqueous solution of LiOH (186 mg) (3 ml) was added dropwise to the solution, and the mixture was stirred overnight at -2°C. HCl was added to the reaction mixture, and the mixture was stirred for 1 hour. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated to give the target compound (133 mg).

[0152] Reference Example 9: Synthesis of Ethyl 5-(cyclohexylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 5-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (780 mg), zinc bromide solution (5.08 ml), and Pd(Ph3P)4 (267 mg) were dissolved in THF (3 ml), and the solution was stirred at 50°C for 4 hours under an argon atmosphere. Water and an aqueous solution of NH4Cl were added to the reaction mixture, and the resulting mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (177 mg).

[0153] Reference Example 10: Synthesis of Ethyl 5-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate Phosphorus oxybromide (14.58 g) was added to a solution of 7.0 g of 5-sidekto-7-(trifluoromethyl)-4H-pyrazolo[1,5-a]pyrimidine-2-carboxylate in 70 ml of 1,4-dimethylethane. The mixture was stirred at 90 °C for 4 hours. After cooling, the reaction mixture was poured into ice water, and the precipitate was collected by filtration to give the target compound (8.09 g).

[0154] Reference Example 11: Synthesis of 5-(cyclopentylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid A solution of 5-cyclopentyl-1,1,1-trifluoropentane-2,4-dione (8.55 g) and 5-amino-1H-pyrazol-3-carboxylic acid (4.89 g) in AcOH (50 ml) was heated to reflux and maintained for 2 hours. The reaction mixture was concentrated, and AcOEt was added to the residue. The resulting mixture was extracted with 5N NaOH. The aqueous layer was acidified by adding 5N HCl, and the mixture was extracted with AcOEt. The organic layer was concentrated to give the target compound (8.80 g).

[0155] Reference Example 12: Synthesis of 5-cyclopentyl-1,1,1-trifluoropentane-2,4-dione KOtBu (5.03 g) was added to a solution of 1-cyclopentylprop-2-one (2.83 g) and ethyl trifluoroacetate (3.20 ml) in THF (30 ml) while ice-cooled, and the mixture was stirred overnight at room temperature. 1N HCl was added to the reaction mixture, and the resulting mixture was extracted with Et2O. The organic layer was concentrated to give the target compound (4.39 g).

[0156] Reference Example 15: Synthesis of 5-(cyclohexylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid Ethyl 5-(cyclohexylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4.86 g) in EtOH (50 ml) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated. Water was added to the residue, and the mixture was acidified by adding 5N HCl. The precipitate was collected by filtration to give the target compound (4.28 g).

[0157] Reference Example 16: Synthesis of Ethyl 5-(cyclohexylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate 10% Pd / C (1.3 g) was added to a solution of ethyl 5-(cyclohexylmethyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate (12.9 g) in an AcOEt (65 ml). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the target compound (10.7 g).

[0158] Reference Example 17: Synthesis of Ethyl 5-(cyclohexylmethyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (14 g), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborane (9.14 ml), PdCl2(dppf)DCM (0.355 g) and K3PO4 (18.47 g) in 1,4-dioxane (120 ml)-water (30 ml) was heated to reflux under a nitrogen atmosphere and maintained for 5 hours. The reaction mixture was concentrated. Water was added to the residue, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (12.9 g).

[0159] Reference Example 18: Synthesis of Ethyl 7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate A solution of ethyl 5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (17.2 g) in toluene (170 ml) was mixed with phosphorus oxychloride (13.21 ml) and DIPEA (9.90 ml), and the mixture was heated to reflux and held for 4.5 hours. The reaction mixture was concentrated. Ice water was added to the residue, and the mixture was neutralized by adding a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with AcOEt, and the organic layer was concentrated to give the target compound (18.4 g).

[0160] Reference Example 19: Synthesis of Ethyl 5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate To a suspension of ethyl 4-cyclohexyl-3-sideoxybutyrate (8.35 g) and 5-amino-1H-pyrazol-3-carboxylic acid (5.00 g) in EtOH (50 ml), p-TsOH·H2O (3.74 g) was added, and the mixture was heated to reflux and held for 5 hours. The reaction mixture was concentrated. Water was added to the residue, and the precipitate was collected by filtration to give the target compound (13.9 g).

[0161] Reference Example 20: Synthesis of azircycloheptane-1-yl-[7-(cyclohexen-1-yl)-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone. A solution of azircycloheptane-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone (500 mg), 1-cyclohexen-1-yl-boronic acid pinacol ester (305 mg), PdCl2(dppf)DCM (109 mg), and K3PO4 (566 mg) in 1,4-diane (6 ml)-water (3 ml) was heated to reflux under a nitrogen atmosphere and maintained for 3 hours. Water was added to the mixture, and the resulting mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to obtain the target compound (570 mg).

[0162] Reference Example 21: Synthesis of Azacycloheptane-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone A solution of azacycloheptane-1-yl-[5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidin-2-yl] ketone (7.4 g) in toluene (40 ml) was mixed with phosphorus oxychloride (5.80 ml) and DIPEA (3.63 ml), and the mixture was heated to reflux and held for 5 hours. The reaction mixture was concentrated. Ice water was added to the residue, and the mixture was neutralized by adding a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with AcOEt, and the organic layer was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the target compound (5.2 g).

[0163] Reference Example 22: Synthesis of Azacycloheptan-1-yl-[5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidin-2-yl]methyl ketone A solution of 5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidin-2-carboxylic acid (4.78 g) in DMF (50 ml) was mixed with HATU (7.92 g), TEA (2.90 ml), and hexamethyleneimine (2.348 ml) and stirred overnight at room temperature. HCl and water were added to the reaction mixture and the mixture was stirred. The precipitate was collected by filtration to give the target compound (5.6 g).

[0164] Reference Example 31: Synthesis of Ethyl 5-(cyclopentylmethyl)-7-pent-3-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate A suspension of ethyl 7-chloro-5-(cyclopentylmethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (500 mg), copper iodide (I) (30.9 mg), and lithium chloride (68.9 mg) in NMP (5 ml) was mixed with 0.5N 1-ethylpropyl zinc bromide solution (4.87 ml). The mixture was stirred at 50°C for 5 hours. Water and AcOEt were added to the mixture, and the mixture was filtered through diatomaceous earth. The filtrate was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give the target compound (222 mg).

[0165] Reference Example 43: Synthesis of Ethyl 5-(2-cyclohexylethyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate. A solution of 5-aminopyrazole-1,3-dicarboxylate (3.08 g) in methanesulfonic acid (15 ml) was stirred at 120 °C for 4 hours. EtOH (30 ml) and ethyl 5-cyclohexyl-3-sphenoxyvalerate (3.22 g) were added to the reaction mixture, and the mixture was heated to reflux and held for 3 hours. After cooling to room temperature, water was added to the mixture. The resulting mixture was concentrated. Water was added to the residue, and the mixture was stirred. The precipitate was collected by filtration to give the target compound (3.07 g).

[0166] Reference Example 44: Synthesis of Diethyl 5-aminopyrazole-1,3-dicarboxylate TFA (94 ml) was added to a suspension of (Z)-1-cyano-3-ethoxy-3-t-oxyprop-1-en-2-olide (109 g) and ethyl hydrazine carboxylate (66.5 g) in MeCN (1000 ml), and the mixture was stirred at room temperature for 2 hours. TEA (339 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The resulting mixture was then concentrated. IPE and water were added to the residue, and the mixture was stirred. The solid was collected by filtration to give the target compound (100.7 g).

[0167] Reference Example 49: Synthesis of Ethyl 4-(4-methylcyclohexyl)-3-sideoxybutyrate A solution of 4-methylcyclohexaneacetic acid (2 g) in CPME (40 ml) was added with CDI (2.283 g), and the mixture was stirred at room temperature for 1 hour. Monoethyl potassium malonate (2.397 g) and magnesium chloride (1.341 g) were added to the mixture, and the mixture was stirred at 70 °C for 4 hours. 1 N HCl was added to the reaction mixture, and the mixture was stirred briefly and extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (2.65 g).

[0168] Reference Example 84: Synthesis of terbutyl 4-[5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl]-3,3-dimethylpiperazine-1-carboxylic acid HATU (312 mg) and TEA (0.114 ml) were added to a suspension of 5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (200 mg) in DCM (5 ml). After ten (10) minutes, 1-Boc-3,3-dimethylpiperazine (176 mg) was added to the mixture, and the mixture was stirred overnight at room temperature. Water and an aqueous solution of Na2CO3 were added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt). The product was recrystallized from IPE-hexane to give the target compound (167 mg).

[0169] Reference Example 86: Synthesis of Ethyl 5-cyclohexyl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate A solution of 1-cyclohexyl-4,4,4-trifluorobutane-1,3-dione (1.18 g) and ethyl 5-amino-1H-pyrazol-3-carboxylate (0.824 g) in AcOH (15 ml) was heated to reflux and kept overnight. The reaction mixture was concentrated. AcOEt was added to the residue, and the mixture was filtered. A saturated aqueous solution of Na2CO3 was added to the filtrate, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (1.07 g).

[0170] Reference Example 93: Synthesis of Ethyl 5-(1-methylcyclohexyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (100 mg), 1-methylcyclohexanecarboxylic acid (165 mg), ammonium persulfate (440 mg), and silver nitrate (262 mg) were dissolved in MeCN-water (6 ml), and the solution was stirred at 60 °C for 2 hours. Water was added to the mixture, and the mixture was extracted with AcOEt. The resulting mixture was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the target compound (114 mg).

[0171] Reference Example 99: Synthesis of 2,2-Dimethylazircycloheptane hydrochloride Palladium hydroxide / carbon (0.122 g) and 2,2-dichloropropane (0.311 ml) were added to a solution of 1-benzyl-2,2-dimethylazircycloheptane (0.54 g) in EtOH (15 ml), and the mixture was stirred at 35 °C for 2.5 h under a hydrogen atmosphere. After nitrogen substitution, the reaction mixture was filtered through diatomaceous earth and washed with AcOEt. 4N HCl / AcOEt (0.7 ml) was added to the filtrate, and the mixture was sonicated and then concentrated to give the target compound (0.33 g).

[0172] Reference Example 100: Synthesis of 2,2,4,4-Tetramethylpiperidin-3-one hydrochloride Pd-C (200 mg) was added to a solution of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one (1.00 g) in AcOEt (10 ml), and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The reaction mixture was then filtered through diatomaceous earth. HCl / AcOEt (5.00 ml) was added to the filtrate, and the precipitate was collected by filtration to give the target compound (754 mg).

[0173] Reference Example 101: Synthesis of 1-Benzyl-2,2,4,4-Tetramethylpiperidin-3-one A solution of 1-benzyl-2,2-dimethylpiperidin-3-one (100 mg) in THF (1 ml) was mixed with KOtBu (207 mg) and iodomethane (0.086 ml) and stirred at room temperature for 30 minutes. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (89 mg).

[0174] Reference Example 108: Synthesis of Ethyl 5-(1-adamantylamino)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 5-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (500 mg), 1-adamantaneamine (268 mg) and K2CO3 (266 mg) were dissolved in DMF, and the solution was stirred at 100°C for 1 hour. Water was added to the reaction mixture, and the precipitate was collected by filtration to give the target compound (614 mg).

[0175] Reference Example 109: Synthesis of 5-(1-adamantyl)-7-propoxypyrazolo[1,5-a]pyrimidine-2-carboxylic acid A solution of ethyl 5-(1-adamantyl)-7-chloropyrazolo[1,5-a]pyrimidine-2-carboxylic acid (200 mg) in THF (2.5 ml) was mixed with 0.831 ml of 1-propanol and 0.695 ml of 4N LiOH, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was weakly acidified by adding 1N HCl while being ice-cooled, and the precipitate was collected by filtration to give the target compound (180 mg).

[0176] Reference Example 115: Synthesis of Ethyl 5-(cyclopentyloxymethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate To a solution of ethyl 5-(cyclopentyloxymethyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate (150 mg) in AcOEt (5 ml), a palladium-activated carbon ethylenediamine complex (10 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the target compound (110 mg).

[0177] Reference Example 132: Synthesis of 5-piperidin-1-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid Ethyl 5-piperidin-1-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (471 mg) was added to a solution of 2N LiOH (2 ml) in THF / EtOH (5 ml). The mixture was stirred at 0°C for 2 hours, followed by the addition of an aqueous HCl solution. The reaction mixture was extracted with AcOEt and concentrated. AcOH (2 ml) was added to the residue, and the mixture was stirred at 100°C for 3 hours. The resulting mixture was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (233 mg).

[0178] Reference Example 133: Synthesis of Ethyl 5-piperidin-1-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 5-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (482 mg), piperidine (0.17 ml), and K2CO3 (256 mg) were dissolved in DMF (1.5 ml), and the mixture was stirred at 100 °C for 1 hour. Water was added to the reaction mixture, and the precipitate was collected by filtration to give the target compound (411 mg).

[0179] Reference Example 143: Synthesis of 2,2,4,4-Tetramethylpiperidin-3-one hydrochloride Pd / C (20 mg) was added to a solution of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one (100 mg) in AcOEt (2 ml), and the mixture was stirred at room temperature for 30 minutes under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth. 4N HCl / AcOEt (1.00 ml) was added to the filtrate, and the mixture was stirred. The precipitate was then collected to give the target compound (58 mg).

[0180] Reference Example 144: Synthesis of 1-Benzyl-2,2,4,4-Tetramethylpiperidin-3-one A solution of 1-benzyl-2,2-dimethylpiperidin-3-one (100 mg) in THF (1 ml) was mixed with KOtBu (207 mg) and iodomethane (0.086 ml) and stirred at room temperature for 30 minutes. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give the target compound (89 mg).

[0181] Reference Example 145: Synthesis of 2,2,3-Trimethylpiperidin-3-ol Hydrochloride Pd / C (200 mg) was added to a solution of 1-benzyl-2,2,3-trimethylpiperidin-3-ol (948 mg) in EtOH (10 ml), and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth. 1N HCl / AcOEt (8.12 ml) was added to the filtrate, and the mixture was concentrated to give the target compound (744 mg).

[0182] Reference Example 146: Synthesis of 1-benzyl-2,2,3-trimethylpiperidin-3-ol Methylmagnesium bromide (1.350 ml) was added to a solution of 1-benzyl-2,2-dimethylpiperidin-3-one (157 mg) in THF (3 ml) while ice-cooling, and the mixture was stirred for 1 hour while ice-cooling. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give the target compound (135 mg).

[0183] Reference Example 149: Synthesis of [5-(cyclohexylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]-(2,2-dimethylpiperazine-1-yl) ketone: While ice-cooled, TFA (2.12 ml) was added to a solution of 1.37 g of 4-[5-(cyclohexylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidin-2-carbonyl]-3,3-dimethylpiperazine-1-carboxylic acid tributyl ester in DCM (13 ml), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was neutralized by adding a saturated aqueous solution of Na₂CO₃. The resulting mixture was extracted with AcOEt, and the organic layer was concentrated to give the target compound (1.06 g).

[0184] Reference Example 152: Synthesis of 1-Benzyl-2,2,4,4-Tetramethylpiperidin-3-ol NaBH4 (0.136 g) was added to a solution of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one (1.77 g) in MeOH (20 ml) while ice-cooled. The mixture was stirred at room temperature for 30 minutes, followed by the addition of water. The resulting mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give the target compound (1.45 g).

[0185] Reference Example 155: Synthesis of Tributyl 2,2-Dimethyl-3-methylenepiperidine-1-carboxylate Potassium tributoxide (150 mg) was added to a solution of (methyl)triphenylphosphonium bromide (479 mg) in THF (4 mL), and the mixture was stirred at room temperature for 30 minutes. A solution of 2,2-dimethyl-3-methylenepiperidine-1-carboxylate (203 mg) in THF (5 mL) was added to the mixture, and the mixture was stirred at room temperature for 1 hour. Water was added to the mixture, and the resulting mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give the target compound (39 mg).

[0186] Reference Example 156: Synthesis of Ethyl 5-(1-adamantyl)-7-pentylpyrazolo[1,5-a]pyrimidine-2-carboxylate Hexanal (0.761 ml) was added to a solution of 1-(1-adamantyl)-2-(biphenyl-λ5-phosphinevinyl) ketone (1.39 g) in toluene (40 ml), and the mixture was heated to reflux and held for 3 hours. The reaction mixture was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give an intermediate compound (697 mg). The intermediate compound was dissolved in DMF (10.5 ml), and ethyl 5-amino-1H-pyrazol-3-carboxylate (0.492 g) and K2CO3 (0.876 g) were added to the solution. The mixture was then stirred overnight at 100 °C. A saturated aqueous solution of NH4Cl was added to the reaction mixture, and the resulting mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to obtain the target compound (329 mg).

[0187] The compounds of Reference Examples 13, 14, 23 to 30, 32 to 42, 45 to 48, 50 to 83, 85, 87 to 92, 94 to 98, 102 to 107, 110 to 114, 116 to 131, 134 to 142, 147, 148, 150, 151, 153, 154 and 157 to 236 were prepared in the same manner as those of Reference Examples 1 to 12, 15 to 22, 31, 43, 44, 49, 84, 86, 93, 99 to 101, 108, 109, 115, 132, 133, 143 to 146, 149, 152, 155 and 156. The structural formulas and physicochemical information of the compounds of Reference Examples 1 to 236 are shown in Tables 1-1 to 1-32.

[0188] [Table 1-1] REX STR RProp material 1 1 NMR1: 13.6-12.7 (brs, 1H), 7.20 (s, 1H), 6.99 (s, 1H), 3.15 – 3.07 (m, 2H), 2.12 – 2.05 (m, 3H), 2.01 – 1.96 (m, 6H), 1.90 – 1.79 (m, 2H), 1.79 – 1.72 (m, 6H), 0.99 (t, J = 7.4 Hz, 3H). 2 2 NMR2: 7.12 (s, 1H), 6.83 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.21 (td, J = 7.7, 0.9 Hz, 2H), 2.17 – 2.12 (m, 3H), 2.04 – 1.98 (m, 6H), 1.95-1.87 (m, 2H), 1.86 – 1.75 (m, 6H), 1.44 (t, J = 7.2 Hz, 3H), 1.09 (t, J = 7.4 Hz, 3H)。 3 3 NMR1: 13.9-12.7 (brs, 1H), 7.11 (s, 1H), 7.00 (s, 1H), 3.83 – 3.71 (m, 1H), 2.13 – 2.05 (m, 3H), 2.02 – 1.97 (m, 6H), 1.79 – 1.73 (m, 6H), 1.40 (d,J= 6.9 Hz, 6H)。 4 4 NMR2: 7.12 (s, 1H), 6.83 (s, 1H), 4.47 (q,J= 7.1 Hz, 2H), 4.07 – 3.93 (m, 1H), 2.17 – 2.13 (m, 3H), 2.07 – 2.00 (m, 6H), 1.89 – 1.73 (m, 6H), 1.48 – 1.40 (m, 9H)。 5 5 NMR2: 7.15 (s, 1H), 6.92 (s, 1H), 6.20 – 6.15 (m, 1H), 5.71 – 5.65 (m, 1H), 4.45 (q,J= 7.1 Hz, 2H), 2.36 (s, 3H), 2.18 – 2.12 (m, 3H), 2.06 – 2.01 (m, 6H), 1.90 – 1.74 (m, 6H), 1.43 (t,J= 7.1 Hz, 3H)。 6 6 NMR2: 7.22 (s, 1H), 7.14 (s, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.18 – 2.14 (m, 3H), 2.04 – 1.99 (m, 6H), 1.87 – 1.74 (m, 6H), 1.45 (t, J = 7.1 Hz, 3H). [Table 1-2] REX STR RProp Data 7 7 NMR2: 9.39 (s, 1H), 6.53 (s, 1H), 5.87 (d, J = 2.2 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 2.18 – 2.13 (m, 3H), 2.01 - 1.93 (m, 6H), 1.86 – 1.69 (m, 6H), 1.33 (t, J = 7.1 Hz, 3H). 8 8 NMR1: 13.54 (s, 1H), 7.73 (s, 1H), 7.24 (s, 1H), 2.80 (d, J = 7.1 Hz, 2H), 1.93 – 1.82 (m, 1H), 1.73 – 1.53 (m, 5H), 1.30 – 0.94 (m, 5H). 9 9 NMR2: 7.24 (s, 1H), 7.11 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.79 (d, J = 7.2 Hz, 2H), 1.92 – 1.81 (m, 1H), 1.77 – 1.63 (m, 5H), 1.44 (t, J = 7.1 Hz, 3H), 1.33 – 1.02 (m, 5H). 10 10 NMR2: 7.39 (s, 1H), 7.30 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 3H). 11 11 NMR1: 13.52 (s, 1H), 7.75 (s, 1H), 7.25 (s, 1H), 2.93 (d, J = 7.5 Hz, 2H), 2.41 – 2.31 (m, 1H), 1.77 – 1.68 (m, 2H), 1.68 – 1.56 (m, 2H), 1.56 – 1.45 (m, 2H), 1.28 – 1.18 (m, 2H). 12 12 NMR2: 5.95 – 3.69 (m, 2H), 2.62 – 2.31 (m, 2H), 2.25 – 2.13 (m, 1H), 1.90 – 1.51 (m, 6H), 1.19 – 1.09 (m, 2H). 13 11 NMR1: 13.52 (s, 1H), 7.77 (s, 1H), 7.23 (s, 1H), 2.98 – 2.89 (m, 2H), 1.90 – 1.71 (m, 5H), 1.66 – 1.43 (m, 4H), 1.21 – 1.08 (m, 2H). 14 12 NMR2: 5.92 (s, 1H), 2.49 – 2.41 (m, 3H), 1.84 – 1.49 (m, 9H), 1.20 – 1.01 (m, 2H). [Table 1-3] REX STR RProp Data 15 15 NMR1: 13.23 (s, 1H), 7.01 – 6.96 (m, 2H), 3.82 – 3.67 (m, 1H), 2.69 (d,J= 7.1 Hz, 2H), 1.92 – 1.76 (m, 1H), 1.73 – 1.54 (m, 5H), 1.37 (d,J= 6.9 Hz, 6H), 1.27 – 0.92 (m, 5H)。 16 16 NMR2: 7.08 (s, 1H), 6.61 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 2.70 (d, J = 7.2 Hz, 2H), 1.89 – 1.61 (m, 6H), 1.48 – 1.39 (m, 9H), 1.31 – 0.99 (m, 5H)。 17 17 NMR2: 7.11 (s, 1H), 6.71 (s, 1H), 6.29 – 6.24 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.71 (d, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.89 – 1.80 (m, 1H), 1.76-1.63 (m, 5H), 1.43 (t, J = 7.1 Hz, 3H), 1.31 – 0.99 (m, 5H)。 18 18 NMR2: 7.20 (s, 1H), 6.94 (s, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.72 (d,J= 7.2 Hz, 2H), 1.91 – 1.78 (m, 1H), 1.75 – 1.67 (m, 5H), 1.45 (t,J= 7.1 Hz, 3H), 1.34 – 0.98 (m, 5H)。 19 19 NMR2: 12.31 (s, 1H), 6.63 (s, 1H), 5.76 (d, J = 1.9 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.66 (d, J = 7.1 Hz, 2H), 1.73 – 1.52 (m, 6H), 1.21 (t, J = 7.1 Hz, 3H), 1.18 – 0.88 (m, 5H). 20 20 NMR1: 7.03 – 6.96 (m, 1H), 6.92 (s, 1H), 6.78 (s, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.60 (t, J = 6.0 Hz, 2H), 2.67 (d, J = 7.2 Hz, 2H), 2.58 – 2.54 (m, 2H), 2.34 – 2.26 (m, 2H), 1.88 – 1.51 (m, 14H), 1.32 – 1.09 (m, 7H), 1.07 – 0.94 (m, 2H). 21 21 NMR2: 6.95 (s, 一氢), 6.87 (s, 1H), 3.77 – 3.70 (m, 4H), 2.70 (d, J = 7.2 Hz, 2H), 1.92 – 1.73 (m, 5H), 1.76 – 1.61 (m, 9H), 1.33 – 0.96 (m, 5H). [Table 1-4] REX STR RProp Data 22 22 NMR2: 11.72 (s, 1H), 5.89 (s, 1H), 5.63 (s, 1H), 3.77 (t, J = 6.0 Hz, 2H), 3.71 – 3.63 (m, 2H), 2.37 (d, J = 6.8 Hz, 2H), / (m, 2H), 1.71 – 1.47 (m, 12H), 1.22 – 0. / (m, 5H). 23 It should be noted that in the translation of the NMR data part, there may be some inaccuracies due to the complexity of NMR data representation. It is recommended to double-check with relevant NMR knowledge and the original context for more accurate understanding. 1 NMR1: 13.23 (s, 1H), 7.04 – 7.01 (m, 1H), 6.99 (s, 1H), 3.13 (q,J= 7.4 Hz, 2H), 2.80 (d,J= 7.5 Hz, 2H), 2.39 – 2.26 (m, 1H), 1.76 – 1.43 (m, 6H), 1.36 (t,J= 7.5 Hz, 3H), 1.29 – 1.16 (m, 2H)。 24 2 NMR2: 7.09 (s, 1H), 6.67 (s, 1H), 4.48 (q,J= 7.1 Hz, 2H), 3.27 (q,J= 7.5 Hz, 2H), 2.83 (d,J= 7.5 Hz, 2H), 2.40 – 2.24 (m, 1H), 1.84 – 1.62 (m, 4H), 1.59 – 1.51 (m, 2H), 1.44 (t,J= 7.1 Hz, 6H), 1.34 – 1.18 (m, 2H)。 25 6 NMR2: 7.19 (s, 1H), 6.97 (s, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.85 (d,J= 7.5 Hz, 2H), 2.40 – 2.24 (m, 1H), 1.85 – 1.51 (m, 6H), 1.45 (t,J= 7.1 Hz, 3H), 1.33 – 1.20 (m, 2H)。 26 7 NMR2: 12.34 (s, 1H), 6.62 (s, 1H), 5.80 (s, 1H), 4.30 (q,J= 7.1 Hz, 2H), 2.80 (d,J= 7.5 Hz, 2H), 2.36 – 2.20 (m, 1H), 1.81 – 1.40 (m, 6H), 1.28 – 1.15 (m, 5H)。 27 1 NMR1: 13.23 (s, 1H), 7.01 (s, 1H), 6.99 (s, 1H), 3.82 – 3.67 (m, 1H), 2.81 (d, J = 7.5 Hz, 2H), 2.41 – 2.25 (m, 1H), 1.75 – 1.43 (m, 6H), 1.37 (d, J = 6.9 Hz, 6H), 1.29 – 1.16 (m, 2H). 28 4 NMR2: 7.08 (s, 1H), 6.65 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 2.83 (d, J = 7.5 Hz, 2H), 2.40 – 2.25 (m, 1H), 1.84 – 1.51 (m, 6H), 1.48 – 1.39 (m, 9H), 1.34 – 1.20 (m, 2H). 29 2 NMR2: 7.11 (s, 1H), 6.74 (s, 1H), 6.29 – 6.24 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.84 (d, J = 7.5 Hz, 2H), 2.41 – 2.25 (m, 4H), 1.85 – 1.50 (m, 6H), 1.43 (t, J = 7.1 Hz, 3H), 1.34 – 1.21 (m, 2H). [Table 1-5] REX STR RProp Data 30 1 NMR2: 7.20 (s, 1H), 6.64 (s, 1H), 3.81 – 3.69 (m, 1H), 2.86 (d, J = 7.5 Hz, 2H), 2.38 – 2.26 (m, 1H), 1.98 – 1.47 (m, 10H), 1.34 – 1.20 (m, 2H), 0.88 (t, J = 7.4 Hz, 6H). 31 31 NMR2: δ 7.07 (s, 1H), 6.59 (s, 1H), 4.52 – 4.42 (m, 2H), 3.86 – 3.75 (m, 1H), 2.83 (d,J= 7.5 Hz, 2H), 2.37 – 2.24 (m, 1H), 1.96 – 1.49 (m, 10H), 1.42 (t,J= 7.2 Hz, 3H), 1.33 – 1.20 (m, 2H), 0.87 (t,J= 7.4 Hz, 6H)。 32 1 NMR1: 13.24 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 3.80 – 3.69 (m, 1H), 2.86 – 2.78 (m, 2H), 1.87 – 1.68 (m, 5H), 1.65 – 1.44 (m, 4H), 1.37 (d,J= 6.9 Hz, 6H), 1.19 – 1.10 (m, 2H)。 33 4 NMR2: 7.08 (s, 1H), 6.65 (s, 1H), 4.47 (q,J= 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 2.88 – 2.80 (m, 2H), 1.92 – 1.74 (m, 4H), 1.70 – 1.49 (m, 4H), 1.48 – 1.39 (m, 10H), 1.24 – 1.11 (m, 2H)。 34 2 NMR2: 7.11 (s, 1H), 6.74 (s, 1H), 6.28 – 6.22 (m, 1H), 5.74 – 5.68 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.90 – 2.81 (m, 2H), 2.38 – 2.33 (m, 3H), 1.92 – 1.75 (m, 3H), 1.70 – 1.49 (m, 6H), 1.43 (t, J = 7.1 Hz, 3H), 1.24 – 1.13 (m, 2H). 35 6 NMR2: 7.19 (s, 1H), 6.98 (s, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.90 – 2.82 (m, 2H), 1.91 – 1.75 (m, 5H), 1.70 – 1.49 (m, 4H), 1.45 (t, J = 7.1 Hz, 3H), 1.24 – 1.07 (m, 2H). 36 7 NMR1: 12.46 (s, 1H), 6.49 (s, 1H), 5.73 (d, J = 1.6 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.63 – 2.55 (m, 2H), 1.87 – 1.40 (m, 9H), 1.33 (t, J = 7.1 Hz, 3H), 1.20 – 1.08 (m, 2H). [Table 1-6] REX STR RProp Data 37 1 NMR2: 7.19 (s, 1H), 6.71 (s, 1H), 3.24 – 3.15 (m, 2H), 2.85 (d, J = 7.6 Hz, 2H), 2.38 – 2.26 (m, 1H), 1.99 – 1.85 (m, 2H), 1.84 – 1.48 (m, 6H), 1.34 – 1.21 (m, 2H), 1.10 (t, J = 7.4 Hz, 3H). 38 2 NMR2: 7.08 (s, 1H), 6.65 (s, 1H), 4.48 (q,J= 7.1 Hz, 2H), 3.25 – 3.16 (m, 2H), 2.82 (d,J= 7.5 Hz, 2H), 2.39 – 2.23 (m, 1H), 1.98 – 1.84 (m, 2H), 1.83 – 1.50 (m, 6H), 1.44 (t,J= 7.1 Hz, 3H), 1.33 – 1.22 (m, 2H), 1.09 (t,J= 7.4 Hz, 3H)。 39 1 NMR1: 13.20 (s, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 3.82 – 3.67 (m, 1H), 2.86 – 2.77 (m, 2H), 1.80 – 1.54 (m, 7H), 1.37 (d,J= 6.9 Hz, 6H), 1.34 – 1.07 (m, 4H), 1.00 – 0.86 (m, 2H)。 40 4 NMR1: 7.04 (s, 1H), 7.03 (s, 1H), 4.38 (q,J= 7.1 Hz, 2H), 2.86 – 2.78 (m, 2H), 1.80 – 1.55 (m, 8H), 1.40 – 1.31 (m, 9H), 1.31 – 1.09 (m, 4H), 1.00 – 0.86 (m, 2H)。 41 2 NMR1: 7.12 (s, 1H), 7.07 (s, 1H), 6.35 – 6.30 (m, 1H), 5.82 – 5.76 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.87 – 2.79 (m, 2H), 2.33 – 2.27 (m, 3H), 1.80 – 1.54 (m, 7H), 1.35 (t, J = 7.1 Hz, 3H), 1.32 – 1.04 (m, 4H), 0.99 – 0.82 (m, 2H). 42 6 NMR1: 7.58 (s, 1H), 7.19 (s, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.88 – 2.79 (m, 2H), 1.79 – 1.54 (m, 7H), 1.35 (t, J = 7.1 Hz, 3H), 1.35 – 1.05 (m, 4H), 0.99 – 0.82 (m, 2H). 43 43 NMR1: 12.45 (s, 1H), 6.48 (s, 1H), 5.72 (s, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.63 – 2.55 (m, 2H), 1.77 – 1.49 (m, 7H), 1.33 (t, J = 7.1 Hz, 3H), 1.28 – 1.04 (m, 4H), 0.99 – 0.85 (m, 2H). [Table 1-7] REX STR RProp Data 44 44 NMR1: 6.57 (s, 2H), 5.68 (s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H). 45[[ID=]] 1 NMR1: 13.23 (s, 1H), 7.00 (s, 1H), 6.99 (s, 1H), 3.12 (q,J= 7.5 Hz, 2H), 2.68 (d,J= 7.2 Hz, 2H), 1.88 – 1.78 (m, 1H), 1.70 – 1.56 (m, 5H), 1.36 (t,J= 7.5 Hz, 3H), 1.28 – 0.90 (m, 5H)。 46 2 NMR2: 7.09 (s, 1H), 6.64 (s, 1H), 4.48 (q,J= 7.1 Hz, 2H), 3.32 – 3.21 (m, 2H), 2.70 (d,J= 7.2 Hz, 2H), 1.93 – 1.61 (m, 6H), 1.48 – 1.40 (m, 6H), 1.34 – 0.96 (m, 5H)。 47 11 NMR2: 7.35 (s, 1H), 7.20 – 7.14 (m, 1H), 2.98 – 2.77 (m, 2H), 2.15 – 2.07 (m, 1H), 1.89 – 1.61 (m, 2H), 1.59 – 1.27 (m, 5H), 1.19 – 1.04 (m, 1H), 1.02 – 0.85 (m, 4H)。 48 12 NMR2: 5.92 – 5.86 (m, 1H), 3.79 – 3.71 (m, 1H), 2.44 – 2.24 (m, 2H), 2.08 – 1.17 (m, 8H), 1.09 – 0.84 (m, 5H)。 49 49 NMR2: 4.25 – 4.14 (m, 2H), 3.41 (d, J = 5.2 Hz, 2H), 2.54 – 2.36 (m, 2H), 2.19 – 2.02 (m, 1H), 1.82 – 1.45 (m, 4H), 1.42 – 1.09 (m, 6H), 1.05 – 0.80 (m, 5H). 50 1 NMR2: 7.22 – 7.17 (m, 1H), 6.70 – 6.64 (m, 1H), 3.99 – 3.88 (m, 1H), 2.86 – 2.69 (m, 2H), 2.13 – 1.61 (m, 3H), 1.57 – 1.47 (m, 3H), 1.44 (d, J = 6.9 Hz, 6H), 1.41 – 1.29 (m, 2H), 1.17 – 0.82 (m, 5H). 51 4 NMR2: 7.10 – 7.06 (m, 1H), 6.65 – 6.59 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.05 – 3.94 (m, 1H), 2.86 – 2.64 (m, 2H), 1.77 – 1.61 (m, 2H), 1.55 – 1.30 (m, 15H), 1.15 – 0.79 (m, 5H). 52 2 NMR2: 7.11 (s, 1H), 6.75 – 6.69 (m, 1H), 6.30 – 6.24 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.85 – 2.64 (m, 2H), 2.38 – 2.33 (m, 3H), 2.14 – 1.62 (m, 3H), 1.56 – 1.30 (m, 8H), 1.16 – 0.82 (m, 5H). [Table 1-8] REX STR RProp Data 53 6 NMR2: 7.20 (s, 1H), 6.98 – 6.92 (m, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.85 – 2.67 (m, 2H), 2.09 – 2.02 (m, 1H), 1.84 – 1.62 (m, 2H), 1.55 – 1.28 (m, 8H), 1.16 – 0.84 (m, 5H)。 54 7 NMR2: 12.05 (s, 1H), 6.61 (s, 1H), 5.80 – 5.74 (m, 1H), 4.30 (q,J= 7.1 Hz, 2H), 2.80 – 2.60 (m, 2H), 2.03 – 1.98 (m, 1H), 1.78 – 1.64 (m, 2H), 1.52 – 1.16 (m, 8H), 1.07 – 0.75 (m, 5H)。 55 1 NMR2: 7.20 (s, 1H), 6.91 (s, 1H), 2.18 – 2.13 (m, 3H), 2.05 – 2.01 (m, 6H), 1.86 – 1.76 (m, 6H), 1.64 (s, 9H)。 56 1 NMR1: 13.50 (s, 1H), 7.82 (s, 1H), 7.26 (s, 1H), 2.13 – 2.07 (m, 3H), 2.04 – 1.99 (m, 6H), 1.79 – 1.73 (m, 6H)。 57 11 NMR2: 7.37 (s, 1H), 7.11 (s, 1H), 2.71 (s, 2H), 2.22 – 2.09 (m, 1H), 2.04 – 1.90 (m, 4H), 1.80 – 1.51 (m, 10H)。 58 20 NMR1: 7.83 (t, J = 2.4 Hz, 1H), 6.97 (s, 1H), 6.84 (s, 1H), 3.69 (t, J = 6.0 Hz, 2H), 3.65 – 3.58 (m, 2H), 2.97 – 2.82 (m, 2H), 2.70 (d, J = 7.1 Hz, 4H), 2.06 – 1.94 (m, 2H), 1.92 – 1.49 (m, 14H), 1.27 – 0.89 (m, 5H). 59 1 NMR1: 13.24 (s, 1H), 7.03 (s, 1H), 6.99 (s, 1H), 3.82 – 3.67 (m, 1H), 2.84 – 2.72 (m, 1H), 1.94 – 1.66 (m, 5H), 1.62 – 1.48 (m, 2H), 1.46 – 1.14 (m, 9H). [Table 1-9] REX STR<​​​​​​​​​​​​​​​​​​​​​​​NMR2: 7.19 (s, 1H), 6.65 (s, 1H), 3.98 – 3.87 (m, 1H), 2.95 (d,J= 7.6 Hz, 2H), 2.87 – 2.72 (m, 1H), 2.18 – 2.06 (m, 2H), 1.98 – 1.75 (m, 4H), 1.43 (d,J= 6.9 Hz, 6H)。 63 1 NMR2: 7.18 (s, 1H), 6.67 (s, 1H), 3.98 – 3.86 (m, 1H), 2.75 (d,J= 7.4 Hz, 2H), 2.47 – 1.48 (m, 11H), 1.44 (d,J= 6.9 Hz, 6H), 1.36 – 1.21 (m, 2H)。 64 1 NMR2: 7.21 (s, 1H), 6.63 (s, 1H), 3.88 – 3.78 (m, 1H), 2.73 (d,J= 7.1 Hz, 2H), 2.01 – 1.57 (m, 8H), 1.40 (d,J= 7.0 Hz, 3H), 1.34 – 1.00 (m, 5H), 0.97 (t,J= 7.4 Hz, 3H)。 65 1 NMR2: 7.21 (s, 1H), 6.62 (s, 1H), 3.82 – 3.70 (m, 1H), 2.77 (d,J= 7.4 Hz, 2H), 2.18 – 1.20 (m, 17H), 0.88 (t,J= 7.4 Hz, 6H)。 66 31 NMR2: 7.09 (s, 1H), 6.84 (s, 1H), 4.45 (q,J= 7.1 Hz, 2H), 2.18 – 2.12 (m, 3H), 2.05 – 2.00 (m, 6H), 1.86 – 1.76 (m, 6H), 1.64 (s, 9H), 1.43 (t,J= 7.1 Hz, 3H)。 67 12 NMR2: 5.83 – 5.51 (m, 1H), 2.19 – 2.02 (m, 3H), 1.98 – 1.94 (m, 6H), 1.77 – 1.47 (m, 9H). [Table 1-10] REX STR RProp Data 68 4 NMR2: 7.08 (s, 1H), 6.66 (s, 1H), 4.47 (q,J = 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 2.80 – 2.68 (m, 1H), 2.03 – 1.72 (m, 5H), 1.65 – 1.51 (m, 2H), 1.50 – 1.27 (m, 12H). 69 2 NMR2: 7.12 (s, 1H), 6.76 (s, 1H), 6.23 (s, 1H), 5.74 – 5.67 (m, 1H), 4.46 (q,J = 7.1 Hz, 2H), 2.82 – 2.70 (m, 1H), 2.36 (s, 3H), 2.05 – 1.72 (m, 5H), 1.66 – 1.51 (m, 2H), 1.51 – 1.23 (m, 6H). 70 6 NMR2: 7.20 (s, 1H), 6.99 (s, 1H), 4.50 (q,J = 7.1 Hz, 2H), 2.82 – 2.70 (m, 1H), 2.04 – 1.74 (m, 5H), 1.64 – 1.50 (m, 3H), 1.49 – 1.22 (m, 5H). 71 7 NMR1: 12.32 (s, 1H), 6.48 (s, 1H), 5.69 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.59 – 2.51 (m, 1H), 1.93 – 1.64 (m, 5H), 1.54 – 1.15 (m, 8H). 72 31 NMR2: 7.07 (s, 1H), 6.61 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.94 – 3.81 (m, 1H), 2.83 (d, J = 7.5 Hz, 2H), 2.39 – 2.23 (m, 1H), 1.96 – 1.50 (m, 7H), 1.44 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 6.9 Hz, 3H), 1.33 – 1.19 (m, 3H), 0.95 (t, J = 7.4 Hz, 3H). 73 31 NMR2: 7.06 (s, 1H), 6.66 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.79 – 2.67 (m, 1H), 2.02 – 1.73 (m, 5H), 1.64 (s, 9H), 1.61 – 1.54 (m, 2H), 1.49 – 1.28 (m, 6H). 74 4 NMR1: 7.04 (s, 1H), 6.99 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 3.83 – 3.68 (m, 1H), 2.92 (d, J = 7.6 Hz, 2H), 2.83 – 2.71 (m, 1H), 2.11 – 1.96 (m, 2H), 1.91 – 1.68 (m, 4H), 1.42 – 1.31 (m, 9H). [Table 1-11] REX STR RProp Data 75 2 NMR1: 7.10 – 7.04 (m, 2H), 6.35 – 6.29 (m, 1H), 5.83 – 5.77 (m, 1H), 4.38 (q,J= 7.1 Hz, 2H), 2.94 (d,J= 7.6 Hz, 2H), 2.85 – 2.73 (m, 1H), 2.29 (s, 3H), 2.10 – 1.96 (m, 2H), 1.92 – 1.70 (m, 4H), 1.34 (t,J= 7.1 Hz, 3H)。 76 6 NMR2: 7.19 (s, 1H), 6.92 (s, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.94 (d,J= 7.6 Hz, 2H), 2.88 – 2.70 (m, 1H), 2.19 – 2.06 (m, 2H), 1.99 – 1.74 (m, 4H), 1.45 (t,J= 7.1 Hz, 3H)。 77 43 NMR1: 12.44 (s, 1H), 6.48 (s, 1H), 5.67 (s, 1H), 4.33 (q,J= 7.1 Hz, 2H), 2.72 – 2.57 (m, 3H), 2.10 – 1.98 (m, 2H), 1.91 – 1.68 (m, 4H), 1.33 (t,J= 7.1 Hz, 3H)。 78 4 NMR2: 7.08 (s, 1H), 6.63 (s, 1H), 4.48 (q,J= 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 2.73 (d,J= 7.4 Hz, 2H), 2.07 – 2.02 (m, 1H), 1.76 – 1.47 (m, 9H), 1.48 – 1.36 (m, 9H), 1.36 – 1.22 (m, 3H)。 79 2 NMR2: 7.12 (s, 1H), 6.72 (s, 1H), 6.27 (s, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.75 (d, J = 7.4 Hz, 2H), 2.38 – 2.33 (m, 3H), 2.13 – 2.01 (m, 1H), 1.81 – 1.36 (m, 12H), 1.36 – 1.22 (m, 3H). 80 6 NMR2: 7.20 (s, 1H), 6.96 (s, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.75 (d, J = 7.4 Hz, 2H), 2.14 – 2.01 (m, 1H), 1.77 – 1.37 (m, 12H), 1.36 – 1.23 (m, 3H). 81 7 NMR2: 12.32 (s, 1H), 6.64 (s, 1H), 5.77 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.70 (d, J = 7.4 Hz, 2H), 2.07 – 1.92 (m, 1H), 1.82 – 1.13 (m, 15H). 82 31 NMR2: 7.08 (s, 1H), 6.58 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.92 – 3.83 (m, 1H), 2.70 (d, J = 7.2 Hz, 2H), 1.97 – 1.62 (m, 8H), 1.44 (t, J = 7.1 Hz, 3H), 1.38 (d, J = 6.9 Hz, 3H), 1.31 – 1.14 (m, 3H), 1.12 – 0.98 (m, 2H), 0.95 (t, J = 7.5 Hz, 3H). [Table 1-12] REX STR RProp Data 83 31 NMR2: 7.08 (s, 1H), 6.57 (s, 1H), 4.47 (d,J= 7.2 Hz, 2H), 4.18 – 4.07 (m, 1H), 3.86 – 3.75 (m, 1H), 2.74 (d,J= 7.4 Hz, 2H), 2.22 – 1.15 (m, 19H), 0.88 (t,J= 7.5 Hz, 6H)。 84 84 NMR2: 7.26 (s, 1H), 7.06 – 7.01 (m, 1H), 4.01 – 3.94 (m, 2H), 3.58 – 3.47 (m, 4H), 2.19 – 2.15 (m, 3H), 2.02 (d, J = 2.9 Hz, 6H), 1.81 (q, J = 12.6 Hz, 6H), 1.62 (s, 6H), 1.48 (s, 9H)。 85 1 NMR1: 13.46 (s, 1H), 7.77 (s, 1H), 7.24 (s, 1H), 2.92 (tt, J = 11.7, 3.4 Hz, 1H), 2.00 – 0.91 (m, 10H)。 86 86 NMR2: 7.24 (s, 1H), 7.17 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.83 (tt, J = 11.8, 3.4 Hz, 1H), 2.07 – 1.73 (m, 5H), 1.68 – 1.19 (m, 8H)。 87 1 NMR1: 13.29 (s, 1H), 7.72 (s, 1H), 7.22 (s, 1H), 3.47 – 3.36 (m, 1H), 2.14 – 1.47 (m, 8H)。 88 86 NMR2: 7.23 (s, 1H), 7.16 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.38 – 3.25 (m, 1H), 2.21 – 2.08 (m, 2H), 1.96 – 1.71 (m, 6H), 1.44 (t, J = 7.1 Hz, 3H). 89 1 NMR1: 13.56 (s, 1H), 7.82 (s, 1H), 7.28 (s, 1H), 3.18 – 3.07 (m, 1H), 2.22 – 1.72 (m, 8H). [Table 1-13] REX STR RProp Data 90 86 NMR2: 7.27 (s, 1H), 7.19 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 3.01 – 2.89 (m, 1H), 2.48 – 2.23 (m, 2H), 2.16 – 1.70 (m, 6H), 1.45 (t, J = 7.1 Hz, 3H). 91 12 NMR2: 5.96 (s, 1H), 2.45 – 2.40 (m, 2H), 2.27 – 1.65 (m, 8H). 92 1 NMR1: 13.54 (s, 1H), 7.78 (s, 1H), 7.28 (s, 1H), 2.25 – 2.16 (m, 2H), 1.64 – 1.19 (m, 11H). 93 93 NMR2: 7.32 (s, 1H), 7.27 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.23 – 2.14 (m, 2H), 1.70 – 1.57 (m, 3H), 1.53 – 1.38 (m, 8H), 1.30 (s, 3H). 94 1 NMR2: 7.38 – 7.32 (m, 1H), 7.27 – 7.20 (m, 1H), 3.01 – 2.75 (m, 1H), 2.45 – 2.26 (m, 1H), 2.11 –1.49 (m, 6H), 1.44 – 1.03 (m, 8H), 0.95 – 0.79 (m, 3H). 95 93 NMR2: 7.26 – 7.23 (m, 1H), 7.21 – 7.15 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.02 – 2.72 (m, 1H), 2.08 – 1.89 (m, 4H), 1.86 – 1.73 (m, 1H), 1.71 – 1.52 (m, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.41 – 1.22 (m, 6H), 1.16 – 1.01 (m, 2H), 0.93 – 0.84 (m, 3H). 96 84 NMR2: 6.82 (s, 1H), 6.77 (s, 1H), 3.95 – 3.89 (m, 2H), 3.85 – 3.75 (m, 1H), 3.59 – 3.47 (m, 4H), 2.17 – 2.11 (m, 3H), 2.05 – 1.99 (m, 6H), 1.86 – 1.74 (m, 6H), 1.65 – 1.60 (m, 6H), 1.48 (s, 9H), 1.45 – 1.38 (m, 6H). [Table 1-14] REX STR RProp Data 97 1 NMR2: 7.32 (s, 1H), 7.19 (s, 1H), 3.03 (tt, J = 10.2, 3.8 Hz, 1H), 2.09 – 1.99 (m, 2H), 1.94 – 1.62 (m, 10H)。 98 93 NMR2: 7.23 (s, 1H), 7.14 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.01 (tt, J = 10.2, 3.8 Hz, 1H), 2.08 – 1.99 (m, 2H), 1.94 – 1.57 (m, 10H), 1.44 (t, J = 7.1 Hz, 3H)。 99 99 NMR1: 8.91 (s, 2H), 3.04 – 2.97 (m, 2H), 1.85 – 1.77 (m, 2H), 1.71 – 1.64 (m, 2H), 1.62 – 1.52 (m, 4H), 1.30 (s, 6H)。 100 100 NMR2: 10.23 (s, 2H), 3.46 – 3.39 (m, 2H), 2.23 – 2.16 (m, 2H), 1.68 (s, 6H), 1.26 (s, 6H)。 101 101 NMR2: 7.41 – 7.19 (m, 5H), 3.61 (s, 2H), 2.64 (t, J = 6.4 Hz, 2H), 1.68 (t, J = 6.4 Hz, 2H), 1.32 (s, 6H), 1.19 (s, 6H)。 102 1 NMR2: 7.19 (s, 1H), 6.61 (s, 1H), 3.70 (q, J = 6.8 Hz, 1H), 2.73 (d, J = 7.3 Hz, 2H), 1.97 – 1.76 (m, 5H), 1.76 – 1.60 (m, 5H), 1.32 – 0.97 (m, 5H), 0.88 (t, J = 7.4 Hz, 6H). 103 31 NMR2: 7.07 (s, 1H), 6.55 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.86 – 3.74 (m, 1H), 2.70 (d, J = 7.2 Hz, 2H), 1.96 – 1.74 (m, 4H), 1.76 – 1.62 (m, 6H), 1.43 (t, J = 7.1 Hz, 3H), 1.31 – 0.96 (m, 5H), 0.87 (t, J = 7.4 Hz, 6H). 104 1 NMR2: 7.29 (s, 1H), 7.07 (s, 1H), 2.79 (d, J = 7.2 Hz, 2H), 2.35 (t, J = 19.1 Hz, 3H), 1.94 – 1.80 (m, 1H), 1.77 – 1.64 (m, 5H), 1.34 – 1.00 (m, 5H). [Table 1-15] REX STR RProp Data 105 86 NMR2: 7.17 (s, 1H), 7.02 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.76 (d, J = 7.2 Hz, 2H), 2.36 (t, J = 19.2 Hz, 3H), 1.91 – 1.79 (m, 1H), 1.71 (d, J = 12.4 Hz, 5H), 1.43 (t, J = 7.1 Hz, 3H), 1.33 – 0.99 (m, 5H)。 106 12 NMR2: 14.91 (s, 1H), 5.88 (d,J= 0.9 Hz, 1H), 2.32 – 2.22 (m, 2H), 1.85 – 1.61 (m, 7H), 1.35 – 0.83 (m, 7H)。 107 1 NMR1: 13.16 (s, 1H), 7.55 (s, 1H), 7.02 (s, 1H), 6.46 (s, 1H), 2.14 – 2.06 (m, 9H), 1.70 – 1.62 (m, 6H)。 108 108 NMR1: 7.59 (s, 1H), 7.04 (s, 1H), 6.52 (s, 1H), 4.33 (q, J = 7.1 Hz, 2H), 2.17 – 2.04 (m, 9H), 1.76 – 1.62 (m, 6H), 1.31 (t, J = 7.1 Hz, 3H)。 109 109 NMR1: 6.89 (s, 1H), 6.72 (s, 1H), 4.46 (t, J = 6.7 Hz, 2H), 2.12 – 2.05 (m, 3H), 2.02 – 1.97 (m, 6H), 1.97 – 1.84 (m, 2H), 1.79 – 1.73 (m, 6H), 1.05 (t, J = 7.4 Hz, 3H)。 110 1 NMR2: 7.37 (singlet, 1H), 7.31 (singlet, 1H), 3.16 (singlet, 1H), 2.66 – 2.61 (multiplet, 2H), 2.12 – 1.76 (multiplet, 10H), 1.71 – 1.64 (multiplet, 2H). 111 31 NMR2: 7.31 – 7.22 (multiplet, 2H), 4.48 (quartet, J = 7.1 Hz, 2H), 3.14 (singlet, 1H), 2.65 – 2.60 (multiplet, 2H), 2.08 – 2.01 (multiplet, 3H), 1.98 – 1.82 (multiplet, 5H), 1.80 (singlet, 2H), 1.70 – 1.63 (multiplet, 2H), 1.44 (quartet, J = 7.1 Hz, 3H). [Table 1-16] REX STR RProp Data 112 1 NMR2: 7.37 – 7.31 (multiplet, 2H), 1.95 – 1.89 (multiplet, 6H), 1.81 – 1.71 (multiplet, 7H). 113 93<00​​​​​​​​​​​ 115 NMR2: 7.11 (singlet, 1H), 7.02 (doublet, J = 0.6 Hz, 1H), 4.60 (singlet, 2H), 4.48 (quartet, J = 7.1 Hz, 2H), 4.11 – 3.97 (multiplet, 2H), 1.83 – 1.72 (multiplet, 8H), 1.50 – 1.40 (multiplet, 9H). 116 2 NMR2: 7.14 (singlet, 1H), 7.10 (singlet, 1H), 6.36 – 6.31 (multiplet, 1H), 5.78 – 5.72 (multiplet, 1H), 4.61 (singlet, 2H), 4.46 (quartet, J = 7.1 Hz, 2H), 4.08 (singlet, 1H), 2.39 – 2.34 (multiplet, 3H), 1.85 – 1.73 (multiplet, 6H), 1.61 – 1.54 (multiplet, 2H), 1.44 (triplet, J = 7.1 Hz, 3H). <s 117 [[ID=1S]]6 NMR2: 7.34 (singlet, 1H), 7.22 (singlet, 1H), 4.60 (singlet, 2H), 4.51 (quartet, J = 7.1 Hz, 2H), 4.15 – 4.00 (multiplet, 1H), 1.88 – 1.68 (multiplet, 6H), 1.64 – 1.56 (multiplet, 2H), 1.46 (triplet, J = 7.1 Hz, 3H). 118 7 NMR2: 9.51 (singlet, 1H), 6.65 (singlet, 1H), 5.82 – 5.77 (multiplet, 1H), 4.52 (singlet, 2H), 4.41 (quartet, J = 7.1 Hz, 2H), 4.13 – 4.05 (multiplet, 1H), 1.90 – 1.66 (multiplet, 6H), 1.59 (doublet, J = 8.7 Hz, 2H), 1.37 (triplet, J = 7.1 Hz, 3H). [Table 1-17] REX STR RProp Data 119 1 NMR2: 7.19 (s, 1H), 7.11 (s, 1H), 4.64 (s, 2H), 4.01 – 3.88 (m, 1H), 3.61 (tt, J = 8.0, 4.3 Hz, 1H), 2.03 – 1.91 (m, 2H), 1.81 – 1.63 (m, 4H), 1.61 – 1.52 (m, 4H), 1.49 – 1.37 (m, 8H)。 120 115 NMR2: 7.10 (s, 1H), 7.05 (d, J = 0.6 Hz, 1H), 4.62 (s, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.10 – 3.95 (m, 1H), 3.65 – 3.55 (m, 1H), 2.02 – 1.91 (m, 2H), 1.80 – 1.64 (m, 4H), 1.60 – 1.51 (m, 4H), 1.48 – 1.38 (m, 11H)。 121 2 NMR2: 7.13 (s, 2H), 6.37 – 6.32 (m, 1H), 5.78 – 5.73 (m, 1H), 4.64 (s, 2H), 4.46 (q, J = 7.1 Hz, 2H), 3.62 (tt, J = 8.0, 4.3 Hz, 1H), 2.37 (t, J = 1.2 Hz, 3H), 2.02 – 1.90 (m, 2H), 1.80 – 1.67 (m, 4H), 1.63 – 1.53 (m, 4H), 1.48 – 1.38 (m, 5H)。 122 6 NMR2: 7.37 (s, 1H), 7.21 (s, 1H), 4.63 (s, 2H), 4.50 (q, J = 7.1 Hz, 2H), 3.68 – 3.57 (m, 1H), 2.07 – 1.90 (m, 2H), 1.80 – 1.64 (m, 4H), 1.61 – 1.54 (m, 4H), 1.50 – 1.39 (m, 5H). 123 7 NMR2: 10.01 (s, 1H), 6.64 (s, 1H), 5.82 (s, 1H), 4.56 (d, J = 0.9 Hz, 2H), 4.40 (q, J = 7.2 Hz, 2H), 3.63 (tt, J = 8.1, 4.4 Hz, 1H), 2.00 – 1.89 (m, 2H), 1.74 – 1.61 (m, 4H), 1.59 – 1.52 (m, 4H), 1.45 – 1.25 (m, 5H). 124 1 NMR1: 13.24 (s, 1H), 7.00 (s, 1H), 6.97 (s, 1H), 3.83 – 3.68 (m, 1H), 2.80 – 2.68 (m, 1H), 1.89 – 1.49 (m, 5H), 1.41 – 1.35 (m, 7H), 1.28 – 0.86 (m, 8H). <000114⑧>125 4 NMR2: 7.09 (s, 1H), 6.60 (d, J = 0.7 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.07 – 3.9② (m, 1H), 2.74 – 2.62 (m, 1H), 1.89 (d, J = 12.5 Hz, 1H), 1.82 –①.71 (m, 1H), 1.70 – 1.61 (m, 3H), 1.47 – 1.39 (m, 10H), 1.33 – 0.83 (m, 8H). [Table 1-18] REX STR Note: There seems to be a small error in the original text where "3.9②" should probably be "3.92". Also, "①.71" should be "1.71". These have been corrected in the translation for clarity. RProp Data 126 2 NMR2: 7.12 (s, 1H), 6.70 (s, 1H), 6.27 – 6.22 (m, 1H), 5.74 – 5.68 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.76 – 2.64 (m, 1H), 2.36 (t, J = 1.1 Hz, 3H), 1.89 (d, J = 12.9 Hz, 1H), 1.77 (d, J = 13.0 Hz, 1H), 1.72 – 1.59 (m, 3H), 1.49 – 1.39 (m, 4H), 1.35 – 0.85 (m, 8H). 127 6 NMR2: 7.20 (s, 1H), 6.93 (s, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.77 – 2.65 (m, 1H), 1.91 – 1.83 (m, 1H), 1.81 – 1.73 (m, 1H), 1.71 – 1.59 (m, 3H), 1.50 – 1.37 (m, 4H), 1.30 (d, J = 6.9 Hz, 3H), 1.28 – 0.91 (m, 5H). 128 7 NMR2: 11.03 (s, 1H), 6.59 (s, 1H), 5.76 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.64 – 2.52 (m, 1H), 1.87 – 1.79 (m, 1H), 1.77 – 1.70 (m, 1H), 1.68 – 1.52 (m, 4H), 1.31 (d, J = 7.0 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 1.19 – 0.88 (m, 5H). 129 49 NMR2: 4.24 – 4.07 (m, 3H), 3.46 (s, 2H), 2.53 – 2.41 (m, 1H), 1.84 – 1.58 (m, 8H), 1.37 – 0.82 (m, 8H). 130 1 NMR1: 13.21 (s, 1H), 12.43 (s, 1H), 6.44 (s, 1H), 5.66 (s, 1H), 2.46 (d, J = 7.1 Hz, 2H), 1.80 – 1.52 (m, 6H), 1.32 – 0.86 (m, 5H). 131 86 NMR2: 7.33 (s, 1H), 7.26 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 2.20 – 2.16 (m, 3H), 2.07 – 2.00 (m, 6H), 1.89 – 1.65 (m, 6H), 1.44 (t, J = 7.1 Hz, 3H). 132 132<000118所4>NMR1: 13.20 (s, 1H), 7.41 (s, 1H), 6.51 (s, 1H), 3.78 – 3.71 (m, 4H), 1.70 – 1.48 (m, 6H). [Table 1-19] REX STR RProp Data 133 133 NMR2: 6.84 (s, 1H), 6.66 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H), 3.75 – 3.68 (m, 4H), 1.80 – 1.64 (m, 6H), 1.42 (t, J = 7.1 Hz, 3H). 134 3 NMR2: 7.23 – 7.18 (m, 1H), 6.68 – 6.62 (m, 1H), 3.98 – 3.87 (m, 1H), 2.80 – 2.73 (m, 2H), 1.79 – 1.20 (m, 14H), 0.99 – 0.90 (m, 5H)。 135 4 NMR2: 7.10 (s, 1H), 6.61 (s, 1H), 4.48 (q,J= 7.1 Hz, 2H), 4.07 – 3.94 (m, 1H), 2.75 (s, 2H), 1.64 – 1.25 (m, 19H), 0.96 (s, 3H)。 136 5 NMR2: 7.14 (s, 1H), 6.71 (s, 1H), 6.29 – 6.24 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q,J= 7.1 Hz, 2H), 2.77 (s, 2H), 2.35 (s, 3H), 1.59 – 1.30 (m, 13H), 0.98 (s, 3H)。 137 6 NMR2: 7.22 (s, 1H), 6.93 (s, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.76 (s, 2H), 1.62 – 1.27 (m, 13H), 0.98 (s, 3H)。 138 7 NMR2: 11.43 (s, 1H), 6.63 (s, 1H), 5.74 (d,J= 1.8 Hz, 1H), 4.32 (q,J= 7.2 Hz, 2H), 2.70 (s, 2H), 1.55 – 1.31 (m, 10H), 1.25 (t,J= 7.1 Hz, 3H), 0.98 (s, 3H)。 139 49 NMR2: 4.23 – 4.14 (m, 2H), 3.42 (s, 2H), 2.46 (s, 2H), 1.50 – 1.21 (m, 13H), 1.05 – 1.00 (m, 3H). 140 3 NMR1: 13.17 (s, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 2.71 (s, 3H), 2.65 (d, J = 7.2 Hz, 2H), 1.89 – 1.75 (m, 1H), 1.70 – 1.60 (m, 5H), 1.28 – 1.09 (m, 3H), 1.07 – 0.93 (m, 2H). 141 2 NMR2: 7.10 (s, 1H), 6.66 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 2.68 (d, J = 7.2 Hz, 2H), 1.90 – 1.76 (m, 1H), 1.76 – 1.65 (m, 5H), 1.45 (t, J = 7.1 Hz, 3H), 1.32 – 1.13 (m, 3H),​​​​​​​​​​​​​​​​​​​​​​​NMR2: 3.46 – 3.38 (m, 2H), 2.22 – 2.15 (m, 2H), 1.67 (s, 6H), 1.26 (s, 6H)。 144 144 NMR2: 7.42 – 7.28 (m, 4H), 7.26 – 7.19 (m, 1H), 3.61 (s, 2H), 2.64 (t,J= 6.4 Hz, 2H), 1.68 (t,J= 6.4 Hz, 2H), 1.32 (s, 6H), 1.19 (s, 6H)。 145 145 NMR1: 9.06 (s, 1H), 8.12 (s, 1H), 4.41 (s, 1H), 3.06 – 2.78 (m, 2H), 2.03 – 1.82 (m, 1H), 1.81 – 1.68 (m, 1H), 1.57 – 1.45 (m, 2H), 1.28 (s, 3H), 1.27 (s, 3H), 1.09 (s, 3H)。 146 146 NMR2: 7.31 (d,J= 4.4 Hz, 4H), 7.27 – 7.18 (m, 1H), 3.98 (d,J= 13.8 Hz, 1H), 3.61 (s, 1H), 3.08 (d,J= 13.8 Hz, 1H), 2.52 – 2.42 (m, 1H), 2.40 – 2.29 (m, 1H), 1.79 – 1.61 (m, 2H), 1.56 – 1.32 (m, 2H), 1.25 (s, 3H), 1.19 (s, 3H), 1.09 (s, 3H)。 147 84 NMR2: 7.25 (s, 1H), 7.04 (s, 1H), 3.70 – 3.66 (m, 2H), 3.57 – 3.50 (m, 4H), 2.19 – 2.15 (m, 3H), 2.07 – 1.96 (m, 8H), 1.88 – 1.75 (m, 6H), 1.60 (s, 6H), 1.49 (s, 9H). [Table 1-21] REX STR RProp Data 148 20 NMR2: 6.90 (s, 1H), 6.53 (s, 1H), 6.52 (t, J = 6.6 Hz, 1H), 3.85 – 3.77 (m, 2H), 3.76 – 3.69 (m, 2H), 2.70 – 2.61 (m, 4H), 2.44 – 2.35 (m, 3H), 1.93 – 1.58 (m, 19H), 1.32 – 1.16 (m, 3H), 1.11 – 0.99 (m, 2H). 149 149 NMR1: 6.90 (s, 1H), 6.68 (s, 1H), 3.74 – 3.60 (m, 1H), 3.50 – 3.43 (m, 2H), 2.87 – 2.80 (m, 2H), 2.69 (s, 2H), 2.67 (d, J = 7.1 Hz, 2H), 1.87 – 1.76 (m, 1H), 1.70 – 1.57 (m, 6H), 1.47 (s, 6H), 1.36 (d, J = 6.9 Hz, 6H), 1.28 – 1.07 (m, 3H), 1.07 – 0.93 (m, 2H). 150 84 NMR1: 6.91 (s, 1H), 6.73 (s, 1H), 3.81 – 3.77 (m, 2H), 3.73 – 3.62 (m, 1H), 3.48 (s, 2H), 3.45 – 3.34 (m, 2H), 2.67 (d,J= 7.1 Hz, 2H), 1.87 – 1.77 (m, 1H), 1.69 – 1.60 (m, 5H), 1.50 (s, 6H), 1.42 (s, 9H), 1.37 (d,J= 6.9 Hz, 6H), 1.25 – 1.10 (m, 3H), 1.07 – 0.94 (m, 2H)。 151 145 NMR1: 8.88 (s, 2H), 5.44 (d,J= 6.4 Hz, 1H), 3.14 – 3.03 (m, 2H), 2.99 – 2.90 (m, 1H), 1.62 (td,J= 13.6, 12.9, 4.3 Hz, 1H), 1.52 (dt,J= 14.4, 3.1 Hz, 1H), 1.31 (s, 3H), 1.21 (s, 3H), 0.94 (s, 3H), 0.92 (s, 3H)。 152 152 NMR2: 7.39 – 7.27 (m, 4H), 7.26 – 7.17 (m, 1H), 3.89 (d,J= 14.1 Hz, 1H), 3.21 (d,J= 14.1 Hz, 1H), 3.10 (d,J= 7.3 Hz, 1H), 2.42 – 2.31 (m, 2H), 1.73 (d,J= 7.3 Hz, 1H), 1.43 – 1.28 (m, 2H), 1.29 (s, 3H), 1.07 (s, 3H), 1.01 (s, 3H), 0.95 (s, 3H)。 153 3 NMR1: 13.23 (s, 1H), 7.05 (s, 1H), 6.99 (s, 1H), 3.13 (q, J = 7.4 Hz, 2H), 2.77 (tt, J = 11.7, 3.4 Hz, 1H), 1.95 – 1.87 (m, 2H), 1.86 – 1.77 (m, 2H), 1.75 – 1.68 (m, 1H), 1.62 – 1.48 (m, 2H), 1.46 – 1.18 (m, 6H). 154 2 NMR2: 7.10 (s, 1H), 6.69 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.26 (q, J = 7.4 Hz, 2H), 2.75 (tt, J = 11.9, 3.4 Hz, 1H), 2.03 – 1.85 (m, 4H), 1.79 – 1.75 (m, 1H), 1.65 – 1.24 (m, 11H). [Table 1-22] REX STR RProp Data 155 155 NMR2: 4.86 (d, J = 1.1 Hz, 1H), 4.76 – 4.71 (m, 1H), 3.31 (t, J = 6.5 Hz, 2H), 2.40 – 2.31 (m, 2H), 1.82 – 1.70 (m, 2H), 1.54 (s, 6H), 1.47 (s, 9H). 156 156 NMR2: 7.12 (s, 1H), 6.83 (s, 1H), 4.47 (q, J = 7.1 Hz, 2H), 3.26 – 3.18 (m, 2H), 2.17 – 2.13 (m, 3H), 2.05 – 2.00 (m, 6H), 1.92 – 1.74 (m, 9H), 1.51 – 1.34 (m, 7H), 1.31 – 1.22 (m, 2H). 157 3 NMR1: 13.21 (s, 1H), 6.98 (s, 1H), 6.97 (s, 1H), 3.59 – 3.44 (m, 1H), 2.79 (d,J= 7.5 Hz, 2H), 2.39 – 2.24 (m, 1H), 2.09 – 2.02 (m, 2H), 1.93 – 1.39 (m, 13H), 1.37 – 1.15 (m, 3H)。 158 4 NMR2: 7.06 (s, 1H), 6.63 (s, 1H), 4.47 (q,J= 7.1 Hz, 2H), 3.73 (tt,J= 11.8, 3.2 Hz, 1H), 2.82 (d,J= 7.5 Hz, 2H), 2.38 – 2.22 (m, 1H), 2.21 – 2.14 (m, 2H), 1.95 – 1.62 (m, 9H), 1.59 – 1.18 (m, 10H)。 159 5 NMR2: 7.13 – 7.08 (m, 1H), 7.08 (s, 1H), 6.69 (s, 1H), 4.45 (q,J= 7.1 Hz, 2H), 2.82 (d,J= 7.5 Hz, 2H), 2.66 – 2.58 (m, 2H), 2.41 – 2.27 (m, 2H), 1.90 – 1.72 (m, 7H), 1.72 – 1.61 (m, 2H), 1.57 – 1.49 (m, 2H), 1.44 (t,J= 7.1 Hz, 3H), 1.34 – 1.20 (m, 2H)。 160 3 NMR1: 13.22 (s, 1H), 7.02 (s, 1H), 6.98 (s, 1H), 3.12 (q,J= 7.4 Hz, 2H), 3.00 – 2.88 (m, 1H), 1.98 – 1.87 (m, 2H), 1.84 – 1.45 (m, 10H), 1.36 (t,J= 7.5 Hz, 3H)。 161 2 NMR2: 7.08 (s, 1H), 6.68 – 6.63 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.31 – 3.21 (m, 2H), 2.97 – 2.85 (m, 1H), 2.07 – 1.96 (m, 2H), 1.93 – 1.53 (m, 10H), 1.48 – 1.40 (m, 6H). [Table 1-23] REX<0> STR RProp Data 162 6 NMR2: 7.18 (s, 1H), 6.96 (s, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.99 – 2.87 (m, 1H), 2.06 – 1.96 (m, 2H), 1.94 – 1.53 (m, 10H), 1.45 (t, J = 7.1 Hz, 3H). 163 7 NMR1: 12.33 (s, 1H), 6.48 (s, 1H), 5.70 (d, J = 1.9 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 2.73 – 2.62 (m, 1H), 1.95 – 1.85 (m, 2H), 1.83 – 1.42 (m, 10H), 1.33 (t, J = 7.1 Hz, 3H). 164 3 NMR1: 13.23 (s, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 4.23 – 4.10 (m, 1H), 2.70 (d,J= 7.1 Hz, 2H), 2.51 – 2.42 (m, 1H), 2.34 – 2.21 (m, 2H), 2.21 – 2.06 (m, 1H), 1.96 – 1.80 (m, 2H), 1.70 – 1.57 (m, 6H), 1.28 – 1.10 (m, 3H), 1.10 – 0.94 (m, 2H)。 165 31 NMR2: 7.07 (s, 1H), 6.66 (s, 1H), 4.46 (q,J= 7.1 Hz, 2H), 4.39 – 4.28 (m, 1H), 2.71 (d,J= 7.2 Hz, 2H), 2.68 – 2.57 (m, 2H), 2.32 – 2.15 (m, 3H), 2.02 – 1.78 (m, 1H), 1.75 – 1.63 (m, 6H), 1.43 (t,J= 7.1 Hz, 3H), 1.29 – 1.14 (m, 3H), 1.13 – 1.00 (m, 2H)。 166 3 NMR2: 7.21 (s, 1H), 6.69 – 6.64 (m, 1H), 4.03 – 3.89 (m, 1H), 2.85 – 2.69 (m, 2H), 2.13 – 2.03 (m, 1H), 1.85 – 1.70 (m, 4H), 1.54 – 1.28 (m, 7H), 1.26 – 0.99 (m, 4H), 0.96 – 0.82 (m, 5H)。 167 4 NMR2: 7.08 (s, 1H), 6.64 – 6.59 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.05 – 3.94 (m, 1H), 2.82 – 2.66 (m, 2H), 2.07 – 2.02 (m, 1H), 1.83 – 1.68 (m, 4H), 1.54 – 0.98 (m, 14H), 0.96 – 0.82 (m, 5H). 168 5 NMR2: 7.11 (s, 1H), 6.74 – 6.69 (m, 1H), 6.30 – 6.24 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.84 – 2.68 (m, 2H), 2.36 (s, 3H), 1.79 – 1.71 (m, 4H), 1.54 – 0.99 (m, 9H), 0.95 – 0.80 (m, 5H). [Table 1-24] REX STR RProp Data 169 6 NMR2: 7.20 (s, 1H), 6.98 – 6.92 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.84 – 2.69 (m, 2H), 1.85 – 1.69 (m, 3H), 1.54 – 0.99 (m, 10H), 0.96 – 0.79 (m, 5H). 170 7 NMR2: 12.31 (s, 1H), 6.63 (s, 1H), 5.80 – 5.74 (m, 1H), 4.30 (q, J = 7.2 Hz, 2H), 2.81 – 2.63 (m, 2H), 1.84 – 1.52 (m, 4H), 1.47 – 1.11 (m, 6H), 1.08 – 0.91 (m, 3H), 0.87 – 0.71 (m, 5H). 171 49 NMR2: 4.24 – 4.14 (m, 2H), 3.47 – 3.25 (m, 2H), 2.57 – 2.00 (m, 2H), 1.88 – 1.40 (m, 7H), 1.39 – 1.12 (m, 5H), 1.10 – 0.76 (m, 6H)。 172 3 NMR2: 7.20 (s, 1H), 6.65 (s, 1H), 3.87 – 3.77 (m, 1H), 2.76 (d,J= 7.4 Hz, 2H), 2.15 – 2.01 (m, 1H), 1.98 – 1.42 (m, 15H), 1.37 – 1.24 (m, 2H), 0.96 (t,J= 7.4 Hz, 3H)。 173 31 NMR2: 7.08 (s, 1H), 6.59 (s, 1H), 4.47 (q,J= 7.1 Hz, 2H), 3.94 – 3.81 (m, 1H), 2.73 (d,J= 7.4 Hz, 2H), 2.15 – 1.35 (m, 18H), 1.35 – 1.21 (m, 3H), 0.95 (t,J= 7.4 Hz, 3H)。 174 3 NMR2: 7.20 (s, 1H), 6.73 – 6.68 (m, 1H), 3.24 (qd,J= 7.5, 1.0 Hz, 2H), 2.76 (d,J= 7.4 Hz, 2H), 2.16 – 2.03 (m, 1H), 1.79 – 1.38 (m, 13H), 1.37 – 1.24 (m, 2H)。 175 2 NMR2: 7.10 (s, 1H), 6.68 – 6.62 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 3.26 (qd, J = 7.5, 1.1 Hz, 2H), 2.73 (d, J = 7.4 Hz, 2H), 2.14 – 2.01 (m, 1H), 1.77 – 1.36 (m, 14H), 1.36 – 1.22 (m, 4H). 176 3 NMR2: 7.19 (s, 1H), 6.67 (s, 1H), 2.72 (d, J = 7.2 Hz, 2H), 1.96 – 1.77 (m, 1H), 1.77 – 1.66 (m, 5H), 1.64 (s, 9H), 1.33 – 1.14 (m, 3H), 1.13 – 1.00 (m, 2H). [Table 1-25] REX STR RProp Data 177 31 NMR2: 7.05 (s, 1H), 6.61 (s, 1H), 4.45 (q, J = 7.1 Hz, 2H), 2.69 (d, J = 7.2 Hz, 2H), 1.87 – 1.78 (m, 1H), 1.75 – 1.67 (m, 5H), 1.64 (s, 9H), 1.43 (t, J = 7.1 Hz, 3H), 1.30 – 1.14 (m, 3H), 1.12 – 0.99 (m, 2H). 178 3 NMR2: 7.16 (s, 1H), 6.68 (s, 1H), 2.84 (d, J = 7.5 Hz, 2H), 2.40 – 2.24 (m, 1H), 1.85 – 1.48 (m, 15H), 1.36 – 1.21 (m, 2H). 179 31 NMR2: 7.05 (s, 1H), 6.65 (s, 1H), 4.45 (q,J= 7.1 Hz, 2H), 2.82 (d,J= 7.5 Hz, 2H), 2.37 – 2.25 (m, 1H), 1.81 – 1.65 (m, 6H), 1.64 (s, 9H), 1.43 (t,J= 7.1 Hz, 3H), 1.34 – 1.20 (m, 2H)。 180 3 NMR2: 7.12 (s, 1H), 6.78 (s, 1H), 3.99 – 3.85 (m, 1H), 1.99 (dd,J= 7.8, 5.6 Hz, 1H), 1.72 – 1.23 (m, 16H), 1.18 – 1.11 (m, 1H), 0.96 (dd,J= 7.8, 4.5 Hz, 1H)。 181 4 NMR2: 7.03 (s, 1H), 6.73 (s, 1H), 4.46 (q,J= 7.2 Hz, 2H), 4.03 – 3.92 (m, 1H), 1.97 (dd,J= 7.8, 5.6 Hz, 1H), 1.68 – 1.20 (m, 19H), 1.16 – 1.10 (m, 1H), 0.98 – 0.84 (m, 1H)。 182 5 NMR2: 7.06 (s, 1H), 6.83 (s, 1H), 6.28 – 6.20 (m, 1H), 5.74 – 5.67 (m, 1H), 4.45 (q,J= 7.1 Hz, 2H), 2.36 (s, 3H), 1.98 (dd,J= 7.8, 5.6 Hz, 1H), 1.68 – 1.22 (m, 13H), 1.17 – 1.10 (m, 1H), 0.99 – 0.92 (m, 1H)。 183 6 NMR2: 7.19 (s, 1H), 6.96 (s, 1H), 5.46 – 5.40 (m, 1H), 4.55 – 4.42 (m, 3H), 2.99 – 2.82 (m, 2H), 2.45 – 2.37 (m, 2H), 2.00 – 1.90 (m, 3H), 1.71 – 1.30 (m, 6H), 1.00 (dd,J= 7.8, 4.5 Hz, 1H). 184 7 NMR2: 11.43 (s, 1H), 6.56 (s, 1H), 5.78 (s, 1H), 4.40 – 4.28 (m, 2H), 2.89 – 2.80 (m, 1H), 2.36 (t,J= 7.7 Hz, 1H), 2.02 – 1.32 (m, 10H), 1.26 (t,J= 7.1 Hz, 3H), 1.03 – 0.91 (m, 1H). [Table 1-26] REX STR RProp Data 185 49 NMR2: 4.24 – 4.16 (m, 2H), 3.56 (s, 2H), 1.91 (dd,J= 7.4, 5.4 Hz, 1H), 1.79 – 1.39 (m, 8H), 1.37 – 1.21 (m, 6H), 0.91 (dd,J= 7.4, 4.0 Hz, 1H). 186 3 NMR2: 7.19 (s, 1H), 6.67 (s, 1H), 4.01 – 3.86 (m, 1H), 2.75 (d,J= 7.2 Hz, 2H), 1.83 – 1.69 (m, 1H), 1.57 – 1.49 (m, 2H), 1.44 (d,J= 6.9 Hz, 6H), 1.41 – 1.34 (m, 2H), 1.30 – 1.12 (m, 4H), 0.89 (s, 6H). 187 4 NMR2: 7.08 (s, 1H), 6.62 (s, 1H), 4.48 (q,J= 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 2.73 (d,J= 7.3 Hz, 2H), 1.80 – 1.69 (m, 1H), 1.56 – 1.48 (m, 2H), 1.48 – 1.34 (m, 12H), 1.33 – 1.12 (m, 3H), 0.89 (s, 6H)。 188 5 NMR2: 7.11 (s, 1H), 6.71 (s, 1H), 6.30 – 6.25 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q,J= 7.1 Hz, 2H), 2.74 (d,J= 7.2 Hz, 2H), 2.38 – 2.33 (m, 3H), 1.84 – 1.71 (m, 1H), 1.56 – 1.49 (m, 3H), 1.43 (t,J= 7.1 Hz, 3H), 1.41 – 1.34 (m, 2H), 1.34 – 1.12 (m, 3H), 0.89 (s, 6H)。 189 6 NMR2: 7.19 (s, 1H), 6.95 (s, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.75 (d,J= 7.2 Hz, 2H), 1.83 – 1.69 (m, 1H), 1.56 – 1.48 (m, 2H), 1.45 (t,J= 7.1 Hz, 3H), 1.41 – 1.35 (m, 2H), 1.34 – 1.12 (m, 4H), 0.89 (s, 6H)。 190 7 NMR2: 11.82 (s, 1H), 6.61 (s, 1H), 5.76 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.67 (d, J = 7.3 Hz, 2H), 1.75 – 1.58 (m, 2H), 1.56 – 1.47 (m, 1H), 1.37 – 1.29 (m, 2H), 1.26 – 1.01 (m, 7H), 0.86 (s, 3H), 0.83 (s, 3H). 191 3 NMR2: 7.23 – 7.18 (m, 1H), 6.69 – 6.63 (m, 1H), 4.96 – 4.37 (m, 1H), 4.03 – 3.88 (m, 1H), 2.83 – 2.71 (m, 2H), 2.20 – 1.76 (m, 4H), 1.63 – 1.39 (m, 10H), 1.23 – 1.09 (m, 1H). [Table 1-27] REX [[ID=1***]]STR RProp Data 192 4 NMR2: 7.09 (s, 1H), 6.64 – 6.57 (m, 1H), 4.96 – 4.35 (m, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.07 – 3.93 (m, 1H), 2.78 – 2.68 (m, 2H), 2.18 – 1.75 (m, 4H), 1.64 – 1.38 (m, 13H), 1.30 – 1.07 (m, 1H). 193 5 It should be noted that in the original text, there is a possible error in the "1***" in the line . It is likely a misprint. The above translation is based on the corrected understanding. If this is not the case, please provide more context or clarify the issue.NMR2: 7.12 (s, 1H), 6.73 – 6.67 (m, 1H), 6.31 – 6.25 (m, 1H), 5.76 – 5.70 (m, 1H), 4.96 – 4.39 (m, 1H), 4.46 (q,J= 7.1 Hz, 2H), 2.79 – 2.70 (m, 2H), 2.38 – 2.33 (m, 3H), 2.16 – 1.77 (m, 3H), 1.67 – 1.36 (m, 8H), 1.30 – 1.11 (m, 1H)。 194 6 NMR2: 7.20 (s, 1H), 6.97 – 6.91 (m, 1H), 4.95 – 4.40 (m, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.82 – 2.69 (m, 2H), 2.16 – 1.77 (m, 5H), 1.54 – 1.37 (m, 5H), 1.21 – 1.05 (m, 2H)。 195 7 NMR2: 12.69 – 12.45 (m, 1H), 7.30 – 7.23 (m, 1H), 6.66 – 6.59 (m, 1H), 5.81 – 5.73 (m, 1H), 4.89 – 4.20 (m, 3H), 2.80 – 2.60 (m, 2H), 2.57 – 2.20 (m, 1H), 2.15 – 0.93 (m, 10H)。 196 49 NMR2: 4.90 – 4.34 (m, 1H), 4.25 – 4.14 (m, 2H), 3.47 – 3.35 (m, 2H), 2.53 – 2.37 (m, 1H), 2.32 – 2.22 (m, 1H), 2.16 – 1.22 (m, 11H), 1.15 – 0.97 (m, 1H)。 197 3 NMR2: 7.19 (s, 1H), 6.69 (s, 1H), 4.00 – 3.85 (m, 1H), 2.86 – 2.76 (m, 1H), 2.70 – 2.60 (m, 1H), 2.29 – 2.24 (m, 1H), 2.07 – 2.02 (m, 1H), 2.02 – 1.94 (m, 1H), 1.58 – 1.37 (m, 10H), 1.25 – 1.10 (m, 4H). 198 4 NMR2: 7.08 (s, 1H), 6.64 (s, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.05 – 3.94 (m, 1H), 2.84 – 2.74 (m, 1H), 2.67 – 2.57 (m, 1H), 2.28 – 2.24 (m, 1H), 2.07 – 1.91 (m, 2H), 1.56 – 1.36 (m, 12H), 1.30 – 1.09 (m, 5H). 199 5 NMR2: 7.11 (s, 1H), 6.73 (s, 1H), 6.29 – 6.24 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.85 – 2.76 (m, 1H), 2.69 – 2.59 (m, 1H), 2.38 – 2.33 (m, 3H), 2.29 – 2.24 (m, 1H), 2.07 – 2.03 (m, 1H), 2.03 – 1.93 (m, 1H), 1.55 – 1.39 (m, 6H), 1.34 – 1.12 (m, 5H). [Table 1-28] REX STR RProp Data 200 6 NMR2: 7.20 (s, 1H), 6.97 (s, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.86 – 2.76 (m, 1H), 2.69 – 2.59 (m, 1H), 2.30 – 2.25 (m, 1H), 2.06 – 1.91 (m, 2H), 1.53 – 1.38 (m, 6H), 1.26 – 1.10 (m, 5H)。 201 7 NMR2: 11.67 (s, 1H), 6.60 (s, 1H), 5.78 (s, 1H), 4.31 (q,J= 7.1 Hz, 2H), 2.75 – 2.64 (m, 1H), 2.64 – 2.54 (m, 1H), 2.24 – 2.20 (m, 1H), 2.06 – 2.01 (m, 1H), 1.94 – 1.84 (m, 1H), 1.51 – 1.41 (m, 2H), 1.32 – 1.26 (m, 1H), 1.23 (t,J= 7.1 Hz, 3H), 1.16 – 1.06 (m, 5H)。 202 3 NMR2: 7.14 (s, 1H), 6.64 (s, 1H), 3.97 – 3.85 (m, 1H), 2.76 – 2.64 (m, 2H), 1.88 – 1.84 (m, 1H), 1.76 – 0.83 (m, 22H)。 203 4 NMR2: 7.10 – 7.05 (m, 1H), 6.65 – 6.58 (m, 1H), 4.48 (q,J= 7.1 Hz, 2H), 4.05 – 3.94 (m, 1H), 2.75 – 2.62 (m, 2H), 1.91 – 1.79 (m, 1H), 1.76 – 1.14 (m, 25H)。 204 5 NMR2: 7.14 – 7.09 (m, 1H), 6.75 – 6.68 (m, 1H), 6.30 – 6.25 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q, J = 7.1 Hz, 2H), 2.77 – 2.65 (m, 2H), 2.38 – 2.33 (m, 3H), 1.92 – 1.82 (m, 1H), 1.78 – 1.03 (m, 19H). 205 6 NMR2: 7.22 – 7.19 (m, 1H), 6.98 – 6.91 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 2.81 – z.65 (m, 2H), 1.94 – 1.80 (m, 1H), 1.76 – 0.88 (m, 19H). 206 7 NMR2: 11.37 (s, 1H), 6.62 – 6.57 (m, 1H), 5.78 – 5.73 (m, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.67 – 2.61 (m, 2H), 1.84 – 0.90 (m, 20H). 207 49 NMR2: 4.24 – 4.15 (m, 2H), 3.46 – 3.38 (m, 2H), 2.49 – 2.33 (m, 2H), 2.12 – 1.99 (m, 1H), 1.91 – 0.99 (m, 19H). [Table 1-29] REX STR RProp Data 208 3 It should be noted that in the translation of the NMR data in line , there seems to be a typo in the original text "2.81 – z.65 (m, 2H)", which is translated as "2.81 – z.65 (m, 2H)" here. It might need to be corrected in the original text for a more accurate translation.NMR2: 7.19 (s, 1H), 6.69 – 6.63 (m, 1H), 3.98 – 3.87 (m, 1H), 2.91 – 2.72 (m, 2H), 2.32 – 2.09 (m, 1H), 2.00 – 1.82 (m, 3H), 1.76 – 1.69 (m, 2H), 1.64 – 1.55 (m, 2H), 1.44 (d, J = 6.9 Hz, 6H), 1.41 – 1.27 (m, 1H), 1.18 – 1.08 (m, 1H)。 209 4 NMR2: 7.09 (s, 1H), 6.64 – 6.58 (m, 1H), 4.53 – 4.43 (m, 2H), 4.06 – 3.95 (m, 1H), 2.89 – 2.70 (m, 2H), 2.33 – 2.08 (m, 1H), 2.00 – 1.83 (m, 3H), 1.78 – 1.68 (m, 2H), 1.63 – 1.57 (m, 2H), 1.48 – 1.29 (m, 10H), 1.17 – 1.03 (m, 1H)。 210 5 NMR2: 7.12 (s, 1H), 6.74 – 6.68 (m, 1H), 6.31 – 6.25 (m, 1H), 5.76 – 5.70 (m, 1H), 4.46 (q,J= 7.1 Hz, 2H), 2.90 – 2.71 (m, 2H), 2.36 (s, 3H), 2.33 – 2.08 (m, 1H), 2.04 – 1.83 (m, 3H), 1.78 – 1.68 (m, 2H), 1.68 – 1.57 (m, 2H), 1.47 – 1.40 (m, 3H), 1.38 – 1.22 (m, 1H), 1.19 – 1.04 (m, 1H)。 211 6 NMR2: 7.20 (s, 1H), 6.94 (d, J = 6.8 Hz, 1H), 4.55 – 4.45 (m, 2H), 2.90 – 2.71 (m, 2H), 2.32 – 2.07 (m, 1H), 2.06 – 1.80 (m, 3H), 1.77 – 1.68 (m, 2H), 1.63 – 1.54 (m, 2H), 1.45 (t, J = 7.2 Hz, 3H), 1.38 – 1.27 (m, 1H), 1.18 – 1.04 (m, 1H). 212 7 NMR2: 12.57 (s, 1H), 6.63 – 6.57 (m, 1H), 5.82 – 5.75 (m, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.93 – 2.70 (m, 2H), 2.33 – 1.44 (m, 8H), 1.30 – 1.16 (m, 4H), 1.10 – 0.96 (m, 1H). 213 49 NMR2: 4.25 – 4.14 (m, 2H), 3.46 – 3.39 (m, 2H), 2.61 – 2.42 (m, 2H), 2.04 – 1.79 (m, 3H), 1.77 – 1.46 (m, 6H), 1.42 – 1.22 (m, 3H), 1.04 – 0.90 (m, 1H). 214 3 NMR2: 7.23 – 7.17 (m, 1H), 6.70 (s, 1H), 3.98 – 3.85 (m, 1H), 2.93 – 2.85 (m, 1H), 2.69 – 2.49 (m, 1H), 2.47 – 2.35 (m, 1H), 2.26 – 2.13 (m, 1H), 2.08 – 1.80 (m, 1H), 1.73 – 1.52 (m, 3H), 1.52 – 1.25 (m, 8H), 1.23 – 1.12 (m,​​​​ STR RProp Data 215 4 NMR2: 7.13 – 7.06 (m, 1H), 6.65 (s, 1H), 4.52 – 4.42 (m, 2H), 4.05 – 3.91 (m, 1H), 2.92 – 2.83 (m, 1H), 2.66 – 2.36 (m, 2H), 2.25 – 2.14 (m, 1H), 1.72 – 1.57 (m, 3H), 1.48 – 1.38 (m, 10H), 1.38 – 1.22 (m, 2H), 1.22 – 1.13 (m, 1H). 216 5 NMR2: 7.16 – 7.09 (m, 1H), 6.77 – 6.72 (m, 1H), 6.26 – 6.19 (m, 1H), 5.72 – 5.66 (m, 1H), 4.51 – 4.40 (m, 2H), 2.93 – 2.85 (m, 1H), 2.70 – 2.37 (m, 2H), 2.37 – 2.32 (m, 3H), 2.26 – 2.15 (m, 1H), 1.73 – 1.56 (m, 3H), 1.52 – 1.09 (m, 7H). 217 6 NMR2: 7.20 (s, 1H), 7.01 – 6.95 (m, 1H), 4.57 – 4.44 (m, 2H), 2.91 – 2.83 (m, 1H), 2.68 – 2.39 (m, 2H), 2.38 – 2.32 (m, 3H), 2.23 – 2.12 (m, 1H), 1.72 – 1.15 (m, 7H). 218 7 NMR1: 12.36 – 12.16 (m, 1H), 6.49 – 6.44 (m, 1H), 5.81 – 5.64 (m, 1H), 4.39 – 4.29 (m, 2H), 3.19 – 3.11 (m, 1H), 2.71 – 2.58 (m, 1H), 2.48 – 2.42 (m, 1H), 2.35 – 2.31 (m, 1H), 1.91 – 1.11 (m, 10H)。 219 3 NMR2: 7.21 – 7.16 (m, 1H), 6.70 – 6.63 (m, 1H), 3.98 – 3.86 (m, 1H), 3.26 – 2.36 (m, 2H), 2.18 – 1.07 (m, 16H), 1.07 – 0.94 (m, 3H)。 220 4 NMR2: 7.12 – 7.06 (m, 1H), 6.65 – 6.58 (m, 1H), 4.47 (q,J= 7.1 Hz, 2H), 4.07 – 3.92 (m, 1H), 3.26 – 2.34 (m, 2H), 2.17 – 1.07 (m, 19H), 1.06 – 0.94 (m, 3H)。 221 5 NMR2: 7.14 – 7.09 (m, 1H), 6.76 – 6.67 (m, 1H), 6.29 – 6.23 (m, 1H), 5.75 – 5.69 (m, 1H), 4.46 (q,J= 7.1 Hz, 2H), 3.25 – 2.39 (m, 2H), 2.38 – 2.31 (m, 3H), 2.15 – 1.07 (m, 13H), 1.07 – 0.92 (m, 3H)。 222 6 NMR2: 7.21 – 7.18 (m, 1H), 6.99 – 6.91 (m, 1H), 4.50 (q, J = 7.1 Hz, 2H), 3.25 – 2.39 (m, 2H), 2.18 – 1.07 (m, 13H), 1.06 – 0.93 (m, 3H). [Table 1-31] REX STR RProp Data 223 7 NMR2: 12.36 – 12.28 (m, 1H), 6.66 – 6.57 (m, 1H), 5.84 – 5.74 (m, 1H), 4.29 (q, J = 7.1 Hz, 2H), 3.34 – 2.19 (m, 2H), 2.11 – 0.84 (m, 13H), 0.82 – 0.76 (m, 3H). 224 49 NMR2: 4.25 – 4.13 (m, 2H), 3.46 – 3.39 (m, 2H), 2.79 – 2.20 (m, 2H), 2.18 – 0.91 (m, 13H), 0.90 – 0.80 (m, 3H). 225 3 NMR2: 7.02 (s, 1H), 6.57 (s, 1H), 3.97 – 3.82 (m, 1H), 2.06 – 1.96 (m, 2H), 1.85 – 1.75 (m, 5H), 1.41 (d, J = 6.9 Hz, 6H), 1.39 – 1.26 (m, 4H). 226 31 NMR2: 6.94 (s, 1H), 6.54 (s, 1H), 4.46 (q, J = 7.1 Hz, 2H), 4.04 – 3.91 (m, 1H), 2.06 – 1.96 (m, 2H), 1.86 – 1.73 (m, 5H), 1.47 – 1.21 (m, 13H). 227 6 NMR2: 7.04 (singlet, 1H), 6.86 (singlet, 1H), 4.48 (quartet, J = 7.1 Hz, 2H), 2.07 – 1.94 (multiplet, 2H), 1.86 – 1.73 (multiplet, 5H), 1.44 (triplet, J = 7.1 Hz, 3H), 1.42 – 1.22 (multiplet, 4H). 228 7 NMR2: 11.69 – 11.39 (multiplet, 1H), 6.48 (singlet, 1H), 5.49 – 5.44 (multiplet, 1H), 4.34 – 4.26 (multiplet, 2H), 2.47 – 2.21 (multiplet, 1H), 1.98 – 1.51 (multiplet, 8H), 1.46 – 0.99 (multiplet, 5H). 229 49 NMR2: 4.26 – 4.15 (multiplet, 2H), 3.52 (singlet, 2H), 1.96 – 1.49 (multiplet, 8H), 1.43 – 1.14 (multiplet, 6H). 230 3 NMR2: 7.19 (singlet, 1H), 6.63 (singlet, 1H), 4.01 – 3.86 (multiplet, 1H), 2.90 (doublet, J = 7.6 Hz, 2H), 2.67 – 2.50 (multiplet, 1H), 2.21 – 2.11 (multiplet, 2H), 2.04 – 1.96 (multiplet, 2H), 1.96 – 1.87 (multiplet, 2H), 1.85 – 1.73 (multiplet, 4H), 1.43 (doublet, J = 6.9 Hz, 6H). [Table 1-32] REX STR RProp Data 231 4 NMR2: 7.07 (s, 1H), 6.58 (s, 1H), 4.47 (q,J= 7.1 Hz, 2H), 4.06 – 3.91 (m, 1H), 2.87 (d,J= 7.6 Hz, 2H), 2.66 – 2.49 (m, 1H), 2.20 – 2.10 (m, 2H), 2.03 – 1.96 (m, 2H), 1.95 – 1.87 (m, 2H), 1.85 – 1.72 (m, 4H), 1.48 – 1.38 (m, 9H)。 232 5 NMR2: 7.10 (s, 1H), 6.67 (s, 1H), 6.28 – 6.23 (m, 1H), 5.74 – 5.68 (m, 1H), 4.46 (q,J= 7.1 Hz, 2H), 2.89 (d,J= 7.6 Hz, 2H), 2.65 – 2.51 (m, 1H), 2.37 – 2.32 (m, 3H), 2.21 – 2.11 (m, 2H), 2.04 – 1.96 (m, 2H), 1.96 – 1.87 (m, 2H), 1.85 – 1.73 (m, 4H), 1.43 (t,J= 7.1 Hz, 3H)。 233 6 NMR2: 7.18 (s, 1H), 6.90 (s, 1H), 4.50 (q,J= 7.1 Hz, 2H), 2.89 (d,J= 7.7 Hz, 2H), 2.66 – 2.50 (m, 1H), 2.22 – 2.12 (m, 2H), 2.07 – 1.97 (m, 2H), 1.96 – 1.87 (m, 2H), 1.85 – 1.72 (m, 4H), 1.45 (t,J= 7.1 Hz, 3H)。 234 7 NMR2: 11.89 (s, 1H), 6.59 (s, 1H), 5.73 (s, 1H), 4.31 (q,J= 7.1 Hz, 2H), 2.83 (d,J= 7.7 Hz, 2H), 2.61 – 2.48 (m, 1H), 2.20 – 2.11 (m, 2H), 2.00 – 1.92 (m, 2H), 1.90 – 1.82 (m, 2H), 1.81 – 1.66 (m, 4H), 1.23 (t,J= 7.1 Hz, 3H)。 235 49 NMR2: 4.23 – 4.13 (m, 2H), 3.37 (s, 2H), 2.64 – 2.58 (m, 2H), 2.57 – 2.45 (m, 1H), 2.30 – 2.10 (m, 2H), 2.04 – 1.96 (m, 2H), 1.91 – 1.83 (m, 2H), 1.82 – 1.71 (m, 2H), 1.71 – 1.47 (m, 2H), 1.31 – 1.24 (m, 3H)。 236 1 NMR1: 13.10 (s, 1H), 7.19 (s, 1H), 6.98 (s, 1H), 3.16 – 3.08 (m, 2H), 2.12 – 2.04 (m, 3H), 2.01 – 1.95 (m, 6H), 1.87 – 1.63 (m, 8H), 1.44 – 1.24 (m, 4H), 0.93 – 0.84 (m, 3H)。

[0189] [Example] Example 1: Synthesis of (5-adamantane-1-yl)-7-propylpyrazolo[1,5-a]pyrimidin-2-yl)(azacycloheptane-1-yl) methyl ketone Hexamethyleneimine (0.041 ml), HATU (138 mg), and TEA (0.067 ml) were added to a solution of 5-(1-adamantane)-7-propylpyrazolo[1,5-a]pyrimidin-2-carboxylic acid (81.9 mg) in DCM (5 ml), and the mixture was stirred overnight at room temperature. Saturated sodium bicarbonate was added to the reaction mixture. The resulting mixture was then extracted with DCM. The organic layer was concentrated, and the residue was crystallized from AcOEt / hexane to give the target compound (44.4 mg).

[0190] Example 2: Synthesis of (5-adamantane-1-yl)-7-isopropylpyrazolo[1,5-a]pyrimidin-2-yl)(2,2-dimethylpiperidin-1-yl) ketone A solution of 5-(1-adamantane)-7-propyl-2-ylpyrazolo[1,5-a]pyrimidin-2-carboxylic acid (300 mg) and HATU (504 mg) in DCM (10 ml) was mixed with TEA (0.370 ml) and 2,2-dimethylpiperidin hydrochloride (159 mg). The mixture was stirred overnight at room temperature. Saturated sodium bicarbonate was added to the reaction mixture. The resulting mixture was then extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) and recrystallized from EtOH / water to give the target compound (320 mg).

[0191] Example 3: Synthesis of azircycloheptane-1-yl (5-(cyclohexylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl) ketone A solution of 5-(cyclohexylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-carboxylic acid (60 mg) in DCM (3 ml) was mixed with HATU (105 mg), TEA (0.038 ml), and hexamethyleneimine (0.031 ml) and stirred overnight at room temperature. Saturated sodium bicarbonate was added to the reaction mixture. The resulting mixture was then extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (44 mg).

[0192] Example 4: Synthesis of azircycloheptan-1-yl(5-(cyclopentylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl) ketone A solution of 5-(cyclopentylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-carboxylic acid (250 mg) and hexamethyleneimine (0.135 ml) in DCM (5 ml) was mixed with HATU (455 mg) and TEA (0.334 ml) and stirred at room temperature for 2 hours. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt). The product was recrystallized from EtOH / water to give the target compound (232 mg).

[0193] Example 6: Synthesis of azircycloheptan-1-yl(5-(2-cyclopentylethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl) ketone A solution of 5-(2-cyclopentylethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-carboxylic acid (500 mg) in NMP (10 ml) was mixed with hexamethyleneimine (0.21 ml), HATU (871 mg), and TEA (0.32 ml) and stirred at room temperature for 3 hours. A saturated aqueous solution of Na2CO3 was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (530 mg).

[0194] Example 7: Synthesis of azircycloheptan-1-yl(5-(cyclohexylmethyl)-7-isopropylpyrazolo[1,5-a]pyrimidin-2-yl) ketone A solution of 5-(cyclohexylmethyl)-7-propyl-2-ylpyrazolo[1,5-a]pyrimidin-2-carboxylic acid (368 mg) in NMP (4 ml) was mixed with WSC (281 mg) and HOBt (224 mg) and stirred at room temperature for 10 minutes. Hexamethyleneimine (0.165 ml) was added to the mixture and stirred overnight. A saturated aqueous solution of Na2CO3 was added to the mixture and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt). The product was recrystallized from EtOH / water to give the target compound (304 mg).

[0195] Example 8: Synthesis of azircycloheptane-1-yl (7-cyclohexyl-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl) ketone Under a nitrogen atmosphere, 10% Pd / C (50 mg) was added to a solution of azircycloheptane-1-yl-[7-(cyclohexen-1-yl)-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone (440 mg) in AcOEt (4 ml). The mixture was stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated. The residue was purified by column chromatography (hexane / AcOEt), and the product was recrystallized from EtOH / water to give the target compound (278 mg).

[0196] Example 9: Synthesis of azircycloheptane-1-yl (5-(cyclohexylmethyl)-7-propylpyrazolo[1,5-a]pyrimidin-2-yl) methyl ketone. Azacycloheptane-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] methyl ketone (500 mg), n-propylboronic acid (234 mg), PdCl2(dppf)DCM (109 mg), and K3PO4 (849 mg) were dissolved in 1,4-dimethylethane (5 ml), and the mixture was heated to reflux under a nitrogen atmosphere and held for 6 hours. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (440 mg).

[0197] Example 15: Synthesis of azircycloheptane-1-yl-[5-(cyclopentylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]methyl ketone A solution of 5-(cyclopentylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidin-2-carboxylic acid (2.00 g) and hexamethyleneimine (1.177 ml) in DCM (20 ml) was mixed with HATU (3.18 g) and TEA (2.91 ml) and stirred at room temperature for 1 hour. Water was added to the mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (hexane / AcOEt) to give the target compound (2.24 g).

[0198] Example 28: Synthesis of azircycloheptane-1-yl-[7-tributyl-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone A solution of azircycloheptane-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone (600 mg) in NMP (1.8 ml) was mixed with a solution of 0.5 M tributylzinc bromide in THF (4.81 ml), copper iodide (I) (91 mg), and lithium chloride (102 mg). The mixture was stirred at 50 °C for 6 hours under a nitrogen atmosphere. 1 N HCl was added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt). The product was then recrystallized from EtOH / water to give the target compound (363 mg).

[0199] Example 53: Synthesis of [5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl]-(2,2-dimethylpiperazine-1-yl) ketone: While ice-cooling, TFA (5 ml) was added to a solution of 3.0 g of tributyl 4-[5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-carbonyl]-3,3-dimethylpiperazine-1-carboxylic acid in DCM (30 ml), and the mixture was stirred at room temperature for 5 hours. Water was added to the mixture while ice-cooling, and the resulting mixture was alkalized with an aqueous solution of Na2CO3. The mixture was extracted with DCM, and the organic layer was concentrated. The residue was then purified by column chromatography (MeOH / AcOEt), and the product was recrystallized from EtOH / water to give the target compound (1.65 g).

[0200] Example 87: Synthesis of azircycloheptane-1-yl-[5-(cyclohexylmethyl)-7-ethylsulfonypyrazolo[1,5-a]pyrimidin-2-yl] ketone Sodium ethanethiol (53.8 mg) was added to a solution of azircycloheptane-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone (200 mg) in THF (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (187 mg).

[0201] Example 88: Synthesis of azircycloheptane-1-yl-[5-(cyclohexylmethyl)-3-fluoro-7-prop-2-ylpyrazolo[1,5-a]pyrimidin-2-yl] ketone A solution of azircycloheptane-1-yl-[5-(cyclohexylmethyl)-7-prop-2-ylpyrazolo[1,5-a]pyrimidin-2-yl] ketone (419 mg) in CH3CN (10 ml) was mixed with a selective fluorine reagent (970 mg) and stirred at 40 °C for 3 hours. The reaction mixture was concentrated, and ice was added to the residue. The mixture was then neutralized with an aqueous solution of Na2CO3 and extracted with AcOEt. The organic layer was concentrated, and the residue was purified by alkaline column chromatography (hexane / AcOEt) to give the target compound (95 mg).

[0202] Example 89: Synthesis of azircycloheptane-1-yl-[5-(cyclohexylmethyl)-7-(dipropylamino)pyrazolo[1,5-a]pyrimidin-2-yl] ketone Dipropylamine (439 µl) was added to a solution of azircycloheptane-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone (200 mg) in IPA (2 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (217 mg).

[0203] Example 90: Synthesis of azircycloheptane-1-yl-[5-(cyclohexylmethyl)-7-cyclohexyloxypyrazolo[1,5-a]pyrimidin-2-yl] ketone A solution of azircycloheptane-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl] ketone (200 mg), cyclohexanol (1113 µl) in THF (5 ml) was mixed with KOH (150 mg) and stirred at room temperature for 30 minutes. Water and an aqueous solution of NH4Cl were added to the reaction mixture, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (hexane / AcOEt) to give the target compound (215 mg).

[0204] Example 116: Synthesis of [5-(cyclohexylmethyl)-7-propyl-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]-[4-(2-methoxyethyl)-2,2-dimethylpiperazine-1-yl] ketone [5-(cyclohexylmethyl)-7-propyl-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]-(2,2-dimethylpiperazine-1-yl) ketone (512 mg), 2-bromoethyl methyl ether (0.147 ml) and K2CO3 (267 mg) were dissolved in NMP (5 ml), and the mixture was stirred at room temperature for 3 days. A saturated aqueous solution of Na2CO3 was added to the mixture, and the mixture was extracted with toluene. The organic layer was concentrated, and the residue was purified by silicone column chromatography (hexane / AcOEt) to give the target compound (314 mg).

[0205] The compounds of Examples 5, 10 to 14, 16 to 27, 29 to 52, 54 to 86, 91 to 115 and 117 to 162 were prepared in the same manner as those of Examples 1 to 4, 6 to 9, 15, 28, 53, 87 to 90 and 116. The structural formulas and physicochemical information of the compounds of Examples 1 to 162 are shown in Tables 2-1 to 2-23.

[0206] [Table 2-1] EX STR Prop material 1 1 NMR1: 7.14 (s, 1H), 6.76 (s, 1H), 3.67 – 3.56 (m, 4H), 3.11 – 3.03 (m, 2H), 2.11 – 2.06 (m, 3H), 2.01 – 1.95 (m, 7H), 1.89 – 1.66 (m, 12H), 1.59 – 1.53 (m, 3H), 0.97 (t,J= 7.4 Hz, 3H). 2 2 NMR2: 6.75 (d,J= 2.5 Hz, 2H), 3.91 – 3.79 (m, 1H), 3.56 – 3.50 (m, 2H), 2.17 – 2.12 (m, 3H), 2.02 (d,J= 3.0 Hz, 6H), 1.86 – 1.75 (m, 5H), 1.72 – 1.63 (m, 7H), 1.61 (s, 6H), 1.42 (d,J= 6.9 Hz, 6H)。 3 3 NMR2: 7.09 (d,J= 1.2 Hz, 1H), 7.04 (s, 1H), 3.76 (dt,J= 22.0, 6.0 Hz, 4H), 2.78 (d,J= 7.2 Hz, 2H), 1.91 – 1.78 (m, 6H), 1.77 – 1.59 (m, 8H), 1.36 – 0.99 (m, 5H)。 4 4 NMR2: 7.09 (s, 1H), 7.07 (s, 1H), 3.76 (dt,J= 22.7, 6.1 Hz, 4H), 2.91 (d,J= 7.6 Hz, 2H), 2.40 – 2.27 (m, 1H), 1.92 – 1.75 (m, 6H), 1.75 – 1.50 (m, 8H), 1.34 – 1.22 (m, 2H)。 5 1 NMR2: 7.04 (s, 1H), 6.98 (s, 1H), 4.14 – 4.05 (m, 1H), 3.97 – 3.88 (m, 1H), 3.47 – 3.38 (m, 1H), 2.77 (d, J = 7.2 Hz, 2H), 2.19 – 2.10 (m, 1H), 1.94 – 1.60 (m, 10H), 1.57 – 1.43 (m, 6H), 1.31 – 1.00 (m, 5H)。 6 6 NMR1: 7.70 (s, 1H), 7.03 (s, 1H), 3.65 – 3.56 (m, 4H), 2.97 – 2.88 (m, 2H), 1.89 – 1.41 (m, 17H), 1.19 – 1.10 (m, 2H). 7 7 NMR2: 6.87 (s, 1H), 6.54 (s, 1H), 3.86 – 3.69 (m, 5H), 2.68 (d,J= 7.2 Hz, 2H), 1.92 – 1.75 (m, 5H), 1.75 – 1.61 (m, 9H), 1.42 (d,J= 6.9 Hz, 6H), 1.31 – 0.98 (m, 5H). [Table 2-2] EX STR Prop Data 8 8 NMR1: 6.87 (s, 1H), 6.75 (s, 1H), 3.64 (dt,J= 23.7, 6.0 Hz, 4H), 3.42 – 3.26 (m, 1H), 2.66 (d,J= 7.1 Hz, 3H), 2.11 – 2.03 (m, 2H), 1.90 – 0.93 (m, 26H). 9 9 NMR1: 6.94 (s, 1H), 6.75 (s, 1H), 3.63 (dt,J= 18.4, 6.1 Hz, 4H), 3.09 – 3.01 (m, 2H), 2.66 (d,J= 7.1 Hz, 2H), 1.89 – 1.47 (m, 15H), 1.30 – 1.10 (m, 4H), 1.07 – 0.93 (m, 5H). 10 9 NMR1: 6.94 (s, 1H), 6.75 (s, 1H), 3.63 (dt,J= 20.6, 6.0 Hz, 4H), 3.11 – 3.03 (m, 2H), 2.65 (d,J= 7.2 Hz, 2H), 1.89 – 1.47 (m, 15H), 1.39 (dq,J= 14.6, 7.3 Hz, 2H), 1.26 – 0.96 (m, 6H), 0.92 (t,J= 7.4 Hz, 3H)。 11 1 NMR2: 6.72 (s, 1H), 6.61 – 6.56 (m, 1H), 3.53 (t,J= 3.7 Hz, 2H), 3.22 – 3.12 (m, 2H), 2.80 (d,J= 7.5 Hz, 2H), 2.37 – 2.23 (m, 1H), 1.82 – 1.62 (m, 10H), 1.61 (s, 6H), 1.59 – 1.49 (m, 2H), 1.42 (t,J= 7.5 Hz, 3H), 1.33 – 1.19 (m, 2H)。 12 1 NMR2: 6.74 (s, 1H), 6.58 – 6.54 (m, 1H), 3.92 – 3.77 (m, 1H), 3.60 – 3.50 (m, 2H), 2.80 (d,J= 7.5 Hz, 2H), 2.38 – 2.22 (m, 1H), 1.83 – 1.63 (m, 7H), 1.61 (s, 6H), 1.60 – 1.50 (m, 6H), 1.41 (d,J= 6.9 Hz, 6H), 1.33 – 1.21 (m, 1H)。 13 1 NMR2: 6.75 (s, 1H), 6.51 (s, 1H), 3.64 – 3.51 (m, 3H), 2.81 (d, J = 7.6 Hz, 2H), 2.35 – 2.23 (m, 1H), 1.92 – 1.78 (m, 4H), 1.77 – 1.61 (m, 10H), 1.61 (s, 6H), 1.59 – 1.50 (m, 2H), 1.32 – 1.19 (m, 2H), 0.86 (t, J = 7.4 Hz, 6H). 14 1 NMR1: 6.95 (s, 1H), 6.76 (s, 1H), 3.71 – 3.57 (m, 5H), 2.85 – 2.76 (m, 2H), 1.89 – 1.65 (m, 7H), 1.64 – 1.42 (m, 9H), 1.37 (d, J = 6.9 Hz, 6H), 1.24 – 1.05 (m, 3H). [Table 2-3] EX STR Prop Data 15 1 NMR2: 6.87 (s, 1H), 6.58 (s, 1H), 3.87 – 3.70 (m, 5H), 2.81 (d, J = 7.5 Hz, 2H), 2.39 – 2.23 (m,1H), 1.93 – 1.72 (m, 7H), 1.71 – 1.51 (m, 7H), 1.42 (d, J = 6.9 Hz, 6H), 1.33 – 1.20 (m, 2H). 16 1 NMR2: 6.85 (s, 1H), 6.59 (s, 1H), 3.78 – 3.70 (m, 4H), 3.14 – 3.05 (m, 2H), 2.80 (d,J= 7.5 Hz, 2H), 2.37 – 2.24 (m, 1H), 1.95 – 1.72 (m, 8H), 1.70 – 1.51 (m, 8H), 1.26 (ddt,J= 14.0, 12.1, 5.0 Hz, 2H), 1.06 (t,J= 7.4 Hz, 3H)。 17 1 NMR1: 6.94 (s, 1H), 6.76 (s, 1H), 3.71 – 3.57 (m, 5H), 2.84 – 2.76 (m, 2H), 1.80 – 1.52 (m, 16H), 1.37 (d,J= 6.9 Hz, 6H), 1.30 – 1.09 (m, 3H), 0.93 (qd,J= 11.9, 3.3 Hz, 2H)。 18 1 NMR2: 6.84 (s, 1H), 6.58 (s, 1H), 3.88 (t,J= 5.8 Hz, 2H), 3.85 – 3.71 (m, 1H), 3.00 (t,J= 5.8 Hz, 2H), 2.81 (d,J= 7.5 Hz, 2H), 2.75 (s, 2H), 2.36 – 2.22 (m, 1H), 1.77 (s, 10H), 1.57 – 1.50 (m, 2H), 1.41 (d,J= 6.9 Hz, 6H), 1.33 – 1.19 (m, 2H)。 19 1 NMR1: 6.94 (s, 1H), 6.76 (s, 1H), 3.63 (dt,J= 17.6, 6.0 Hz, 4H), 3.09 (d,J= 7.5 Hz, 2H), 2.66 (d,J= 7.2 Hz, 2H), 1.94 – 1.46 (m, 14H), 1.35 (t,J= 7.5 Hz, 3H), 1.29 – 0.89 (m, 5H)。 20 1 NMR2: 7.09 (s, 1H), 7.07 – 7.01 (m, 1H), 3.82 – 3.70 (m, 4H), 2.93 – 2.73 (m, 2H), 2.16 – 1.23 (m, 16H), 1.18 – 1.03 (m, 1H), 1.01 – 0.83 (m, 4H). 21 1 NMR2: 6.87 (s, 1H), 6.58 – 6.52 (m, 1H), 3.86 – 3.70 (m, 5H), 2.83 – 2.64 (m, 2H), 1.92 – 1.59 (m, 12H), 1.54 – 1.25 (m, 11H), 1.13 – 0.83 (m, 4H). [Table 2-4] EX STR Prop Data 22 1 NMR2: 6.89 (s, 1H), 6.76 (s, 1H), 3.91 – 3.66 (m, 5H), 2.22 – 2.08 (m, 3H), 2.05 – 2.00 (m, 6H), 1.92 – 1.73 (m, 10H), 1.69 – 1.62 (m, 4H), 1.43 (d, J = 6.9 Hz, 6H). 23 1 NMR2: 6.96 (s, 1H), 6.79 (s, 1H), 3.87 – 3.81 (m, 2H), 3.78 – 3.72 (m, 2H), 2.17 – 2.12 (m, 3H), 2.05 – 2.00 (m, 6H), 1.92 – 1.74 (m, 10H), 1.70 – 1.61 (m, 4H), 1.60 (s, 9H). 24 1 NMR2: 7.24 (s, 1H), 6.95 (s, 1H), 3.54 (t, J = 5.7 Hz, 2H), 2.19 – 2.14 (m, 3H), 2.02 (d, J = 2.9 Hz, 6H), 1.87 – 1.65 (m, 12H), 1.60 (s, 6H). 25 1 NMR1: 7.66 (s, 1H), 7.02 (s, 1H), 3.63 – 3.54 (m, 4H), 2.79 (d, J = 7.1 Hz, 2H), 1.94 – 1.45 (m, 16H), 1.28 – 0.93 (m, 5H). 26 1 NMR2: 7.12 (s, 1H), 6.99 (s, 1H), 3.83 – 3.71 (m, 4H), 2.68 (s, 2H), 2.01 – 1.97 (m, 3H), 1.92 – 1.79 (m, 6H), 1.74 – 1.55 (m, 14H). 27 1 NMR1: 7.66 (s, 1H), 7.01 (s, 1H), 3.67 – 3.60 (m, 2H), 3.60 – 3.53 (m, 2H), 2.79 (d, J = 7.1 Hz, 2H), 1.94 – 1.73 (m, 3H), 1.71 – 1.43 (m, 15H), 1.28 – 0.93 (m, 5H). 28 28 NMR1: 6.86 (s, 1H), 6.79 (s, 1H), 3.75 (t, J = 6.0 Hz, 2H), 3.66 – 3.58 (m, 2H), 2.68 (d, J = 7.1 Hz, 2H), 1.92 – 1.46 (m, 23H), 1.29 – 0.93 (m, 5H). [Table 2-5] EX STR Prop Data 29 1 NMR1: 6.94 (s, 1H), 6.76 (s, 1H), 3.77 – 3.57 (m, 5H), 2.67 (d,J = 7.2 Hz, 2H), 2.23 – 2.13 (m, 2H), 1.87 – 1.45 (m, 20H), 1.24 – 0.90 (m, 5H). 30 1 NMR2: 7.05 (s, 1H), 6.95 (s, 1H), 3.55 (t,J = 5.7 Hz, 2H), 2.90 (d,J = 7.5 Hz, 2H), 2.39 – 2.25 (m, 1H), 1.85 – 1.63 (m, 12H), 1.64 – 1.54 (m, 6H), 1.33 – 1.20 (m, 2H). 31 1 NMR2: 7.02 (s, 1H), 6.95 (s, 1H), 3.55 (t,J = 5.7 Hz, 2H), 2.77 (d,J = 7.2 Hz, 2H), 1.93 – 1.62 (m, 12H), 1.60 (s, 6H), 1.30 – 0.94 (m, 5H). 32 1 NMR2: 6.74 (s, 1H), 6.58 (s, 1H), 3.92 – 3.77 (m, 1H), 3.58 – 3.48 (m, 2H), 2.78 – 2.66 (m, 1H), 2.03 – 1.85 (m, 5H), 1.82 – 1.63 (m, 9H), 1.60 – 1.50 (m, 5H), 1.50 – 1.24 (m, 9H). 33 1 NMR2: 6.88 (s, 1H), 6.53 (s, 1H), 3.79 – 3.70 (m, 4H), 3.59 – 3.47 (m, 1H), 2.82 (d, J = 7.6 Hz, 2H), 2.38 – 2.22 (m, 1H), 1.98 – 1.46 (m, 18H), 1.33 – 1.19 (m, 2H), 0.86 (t, J = 7.4 Hz, 6H). 34 1 NMR2: 6.87 (s, 1H), 6.60 (s, 1H), 3.85 – 3.68 (m, 5H), 2.79 – 2.67 (m, 1H), 2.02 – 1.74 (m, 11H), 1.71 – 1.51 (m, 5H), 1.50 – 1.21 (m, 8H). 35 1 NMR2: 6.72 (s, 1H), 6.55 (s, 1H), 3.55 – 3.51 (m, 2H), 3.17 (d, J = 7.5 Hz, 2H), 2.67 (d, J = 7.2 Hz, 2H), 1.88 – 1.64 (m, 14H), 1.61 (s, 6H), 1.42 (t, J = 7.5 Hz, 3H), 1.28 – 0.95 (m, 3H). 36 9 NMR2: 6.83 (s, 1H), 6.21 (s, 1H), 3.78 – 3.70 (m, 5H), 2.86 – 2.75 (m, 1H), 2.63 (d, J =​​​​​​​​​​​​​​​​NMR2: 6.88 (s, 1H), 6.49 (s, 1H), 3.79 – 3.70 (m, 4H), 3.58 – 3.47 (m, 1H), 2.69 (d,J= 7.3 Hz, 2H), 1.92 – 1.61 (m, 18H), 1.28 – 0.97 (m, 5H), 0.86 (t,J= 7.4 Hz, 6H)。 38 1 NMR2: 6.87 (s, 1H), 6.55 (s, 1H), 3.80 – 3.70 (m, 4H), 3.69 – 3.58 (m, 1H), 2.81 (d,J= 7.5 Hz, 2H), 2.36 – 2.24 (m, 1H), 2.00 – 1.49 (m, 16H), 1.39 (d,J= 7.0 Hz, 3H), 1.33 – 1.19 (m, 2H), 0.94 (t,J= 7.4 Hz, 3H)。 39 1 NMR2: 6.74 (s, 1H), 6.53 (d, J = 0.6 Hz, 1H), 3.89 – 3.76 (m, 1H), 3.58 – 3.51 (m, 2H), 2.67 (d, J = 7.2 Hz, 2H), 1.88 – 1.75 (m, 1H), 1.75 – 1.64 (m, 11H), 1.61 (s, 6H), 1.41 (d, J = 6.9 Hz, 6H), 1.32 – 1.12 (m, 3H), 1.11 – 0.97 (m, 2H)。 40 9 NMR2: 6.87 (s, 1H), 6.52 (s, 1H), 3.79 – 3.70 (m, 4H), 2.97 (d,J= 7.1 Hz, 2H), 2.68 (d,J= 7.2 Hz, 2H), 2.42 – 2.27 (m, 1H), 1.92 – 1.62 (m, 14H), 1.31 – 0.95 (m, 11H)。 41 1 NMR1: 7.68 (s, 1H), 7.02 (s, 1H), 3.67 – 3.60 (m, 2H), 3.60 – 3.53 (m, 2H), 2.92 (d, J = 7.5 Hz, 2H), 2.44 – 2.28 (m, 1H), 1.85 – 1.40 (m, 18H), 1.30 – 1.17 (m, 2H). 42 1 NMR2: 6.77 (s, 1H), 6.54 (s, 1H), 3.89 – 3.75 (m, 2H), 3.65 – 3.54 (m, 1H), 3.54 – 3.4​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​NMR1: 6.89 (s, 1H), 6.76 (s, 1H), 3.73 – 3.57 (m, 5H), 2.90 (d,J= 7.6 Hz, 2H), 2.85 – 2.70 (m, 1H), 2.09 – 1.97 (m, 2H), 1.91 – 1.66 (m, 8H), 1.62 – 1.50 (m, 4H), 1.37 (d,J= 6.9 Hz, 6H)。 46 1 NMR2: 6.87 (s, 1H), 6.56 (s, 1H), 3.86 – 3.68 (m, 5H), 2.72 (d,J= 7.4 Hz, 2H), 2.13 – 1.99 (m, 1H), 1.95 – 1.45 (m, 18H), 1.42 (d,J= 6.9 Hz, 6H), 1.35 – 1.22 (m, 2H)。 47 1 NMR2: 6.87 (s, 1H), 6.52 (s, 1H), 3.79 – 3.70 (m, 4H), 3.70 – 3.57 (m, 1H), 2.68 (d,J= 7.2 Hz, 2H), 2.00 – 1.61 (m, 16H), 1.39 (d,J= 6.9 Hz, 3H), 1.28 – 0.99 (m, 5H), 0.94 (t,J= 7.4 Hz, 3H)。 48 1 NMR2: 6.88 (s, 1H), 6.51 (s, 1H), 3.79 – 3.69 (m, 4H), 3.57 – 3.48 (m, 1H), 2.72 (d,J= 7.4 Hz, 2H), 2.12 – 1.98 (m, 1H), 1.91 – 1.76 (m, 8H), 1.74 – 1.36 (m, 14H), 1.34 – 1.23 (m, 2H), 0.85 (t,J= 7.4 Hz, 6H)。 49 1 NMR2: 6.74 (s, 1H), 6.54 (s, 1H), 3.91 – 3.76 (m, 1H), 3.59 – 3.51 (m, 2H), 2.71 (d, J = 7.4 Hz, 2H), 2.11 – 1.98 (m, 1H), 1.76 – 1.45 (m, 22H), 1.41 (d, J = 6.9 Hz, 6H), 1.35 – 1.21 (m, 2H). 50 1 NMR2: 6.84 (s, 1H), 6.55 (s, 1H), 3.88 (t, J = 5.8 Hz, 2H), 3.84 – 3.70 (m, 1H), 3.00 (d, J = 5.8 Hz, 2H), 2.75 (s, 2H), 2.68 (d, J = 7.2 Hz, 2H), 1.91 – 1.58 (m, 12H), 1.41 (d, J = 6.9 Hz, 6H), 1.32 – 0.96 (m, 5H). 51 1 NMR1: 6.93 (s, 1H), 6.75 (s, 1H), 3.73 – 3.62 (m, 3H), 3.59 (t, J = 6.1 Hz, 2H), 2.80 (d, J = 7.5 Hz, 2H), 2.41 – 2.25 (m, 1H), 1.77 – 1.46 (m, 16H), 1.38 (d, J = 6.9 Hz, 6H), 1.30 – 1.19 (m, 2H). [Table 2-8] EX STR Prop Data 52 1 NMR1: 6.91 (s, 1H), 6.75 (s, 1H), 3.73 – 3.55 (m, 5H), 2.67 (d, J = 7.1 Hz, 2H), 1.91 – 1.47 (m, 16H), 1.38 (d, J = 6.9 Hz, 6H), 1.25 – 0.92 (m, 5H). 53 53 NMR2: 7.25 (s, 1H), 6.98 (s, 1H), 3.68 – 3.62 (m, 2H), 3.03 – 2.97 (m, 2H), 2.79 (s, 2H), 2.20 – 2.14 (m, 3H), 2.04 – 2.00 (m, 6H), 1.87 – 1.75 (m, 7H), 1.57 (s, 6H)。 54 1 NMR2: 7.12 – 7.07 (m, 2H), 3.82 – 3.70 (m, 4H), 2.82 (tt,J= 11.8, 3.4 Hz, 1H), 2.05 – 1.97 (m, 2H), 1.96 – 1.74 (m, 8H), 1.72 – 1.58 (m, 4H), 1.55 – 1.23 (m, 4H)。 55 1 NMR2: 7.11 – 7.05 (m, 2H), 3.82 – 3.69 (m, 4H), 2.21 – 2.07 (m, 2H), 1.95 – 1.71 (m, 10H), 1.67 – 1.57 (m, 5H)。 56 1 NMR2: 7.14 – 7.08 (m, 2H), 3.82 – 3.70 (m, 4H), 2.99 – 2.88 (m, 1H), 2.34 – 2.22 (m, 3H), 2.15 – 1.77 (m, 9H), 1.71 – 1.59 (m, 4H)。 57 1 NMR2: 7.24 (s, 1H), 7.10 (s, 1H), 3.83 – 3.70 (m, 4H), 2.22 – 2.17 (m, 2H), 1.92 – 1.77 (m, 4H), 1.71 – 1.58 (m, 12H), 1.29 (s, 3H)。 58 1 NMR2: 7.14 – 7.05 (m, 2H), 3.84 – 3.70 (m, 4H), 2.96 – 2.72 (m, 1H), 2.08 – 1.72 (m, 7H), 1.71 – 1.53 (m, 7H), 1.41 – 1.21 (m, 7H), 1.16 – 1.01 (m, 2H), 0.95 – 0.87 (m, 3H). [Table 2-9] EX STR Prop Data 59 53 NMR2: 6.77 (s, 1H), 6.77 – 6.74 (m, 1H), 3.91 – 3.76 (m, 1H), 3.65 – 3.58 (m, 2H), 3.01 – 2.94 (m, 2H), 2.78 (s, 2H), 2.17 – 2.12 (m, 3H), 2.02 (d, J = 2.9 Hz, 6H), 1.86 – 1.75 (m, 7H), 1.58 (s, 6H), 1.42 (d, J = 6.9 Hz, 6H). 60 1 [[ID=2,6]]NMR2: 7.10 – 7.03 (m, 2H), 3.85 – 3.69 (m, 4H), 2.99 (tt,J= 10.2, 3.7 Hz, 1H), 2.08 – 1.97 (m, 2H), 1.94 – 1.54 (m, 18H). 61 1 NMR2: 7.23 (s, 1H), 7.01 (s, 1H), 3.50 – 3.43 (m, 2H), 2.20 – 2.14 (m, 3H), 2.05 – 1.96 (m, 6H), 1.93 – 1.70 (m, 11H), 1.66 – 1.53 (m, 9H). 62 1 NMR2: 7.26 (s, 1H), 7.01 (s, 1H), 3.85 – 3.77 (m, 4H), 3.50 (s, 2H), 2.19 – 2.15 (m, 3H), 2.02 (d, J = 2.9 Hz, 6H), 1.87 – 1.74 (m, 6H), 1.55 (s, 6H). 63 1 NMR2: 7.25 (s, 1H), 6.98 (s, 1H), 3.84 – 3.75 (m, 1H), 3.65 – 3.56 (m, 1H), 3.56 – 3.48 (m, 1H), 3.36 (s, 3H), 2.19 – 2.12 (m, 4H), 2.04 – 2.00 (m, 6H), 1.91 (dd, J = 13.6, 4.7 Hz, 1H), 1.87 – 1.75 (m, 7H), 1.70 – 1.58 (m, 7H). 64 1 NMR2: 6.79 (s, 1H), 6.76 (s, 1H), 4.11 – 4.04 (m, 1H), 3.99 – 3.90 (m, 1H), 3.90 – 3.78 (m, 1H), 3.40 – 3.31 (m, 1H), 2.20 – 2.11 (m, 4H), 2.11 – 2.00 (m, 6H), 1.93 – 1.86 (m, 1H), 1.85 – 1.74 (m, 7H), 1.71 (s, 3H), 1.68 – 1.49 (m, 5H), 1.45 – 1.40 (m, 6H). [Table 2-10] EX STR Prop Data 65 1 NMR2: 7.08 (s, 1H), 6.94 (s, 1H), 3.54 (t,J= 5.7 Hz, 2H), 2.86 – 2.76 (m, 1H), 2.04 – 1.97 (m, 2H), 1.95 – 1.87 (m, 2H), 1.83 – 1.75 (m, 1H), 1.75 – 1.65 (m, 3H), 1.63 – 1.52 (m, 11H), 1.49 – 1.24 (m, 3H)。 66 1 NMR2: 7.05 (s, 1H), 7.01 (s, 1H), 3.86 – 3.78 (m, 4H), 3.51 (s, 2H), 2.78 (d,J= 7.2 Hz, 2H), 1.91 – 1.80 (m, 1H), 1.76 – 1.64 (m, 5H), 1.55 (s, 6H), 1.32 – 0.95 (m, 5H)。 67 1 NMR2: 7.09 (s, 1H), 7.03 (s, 1H), 3.87 (t, J = 5.9 Hz, 2H), 3.36 – 3.23 (m, 1H), 3.03 (t, J = 5.8 Hz, 2H), 2.74 (s, 2H), 2.21 – 2.08 (m, 2H), 1.94 – 1.81 (m, 4H), 1.77 – 1.73 (m, 8H)。 68 1 NMR2: 6.91 (s, 1H), 6.56 (s, 1H), 3.63 (t,J= 6.3 Hz, 2H), 3.60 – 3.49 (m, 1H), 2.83 (d,J= 7.5 Hz, 2H), 2.79 – 2.70 (m, 2H), 2.37 – 2.22 (m, 3H), 1.92 – 1.80 (m, 4H), 1.73 (s, 10H), 1.60 – 1.52 (m, 2H), 1.33 – 1.21 (m, 2H), 0.87 (t,J= 7.4 Hz, 6H)。 69 9 NMR1: 6.94 (s, 1H), 6.75 (s, 1H), 3.63 (dt, J = 20.2, 6.1 Hz, 4H), 3.06 (t, J = 7.6 Hz, 2H), 2.65 (d, J = 7.1 Hz, 2H), 1.89 – 1.49 (m, 17H), 1.42 – 0.92 (m, 10H), 0.89 – 0.81 (m, 3H). 70 1 NMR2: 6.86 (s, 1H), 6.56 (s, 1H), 3.75 – 3.67 (m, 2H), 3.61 – 3.49 (m, 1H), 2.83 (d, J = 7.5 Hz, 2H), 2.36 – 2.24 (m, 1H), 2.07 – 1.98 (m, 2H), 1.93 – 1.81 (m, 4H), 1.75 – 1.50 (m, 12H), 1.33 – 1.20 (m, 8H), 0.88 (t, J = 7.4 Hz, 6H). 71 1 NMR2: 6.86 (s, 1H), 6.63 – 6.58 (m, 1H), 3.86 – 3.75 (m, 1H), 3.75 – 3.68 (m, 2H), 2.82 (d, J = 7.5 Hz, 2H), 2.37 – 2.25 (m, '1H), 2.06 – 1.99 (m, 2H), 1.82 – 1.62 (m, 9H), 1.59 – 1.49 (m, 3H), 1.44 (d, J = 6.9 Hz, 6H), 1.33 – 1.20 (m, 8H). [Table 2-11] EX STR Prop Data 72 1 NMR2: 6.75 (s, 1H), 6.51 (s, 1H), 3.77 – 3.68 (m, 1H), 3.66 – 3.55 (m, 1H), 3.45 – 3.33 (m, 4H), 3.15 – 3.07 (m, 1H), 2.80 (d,J= 7.6 Hz, 2H), 2.35 – 2.23 (m, 1H), 2.02 – 1.92 (m, 1H), 1.92 – 1.63 (m, 9H), 1.61 – 1.49 (m, 10H), 1.32 – 1.19 (m, 2H), 0.85 (td,J= 7.4, 2.1 Hz, 6H)。 73 1 NMR2: 6.78 (s, 1H), 6.50 (s, 1H), 4.10 – 4.05 (m, 1H), 4.00 – 3.90 (m, 1H), 3.64 – 3.52 (m, 1H), 3.43 – 3.32 (m, 1H), 2.68 (d,J= 7.2 Hz, 2H), 2.16 – 2.04 (m, 1H), 1.94 – 1.57 (m, 17H), 1.54 (s, 3H), 1.31 – 0.96 (m, 5H), 0.94 – 0.81 (m, 6H)。 74 1 NMR2: 6.83 (s, 1H), 6.58 (d,J= 0.7 Hz, 1H), 3.87 (t,J= 5.8 Hz, 2H), 3.83 – 3.73 (m, 1H), 3.03 – 2.96 (m, 2H), 2.85 – 2.77 (m, 2H), 2.75 (s, 2H), 1.84 – 1.60 (m, 12H), 1.41 (d,J= 6.9 Hz, 6H), 1.38 – 1.09 (m, 5H), 1.04 – 0.88 (m, 2H)。 75 1 NMR2: 6.74 (s, 1H), 6.53 (s, 1H), 3.77 – 3.64 (m, 1H), 3.60 – 3.51 (m, 2H), 2.80 (d, J = 7.5 Hz, 2H), 2.38 – 2.21 (m, 1H), 1.98 – 1.83 (m, 1H), 1.80 – 1.63 (m, 11H), 1.61 (d, J = 2.4 Hz, 8H), 1.38 (d, J = 7.0 Hz, 3H), 1.32 – 1.19 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 76 1 NMR2: 6.79 (s, 1H), 6.56 (s, 1H), 3.88 – 3.73 (m, 5H), 3.50 (s, 2H), 2.68 (d, J = 7.2 Hz, 2H), 1.88 – 1.59 (m, 6H), 1.56 (s, 6H), 1.41 (d, J = 6.9 Hz, 6H), 1.32 – 0.95 (m, 5H). 77 1 NMR2: 7.01 (s, 1H), 6.94 (s, 1H), 3.79 – 3.70 (m, 4H), 2.75 (d, J = 7.2 Hz, 2H), 2.29 (t, J = 19.1 Hz, 3H), 1.92 – 1.59 (m, 14H), 1.33 – 0.98 (m, 5H). 78 1 NMR1: 6.94 (s, 1H), 6.74 (s, 1H), 3.68 – 3.46 (m, 5H), 2.79 (d, J = 7.5 Hz, 2H), 2.38 – 2.24 (m, 1H), 1.97 – 1.83 (m, 1H), 1.80 – 1.44 (m, 17H), 1.36 (d, J = 6.9 Hz, 3H), 1.29 – 1.16 (m, 2H), 0.86 (t, J = 7.4 Hz, 3H). [Table 2-12] EX STR Prop Data 79 1 NMR1: 6.95 (s, 1H), 6.74 (s, 1H), 3.65 (t, J = 5.4 Hz, 2H), 3.59 (t, J = 6.1 Hz, 2H), 3.48 – 3.37 (m, 1H), 2.80 (d, J = 7.5 Hz, 2H), 2.31 (p, J = 7.7 Hz, 1H), 1.95 – 1.43 (m, 19H), 1.30 – 1.16 (m, 3H), 0.78 (t, J = 7.4 Hz, 6H). 80 <~ 1 NMR2: 6.89 (s, 1H), 6.59 (d, J = 0.8 Hz, 1H), 5.90 – 5.72 (m, 2H), 3.88 – 3.71 (m, 5H), 2.82 (d, J = 7.5 Hz, 2H), 2.52 – 2.40 (m, 4H), 2.37 – 2.25 (m, 1H), 1.83 – 1.63 (m, 4H), 1.60 – 1.51 (m, 2H), 1.42 (d, J = 6.9 Hz, 6H), 1.35 – 1.20 (m, 2H). 81 1 NMR2: 6.89 (s, 1H), 6.55 (d, J = 0.8 Hz, 1H), 5.90 – 5.72 (m, 2H), 3.87 – 3.73 (m, 5H), 2.69 (d, J = 7.2 Hz, 2H), 2.52 – 2.40 (m, 5H), 1.89 – 1.62 (m, 5H), 1.42 (d, J = 6.9 Hz, 6H), 1.32 – 0.98 (m, 5H). 82 1 NMR1: 7.49 (s, 1H), 6.95 (s, 1H), 6.26 (s, 1H), 3.58 (dt, J = 14.3, 6.0 Hz, 4H), 2.18 – 2.10 (m, 6H), 1.78 – 1.60 (m, 12H), 1.60 – 1.47 (m, 5H). 83 1 NMR1: 6.65 (s, 2H), 4.45 (t, J = 6.5 Hz, 2H), 3.58 (dt, J = 9.0, 6.0 Hz, 4H), 2.11 – 2.06 (m, 3H), 2.02 – 1.97 (m, 6H), 1.94 – 1.81 (m, 2H), 1.79 – 1.69 (m, 8H), 1.68 – 1.48 (m, 6H), 1.04 (t, J = 7.4 Hz, 3H). 84 1 NMR2: 7.19 (s, 1H), 7.10 (s, 1H), 3.83 – 3.69 (m, 4H), 3.13 (s, 1H), 2.63 (s, 2H), 2.09 – 1.76 (m, 14H), 1.71 – 1.59 (m, 6H). 85 1 NMR2: 7.21 (s, 1H), 7.08 (s, 1H), 3.81 – 3.70 (m, 4H), 1.95 – 1.59 (m, 21H). [Table 2-13] EX STR Prop Data 86 1 NMR2: 6.93 (s, 1H), 6.78 (s, 1H), 4.58 (s, 2H), 4.15 – 3.98 (m, 1H), 3.95 – 3.74 (m, 1H), 3.59 – 3.49 (m, 2H), 1.81 – 1.64 (m, 14H), 1.61 (s, 6H), 1.43 (d, J = 6.9 Hz, 6H)。 87 87 NMR2: 6.86 (s, 1H), 6.50 (s, 1H), 3.80 – 3.69 (m, 4H), 3.14 (q, J = 7.4 Hz, 2H), 2.68 (d, J = 7.2 Hz, 2H), 1.91 – 1.76 (m, 5H), 1.75 – 1.59 (m, 9H), 1.52 (t, J = 7.4 Hz, 3H), 1.28 – 0.98 (m, 5H)。 88 88 NMR2: 6.54 (d, J = 0.7 Hz, 1H), 3.87 – 3.71 (m, 3H), 3.63 (t, J = 6.0 Hz, 2H), 2.70 (d, J = 7.2 Hz, 2H), 1.92 – 1.57 (m, 14H), 1.40 (d, J = 6.9 Hz, 6H), 1.33 – 0.98 (m, 5H)。 89 89 NMR2: 6.65 (s, 1H), 5.81 (s, 1H), 3.78 – 3.66 (m, 8H), 2.55 (d, J = 7.1 Hz, 2H), 1.90 – 1.52 (m, 16H), 1.31 – 0.96 (m, 7H), 0.92 (t, J = 7.4 Hz, 6H)。 90 90 NMR2: 6.72 (s, 1H), 6.03 (s, 1H), 4.72 – 4.61 (m, 1H), 3.74 – 3.58 (m, 4H), 2.65 (d, J = 7.2 Hz, 2H), 2.17 – 2.06 (m, 2H), 2.00 – 0.95 (m, 27H). 91 1 NMR2: 7.04 (s, 1H), 6.57 (d, J = 0.8 Hz, 1H), 4.37 – 3.69 (m, 5H), 2.69 (d, J = 7.2 Hz, 2H), 1.95 – 1.77 (m, 7H), 1.75 – 1.62 (m, 5H), 1.43 (d, J = 6.9 Hz, 5H), 1.35 – 0.97 (m, 6H). 92 1 NMR2: 6.97 (d, J = 0.6 Hz, 1H), 6.77 (s, 1H), 4.61 (s, 2H), 3.94 – 3.80 (m, 1H), 3.63 – 3.51 (m, 3H), 2.02 – 1.90 (m, 2H), 1.78 – 1.63 (m, 11H), 1.61 (s, 6H), 1.60 – 1.50 (m, 4H), 1.43 (d, J = 6.9 Hz, 7H). 93 1 NMR2: 6.88 (s, 1H), 6.53 (d, J = 0.7 Hz, 1H), 3.86 – 3.70 (m, 5H), 2.72 – 2.61 (m, 1H), 1.93 – 1.72 (m, 6H), 1.72 – 1.57 (m, 8H), 1.43 (dd, J = 6.9, 0.7 Hz, 6H), 1.29 (d, J = 7.0 Hz, 3H), 1.26 –​​​​​​​​​​​​ 1 NMR2: 7.25 (s, 1H), 7.10 (s, 1H), 3.82 – 3.70 (m, 4H), 2.19 – 2.15 (m, 3H), 2.05 – 2.00 (m, 6H), 1.92 – 1.75 (m, 10H), 1.68 – 1.60 (m, 4H)。 95 1 NMR2: 6.76 (s, 1H), 6.50 (s, 1H), 3.80 – 3.73 (m, 2H), 3.73 – 3.66 (m, 6H), 1.88 – 1.57 (m, 14H)。 96 1 NMR2: 7.29 (s, 1H), 7.12 (s, 1H), 3.61 (t, J = 6.3 Hz, 2H), 2.78 – 2.70 (m, 2H), 2.37 – 2.25 (m, 2H), 2.21 – 2.15 (m, 3H), 2.03 (d, J = 2.9 Hz, 6H), 1.89 – 1.74 (m, 6H), 1.71 (s, 6H)。 97 1 NMR2: 6.79 (s, 1H), 6.77 (s, 1H), 3.88 – 3.79 (m, 1H), 3.68 – 3.50 (m, 3H), 2.17 – 2.12 (m, 3H), 2.06 – 1.92 (m, 8H), 1.86 – 1.66 (m, 9H), 1.66 – 1.60 (m, 6H), 1.42 (d, J = 6.9 Hz, 6H)。 98 1 NMR2: 6.89 (s, 1H), 6.54 (s, 1H), 3.84 – 3.71 (m, 5H), 2.74 (s, 2H), 1.94 – 1.73 (m, 5H), 1.71 – 1.54 (m, 7H), 1.53 – 1.27 (m, 12H), 0.96 (s, 3H). 99 1 NMR2: 6.71 (s, 1H), 6.60 – 6.54 (m, 1H), 3.56 – 3.49 (m, 2H), 2.75 (d, J = 1.0 Hz, 3H), 2.66 (d, J = 7.2 Hz, 2H), 1.88 – 1.75 (m, 1H), 1.75 – 1.65 (m, 11H), 1.61 (s, 6H), 1.30 – 1.13 (m, 3H), 1.10 – 0.97 (m, 2H). 100 1 NMR2: 7.25 (s, 1H), 6.98 (s, 1H), 3.70 – 3.48 (m, 3H), 2.20 – 2.13 (m, 3H), 2.OP5 – 1.91 (m, 9H), 1.89 – 1.68 (m, 8H), 1.66 (s, 3H), 1.58 (s, 3H). [Table 2-15] EX STR Prop Data 101 53 NMR2: 6.84 (s, 1H), 6.78 (s, 1H), 3.78 – 3.61 (m, 2H), 3.06 – 2.93 (m, 2H), 2.79 (s, 2H), 2.22 – 2.08 (m, 3H), 2.07 – 1.97 (m, 6H), 1.87 – 1.73 (m, 6H), 1.66 – 1.32 (m, 16H). 102 1 NMR2: 7.25 (s, 1H), 6.98 (s, 1H), 4.13 – 4.04 (m, 1H), 3.96 – 3.88 (m, 1H), 3.45 – 3.37 (m, 1H), 2.20 – 2.09 (m, 4H), 2.04 – 2.00 (m, 6H), 1.93 – 1.73 (m, 8H), 1.70 (s, 3H), 1.68 – 1.59 (m, 1H), 1.55 (s, 3H), 1.53 – 1.50 (m, 1H)。 103 1 NMR2: 6.91 (s, 1H), 6.61 (s, 1H), 3.88 – 3.75 (m, 1H), 3.64 (t, J = 6.3 Hz, 2H), 2.83 (d, J = 7.5 Hz, 2H), 2.78 – 2.70 (m, 2H), 2.39 – 2.22 (m, 3H), 1.60 – 1.54 (m, 10H), 1.57 – 1.52 (m, 2H), 1.44 (d, J = 6.9 Hz, 6H), 1.34 – 1.20 (m, 2H)。 104 1 NMR2: 6.78 (s, 1H), 6.53 (s, 1H), 3.68 – 3.49 (m, 4H), 2.81 (d, J = 7.5 Hz, 2H), 2.36 – 2.21 (m, 1H), 2.17 – 2.09 (m, 1H), 2.03 – 1.93 (m, 1H), 1.92 – 1.62 (m, 13H), 1.61 – 1.47 (m, 6H), 1.32 – 1.19 (m, 2H), 0.86 (t, J = 7.4 Hz, 6H)。 105 1 NMR2: 7.10 (s, 1H), 7.07 (s, 1H), 3.75 – 3.68 (m, 2H), 2.92 (d, J = 7.5 Hz, 2H), 2.41 – 2.28 (m, 1H), 2.09 – 2.02 (m, 2H), 1.86 – 1.65 (m, 10H), 1.61 – 1.56 (m, 2H), 1.34 – 1.21 (m, 8H). 106 1 NMR2: 6.78 (s, 1H), 6.53 (s, 1H), 4.10 – 4.06 (m, 1H), 3.95 (ddd, J = 14.2, 6.9, 4.0 Hz, 1H), 3.64 – 3.53 (m, 1H), 3.38 (ddd, J = 14.2, 9.0, 3.5 Hz, 1H), 2.81 (d, J = 7.5 Hz, 2H), 2.36 – 2.21 (m, 1H), 2.13 – 2.05 (m, 1H), 1.94 – 1.58 (m, 20H), 1.32 – 1.19 (m, 2H), 0.86 (td, J = 7.4, 2.8 Hz, 6H). 107 1 NMR2: 6.81 (s, 1H), 6.56 (s, 1H), 3.91 – 3.76 (m, 2H), 3.57 – 3.45 (m, 1H), 2.68 (d, J = 7.2 Hz, 2H), 1.93 – 1.60 (m, 17H), 1.42 (dd, J = 6.9, 0.9 Hz, 6H), 1.30 – 1.13 (m, 6H), 1.11 – 0.98 (m, 2H). [Table 2-16] EX STR Prop Data 108 1 NMR2: 7.07 (s, 1H), 7.05 (s, 1H), 3.88 (t, J = 5.9 Hz, 2H), 3.04 (t, J = 5.8 Hz, 2H), 2.91 (d, J = 7.5 Hz, 2H), 2.74 (s, 2H), 2.41 – 2.25 (m, 1H), 1.85 – 1.58 (m, 12H), 1.33 – 1.20 (m, 2H)。 109 1 NMR2: 6.74 (s, 1H), 6.56 – 6.50 (m, 1H), 3.89 – 3.78 (m, 1H), 3.61 – 3.46 (m, 2H), 2.81 – 2.57 (m, 2H), 2.06 – 2.02 (m, 1H), 1.77 – 1.65 (m, 8H), 1.61 (s, 6H), 1.55 – 1.24 (m, 11H), 1.14 – 1.01 (m, 1H), 0.98 – 0.83 (m, 4H)。 110 53 NMR2: 7.25 (s, 1H), 7.04 (s, 1H), 3.67 – 3.58 (m, 2H), 3.01 – 2.96 (m, 2H), 2.94 (s, 2H), 2.21 – 2.13 (m, 4H), 2.11 – 1.94 (m, 13H), 1.89 – 1.74 (m, 7H)。 111 1 NMR1: 7.66 (s, 1H), 6.94 (s, 1H), 5.02 (d, J = 5.0 Hz, 1H), 3.50 – 3.41 (m, 2H), 3.29 – 3.21 (m, 1H), 2.90 (tt, J = 11.7, 3.4 Hz, 1H), 1.97 – 1.91 (m, 2H), 1.86 – 1.49 (m, 12H), 1.44 – 1.32 (m, 5H), 1.32 – 1.19 (m, 1H)。 112 1 NMR2: 7.17 (s, 1H), 6.95 (s, 1H), 3.56 (t, J = 5.7 Hz, 2H), 3.14 – 3.10 (m, 1H), 2.64 – 2.60 (m, 2H), 2.07 – 2.00 (m, 3H), 1.98 – 1.82 (m, 6H), 1.82 – 1.77 (m, 2H), 1.77 – 1.63 (m, 7H), 1.60 (s, 6H). 113 1 NMR2: 7.06 (s, 1H), 6.97 (s, 1H), 3.81 (ddd, J = 14.0, 8.6, 3.9 Hz, 1H), 3.67 – 3.50 (m, 2H), 3.36 (s, 3H), 2.90 (d, J = 7.5 Hz, 2H), 2.39 – 2.27 (m, 1H), 2.20 – 2.10 (m, 1H), 1.91 (ddd, J = 13.7, 4.8, 1.0 Hz, 1H), 1.85 – 1.61 (m, 8H), 1.61 – 1.54 (m, 6H), 1.33 – 1.20 (m, 2H),. [Table 2-17] EX STR Prop material 114 1 NMR2: 6.76 (s, 1H), 6.57 (d, J = 0.7 Hz, 1H), 3.89 – 3.75 (m, 2H), 3.65 – 3.54 (m, 1H), 3.49 (ddd, J = 14.0, 7.8, 3.9 Hz, 1H), 3.36 (s, 3H), 2.81 (d, J = 7.5 Hz, 2H), 2.37 – 2.25 (m, 1H), 2.18 – 2.06 (m, 1H), 1.92 (ddd, J = 13.6, 4.8, 1.1 Hz, 1H), 1.83 – 1.72 (m, 2H), 1.71 – 1.61 (m, 6H), 1.60 – 1.51 (m, 6H), 1.41 (dd, J = 6.9, 0.9 Hz, 6H), 1.33 – 1.21 (m, 2H)。 115 8 NMR1: 6.90 (s, 1H), 6.76 (s, 1H), 3.69 (t, J = 6.0 Hz, 2H), 3.61 (t, J = 6.1 Hz, 2H), 3.57 – 3.48 (m, 1H), 2.66 (d, J = 7.1 Hz, 2H), 2.06 – 1.96 (m, 2H), 1.86 – 1.70 (m, 10H), 1.69 – 1.53 (m, 14H), 1.25 – 1.10 (m, 3H), 1.07 – 0.93 (m, 2H)。 116 116 NMR1: 6.90 (s, 1H), 6.68 (s, 1H), 3.72 – 3.61 (m, 1H), 3.56 – 3.39 (m, 4H), 3.24 (s, 3H), 2.67 (d, J = 7.1 Hz, 2H), 2.49 – 2.43 (m, 4H), 2.34 (s, 2H), 1.90 – 1.75 (m, 1H), 1.70 – 1.56 (m, 5H), 1.46 (s, 6H), 1.36 (d, J = 6.9 Hz, 6H), 1.25 – 0.94 (m, 5H)。 117 1 NMR2: 6.77 (s, 1H), 6.58 (s, 1H), 3.89 – 3.76 (m, 1H), 3.69 – 3.49 (m, 3H), 2.81 (d, J = 7.5 Hz, 2H), 2.37 – 2.24 (m, 1H), 2.11 – 2.06 (m, 1H), 2.03 – 1.91 (m, 1H), 1.87 – 1.62 (m, 12H), 1.61 – 1.49 (m, 3H), 1.41 (d, J = 6.9 Hz, 6H), 1.33 – 1.19 (m, 2H)。 118 1 NMR2: 6.77 (s, 1H), 6.55 (s, 1H), 4.12 – 4.03 (m, 1H), 4.00 – 3.90 (m, 1H), 3.90 – 3.75 (m, 1H), 3.38 (ddd, J = 14.1, 9.0, 3.5 Hz, 1H), 2.68 (d, J = 7.2 Hz, 2H), 2.17 – 2.02 (m, 1H), 1.90 (ddd, J = 13.3, 4.8, 1.4 Hz, 1H), 1.85 – 1.75 (m, 1H), 1.74 – 1.58 (m, 14H), 1.42 (dd, J = 6.9, 1.4 Hz, 6H), 1.31 – 1.13 (m, 3H), 1.11 – 0.98 (m, 2H)。 119 1 NMR2: 6.86 (s, 1H), 6.57 (d, J = 0.7 Hz, 1H), 3.86 – 3.73 (m, 1H), 3.76 – 3.68 (m, 2H), 2.69 (d, J = 7.2 Hz, 2H), 2.06 – 1.98 (m, 2H), 1.89 – 1.75 (m, 7H), 1.75 – 1.63 (m, 6H), 1.44 (d, J = 6.9 Hz, 6H), 1.28 (s, 6H), 1.26 – 1.13 (m, 2H), 1.12 – 0.98 (m, 2H)。 [Table 2-18] EX STR Prop Data 120 1 NMR2: 6.77 (s, 1H), 6.54 (s, 1H), 3.91 – 3.73 (m, 2H), 3.45 – 3.32 (m, 2H), 2.68 (d, J = 7.2 Hz, 2H), 1.89 – 1.61 (m, 10H), 1.57 – 1.52 (m, 5H), 1.42 (dd, J = 6.9, 1.6 Hz, 6H), 1.31 – 1.13 (m, 3H), 1.13 – 0.98 (m, 8H). 121 1 NMR2: 6.72 (s, 1H), 6.63 – 6.58 (m, 1H), 3.55 – 3.48 (m, 2H), 3.23 – 3.12 (m, 2H), 2.78 – 2.66 (m, 1H), 2.02 – 1.94 (m, 2H), 1.94 – 1.84 (m, 2H), 1.82 – 1.73 (m, 1H), 1.70 – 1.51 (m, 14H), 1.49 – 1.22 (m, 6H). 122 1 NMR2: 6.74 (s, 1H), 6.52 (s, 1H), 3.90 – 3.76 (m, 1H), 3.69 (dt, J = 13.9, 4.8 Hz, 1H), 3.56 – 3.44 (m, 1H), 3.24 (s, 3H), 2.67 (d, J = 7.2 Hz, 2H), 1.88 – 1.75 (m, 3H), 1.74 – 1.59 (m, 10H), 1.55 (s, 3H), 1.41 (d, J = 6.9 Hz, 6H), 1.32 – 1.13 (m, 6H), 1.11 – 0.97 (m, 2H). 123 1 NMR2: 6.89 (d, J = 3.8 Hz, 1H), 6.61 – 6.56 (m, 1H), 5.95 – 5.66 (m, 2H), 4.36 – 4.30 (m, 1H), 4.30 – 4.23 (m, 1H), 3.93 (dt, J = 13.7, 6.1 Hz, 2H), 3.87 – 3.75 (m, 1H), 2.82 (d, J = 7.5 Hz, 2H), 2.39 – 2.23 (m, 3H), 2.07 – 1.95 (m, 1H), 1.95 – 1.85 (m, 1H), 1.83 – 1.63 (m, 4H), 1.61 – 1.49 (m, 2H), 1.42 (dd, J = 6.9, 3.0 Hz, 6H), 1.33 – 1.20 (m, 2H). 124 1 NMR2: 6.75 (s, 1H), 6.50 (s, 1H), 3.76 – 3.63 (m, 1H), 3.63 – 3.46 (m, 2H), 2.67 (d, J = 7.2 Hz, 2H), 2.02 – 1.58 (m, 19H), 1.38 (d, J = 7.0 Hz, 3H), 1.33 – 1.12 (m, 4H), 1.10 – 0.98 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). 125 1 NMR2: 6.87 (s, 1H), 6.57 (s, 1H), 4.16 – 4.05 (m, 4H), 3.84 – 3.71 (m, 1H), 2.76 (dt, J = 21.3, 5.1 Hz, 4H), 2.69 (d, J = 7.2 Hz, 2H), 1.88 – 1.76 (m, 1H), 1.74 – 1.61 (m, 5H), 1.43 (d, J = 6.9 Hz, 6H), 1.31 – 1.13 (m, 3H), 1.11 – 0.98 (m, 2H). [Table 2-19] EX STR Prop Data 126 1 NMR2: 6.89 (d, J = 3.4 Hz, 1H), 6.58 – 6.53 (m, 1H), 5.94 – 5.68 (m, 2H), 4.36 – 4.30 (m, 1H), 4.30 – 4.24 (m, 1H), 3.93 (dt, J = 13.5, 6.1 Hz, 2H), 3.87 – 3.75 (m, 1H), 2.68 (d, J = 7.2 Hz, 2H), 2.37 – 2.26 (m, 2H), 2.07 – 1.95 (m, 1H), 1.95 – 1.77 (m, 2H), 1.74 – 1.67 (m, 5H), 1.43 (dd, J = 6.9, 2.9 Hz, 6H), 1.31 – 1.12 (m, 3H), 1.11 – 0.98 (m, 2H). 127 1 NMR2: 6.87 (d, J = 4.0 Hz, 1H), 6.60 – 6.55 (m, 1H), 4.05 – 3.46 (m, 5H), 2.85 – 2.78 (m, 2H), 2.37 – 2.25 (m, 1H), 2.07 – 1.48 (m, 12H), 1.42 (dd, J = 6.9, 2.0 Hz, 6H), 1.36 – 1.20 (m, 3H), 0.98 (dd, J = 13.2, 6.7 Hz, 3H). 128 1 NMR2: 6.87 (s, 1H), 6.55 (s, 1H), 4.14 – 4.08 (m, 4H), 3.66 – 3.56 (m, 1H), 2.82 – 2.71 (m, 4H), 2.69 (d, J = 7.2 Hz, 2H), 2.00 – 1.62 (m, 8H), 1.39 (d, J = 7.0 Hz, 3H), 1.28 – 1.13 (m, 3H), 1.11 – 0.98 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 129 1 NMR2: 6.82 (s, 1H), 6.57 (s, 1H), 4.97 – 4.92 (m, 1H), 4.86 – 4.81 (m, 1H), 3.89 – 3.75 (m, 1H), 3.44 (t, J = 6.4 Hz, 2H), 2.81 (d, J = 7.5 Hz, 2H), 2.53 – 2.45 (m, 2H), 2.37 – 2.22 (m, 1H), 2.02 – 1.90 (m, 2H), 1.82 – 1.49 (m, 12H), 1.42 (d, J = 6.9 Hz, 6H), 1.33 – 1.20 (m, 2H)。 130 1 NMR2: 6.75 (s, 1H), 6.49 (s, 1H), 3.65 – 3.46 (m, 3H), 2.71 (d, J = 7.4 Hz, 2H), 2.12 – 1.98 (m, 1H), 1.92 – 1.76 (m, 4H), 1.76 – 1.54 (m, 13H), 1.54 – 1.35 (m, 5H), 1.34 – 1.21 (m, 4H), 0.96 – 0.81 (m, 8H)。 131 1 NMR2: 6.66 (s, 1H), 5.81 (s, 1H), 3.82 (q, J = 7.0 Hz, 2H), 3.78 – 3.56 (m, 6H), 2.55 (d, J = 7.1 Hz, 2H), 1.91 – 1.50 (m, 11H), 1.33 – 1.10 (m, 10H), 1.08 – 0.78 (m, 6H)。 132 1 NMR2: 6.81 (s, 1H), 6.58 – 6.52 (m, 1H), 3.88 – 3.68 (m, 5H), 2.79-2.67 (m, 2H), 2.13 – 1.95 (m, 1H), 1.74 – 1.57 (m, 7H), 1.56 – 1.24 (m, 12H), 1.15 – 1.00 (m, 1H), 0.98 – 0.84 (m, 4H). [Table 2-20] EX STR Prop Data 133 1 NMR1: 7.15 (s, 1H), 6.76 (s, 1H), 3.62 (dt, J = 13.9, 6.0 Hz, 4H), 3.12 – 3.04 (m, 2H), 2.11 – 2.06 (m, 3H), 2.00 – 1.95 (m, 6H), 1.85 – 1.65 (m, 12H), 1.62 – 1.49 (m, 4H), 1.40 – 1.28 (m, 4H), 0.91 – 0.83 (m, 3H). 134 1 NMR1: 6.90 (s, 1H), 6.75 (s, 1H), 3.67 (t, J = 6.0 Hz, 2H), 3.61 (t, J = 6.1 Hz, 2H), 2.78 (d, J = 7.5 Hz, 2H), 2.37 – 2.25 (m, 1H), 2.11 – 2.03 (m, 2H), 1.89 – 1.81 (m, 2H), 1.79 – 1.14 (m, 23H). 135 89 NMR1: 6.50 (s, 1H), 6.12 (s, 1H), 3.93 – 3.85 (m, 2H), 3.69 (t, J = 6.0 Hz, 2H), 3.63 – 3.56 (m, 2H), 3.17 (s, 3H), 2.53 (d, J = 7.2 Hz, 2H), 1.85 – 1.48 (m, 16H), 1.26 – 1.09 (m, 3H), 1.05 – 0.92 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H)。 136 1 NMR1: 6.96 (s, 1H), 6.75 (s, 1H), 3.62 (dt, J = 14.9, 6.0 Hz, 4H), 3.08 (q, J = 7.4 Hz, 2H), 2.92 (tt, J = 9.8, 7.5, 3.2 Hz, 1H), 1.97 – 1.86 (m, 2H), 1.84 – 1.46 (m, 18H), 1.35 (t, J = 7.4 Hz, 3H)。 137 1 NMR2: 6.87 (s, 1H), 6.57 (s, 1H), 4.23 – 4.10 (m, 1H), 3.74 (dt, J = 10.4, 6.0 Hz, 4H), 2.70 (d, J = 7.2 Hz, 2H), 2.63 – 2.51 (m, 2H), 2.34 – 2.12 (m, 3H), 2.02 – 1.91 (m, 1H), 1.91 – 1.74 (m, 4H), 1.74 – 1.56 (m, 10H), 1.29 – 1.14 (m, 3H), 1.12 – 0.99 (m, 2H)。 138 1 NMR2: 6.81 (s, 1H), 6.58 – 6.52 (m, 1H), 3.88 – 3.68 (m, 5H), 2.81 – 2.65 (m, 2H), 1.83 – 1.00 (m, 22H), 0.97 – 0.82 (m, 5H)。 139 1 NMR2: 6.87 (s, 1H), 6.58 – 6.52 (m, 1H), 3.86 – 3.67 (m, 5H), 2.81 – 2.65 (m, 2H), 1.92 – 1.40 (m, 18H), 1.39 – 0.76 (m, 11H). [Table 2-21] EX STR Prop Data 140 1 NMR2: 6.81 (s, 1H), 6.54 (s, 1H), 3.88 – 3.64 (m, 5H), 2.68 (d, J = 7.2 Hz, 2H), 1.87 – 1.77 (m, 1H), 1.74 – 1.67 (m, 11H), 1.42 (d, J = 6.9 Hz, 6H), 1.32 – 1.11 (m, 3H), 1.11 – 0.98 (m, 2H). 141 1 NMR2: 6.82 (s, 1H), 6.55 (s, 1H), 3.80 – 3.60 (m, 5H), 2.81 (d, J = 7.5 Hz, 2H), 2.36 – 2.24 (m, 1H), 2.00 – 1.85 (m, 1H), 1.80 – 1.48 (m, 13H), 1.39 (d, J = 7.0 Hz, 3H), 1.33 – 1.19 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H). 142 1 NMR2: 6.98 (s, 1H), 6.60 – 6.55 (m, 1H), 3.97 – 3.67 (m, 5H), 2.69 (dd, J = 7.3, 1.2 Hz, 2H), 2.48 – 2.29 (m, 2H), 2.22 – 1.61 (m, 10H), 1.43 (dd, J = 6.9, 1.8 Hz, 6H), 1.32 – 1.14 (m, 3H), 1.12 – 0.99 (m, 2H)。 143 1 NMR2: 6.88 (s, 1H), 6.51 (s, 1H), 3.79 – 3.57 (m, 5H), 2.68 (d, J = 7.2 Hz, 2H), 2.01 – 1.86 (m, 3H), 1.81 – 1.61 (m, 15H), 1.39 (d, J = 6.9 Hz, 3H), 1.31 – 1.13 (m, 3H), 1.11 – 0.99 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H)。 144 1 NMR2: 6.88 (s, 1H), 6.53 (s, 1H), 3.79 – 3.57 (m, 5H), 2.72 (d, J = 7.5 Hz, 2H), 2.13 – 2.00 (m, 1H), 2.01 – 1.86 (m, 3H), 1.81 – 1.61 (m, 14H), 1.54 – 1.36 (m, 7H), 1.34 – 1.22 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H)。 145 1 NMR2: 6.85 (s, 1H), 6.60 (s, 1H), 3.76 – 3.65 (m, 4H), 3.15 (q, J = 7.4 Hz, 2H), 2.81 (d, J = 7.5 Hz, 2H), 2.38 – 2.26 (m, 1H), 1.92 – 1.86 (m, 2H), 1.83 – 1.49 (m, 14H), 1.43 (t, J = 7.5 Hz, 3H), 1.33 – 1.20 (m, 2H). 146 1 NMR2: 6.86 (s, 1H), 6.57 (s, 1H), 3.76 – 3.65 (m, 4H), 3.15 (q, J = 7.5 Hz, 2H), 2.68 (d, J = 7.2 Hz, 2H), 1.95 – 1.60 (m, 16H), 1.43 (t, J = 7.5 Hz, 3H), 1.30 – 1.13 (m, 3H), 1.11 – 0.98 (m, 2H). [Table 2-22] EX STR Prop Data 147 1 NMR2: 6.86 (s, 1H), 6.58 (s, 1H), 3.76 – 3.65 (m, 4H), 3.15 (q, J = 7.5 Hz, 2H), 2.72 (d, J = 7.4 Hz, 2H), 2.13 – 2.00 (m, 1H), 1.94 – 1.84 (m, 2H), 1.78 – 1.37 (m, 21H), 1.35 – 1.22 (m, 2H). 148 1 NMR2: 6.86 (s, 1H), 6.58 (s, 1H), 3.74 (td, J = 6.0, 1.2 Hz, 4H), 3.16 (qd, J = 7.4, 0.9 Hz, 2H), 2.72 (d, J = 7.4 Hz, 2H), 2.13 – 1.99 (m, 1H), 1.92 – 1.83 (m, 2H), 1.83 – 1.36 (m, 18H), 1.35 – 1.22 (m, 3H)。 149 1 NMR2: 6.88 (s, 1H), 6.53 (s, 1H), 3.80 – 3.71 (m, 4H), 3.71 – 3.58 (m, 1H), 2.72 (d, J = 7.4 Hz, 2H), 2.12 – 2.01 (m, 1H), 2.00 – 1.36 (m, 23H), 1.35 – 1.22 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H)。 150 1 NMR2: 6.93 (s, 1H), 6.59 (s, 1H), 3.87 – 3.80 (m, 2H), 3.74 – 3.67 (m, 2H), 2.81 (d, J = 7.5 Hz, 2H), 2.37 – 2.25 (m, 1H), 1.92 – 1.87 (m, 2H), 1.82 – 1.74 (m, 4H), 1.72 – 1.50 (m, 18H), 1.31 – 1.20 (m, 3H)。 151 1 NMR2: 6.80 (s, 1H), 6.66 (s, 1H), 3.83 – 3.70 (m, 5H), 2.00 – 1.92 (m, 1H), 1.92 – 1.74 (m, 4H), 1.69 – 1.59 (m, 5H), 1.56 – 1.21 (m, 14H), 1.16 – 1.09 (m, 1H), 0.95 – 0.84 (m, 2H)。 152 1 NMR2: 6.87 (singlet, 1H), 6.55 (singlet, 1H), 3.85 – 3.70 (multiplet, 5H), 2.71 (doublet, J = 7.3 Hz, 2H), 1.92 – 1.60 (multiplet, 9H), 1.56 – 1.48 (multiplet, 2H), 1.42 (doublet, J = 6.9 Hz, 6H), 1.40 – 1.11 (multiplet, 6H), 0.89 (singlet, 6H). 153 1 NMR2: 6.88 (singlet, 1H), 6.57 – 6.51 (multiplet, 1H), 3.84 – 3.71 (multiplet, 5H), 2.76 – 2.67 (multiplet, 2H), 2.14 – 1.75 (multiplet, 8H), 1.71 – 1.40 (multiplet, 15H), 1.21 – 1.07 (multiplet, 1H). 154 1 NMR2: 6.87 (singlet, 1H), 6.57 (singlet, 1H), 3.85 – 3.70 (multiplet, 5H), 2.83 – 2.73 (multiplet, 1H), 2.66 – 2.56 (multiplet, 1H), 2.27 – 2.23 (multiplet, 1H), 2.02 – 1.88 (multiplet, 1H), 1.91 – 1.82 (multiplet, 2H), 1.85 – 1.75 (multiplet, 2H), 1.72 – 1.56 (multiplet, 5H), 1.55 – 1.40 (multiplet, 10H), 1.23 – 1.09 (multiplet, 4H). [Table 2 - 23] EX STR Prop Data 155 1 NMR2: 6.90 – 6.85 (multiplet, 1H), 6.58 – 6.51 (multiplet, 1H), 3.85 – 3.70 (multiplet, 5H), 2.74 – 2.62 (multiplet, 2H), 1.92 – 1.59 (multiplet, 13H), 1.55 – 1.11 (multiplet, 18H). 156 1 NMR2: 6.91 – 6.86 (m, 1H), 6.57 – 6.51 (m, 1H), 3.87 – 3.71 (m, 5H), 2.87 – 2.65 (m, 2H), 2.33 – 1.55 (m, 13H), 1.46 – 1.24 (m, 10H), 1.17 – 1.02 (m, 1H)。 157 1 NMR2: 6.90 – 6.84 (m, 1H), 6.61 – 6.56 (m, 1H), 3.83 – 3.70 (m, 5H), 2.91 – 2.82 (m, 1H), 2.66 – 2.33 (m, 2H), 2.23 – 2.13 (m, 1H), 1.91 – 1.74 (m, 5H), 1.71 – 1.56 (m, 7H), 1.47 – 1.38 (m, 7H), 1.36 – 1.12 (m, 2H)。 158 1 NMR2: 6.89 – 6.85 (m, 1H), 6.58 – 6.51 (m, 1H), 3.86 – 3.66 (m, 5H), 3.23 – 2.33 (m, 2H), 2.16 – 2.06 (m, 1H), 1.97 – 1.75 (m, 5H), 1.75 – 1.59 (m, 6H), 1.59 – 1.45 (m, 2H), 1.43 – 1.07 (m, 9H), 1.04 – 0.93 (m, 4H)。 159 1 NMR2: 6.73 (s, 1H), 6.46 (s, 1H), 3.82 – 3.69 (m, 5H), 2.07 – 1.96 (m, 2H), 1.91 – 1.71 (m, 9H), 1.71 – 1.58 (m, 4H), 1.44 – 1.26 (m, 10H)。 160 1 NMR2: 6.86 (s, 1H), 6.51 (s, 1H), 3.84 – 3.70 (m, 5H), 2.86 (d, J = 7.7 Hz, 2H), 2.65 – 2.49 (m, 1H), 2.18 – 2.09 (m, 2H), 2.03 – 1.95 (m, 2H), 1.95 – 1.71 (m, 10H), 1.70 – 1.60 (m, 4H), 1.41 (d, J = 6.9 Hz, 6H)。 161 1 NMR2: 6.82 (s, 1H), 6.54 (s, 1H), 3.63 (t, J = 5.6 Hz, 2H), 2.66 (d, J = 7.2 Hz, 2H), 1.88 – 1.64 (m, 12H), 1.63 – 1.58 (m, 15H), 1.29 – 1.18 (m, 3H), 1.11 – 0.97 (m, 2H)。 162 1 NMR2: 7.07 (s, 1H), 6.93 (s, 1H), 3.58 – 3.50 (m, 2H), 3.35 – 3.22 (m, 1H), 2.17 – 2.08 (m, 2H), 1.94 – 1.80 (m, 4H), 1.79 – 1.64 (m, 8H), 1.60 (s, 6H)。

[0207] [Test Example] Test Example 1: Intracellular Calcium Concentration Measurement HEK293 cells derived from human embryonic kidneys, cultured in MEM medium supplemented with 10% fetal bovine serum (10% FBS) (Invitrogen), were adjusted to 4 × 10⁵ cells / mL using MEM medium supplemented with 1% FBS. Cells were then seeded at 25 μL / well onto 384-well black culture dishes (clear bottom) (Greiner) coated with poly-D-lysine. The seeded cells were cultured in a CO₂ incubator for 2 days. Cells were treated with 20 μL of wash-free Fluo-8 calcium assay kit (AAT Bioquest) adjusted with Hanks-10 mM Hepes buffer (0.1% BSA-HHBS) containing 0.1% bovine serum albumin and 5 μL of test compound solution adjusted with 0.1% BSA-HHBS. The cells were then cultured in a CO₂ incubator for 30 minutes. SLIGKV-NH2 (Sigma-Aldrich) diluted with 0.1% BSA-HHBS buffer was added to 384-well polypropylene culture dishes (Greiner) to obtain stimulator culture dishes. Cell culture dishes treated with the test compound and stimulator culture dishes were placed in an FDSS / µCELL (Hamamatsu Photonics KK). Ten (10) μL of SLIGKV-NH2 solution from the stimulator culture dish was added to the cell culture dish using the built-in automated pipetting system (final concentration: 10 μM). Immediately after adding the SLIGKV-NH2 solution, fluorescence changes were detected for 180 seconds at 37°C using a CCD camera in the FDSS / µCELL to determine changes in intracellular calcium. IC50 values ​​(nM) are shown in Tables 3-1 and 3-2.

[0208] [Table 3-1] Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 1 173 twenty three 30 45 632 67 174 2 31 24 9 46 99 68 15 3 23 25 49 47 146 69 286 4 109 26 80 48 105 70 51 5 130 27 138 49 119 71 115 6 149 28 60 50 43 72 41 7 113 29 467 51 209 73 33 8 95 30 102 52 107 74 386 9 74 31 81 53 404 75 89 10 178 32 118 54 355 76 121 11 252 33 51 55 569 77 273 12 76 34 265 56 283 78 247 13 69 35 130 57 308 79 145 14 186 36 369 58 464 80 250 15 150 37 88 59 357 81 246 16 259 38 102 60 234 82 76 17 232 39 64 61 96 84 274 18 36 40 184 62 52 85 310 19 131 41 246 63 12 86 338 20 twenty four 42 40 64 17 89 243 twenty one 298 43 185 65 107 91 522 twenty two 137 44 208 66 241 93 236 [Table 3-2] Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) Example IC 50 (nM) 94 141 112 113 130 297 148 144 95 742 113 263 131 225 149 208 96 10 114 234 132 197 150 180 97 20 115 236 133 360 151 149 98 270 116 233 134 382 152 132 99 336 117 169 135 386 153 282 100 23 118 253 136 452 154 47 101 70 119 185 137 482 155 218 102 37 120 298 138 72 156 103 103 63 121 245 139 95 157 319 104 46 122 178 140 266 158 117 105 83 123 135 141 304 159 394 106 96 124 144 142 171 160 147 107 67 125 256 143 91 161 296 108 78 126 207 144 257 162 304 109 85 127 229 145 252 110 228 128 151 146 136 111 250 129 208 147 163

[0209] Test Example 2: Scratching Behavior Test under PAR2 Agonist Peptide Administration Under 3.5% isoflurane inhalation anesthesia, a magnet (Neuroscience, Inc.) for measuring scratching behavior was implanted into the legs of 6- to 7-week-old female ICR mice. Approximately one week later, the mice were allowed to acclimatize overnight in a cylindrical cage used for the scratching behavior measurement device (Microact: Neuroscience Co., Ltd.). Under isoflurane inhalation anesthesia, the upper back was shaved approximately 2 × 3 cm with a scalpel, and 40 μL of a 6% test compound solution was administered using a microdropper. The animals were then held in a dedicated cage for 1 hour. The solvents used were a 1:1 mixture of acetone and methanol (acetone / methanol in Table 4 below), 100% ethanol, or 70% ethanol. Next, under isoflurane inhalation anesthesia, 10 μL of a 25 mg / mL solution of PAR2 agonist peptide (SLIGRL-NH2) in distilled water was administered percutaneously using a needle attached to a Hamilton syringe. The animals were returned to their cages, and scratching frequency was measured for 30 minutes, starting 10 to 40 minutes after administration. The inhibitory effect of the test compound on scratching behavior was calculated as a percentage of scratching frequency in the solvent-administered group and the PAR2 agonist peptide-treated group, and is presented as a percentage in Table 4.

[0210] [Table 4] Example solvent Scratching behavior inhibition rate 1 100% ethanol 35% 2 100% ethanol 46% 3 70% ethanol 33% 5 100% ethanol 36% 7 100% ethanol 32% 8 100% ethanol 30% 10 100% ethanol 41% 12 100% ethanol 51% 13 100% ethanol 37% 15 100% ethanol 44% 16 100% ethanol 47% 18 100% ethanol 39% 19 100% ethanol 42% 32 100% ethanol 41% 37 100% ethanol 30% 53 Acetone / Methanol 44% 54 Acetone / Methanol 25% 55 Acetone / Methanol 47% 59 Acetone / Methanol 28% 65 100% ethanol 27% 70 100% ethanol 33% 71 100% ethanol 27% 94 Acetone / Methanol 44% 105 100% ethanol 27% 110 Acetone / Methanol 25% 117 100% ethanol 34%

[0211] Test Example 3: Scratching Behavior Test Using an Atopic Dermatitis Model Under anesthesia, magnets for measuring scratching behavior were implanted into the legs of 7-week-old female NC / Nga mice. Approximately one week later, under isoflurane anesthesia, a 2 × 3 cm area on the upper back was shaved with a razor and then depilated with hair removal cream. Next, under anesthesia, 100 μL of 4% SDS was applied to the shaved area. Two hours later, an appropriate amount (approximately 100 μg) of mite antigen ointment (Biota AD: Biota Co., Ltd.) was applied. This sensitization by application of SDS and mite antigen ointment was performed 6 times over 14 days. Before the last sensitization, the animals' skin symptoms were scored on redness (7-point scale) and edema (7-point scale) using the scoring criteria shown below. Animals with a total score (dermatitis score) of 2 or higher were selected as test candidates. Transdermal water loss (TEWL) in these animals was measured using a Tewameter TM300 (Courage+Khazaka). Animals were then grouped using dermatitis scores and TEWL values ​​as indicators, and final sensitization was performed. After grouping, mice were acclimatized overnight in cylindrical cages used in a scratching behavior measurement device (Microact: Neuroscience Inc.). The following morning, under anesthesia, 60 µL of each solution of the test compound in solvents (1%, 3%, or 6%) was administered, and the number of scratches was measured using the device 7 hours after administration. The solvents used were a 1:1 mixture of acetone and methanol (acetone / methanol in Table 5 below), 100% ethanol, and 70% ethanol. The number of scratches in unsensitized animals treated with solvents was converted to a 100% inhibition rate, and the number of scratches in sensitized animals treated with solvents was converted to a 0% inhibition rate. The inhibitory effects of the example compounds on scratching are then presented as percentages in Table 5. Red rating Edema score 0 No redness No edema 0.5 Redness less than a score of 1 Edema area less than 15% 1 Slight redness The edema area is not less than 15% but less than 30%. 1.5 Redness between rating 1 and rating 2 The edema area is not less than 30% but less than 45%. 2 Noticeably red The edema area is not less than 45% but less than 60%. 2.5 Redness between rating 2 and rating 3 The edema area is not less than 60% but less than 75%. 3 Significant redness The edema area is not less than 75%.

[0212] [Table 5] Example Assess concentration solvent Scratching behavior inhibition rate 1 6% 100% ethanol 76% 3 6% 70% ethanol 71% 4 6% 70% ethanol 56% 6 6% 100% ethanol 60% 7 6% 100% ethanol 70% 8 6% 100% ethanol 50% 10 1% 100% ethanol 48% 11 6% 100% ethanol 80% 12 6% 100% ethanol 102% 14 6% 100% ethanol 95% 15 3% 100% ethanol 52% 17 6% 100% ethanol 60% 19 1% 100% ethanol 70% 55 6% Acetone / Methanol 54%

[0213] Test Example 4: Cumulative Skin Stimulation Test in Rabbits Female NZW rabbits aged 18 to 20 weeks (Natsume Seisakusho Co., Ltd.) with shaved backs were fitted with collars. A 2.5 cm × 2.5 cm frame was placed on the rabbit's back, and 50 μL of each compound in a 3% solution of 70% ethanol was applied to this location in 2 or 3 rabbits. The next day (approximately 24 hours later), the compound applied the previous day was wiped with a cotton pad soaked in warm water, and approximately 30 minutes later, erythema (5-point scale) and edema (5-point scale) were assessed according to the scoring criteria shown below. After the scoring assessment, the compound was applied again. This process was repeated for 7 days, and the stimulation was assessed by the average of the total score for erythema and edema on the last day of assessment (Day 7) and the maximum (total) score during the test period. The scoring assessment criteria are as follows. Erythema score Edema score 0 No erythema No edema 1 Very mild erythema (almost indistinguishable) Very mild edema (almost imperceptible) 2 Clear erythema Mild edema (defined by a noticeable elevation at the periphery of the affected area) 3 Moderate to severe erythema Moderate edema (approximately 1 mm elevation) 4 Severe erythema (flesh-red) to crust formation that hinders erythema classification Severe edema (elevation exceeding 1 mm and extending beyond the exposed area)

[0214] [Table 6] Example Stimulus rating Day 7 maximum 3 1.5 1.5 7 0.3 1.3 12 0.0 0.0 14 2.0 2.0 15 0.0 0.7 17 0.7 1.3

Claims

1. A compound represented by general formula [I]: wherein R1 is a C1-6 alkyl, C3-8 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C3-8 cycloalkoxy, C1-6 alkylthio or mono- or di-C1-6 alkylamino; R2 is, as appropriate, a C4-8 cycloalkyl substituted with halogen or C1-6 alkyl; a C4-10 bicycloalkyl substituted with halogen or C1-6 alkyl; a C5-13 spiroalkyl; a C6-12 tricycloalkyl; a C3-8 cycloalkyl-C1-6 alkyl substituted with halogen, C1-6 alkyl or C1-6 haloalkyl; a C3-8 cycloalkoxy-C1-6 alkyl; a C4-10 bicycloalkyl-C1-6 alkyl substituted with halogen or C1-6 alkyl; a C6-12 tricycloalkyl-C1-6 alkyl; a C6-12 tricycloalkyl-amino; or piperidinyl; R3 is hydrogen; A 5 to 9 saturated or partially unsaturated heterocycle or its side oxygen containing a nitrogen atom as a cyclizing atom, which may have halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-C1-6 alkyl, hydroxyl or methylene as substituents, wherein the heterocycle may further have a nitrogen atom, an oxygen atom and / or a sulfur atom as cyclizing atoms; or a salt thereof, except where R2 is piperidinyl and is piperidinyl.

2. The compound of claim 1, wherein in the general formula [I], is piperidinyl, aziridine, aziridine octyl, aziridine nonyl, aziridine, 2,3,4,7-tetrahydroaziridine, 2,3,6,7-tetrahydroaziridine, diaziridine, piperidyl, aziridine, thioaziridine, oxaziridine, or its side oxide, wherein the heterocycle may have a halogen, a C1-6 alkyl, a C1-6 alkoxy, or a hydroxyl group as a substituent, or a salt thereof.

3. The compound of claim 1, wherein in the general formula [I], R1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tributyl, 2-methyl-1-propyl, 2-methyl-1-butyl, 1-pentyl, 3-pentyl, 1-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-methylcyclohexyl, trifluoromethyl, 1,1-difluoroethyl, propoxy, cyclohexyloxy, ethylthio, methylpropylamino, or dipropylamino; R2 is cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4-butylcyclohexyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptylmethyl, bicyclo[4.1.0]heptyl, bicyclo[2.2.2]octyl, decahydronaphthyl, adamantyl (tricyclo[3.3.1]).[1]decyl), spiro[2,5]octyl, spiro[3,3]heptylmethyl, 1-cyclohexylcyclopropyl, 1-methylcyclohexylmethyl, 2-methylcyclohexylmethyl, 3-methylcyclohexylmethyl, 4-methylcyclohexylmethyl, 3,5-dimethylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-butylcyclohexylmethyl, 4-fluorocyclohexylmethyl, 4-methoxycyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, 1-cyclohexylethyl, adamantylmethyl, 4-methylcyclohexylmethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, adamantylamino or piperidinyl; R3 is hydrogen; The compounds are aziridine, aziridine, aziridine, nonidine, 2,3,4,7-tetrahydroaziridine, 2,3,6,7-tetrahydroaziridine, 1,4-diazacycloheptidine, oxaziridine, 2,2-dimethylaziridine, 3-hydroxyaziridine, 4-hydroxyaziridine, 4-methylaziridine, 4,4-difluoroaziridine, 4-methylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-methylene-piperidinyl, 2,2-dimethyl-4-hydroxypiperidinyl, 2,2-dimethyl-3-methoxypiperidinyl, 2,2-dimethyl-4-methoxypiperidinyl. Pyridyl, 2,2,4,4-tetramethylpiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-4-methoxypiperidinyl, 2,2-dimethyl-4-methoxyethylpiperidinyl, 2,2-dimethyl-3-methylenepiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-3-piperidinyl, 2,2-dimethyl-4-thiopiperidinyl, 3,3-dimethyl-4-thiopiperidinyl or oxazineheptyl; or salts thereof.

4. The compound of claim 1, wherein in the general formula [I], R1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 3-pentyl, cyclohexyl, or trifluoromethyl; R2 is cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexyloxymethyl, 1-cyclohexylethyl, 4-methylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, bicyclo[2.2.1]heptylmethyl, spiro[3.3]heptylmethyl, or adamantylamino; R3 is hydrogen; It is piperidinyl, azircycloheptyl, azircyclooctyl, 2,3,4,7-tetrahydroaziryl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-sideoxypiperidinyl, 2,2,4,4-tetramethyl-3-sideoxypiperidinyl or 3,3-dimethyl-4-thiopyrolinyl; or a salt thereof.

5. The compound of claim 1 is selected from the group consisting of: or salts thereof.

6. A pharmaceutical composition comprising a compound or salt thereof, as an active ingredient, such as any one of claims 1 to 5, and a pharmaceutically acceptable carrier or excipient.

7. A therapeutic, preventive and / or diagnostic agent for symptoms and / or diseases caused by PAR2 activation, comprising a compound or a salt thereof as claimed in any one of claims 1 to 5.

8. The therapeutic, preventive and / or diagnostic agents as requested in item 7, wherein the symptom caused by PAR2 activation is pruritus.

9. The therapeutic, preventive and / or diagnostic agents as requested in item 8, wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous abscess, senile pruritus, xerosis, xerosis senile prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis and / or pruritus associated with chronic liver disease.

10. The therapeutic, preventive and / or diagnostic agent as claimed in item 8, wherein the pruritus is caused by sebaceous abscess eczema.

11. The therapeutic, preventive and / or diagnostic agents as claimed in claim 7, wherein the disease caused by PAR2 activation is a skin disease.

12. The therapeutic, preventive and / or diagnostic agents as requested in item 11, wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

13. A therapeutic, preventive and / or diagnostic pharmaceutical composition for symptoms and / or diseases caused by PAR2 activation, comprising a compound or a salt thereof as an active ingredient, such as any one of claims 1 to 5.

14. The therapeutic, preventive and / or diagnostic pharmaceutical composition of claim 13, wherein the symptom caused by PAR2 activation is pruritus.

15. The therapeutic, preventive and / or diagnostic pharmaceutical composition of claim 14, wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous abscess, senile pruritus, xerosis, xerosis senile prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis and / or pruritus associated with chronic liver disease.

16. The therapeutic, preventive and / or diagnostic pharmaceutical composition of claim 14, wherein the pruritus is caused by sebaceous abscess eczema.

17. The therapeutic, preventive and / or diagnostic pharmaceutical composition of claim 13, wherein the disease caused by PAR2 activation is a skin disease.

18. The therapeutic, preventive and / or diagnostic pharmaceutical composition of claim 17, wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

19. A compound or a salt thereof as claimed in any one of claims 1 to 5, for the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

20. The compound of claim 19 or a salt thereof, wherein the symptom caused by PAR2 activation is pruritus.

21. The compound or salt thereof as claimed in claim 20, wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous abscess, senile pruritus, xerosis, xerosis senile prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis, and / or pruritus associated with chronic liver disease.

22. The compound of claim 20 or a salt thereof, wherein the pruritus is caused by sebaceous abscess eczema.

23. The compound or salt thereof as claimed in claim 19, wherein the disease caused by PAR2 activation is a skin disease.

24. The compound or salt thereof as claimed in claim 23, wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

25. Use of a compound or a salt thereof as claimed in any one of claims 1 to 5, for the manufacture of a medicament for the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

26. As used in claim 25, wherein the symptom caused by PAR2 activation is skin itching.

27. As claimed in claim 26, wherein the pruritus is caused by atopic dermatitis, urticaria, eczema, sebaceous abscess, senile pruritus, xerosis, xerosis senile prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, fruit allergy, neurodermatitis, autosensitization dermatitis, pruritus caused by kidney dialysis, and / or pruritus associated with chronic liver disease.

28. As claimed in claim 26, wherein the pruritus is caused by sebaceous abscess eczema.

29. As claimed in claim 25, wherein the disease caused by PAR2 activation is a skin disease.

30. As claimed in claim 29, wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

31. A topical transdermal formulation comprising a compound or salt thereof, as an active ingredient, such as any one of claims 1 to 5, and a pharmaceutically acceptable carrier or excipient.

32. The topical transdermal formulation of claim 31 is in the form of ointment, cream, lotion and foam.