Pyrazolo[1,5-a]pyrimidine compounds for treating skin diseases

Abstract

Provided are pyrazolo[1,5-a]pyrimidine compounds or salts thereof having PAR2 inhibitory activity, and pharmaceutical compositions containing them. TIFF2024520689000092.tif39150 [wherein each symbol is as defined in the specification.]

Description

[Technical Field]

[0001] The present invention relates to a pyrazolo[1,5-a]pyrimidine compound or a pharmaceutically acceptable salt thereof, which has a PAR2 inhibitory activity. [Background technology]

[0002] Protease-activated receptor 2 (PAR2) is a G protein-coupled seven-transmembrane receptor encoded by the F2RL1 gene, and transmits signals into cells via proteases. PAR2 is called a tethered receptor, and when the N-terminus of PAR2 is digested by proteases, primarily serine proteases, the newly exposed N-terminal sequence acts as a ligand to activate the receptor. Artificially synthesized peptides derived from the N-terminal sequence produced by digestion can also activate the receptor (Non-patent Documents 1 and 2).

[0003] PAR2 is expressed in a wide range of sites in the body and is known to be involved in pruritus, allergies, inflammation, pain, and cancer, so PAR2 inhibitors are useful as therapeutic agents for these diseases (Non-Patent Document 3).

[0004] PAR2 is known to be involved in pruritus, particularly in the skin. Exogenous proteases from plants and mites, proteases secreted by keratinocytes in response to skin irritation, and proteases secreted by immune cells such as mast cells activate PAR2 expressed in peripheral nerve terminals, inducing itch through signal transmission to the brain (Non-Patent Document 4). There are several diseases associated with pruritus, some of which are accompanied by skin lesions and some of which are not. In the former type of pruritus accompanied by inflammation and swelling, proteases produced by immune cells and keratinocytes activate PAR2 as prurigenic substances. On the other hand, in the latter type of pruritus that is not accompanied by skin lesions but results in the formation of persistent dry skin, the itch threshold is lowered by peripheral nerve penetration and sprouting, and scratching weakens the skin barrier, creating an environment that is more conducive to PAR2 activation (Non-Patent Document 5). This makes PAR2 inhibitors useful not only for atopic dermatitis and urticaria, but also for pruritus caused by dry skin without skin lesions, such as senile xerosis and underlying diseases (e.g., renal failure and liver disease).

[0005] It has also been reported that activation of PAR2 in keratinocytes increases the expression of matrix metalloproteinases, and that mice that overexpress PAR2 in their skin are prone to itching and skin inflammation, and that these symptoms are exacerbated by mite antigen sensitization (Non-Patent Documents 6 and 7). These findings suggest that PAR2 is involved not only in itching but also in skin barrier function and inflammation, and PAR2 inhibitors are useful for repairing the skin barrier and suppressing inflammation.

[0006] PAR2 is involved not only in the transmission of itch signals but also in pain signals, and has attracted attention as a target for hyperalgesia and allodynia (Non-Patent Document 8). For this reason, PAR2 inhibitors are also useful as therapeutic agents for these diseases.

[0007] The PAR2 inhibitory activity of compounds having a pyrazolo[1,5-a]pyrimidine skeleton is disclosed in Patent Documents 1 to 5. [Prior art documents]

Charter Documents

[0008] [Patent Document 1] Special Opening No. 2003-286171 [Patent Document 2] Special Opening No. 2004-170323 [Patent Document 3] WO2018 / 043461 [Patent Document 4] WO2019 / 163956 [Patent Document 5] Special opening 2020-007262

Non-licensed literature

[0009]

Non-patent document 1

Non-patent document 2

Non-patent document 3

Non-patent document 4

Non-patented document 5

Non-patent document 6

Non-patent document 7

Non-patent document 8

[0010] The present invention provides a pyrazolo[1,5-a]pyrimidine compound or a salt thereof having PAR2 inhibitory activity, a pharmaceutical composition containing the compound, and a pyrazolo[1,5-a]pyrimidine compound or a salt thereof suitable for topical transdermal preparations such as ointments, creams, and lotions. [Means for solving the problem]

[0011] As a result of extensive investigations to solve the above problems, the inventors discovered that pyrazolo[1,5-a]pyrimidine compounds represented by the following formula [I] have PAR2 inhibitory activity, and thus completed the present invention.

[0012] That is, the present invention includes the following aspects. [1-1] General formula [I]: [ka] During the ceremony R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylthio or mono or di C 1-6 alkylamino; R 2 is a halogen or C 1-6 C optionally substituted with alkyl 3-8 Cycloalkyl, halogen or C 1-6 C optionally substituted with alkyl 4-10 Bicycloalkyl, C 5-13Spiroalkyl, C 6-12 Tricycloalkyl, halogen, C 1-6 Alkyl or C 1-6 C optionally substituted with haloalkyl 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkoxy-C 1-6 Alkyl, halogen or C 1-6 C optionally substituted with alkyl 4-10 Bicycloalkyl-C 1-6 Alkyl, C 6-12 Tricycloalkyl-C 1-6 Alkyl, C 6-12 tricycloalkyl-amino or piperidinyl; R 3 is hydrogen, halogen or C 1-6 is alkyl; [ka] is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 a 5- to 9-membered saturated or partially unsaturated heterocycle or its oxo derivative containing one nitrogen atom as a ring-constituting element, which may have alkyl, hydroxy, or methylidene as a substituent, and which may further have one nitrogen atom, one oxygen atom, and / or one sulfur atom as ring-constituting elements; or a salt thereof.

[0013] [1-2] In general formula [I], [ka] is piperidinyl, azepanyl, azocanyl, azonanyl, azepinyl, 2,3,4,7-tetrahydroazepinyl, 2,3,6,7-tetrahydroazepinyl, diazepanyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazepanyl or oxo-forms thereof, and the heterocycle is 1-6 Alkyl, C1-6 optionally having alkoxy or hydroxy as a substituent; The compound or salt thereof according to [1-1],

[0014] [1-3] In general formula [I], R 1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 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; R 2 are cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4-butylcyclohexyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptanylmethyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.2]octanyl, decahydronaphthyl, adamantyl (tricyclo[3.3.1.1]decanyl), spiro[2,5]octanyl, spiro[3,3]heptanylmethyl, 1-cyclohexylcyclopropyl, 1-methylcyclohexylmethyl, 2-methylcyclohexylmethyl, 3-methylcyclohexylmethyl, 3,5-dimethylcyclohexylmethyl, 4-ethylcyclohexylmethyl, 4-butylcyclohexyl cyclohexylmethyl, 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; R 3 is hydrogen; [ka] are azepanil, azocanyl, azonanyl, 2,3,4,7-tetrahydroazepinyl, 2,3,6,7-tetrahydroazepinyl, 1,4-diazepanyl, oxazepanyl, 2,2-dimethylazepanyl, 3-hydroxyazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4,4-difluoroazepanyl, 4-methylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-methylidenepiperidinyl, 2,2-dimethyl-4-hydroxypiperidinyl, 2,2-dimethyl-3-methoxypiperidinyl, 2,2-dimethyl-4-methoxypiperidinyl, 2,2,4,4-tetrahydroazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxy ...3-methylidenepiperidinyl, 2,2-dimethyl-4-hydroxypiperidinyl, 2,2-dimethyl-3-methoxypiperidinyl, 2,2-dimethyl-4-methoxypiperidinyl, 2,2,4,4-tetrahydroazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyaze methylpiperidinyl, 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-dimethylpiperazinyl, 2,2-dimethyl-4-hydroxypiperazinyl, 2,2-dimethylmorpholinyl, 2,2-dimethyl-3-oxopiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-3-oxopiperidinyl, 2,2-dimethyl-4-thiomorpholinyl, 3,3-dimethyl-4-thiomorpholinyl, or oxazepanyl; The compound or salt thereof according to [1-1],

[0015] [1-4] In general formula [I], R 1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 3-pentyl, cyclohexyl or trifluoromethyl; R 2is 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]heptanylmethyl, spiro[3.3]heptanylmethyl or adamantylamino; R 3 is hydrogen; [ka] is piperidinyl, azepanyl, azocanyl, 2,3,4,7-tetrahydroazepinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-oxopiperidinyl, 2,2,4,4-tetramethyl-3-oxopiperidinyl or 3,3-dimethyl-4-thiomorpholinyl; The compound or salt thereof according to [1-1],

[0016] [1-5] A compound according to [1-1] below, or a salt thereof: [ka] [ka]

[0017] [2] A pharmaceutical composition comprising a compound according to any one of [1-1] to [1-5] or a salt thereof as an active ingredient, and a pharmaceutically acceptable carrier or excipient.

[0018] [3-1] A therapeutic, preventive and / or diagnostic agent for symptoms and / or diseases caused by PAR2 activation, comprising the compound according to any one of [1-1] to [1-5] or a salt thereof.

[0019] [3-2] The therapeutic, preventive and / or diagnostic agent according to [3-1], wherein the symptom caused by PAR2 activation is cutaneous pruritus.

[0020] [3-3] The therapeutic, preventive and / or diagnostic agent according to [3-2], wherein the pruritus is pruritus caused by atopic dermatitis, urticaria, eczema, asteatosis, asteatotic eczema, senile pruritus, xerosis, senile xerosis, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, pulp hypersensitivity, neurodermatitis, autosensitization dermatitis, pruritus during renal dialysis and / or pruritus associated with chronic liver disease.

[0021] [3-4] The therapeutic, preventive and / or diagnostic agent according to [3-1], wherein the disease caused by PAR2 activation is a skin disease.

[0022] [3-5] The therapeutic, preventive and / or diagnostic agent according to [3-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0023] [4-1] A pharmaceutical composition for treating, preventing and / or diagnosing symptoms and / or diseases caused by PAR2 activation, comprising as an active ingredient a compound according to any one of [1-1] to [1-5] or a salt thereof.

[0024] [4-2] A pharmaceutical composition for treatment, prevention and / or diagnosis according to [4-1], wherein the symptom caused by PAR2 activation is cutaneous pruritus.

[0025] [4-3] The pharmaceutical composition for treatment, prevention and / or diagnosis according to [4-2], wherein the pruritus is pruritus caused by atopic dermatitis, urticaria, eczema, asteatosis, asteatotic eczema, senile pruritus, xerosis, senile xerosis, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, pulp hypersensitivity, neurodermatitis, autosensitization dermatitis, pruritus during renal dialysis and / or pruritus associated with chronic liver disease.

[0026] [4-4] A pharmaceutical composition for treatment, prevention and / or diagnosis according to [4-1], wherein the disease caused by PAR2 activation is a skin disease.

[0027] [4-5] The pharmaceutical composition for treatment, prevention and / or diagnosis according to [4-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0028] [5-1] A method for treating, preventing and / or diagnosing symptoms and / or diseases caused by PAR2 activation, comprising administering to a human an effective amount of a compound according to any one of [1-1] to [1-5] or a salt thereof.

[0029] [5-2] The therapeutic, preventive and / or diagnostic method according to [5-1], wherein the symptom caused by PAR2 is cutaneous pruritus.

[0030] [5-3] The method for treatment, prevention and / or diagnosis according to [5-2], wherein the pruritus is pruritus caused by atopic dermatitis, urticaria, eczema, asteatosis, asteatotic eczema, senile pruritus, xerosis, senile xerosis, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, pulp hypersensitivity, neurodermatitis, autosensitization dermatitis, pruritus during renal dialysis and / or pruritus associated with chronic liver disease.

[0031] [5-4] The method for treatment, prevention and / or diagnosis according to [5-1], wherein the disease caused by PAR2 activation is a skin disease.

[0032] [5-5] The method for treatment, prevention and / or diagnosis according to [5-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma and dermatitis.

[0033] [6-1] The compound or salt thereof according to any one of [1-1] to [1-5] for use in the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

[0034] [6-2] The compound or salt thereof according to [6-1], wherein the symptom caused by PAR2 activation is cutaneous pruritus.

[0035] [6-3] The compound or salt thereof according to [6-2], wherein the pruritus is pruritus caused by atopic dermatitis, urticaria, eczema, asteatosis, asteatotic eczema, senile pruritus, xerosis, senile xerosis, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, pulp hypersensitivity, neurodermatitis, autosensitization dermatitis, pruritus during renal dialysis, and / or pruritus associated with chronic liver disease.

[0036] [6-4] The compound or salt thereof according to [6-1], wherein the disease caused by PAR2 activation is a skin disease.

[0037] [6-5] The compound or salt thereof according to [6-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma, and dermatitis.

[0038] [7-1] Use of a compound or a salt thereof according to any one of [1-1] to [1-5] in the manufacture of a pharmaceutical for use in the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

[0039] [7-2] The use described in [7-1], wherein the symptom caused by PAR2 activation is pruritus.

[0040] [7-3] The use according to [7-2], wherein the skin pruritus is skin pruritus caused by atopic dermatitis, urticaria, eczema, asteatosis, asteatotic eczema, senile pruritus, xerosis, senile xerosis, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, caterpillar dermatitis, insect bites, photosensitivity, pulp hypersensitivity, neurodermatitis, autosensitization dermatitis, pruritus during renal dialysis and / or pruritus associated with chronic liver disease.

[0041] [7-4] The use described in [7-1], wherein the disease caused by PAR2 activation is a skin disease.

[0042] [7-5] The use according to [7-4], wherein the skin disease is selected from atopic dermatitis, psoriasis, eczema, scleroderma, and dermatitis.

[0043] [8-1] A topical transdermal preparation comprising a compound or a salt thereof according to any one of [1-1] to [1-5] as an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0044] [8-2] The topical transdermal preparation according to [8-1], wherein the topical transdermal preparation is selected from ointments, creams, lotions, and foams. [Effects of the Invention]

[0045] The compound or salt thereof according to the present invention has excellent PAR2 inhibitory activity, and is non-irritating or mildly irritating to the skin, and has excellent skin absorbability. DETAILED DESCRIPTION OF THE INVENTION

[0046] The words and terms used in this specification are explained in detail below.

[0047] In the present specification, "halogen" refers to fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine, more preferably fluorine or chlorine.

[0048] In this specification, "C 1-6 "Alkyl" refers to a group having 1 to 6 carbon atoms (C 1-6 ) is a straight-chain or branched-chain alkyl, and specific examples thereof include methyl, ethyl, n-propyl, isopropyl, 1-methylpropyl, 2-methylpropyl, n-butyl, isobutyl, sec-butyl, tert-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 the like. Also, "C1-6 "Alkyl" refers to a C alkyl group in which 1 to 7 hydrogen atoms have been replaced with deuterium atoms. 1-6 Alkyl is also included.

[0049] In this specification, "C 1-6 Haloalkyl is a group having 1 to 6 carbon atoms (C 1-6 ) is a straight-chain or branched-chain alkyl, and specific examples thereof 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 the like.

[0050] In this specification, "C 3-8 Cycloalkyl" refers to a group having 3 to 8 carbon atoms (C 3-8 ) is a cycloalkyl, specific examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.

[0051] In this specification, "C 4-10 Bicycloalkyl" is a group with 4 to 10 carbon atoms (C 4-10 ) is a bicyclic cycloalkyl, specific examples of which include bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and the like.

[0052] In this specification, "C 6-12 Tricycloalkyl" is a group with 6 to 12 carbon atoms (C 6-12 ) is a tricyclic cycloalkyl, and specific examples thereof include adamantyl and the like.

[0053] In this specification, "C 5-13Examples of "spiroalkyl" include spiro[2,2]pentanyl, spiro[2,3]hexanyl, spiro[2,4]heptanyl, spiro[2,5]octanyl, spiro[2,6]nonanyl, spiro[2,7]decanyl, spiro[3,3]heptanyl, spiro[3,4]octanyl, spiro[3,5]nonanyl, and spiro[3,6]decanyl.

[0054] In this specification, "C 1-6 "Alkoxy" refers to a group having 1 to 6 carbon atoms (C 1-6 ) is a straight-chain or branched-chain alkoxy, and specific examples thereof include methoxy, ethoxy, n-propoxy, isopropoxy, 1-methylpropoxy, 2-methylpropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 3-methylbutoxy, n-pentoxy, isopentoxy, neopentoxy, 3-pentoxy, n-hexoxy, isohexoxy, 3-methylpentoxy, 1,1-dimethylethoxy, 1,2-dimethylethoxy, 2,2-dimethylethoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, and the like.

[0055] In this specification, "C 3-8 Cycloalkoxy is a group with 3 to 8 carbon atoms (C 3-8 ) is a cycloalkyloxy, specific examples of which include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, cyclooctyloxy, and the like.

[0056] In this specification, "C 1-6 "Alkylthio" refers to alkyl groups with 1 to 6 carbon atoms (C 1-6) is a straight-chain or branched-chain alkylthio, and specific examples thereof include methylthio, ethylthio, n-propylthio, isopropylthio, 1-methylpropylthio, 2-methylpropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-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 the like.

[0057] As used herein, "mono or di C 1-6 "Alkylamino" is a group containing 1 to 6 carbon atoms (C 1-6 ) is an amino having one or two straight-chain or branched-chain alkyl groups, and specific examples thereof include methylamino, ethylamino, n-propylamino, isopropylamino, 1-methylpropylamino, 2-methylpropylamino, n-butylamino, isobutylamino, sec-butylamino, tert-butylamino, 3-methylbutylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, methylpropylamino, ethylpropylamino, and the like.

[0058] In this specification, "C 3-8 Cycloalkyl-C 1-6 "Alkyl" refers to a group having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl with 3 to 8 carbon atoms (C 3-8 ) is substituted with a cycloalkyl, specific examples of which include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, cyclooctylethyl, cyclohexyl-2-propyl, and the like.

[0059] In this specification, "C 4-10 Bicycloalkyl-C1-6 "Alkyl" refers to a group having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl with 4 to 10 carbon atoms (C 4-10 ) is substituted with a bicyclic cycloalkyl, specific examples of which include bicyclo[2.2.1]heptylmethyl, bicyclo[2.2.2]octylmethyl, bicyclo[2.2.1]heptylethyl, bicyclo[2.2.2]octylethyl, and the like.

[0060] In this specification, "C 6-12 Tricycloalkyl-C 1-6 "Alkyl" refers to a group having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl with 6 to 12 carbon atoms (C 6-12 ) is substituted with a tricyclic cycloalkyl, specific examples of which include adamantylmethyl, adamantylethyl, adamantylpropyl, and the like.

[0061] In this specification, "C 6-12 Tricycloalkyl-amino" has 6 to 12 carbon atoms (C 6-12 ) is an amine substituted with a tricyclic cycloalkyl, and specific examples thereof include adamantylamino.

[0062] In this specification, "C 3-8 Cycloalkoxy-C 1-6 "Alkyl" refers to a group having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl with 3 to 8 carbon atoms (C 3-8 ) is substituted with a cycloalkoxy, specific examples of which include cyclopropyloxymethyl, cyclobutyloxymethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, cyclooctanoxymethyl, cyclopropyloxyethyl, cyclobutyloxyethyl, cyclopentyloxyethyl, cyclohexyloxyethyl, cycloheptyloxyethyl, cyclooctanoxyethyl, and the like.

[0063] In the present specification, examples of "a 5- to 9-membered saturated or partially unsaturated heterocycle or its oxo form containing one nitrogen atom as a ring-constituting element, wherein the heterocycle may further contain one nitrogen atom, one oxygen atom, and / or one sulfur atom as ring-constituting elements" include pyrrolidinyl, piperidinyl, azepanyl, azocanyl, azonanyl, azepinyl, 2,3,4,7-tetrahydroazepinyl, 2,3,6,7-tetrahydroazepinyl, 1,4-diazepanyl, imidazolidinyl, pyrazolidinyl, piperazinyl, diazepanyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiomorpholinyl, and the like.

[0064] In the present specification, the "condensing agent" is not particularly limited, and specific examples thereof include 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (WSC·HCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), N,N'-carbonyldiimidazole (CDI), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), benzotriazol-1-yloxytris(dimethylamino) Examples of suitable phosphonium hexafluorophosphates include phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), and (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU). Preferred are WSC·HCl, HATU, and COMU.

[0065] In the present specification, the term "magnesium halide" specifically includes magnesium fluoride, magnesium chloride, magnesium bromide, and magnesium iodide.

[0066] In the present specification, the "additive" is not particularly limited, but includes 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), ethyl (hydroxyimino)cyanoacetate (Oxyma), 4-dimethylaminopyridine (DMAP), triethylamine (TEA), diisopropylethylamine (DIPEA), N-methylmorpholine, etc., and preferably HOBt, TEA, and DIPEA.

[0067] In this specification, the "catalyst" used in the reduction reaction is not particularly limited, but examples thereof include palladium-on-carbon (Pd / C) and platinum-on-carbon (Pt / C).

[0068] In the present specification, the "halogenating reagent" is not particularly limited, and examples thereof include fluorinating agents, chlorinating agents, brominating agents, and iodinating agents, such as potassium fluoride, tetrabutylammonium fluoride, (diethylamino)sulfur trifluoride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, trichlorophosphate, bromine, phosphorus oxybromide, phosphorus tribromide, iodine, and sodium iodide.

[0069] In the present specification, the "copper compound" is not particularly limited, but examples thereof include copper iodide, copper bromide, copper chloride, and the like.

[0070] In the present specification, the term "acid" is not particularly limited, and examples thereof include inorganic acids and organic acids. Examples of "inorganic acids" include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid. 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, and 10-camphorsulfonic acid. One or more of these acids may be appropriately selected and mixed for use.

[0071] In the present specification, the "base" is not particularly limited, but examples thereof include inorganic bases and organic bases. Examples of the "inorganic base" include alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide, barium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate, cesium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate, barium carbonate), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate, cesium phosphate), alkaline earth metal phosphates (e.g., magnesium phosphate, calcium phosphate), alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium tert-butoxide), alkali metal hydrides (e.g., sodium hydride, potassium hydride), sodium hydride, and the like. Examples of the "organic base" include trialkylamines (e.g., trimethylamine, triethylamine, N,N-diisopropylethylamine (DIPEA)), dialkylamines (e.g., diethylamine, diisopropylamine), 4-dimethylaminopyridine (DMAP), N-methylmorpholine, picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). One or more of these may be appropriately selected and mixed for use. DMAP and TEA are preferred. These bases can be used alone or in combination of two or more.

[0072] In the present specification, the term "amine" is not particularly limited, and examples thereof 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.

[0073] In the present specification, the term "palladium compound" is not particularly limited, but examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladate(IV) tetrahydrate and potassium hexachloropalladate(IV); [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (Pd(dppf)Cl2·CHCl2), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd Divalent palladium catalysts such as palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium acetylacetonate(II), dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetraamminepalladium(II), dichloro(cycloocta-1,5-diene)palladium(II), palladium trifluoroacetate(II), and 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II)-dichloromethane complex; and zero-valent palladium catalysts such as tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), tris(dibenzylideneacetone)dipalladium chloroform complex(0), and tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4). These palladium compounds may be used singly or in combination of two or more.

[0074] In the present specification, the term "leaving group" specifically refers to halogen, C 1-18 Alkanesulfonyl, lower alkanesulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, perhaloalkanesulfonyloxy, sulfonio, toluenesulfoxy, etc. Preferred leaving groups in this reaction include halogens.

[0075] The "halogen" is fluorine, chlorine, bromine or iodine.

[0076] The above "C 1-18 Examples of alkanesulfonyl include alkanesulfonyl groups with 1 to 18 carbon atoms (C 1-18 ) straight-chain or branched-chain alkanesulfonyl, specific examples of which include methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, and the like.

[0077] Examples of the above "lower alkanesulfonyloxy" include alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) straight-chain or branched-chain alkanesulfonyloxy, specific examples of which include methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, and the like.

[0078] Examples of the above-mentioned "arylsulfonyloxy" include arylsulfonyloxy groups having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl, carbon number 1 to 6 (C 1-6 ) straight-chain or branched-chain alkoxy, nitro, and halogen, which may have 1 to 3 groups selected from the group consisting of phenylsulfonyloxy, naphthylsulfonyloxy, etc. Specific examples of the above "phenylsulfonyloxy which may have a substituent" include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, etc. Specific examples of the above "naphthylsulfonyloxy" include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, etc.

[0079] Examples of the above "aralkylsulfonyloxy" include aralkylsulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl, carbon number 1 to 6 (C 1-6) straight or branched chain alkoxy, nitro and halogen, optionally substituted with phenyl having 1 to 3 groups selected from the group consisting of phenyl, nitro and halogen. 1-6 ) straight or branched alkanesulfonyloxy, naphthyl-substituted carbon atoms having 1 to 6 carbon atoms (C 1-6 ) straight-chain or branched-chain alkanesulfonyloxy, etc. Specific examples of the above-mentioned "alkanesulfonyloxy substituted with phenyl" include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, etc. Specific examples of the above-mentioned "alkanesulfonyloxy substituted with naphthyl" include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy, etc.

[0080] Specific examples of the above-mentioned "perhaloalkanesulfonyloxy" include trifluoromethanesulfonyloxy.

[0081] Specific examples of the above-mentioned "sulfonio" include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, di(2-cyanoethyl)sulfonio, di(2-nitroethyl)sulfonio, di-(aminoethyl)sulfonio, di(2-methylaminoethyl)sulfonio, di-(2-dimethylaminoethyl)sulfonio, di-(2-hydroxyethyl)sulfonio, di-(3-hydroxypropyl)sulfonio, di-(2-methoxyethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carbamoylethyl)sulfonio, di-(2-carboxyethyl)sulfonio, di-(2-methoxycarbonylethyl)sulfonio, and diphenylsulfonio.

[0082] In this specification, the "solvent" used in the reaction may be any solvent inert to the reaction, and examples thereof include water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, cyclopentyl methyl ether, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), halohydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), lower alcohols (e.g., methanol, ethanol, isopropanol), and polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide, acetonitrile). These solvents may be used alone or in combination.

[0083] Each substituent in the compound represented by general formula [I] in this specification (hereinafter referred to as "compound [I]") will be explained below.

[0084] R in compound [I] 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylthio, mono or di C 1-6 It is alkylamino, preferably ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 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.

[0085] R in compound [I] 2 is a halogen or C 1-6 C optionally substituted with alkyl 3-8 Cycloalkyl, halogen or C 1-6 C optionally substituted with alkyl 4-10 Bicycloalkyl, C 5-13 Spiroalkyl, C 6-12 Tricycloalkyl, halogen, C 1-6 Alkyl or C 1-6 C optionally substituted with haloalkyl 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkoxy-C 1-6 Alkyl, halogen or C 1-6 C optionally substituted with alkyl 4-10 Bicycloalkyl-C 1-6 Alkyl, C 6-12 Tricycloalkyl-C 1-6 Alkyl, C 6-12tricycloalkyl-amino or piperidinyl, preferably cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4-butylcyclohexyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptanylmethyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.2]octanyl, decahydronaphthyl, adamantyl (tricyclo[3.3.1.1]decanyl), spiro[2,5]octanyl, spiro[3,3]heptanyl Methyl, 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-dimethylcyclohexyl

[0033] The aryl group is preferably cyclohexylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropyl, cyclohexylbutyl, cycloheptylmethyl, 1-cyclohexylethyl, adamantylmethyl, 4-methylcyclohexylmethyl, cyclopentyloxymethyl, cyclohexyloxymethyl, cycloheptyloxymethyl, adamantylamino, or piperidinyl, and more 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]heptanylmethyl, spiro[3.3]heptanylmethyl, or adamantylamino.

[0086] R in compound [I] 3 is hydrogen, halogen or C 1-6It is alkyl, preferably hydrogen, fluorine, chlorine, bromine or iodine, more preferably hydrogen or fluorine, and even more preferably hydrogen.

[0087] In compound [I] [ka] is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 A 5- to 9-membered saturated or partially unsaturated heterocycle or an oxo thereof containing one nitrogen atom as a ring-constituting element, which may have alkyl, hydroxy, or methylidene as a substituent, and which may further have one nitrogen atom, one oxygen atom, and / or one sulfur atom as ring-constituting elements, is preferably piperidinyl, azepanyl, azocanyl, azonanyl, azepinyl, 2,3,4,7-tetrahydroazepinyl, 2,3,6,7-tetrahydroazepinyl, diazepanyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazepanyl, or an oxo thereof, and which may further have one or more halogen atoms, such as halogen, methyl ... 1-6 Alkyl, C 1-6It may have alkoxy or hydroxy as a substituent, and more preferably, azepanyl, azocanyl, azonanyl, 2,3,4,7-tetrahydroazepinyl, 2,3,6,7-tetrahydroazepinyl, 1,4-diazepanyl, oxazepanyl, 2,2-dimethylazepanyl, 3-hydroxyazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4,4-difluoroazepanyl, 4-methylpiperidinyl 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-methylidenepiperidinyl, 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- tetramethyl-4-methoxypiperidinyl, 2,2-dimethyl-4-methoxyethylpiperidinyl, 2,2-dimethyl-3-methylenepiperidinyl, 2,2-dimethylpiperazinyl, 2,2-dimethylmorpholinyl, 2,2-dimethyl-3-oxopiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-3-oxopiperidinyl, 2,2-dimethyl-4-thiomorpholinyl aryl, 3,3-dimethyl-4-thiomorpholinyl or oxazepanyl, more preferably piperidinyl, azepanyl, azocanyl, 2,3,4,7-tetrahydroazepinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-oxopiperidinyl, 2,2,4,4-tetramethyl-3-oxopiperidinyl or 3,3-dimethyl-4-thiomorpholinyl.

[0088] Specific examples of compound [I] include: [ka] [ka] Examples include:

[0089] In one embodiment of the present invention, there is provided a pharmaceutical composition comprising the compound [I] of the present invention or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0090] In one embodiment, there is provided a therapeutic, preventive and / or diagnostic agent for symptoms and / or diseases caused by PAR2 activation, comprising the compound [I] of the present invention or a salt thereof.

[0091] In one embodiment, there is provided a pharmaceutical composition for treating, preventing and / or diagnosing symptoms and / or diseases caused by PAR2 activation, comprising the compound [I] of the present invention or a salt thereof as an active ingredient.

[0092] In one embodiment, there is provided a method for treating, preventing, and / or diagnosing symptoms and / or diseases caused by PAR2 activation, which comprises administering to a human an effective amount of compound [I] of the present invention or a salt thereof.

[0093] In one embodiment, there is provided the compound [I] of the present invention or a salt thereof for use in the treatment, prevention and / or diagnosis of symptoms and / or diseases caused by PAR2 activation.

[0094] In one embodiment, there is provided the use of compound [I] of the present invention or a salt thereof in the manufacture of a medicament for use in the treatment, prevention and / or diagnosis of conditions and / or diseases caused by PAR2 activation.

[0095] In one embodiment, there is provided a topical transdermal formulation comprising the compound [I] of the present invention or a salt thereof as an active ingredient and a pharmaceutically acceptable carrier or excipient.

[0096] Throughout this specification, the presentation of preferred embodiments and options for different features of the compound [I] or its salts, uses, methods and compositions of the present invention also includes the presentation of combinations of preferred embodiments and options for the different features, as long as they are combinable and not contradictory.

[0097] The production method of compound [I] will be described below. Compound [I] can be produced based on the production methods shown below. These production methods are merely examples, and the production method of compound [I] is not limited to these.

[0098] In the following reaction schemes, alkylation, hydrolysis, amination, esterification, amidation, etherification, nucleophilic substitution, addition, oxidation, reduction, and other reactions are carried out according to methods known per se. Examples of such methods include those described in Experimental Chemistry Lectures (5th ed., edited by the Chemical Society of Japan, Maruzen Co., Ltd.), Organic Functional Group Preparations, 2nd ed., Academic Press, Inc., 1989; Comprehensive Organic Transformations, VCH Publishers Inc., 1989; and Greene's Protective Groups in Organic Synthesis, 4th ed., 2006, by P.G. M. Uts and T.W. Greene.

[0099] General synthetic route to compound [I] (1)

[0100] Step 1 [ka] (wherein the symbols are as defined above).

[0101] The reaction shown in the above synthetic route can produce intermediate [4] of compound [I] of the present invention. Specifically, intermediate [4] can be produced by reacting compound [2] and compound [3] in a reaction-inert solvent in the presence of a condensing agent and magnesium halide.

[0102] Step 2 [ka] (wherein the symbols are as defined above).

[0103] The reaction shown in the above synthetic route can produce intermediate [6] of compound [I] of the present invention. Specifically, intermediate [6] can be produced by ring-closing compound [4] and compound [5] in ethanol in the presence of an acid. The solvent that can be used in this reaction is not limited to ethanol, but alcohols such as methanol and propanol can also be used. In such cases, an alkyl ester resulting from the solvent used will be produced, rather than the ethyl ester intermediate [6].

[0104] Step 3 [ka] (wherein the symbols are as defined above).

[0105] The reaction shown in the above synthetic route can produce intermediate [7a] of compound [I] of the present invention. Specifically, intermediate [7a] can be produced by reacting compound [6] with a halogenating reagent in the presence of an amine in a reaction-inert solvent.

[0106] Step 4-1 [ka] (wherein Y is a leaving group, R 1 ' is R as defined above 1 or a partially unsaturated form thereof, and the other symbols are as defined above.)

[0107] The reaction shown in the above synthetic route can produce intermediate [9] of compound [I] of the present invention. Specifically, intermediate [9] can be produced by Suzuki coupling reaction of compound [7] having a leaving group and boronic acid compound [8] in the presence of a base and a palladium compound in a solvent inert to the reaction.

[0108] The "boronic acid compound" used in this reaction may be either a boronic acid ester compound or a boronic acid compound.

[0109] Step 4-2 [ka] (wherein X and Y are leaving groups, R 1 ' is R as defined above 1 or a partially unsaturated form thereof, and the other symbols are as defined above.)

[0110] The reaction shown in the above synthetic route can also be used to produce intermediate [9] of compound [I] of the present invention. Specifically, intermediate [9] can be produced by reacting compound [7] having a leaving group with organozinc compound

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

[0111] Step 5 [ka] (wherein the symbols are as defined above).

[0112] The reaction shown in the above synthetic route can produce intermediate

[12] of compound [I] of the present invention. Specifically, intermediate

[12] can be produced by hydrogenating compound

[11] in the presence of a catalyst in a solvent inert to the reaction.

[0113] Step 6 [ka] (wherein the symbols are as defined above).

[0114] The reaction shown in the above synthetic route can produce intermediate

[14] of compound [I] of the present invention. Specifically, intermediate

[14] can be produced by deesterifying compound

[13] in a reaction-inert solvent in the presence of a base.

[0115] Step 7 [ka] (wherein the symbols are as defined above).

[0116] The compound [I] of the present invention can be produced by the reaction shown in the above synthetic route. Specifically, the compound [I] can be produced by amidation reaction of the compound

[14] and the cyclic amine compound

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

[0117] Other reaction conditions (reaction temperature, reaction time, etc.) can be appropriately determined based on various known reactions.

[0118] The reactions in the above reaction scheme are general reactions in the present invention, and the order of the reactions may be changed as long as the desired compound is obtained.

[0119] In each reaction in the above reaction scheme, the product can be used in the next reaction as the reaction mixture or as a crude product, or it can be isolated from the reaction mixture in a conventional manner or easily purified by conventional separation means, such as recrystallization, distillation, and chromatography.

[0120] The starting compounds, intermediate compounds, and target compounds in each of the above steps, as well as the compounds of the present invention or their salts, include geometric isomers, stereoisomers, optical isomers, and tautomers. Various isomers can be separated by common optical resolution methods. Alternatively, they can be produced from appropriate optically active starting compounds.

[0121] The compound of the present invention or a salt thereof can be produced by the synthesis method shown in each of the above reaction schemes or a method analogous thereto.

[0122] When a specific method is not described for producing the compound of the present invention or a salt thereof, a starting compound may be commercially available or may be produced by a method known per se or a method similar thereto.

[0123] The starting compounds and target compounds in each of the above steps can be used in the form of suitable salts, such as those exemplified below as salts of compound [I] of the present invention.

[0124] The compounds of the present invention or salts thereof include their salt forms, and may form acid addition salts or salts with bases depending on the type of substituents. Examples of such "acids" include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, etc.). Examples of such "bases" include inorganic bases (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) and organic bases (e.g., methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, etc.) and ammonium salts. Furthermore, it may form a salt with an amino acid such as lysine, arginine, aspartic acid, or glutamic acid.

[0125] The compounds of the present invention or salts thereof include compounds in which one or more atoms are replaced with one or more isotope atoms. Examples of isotope atoms include deuterium ( 2 H), tritium ( 3 H), 13 C. 15 N, 18 O and others.

[0126] The compound [I] of the present invention also includes pharmaceutically acceptable prodrugs. Substituents that can be modified to form prodrugs include reactive functional groups such as -OH, -COOH, and amino. The modifying groups for these functional groups may be appropriately selected from the "substituents" in this specification.

[0127] The compound represented by general formula [I] or a pharmaceutically acceptable salt thereof is useful as a therapeutic agent, preventive agent, agent for preventing the progression of, or diagnostic agent for symptoms and / or diseases associated with hyperactivity of PAR2. Furthermore, the compound represented by general formula [I] or a salt thereof has PAR2 inhibitory activity and is therefore also useful as a research tool for investigating the physiological action of PAR2.

[0128] Specific examples of symptoms and / or diseases associated with hyperactivity of PAR2 include pruritus, skin diseases, allergic diseases, inflammatory diseases, autoimmune diseases, cancer, and the like.

[0129] The compound represented by formula [I] or a salt thereof exhibits excellent antipruritic activity in vivo and is useful as an antipruritic agent for treating or preventing various diseases accompanied by pruritus, such as atopic dermatitis, urticaria, eczema, asteatosis, asteatotic eczema, senile pruritus, xerosis, senile xerosis, prurigo, seborrheic dermatitis, psoriasis, contact dermatitis, insect bites, caterpillar dermatitis, photosensitivity, pulp hypersensitivity, neurodermatitis, autosensitization dermatitis, pruritus during renal dialysis, pruritus associated with chronic liver disease, lichen amyloidosis, tinea, cutaneous candidiasis, scabies, mites, lice, drug eruption, pruritus associated with the administration of opioid analgesics, atopic keratoconjunctivitis, allergic keratoconjunctivitis, infectious keratoconjunctivitis, and vernal conjunctivitis. Further examples of diseases accompanied by pruritus include pruritus caused by internal diseases (malignant tumors, diabetes, liver disease, renal failure, gout, thyroid disease, blood disorders), parasitic, fungal, or viral infections, psychological stress, drug hypersensitivity, or pregnancy.

[0130] Specific diseases include skin diseases (e.g., atopic dermatitis, psoriasis, eczema, scleroderma, and dermatitis), asthma, bronchitis, allergic reactions, allergic contact hypersensitivity, allergic keratoconjunctivitis, arthritis (including osteoarthritis, osteoarthritis, spondyloarthropathy, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, and 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 colon cancer, breast cancer, lung cancer, and prostate cancer; hematopoietic malignancies including leukemia and lymphoma; Hodgkin's disease; aplastic anemia, skin cancer, and familial adenomatous polyposis), hemophilia, cachexia, tumor invasion, tumor growth, tumor metastasis, and the like.

[0131] The dosage and dosage form when the compound of the present invention is used as a pharmaceutical agent for treating, preventing or diagnosing the above-mentioned diseases, containing the compound of the present invention as an active ingredient, will be described below.

[0132] The compound of the present invention can be administered orally or parenterally, and can be used in humans and non-human animals in various dosage forms suitable for oral or parenteral administration as a pharmaceutical composition together with suitable additives, bases, and carriers.For example, when administered orally, it can be administered in commonly used dosage forms such as tablets, capsules, syrups, suspensions, etc.When administered parenterally, it can be administered as an injection or eye drop in the form of a liquid such as a solution, emulsion, or suspension, or as a rectal administration in the form of a suppository, or as a topical transdermal absorption preparation such as an ointment, cream, lotion, or spray.

[0133] Such dosage forms can be prepared according to a general method by mixing the active ingredient with auxiliary agents such as ordinary carriers, excipients, binders, stabilizers, etc. When used in an injection form, the active ingredient is dissolved or suspended in a physiologically acceptable carrier such as water, physiological saline, oil, or aqueous glucose solution, and may contain, as necessary, an emulsifier, stabilizer, salt for adjusting osmotic pressure, solubilizer, or buffer as an auxiliary agent.

[0134] When administered as a topical transdermal preparation, stabilizers, preservatives, emulsifiers, suspending agent stabilizers, antioxidants, fragrances, fillers, or other transdermal absorption enhancers may be added in addition to the base, as needed. Examples of bases for ointments include fatty oils, lanolin, petrolatum, paraffin, plastibase, glycols, higher fatty acids, higher alcohols, etc., and examples of bases for lotions include ethanol, glycerin, glycol, etc. Examples of bases for liquid preparations include ethanol, water, glycol, etc.

[0135] The dosage and frequency of administration vary depending on the target disease, the patient's symptoms, age, body weight, etc., and the dosage form. When administered orally, the active ingredient is usually administered to an adult in the range of about 1 to 1,000 mg per day, preferably about 10 to 500 mg, in one or several divided doses. When administered as an injection, the active ingredient can be administered in the range of about 0.1 to about 500 mg, preferably about 3 to about 100 mg, in one or several divided doses. When administered as a transdermal preparation, an appropriate amount can be applied to the affected area once to several times a day.

[0136] Since the compound of the present invention has excellent percutaneous absorption properties, topical dermatological preparations such as ointments, creams, and lotions are preferred.

[0137] The compounds of the present invention are useful as anti-inflammatory agents, including steroids (e.g., clobetasol propionate, diflucortolone valerate, betamethasone valerate, hydrocortisone butyrate), calcineurin inhibitors (e.g., cyclosporine, 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 drugs (DMARDs, e.g., methotrexate), kappa opioid agonists (e.g., nalfurafine hydrochloride), antiallergic agents, antihistamines (e.g., cromoglycates), sodium, tranist, suplatast tosilate, chlorpheniramine maleate, fexofenadine hydrochloride, olopatadine hydrochloride, bilastine, rupatadine fumarate), moisturizers (e.g., heparinoids, 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 (e.g., lebrikizumab) antibodies, IL-17 antibodies (e.g., secukinumab, ixekizumab), IL-17R antibodies (e.g., brodalumab), IL-23 antibodies (e.g., guselkumab), IL-31R antibodies (e.g., nemolizumab).

[0138] When the compound of the present invention is used in combination with a concomitant drug, the compounds may be administered simultaneously, approximately simultaneously, or at different times. Alternatively, the compound of the present invention and the compound to be used in combination may be mixed and administered as a single formulation.

[0139] The disclosures of all patent and non-patent literature cited herein are hereby incorporated by reference in their entirety. [Example]

[0140] The present invention will be further explained in detail by the following Test Examples, Reference Examples and Examples, but these do not limit the present invention and may be modified within the scope of the present invention. The following abbreviations may be used in this specification:

[0141] [Table 1] [Table 2] [Table 3]

[0142] In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown for mixed solvents are by volume unless otherwise specified. % refers to % by weight unless otherwise specified. 1 H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz)). Mass spectra (MS) were measured using an LC / MS (ACQUITY UPLC H-Class). Electrospray ionization (ESI) was used, and the data reported were the actual values ​​found. Usually, the molecular ion peak ([M+H] + , [MH] - In the case of salts, the free molecular ion peak or fragment ion peak is usually observed. In silica gel column chromatography, when basic is mentioned, aminopropylsilane-bonded silica gel was used. The absolute configuration of the compounds was determined by known X-ray crystal structure analysis methods (e.g., Shigeru Ohba and Shigenobu Yano, "Basic Lectures for Chemists 12: X-Ray Crystal Structure Analysis" (1st ed., 1999)), or estimated from the empirical rules of 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).

[0143] [Reference example] Reference Example 1: Preparation of 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid To a solution of ethyl 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylate (170 mg) in THF (1.7 ml)-MeOH (1.7 ml) was added 4N LiOH (0.578 ml) at 0°C and stirred at room temperature overnight. The reaction mixture was acidified with 1N HCl and extracted with AcOEt. The organic layer was concentrated to give the desired compound (157 mg).

[0144] Reference Example 2: Preparation of ethyl 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylate 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-dioxane (18 ml), K2CO3 (1383 mg) and trans-dichlorobis(triphenylphosphine)palladium(II) (176 mg) were added and the mixture was stirred at 80 °C overnight. Water was added to the reaction mixture, and insoluble materials were removed by filtration. The filtrate was extracted with AcEt, and the organic layer was concentrated. The residue was purified by medium-pressure column chromatography (Hexane / AcOEt) to obtain the target compound (615 mg).

[0145] Reference Example 3: Preparation of 5-(1-adamantyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid To a solution of ethyl 5-(1-adamantyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate (98 mg) in EtOH (3 ml), 1N aqueous NaOH (0.533 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was acidified with water and 1N HCl. After stirring for 30 minutes, the precipitate was collected by filtration to give the target compound (81 mg).

[0146] Reference Example 4: Preparation of ethyl 5-(1-adamantyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate 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), Pd / C (25 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography (Hexane / AcOEt) to give the desired compound (99 mg).

[0147] Reference Example 5: Preparation of ethyl 5-(1-adamantyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate To a solution of ethyl 5-(1-adamantyl)-7-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate (825 mg), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.517 ml) in 1,4-dioxane (10 ml), PdCl(dppf)DCM (187 mg), and 2N aqueous NaCO (3.44 ml) were added and stirred at 90 °C for 5 hours under an argon atmosphere. The reaction mixture was concentrated, and the residue was mixed with water and AcOEt. The mixture was filtered through Celite, and the filtrate was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (Hexane / AcOEt) to give the desired compound (747 mg).

[0148] Reference Example 6: Preparation of ethyl 5-(1-adamantyl)-7-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 5-(1-adamantyl)-7-oxo-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. Aqueous NaCO solution was added, neutralized, extracted with AcOEt, and concentrated. The residue was purified by column chromatography (Hexane / AcOEt) to give the desired compound (825 mg).

[0149] Reference Example 7: Preparation of ethyl 5-(1-adamantyl)-7-oxo-4H-pyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 3-(1-adamantyl)-3-oxopropanoate (7.2 g), ethyl 5-amino-1H-pyrazole-3-carboxylate (4.46 g), and p-TsOH HO (0.547 g) were added to EtOH (80 ml) and refluxed overnight. The reaction mixture was concentrated, water was added to the residue, and the precipitate was collected by filtration to give the target compound (7.59 g).

[0150] Reference Example 8: Preparation 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-carboxylate (138 mg) in THF (10 ml) was cooled to -2 °C. To this solution, an aqueous solution (3 ml) of LiOH (186 mg) was added dropwise, and the mixture was stirred at the same temperature overnight. HCl was added to the reaction mixture, and the mixture was stirred for 1 hour. Water was added, and the mixture was extracted with AcOEt. The organic layer was concentrated to give the target compound (133 mg).

[0151] Reference Example 9: Preparation 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), (cyclohexylmethyl)zinc bromide solution (5.08 ml), and Pd(PhP) (267 mg) were dissolved in THF (3 ml) and stirred at 50 °C for 4 hours under an argon atmosphere. Water and aqueous NHCl were added to the reaction mixture, which was then 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).

[0152] Reference Example 10: Preparation of ethyl 5-bromo-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate To a solution of ethyl 5-oxo-7-(trifluoromethyl)-4H-pyrazolo[1,5-a]pyrimidine-2-carboxylate (7.0 g) in 1,4-dioxane (70 ml), phosphorus oxybromide (14.58 g) was added and the mixture was stirred for 4 hours at 90° C. After cooling, the reaction mixture was poured into ice water, and the precipitate was collected by filtration to obtain the target compound (8.09 g).

[0153] Reference Example 11: Preparation 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-pyrazole-3-carboxylic acid (4.89 g) in AcOH (50 ml) was heated to reflux for 2 hours. The reaction mixture was concentrated, and AcOEt was added to the residue, followed by extraction with 5N aqueous NaOH. The aqueous layer was acidified with 5N HCl and extracted with AcOEt. The organic layer was concentrated to give the desired compound (8.80 g).

[0154] Reference Example 12: Preparation of 5-cyclopentyl-1,1,1-trifluoropentane-2,4-dione To a solution of 1-cyclopentylpropan-2-one (2.83 g), ethyl trifluoroacetate (3.20 ml) and THF (30 ml) was added KOtBu (5.03 g) under ice-cooling and stirred overnight at room temperature. 1N HCl was added to the reaction mixture, which was then extracted with EtO. The organic layer was concentrated to give the target compound (4.39 g).

[0155] Reference Example 15: Preparation of 5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid To a solution of ethyl 5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate (4.86 g) in EtOH (50 ml), 5N aqueous NaOH (5.90 ml) was added and stirred at room temperature for 3 hours. The reaction mixture was concentrated, and the residue was added with water and acidified with 5N HCl. The precipitate was collected by filtration to give the target compound (4.28 g).

[0156] Reference Example 16: Preparation of ethyl 5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate To a solution of ethyl 5-(cyclohexylmethyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate (12.9 g) in AcOEt (65 ml), 10% Pd / C (1.3 g) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography (Hexane / AcOEt) to give the desired compound (10.7 g).

[0157] Reference Example 17: Preparation of ethyl 5-(cyclohexylmethyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate A suspension of ethyl 7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (14 g), 2-isopropenyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (9.14 ml), PdCl(dppf)DCM (0.355 g), and KPO (18.47 g) in 1,4-dioxane (120 ml) and water (30 ml) was heated to reflux under a nitrogen atmosphere for 5 hours. The reaction mixture was concentrated, and water was added to the residue. Extraction with AcOEt was performed, and the organic layer was concentrated. The residue was purified by column chromatography (hexane / AcOEt) to give the desired compound (12.9 g).

[0158] Reference Example 18: Preparation of ethyl 7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate To a solution of ethyl 5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate (17.2 g) in toluene (170 ml), phosphorus oxychloride (13.21 ml) and DIPEA (9.90 ml) were added and the mixture was heated to reflux for 4.5 hours. The reaction mixture was concentrated, and ice water was added to the residue. The mixture was neutralized with saturated aqueous sodium bicarbonate and extracted with AcOEt. The organic layer was concentrated to give the desired compound (18.4 g).

[0159] Reference Example 19: Preparation of ethyl 5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate To a suspension of ethyl 4-cyclohexyl-3-oxobutanoate (8.35 g) and 5-amino-1H-pyrazole-3-carboxylic acid (5.00 g) in EtOH (50 ml), p-TsOH·HO (3.74 g) was added and the mixture was heated under reflux 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).

[0160] Reference Example 20: Preparation of azepan-1-yl-[7-(cyclohexen-1-yl)-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone A solution of azepan-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone (500 mg), 1-cyclohexen-1-yl-boronic acid pinacol ester (305 mg), PdCl(dppf)DCM (109 mg), and KPO (566 mg) in 1,4-dioxane (6 ml) and water (3 ml) was heated to reflux under a nitrogen atmosphere for 3 hours. Water was added to the reaction mixture, which was then extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (Hexane / AcOEt) to give the target compound (570 mg).

[0161] Reference Example 21: Preparation of azepan-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone A solution of azepan-1-yl-[5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidin-2-yl]methanone (7.4 g) in toluene (40 ml) was added with phosphorus oxychloride (5.80 ml) and DIPEA (3.63 ml) and heated to reflux for 5 hours. The reaction mixture was concentrated, and the residue was neutralized with ice water and saturated aqueous sodium bicarbonate. Extraction with AcOEt was performed, and the organic layer was concentrated. The residue was purified by column chromatography (Hexane / AcOEt) to obtain the target compound (5.2 g).

[0162] Reference Example 22: Preparation of azepan-1-yl-[5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidin-2-yl]methanone To a solution of 5-(cyclohexylmethyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylic acid (4.78 g) in DMF (50 ml), HATU (7.92 g), TEA (2.90 ml), and hexamethyleneimine (2.348 ml) were added and stirred at room temperature overnight. HCl and water were added to the reaction mixture, followed by stirring. The precipitate was collected by filtration to give the target compound (5.6 g).

[0163] Reference Example 31: Preparation of ethyl 5-(cyclopentylmethyl)-7-pentan-3-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate To a suspension of ethyl 7-chloro-5-(cyclopentylmethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (500 mg), copper(I) iodide (30.9 mg), and lithium chloride (68.9 mg) in NMP (5 ml), 0.5N 1-ethylpropylzinc bromide solution (4.87 ml) was added and stirred at 50 °C for 5 hours. Water and AcOEt were added to the mixture, which was then filtered through Celite. The filtrate 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 (222 mg).

[0164] Reference Example 43: Preparation of ethyl 5-(2-cyclohexylethyl)-7-hydroxypyrazolo[1,5-a]pyrimidine-2-carboxylate A solution of diethyl 5-aminopyrazole-1,3-dicarboxylate (3.08 g) in methanesulfonic acid (15 ml) was stirred at 120° C. for 4 hours. To this reaction mixture, EtOH (30 ml) and ethyl 5-cyclohexyl-3-oxopentanoate (3.22 g) were added and heated to reflux for 3 hours. After cooling to room temperature, water was added and the mixture was concentrated. Water was added to the residue, and the mixture was stirred. The precipitate was collected by filtration to obtain the target compound (3.07 g).

[0165] Reference Example 44: Preparation of diethyl 5-aminopyrazole-1,3-dicarboxylate To a suspension of potassium (Z)-1-cyano-3-ethoxy-3-oxoprop-1-en-2-olate (109 g) and ethyl carbazate (66.5 g) in MeCN (1000 ml), TFA (94 ml) was added and stirred at room temperature for 2 hours. Then, TEA (339 ml) was added and stirred at room temperature for 2 hours. The reaction mixture was then concentrated, and IPE and water were added to the residue. The mixture was stirred, and the solid was collected by filtration to obtain the target compound (100.7 g).

[0166] Reference Example 49: Preparation of ethyl 4-(4-methylcyclohexyl)-3-oxobutanoate CDI (2.283 g) was added to a solution of 4-methylcyclohexaneacetic acid (2 g) in CPME (40 ml) and stirred at room temperature for 1 hour. To this mixture, potassium monoethyl malonate (2.397 g) and magnesium chloride (1.341 g) were added and stirred at 70°C for 4 hours. 1N HCl was added, and after stirring for a while, the 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 (2.65 g).

[0167] Reference Example 84: Preparation of tert-butyl 4-[5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl]-3,3-dimethylpiperazine-1-carboxylate To a suspension of 5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (200 mg) in DCM (5 ml) was added HATU (312 mg) and TEA (0.114 ml). After 10 minutes, 1-Boc-3,3-dimethyl-piperazine (176 mg) was added and stirred at room temperature overnight. Water and aqueous Na2CO3 were added to the reaction mixture, which was then extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography (Hexane / AcOEt). Recrystallization from IPE-Hexane afforded the target compound (167 mg).

[0168] Reference Example 86: Preparation 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-pyrazole-3-carboxylate (0.824 g) in AcOH (15 ml) was heated to reflux overnight. The reaction mixture was concentrated, and AcOEt was added to the residue, followed by filtration. A saturated aqueous solution of Na2CO3 was added to the filtrate, which was then extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (Hexane / AcOEt) to obtain the target compound (1.07 g).

[0169] Reference Example 93: Preparation 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 peroxodisulfate (440 mg), and silver nitrate (262 mg) were dissolved in MeCN-water (6 ml) and stirred at 60°C for 2 hours. Water was then added to the mixture, and it 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 obtain the target compound (114 mg).

[0170] Reference Example 99: Preparation of 2,2-dimethylazepane hydrochloride Palladium hydroxide on carbon (0.122 g) and 2,2-dichloropropane (0.311 ml) were added to a solution of 1-benzyl-2,2-dimethylazepane (0.54 g) in EtOH (15 ml), and the mixture was stirred under a hydrogen atmosphere at 35°C for 2.5 hours. After purging with nitrogen, the reaction mixture was filtered through Celite and washed with AcOEt. The filtrate was ionized with 4N HCl / AcOEt (0.7 ml), and then concentrated to give the target compound (0.33 g).

[0171] Reference Example 100: Preparation of 2,2,4,4-tetramethylpiperidin-3-one hydrochloride To a solution of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one (1.00 g) in AcOEt (10 ml) was added Pd-C (200 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 30 minutes. The reaction mixture was then filtered through Celite. HCl / AcOEt (5.00 ml) was added to the filtrate, and the precipitate was collected by filtration to give the target compound (754 mg).

[0172] Reference Example 101: Preparation of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one To a solution of 1-benzyl-2,2-dimethylpiperidin-3-one (100 mg) in THF (1 ml), KOtBu (207 mg) and iodomethane (0.086 ml) were added and stirred at room temperature for 30 minutes. Water was added to this mixture, which was then 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).

[0173] Reference Example 108: Preparation 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-adamantanamine (268 mg), and K2CO3 (266 mg) were dissolved in DMF and stirred at 100°C for 1 hour. Water was added to the reaction mixture, and the precipitate was collected by filtration to obtain the target compound (614 mg).

[0174] Reference Example 109: Preparation of 5-(1-adamantyl)-7-propoxypyrazolo[1,5-a]pyrimidine-2-carboxylic acid To a solution of ethyl 5-(1-adamantyl)-7-chloropyrazolo[1,5-a]pyrimidine-2-carboxylate (200 mg) in THF (2.5 ml), 1-propanol (0.831 ml) and 4N aqueous LiOH (0.695 ml) were added and stirred at room temperature for 3 hours. The reaction mixture was made weakly acidic with 1N HCl under ice cooling, and the precipitate was collected by filtration to give the target compound (180 mg).

[0175] Reference Example 115: Preparation of ethyl 5-(cyclopentyloxymethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate Ethyl 5-(cyclopentyloxymethyl)-7-prop-1-en-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylate (150 mg) was dissolved in AcOEt (5 ml), and palladium-activated carbon ethylenediamine complex (10 mg) was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography (Hexane / AcOEt) to give the target compound (110 mg).

[0176] Reference Example 132: Preparation of 5-piperidin-1-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid A solution of ethyl 5-piperidin-1-yl-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylate (471 mg) in THF / EtOH (5 ml) was added with aqueous LiOH (2 ml) and stirred at 0°C for 2 hours. Aqueous HCl was added to the reaction mixture, and the mixture was extracted with AcOEt. After concentration, AcOH (2 ml) was added to the residue, and the mixture was stirred at 100°C for 3 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography (Hexane / AcOEt) to obtain the target compound (233 mg).

[0177] Reference Example 133: Preparation 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 KCO (256 mg) were dissolved in DMF (1.5 ml) and stirred at 100° C. for 1 hour. Water was added to the reaction mixture, and the precipitate was collected by filtration to obtain the target compound (411 mg).

[0178] Reference Example 143: Preparation of 2,2,4,4-tetramethylpiperidin-3-one hydrochloride To a solution of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one (100 mg) in AcOEt (2 ml), Pd / C (20 mg) was added and stirred at room temperature under a hydrogen atmosphere for 30 minutes. The reaction mixture was filtered through Celite. 4N HCl / AcOEt (1.00 ml) was added to the filtrate, followed by stirring. The precipitate was collected by filtration to give the target compound (58 mg).

[0179] Reference Example 144: Preparation of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one To a solution of 1-benzyl-2,2-dimethylpiperidin-3-one (100 mg) in THF (1 ml), KOtBu (207 mg) and iodomethane (0.086 ml) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added with water and 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 (89 mg).

[0180] Reference Example 145: Preparation of 2,2,3-trimethylpiperidin-3-ol hydrochloride To a solution of 1-benzyl-2,2,3-trimethylpiperidin-3-ol (948 mg) in EtOH (10 ml), Pd / C (200 mg) was added and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite. HCl (8.12 ml) was added to the filtrate, and the mixture was concentrated to give the target compound (744 mg).

[0181] Reference Example 146: Preparation of 1-benzyl-2,2,3-trimethylpiperidin-3-ol To a solution of 1-benzyl-2,2-dimethylpiperidin-3-one (157 mg) in THF (3 ml), methylmagnesium bromide (1.350 ml) was added under ice-cooling and stirred for 1 hour. Water was added to this 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 obtain the target compound (135 mg).

[0182] Reference Example 149: Preparation of [5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]-(2,2-dimethylpiperazin-1-yl)methanone To a solution of tert-butyl 4-[5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carbonyl]-3,3-dimethylpiperazine-1-carboxylate (1.37 g) in DCM (13 ml), TFA (2.12 ml) was added under ice cooling and stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was neutralized with saturated aqueous Na2CO3. The resulting mixture was extracted with AcOEt, and the organic layer was concentrated to give the target compound (1.06 g).

[0183] Reference Example 152: Preparation of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-ol To a solution of 1-benzyl-2,2,4,4-tetramethylpiperidin-3-one (1.77 g) in MeOH (20 ml), NaBH4 (0.136 g) was added under ice-cooling and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was then 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 (1.45 g).

[0184] Reference Example 155: Preparation of tert-butyl 2,2-dimethyl-3-methylidenepiperidine-1-carboxylate To a solution of (methyl)triphenylphosphonium bromide (479 mg) in THF (4 mL), potassium tert-butoxide (150 mg) was added and stirred at room temperature for 30 minutes. A solution of tert-butyl 2,2-dimethyl-3-oxopiperidine-1-carboxylate (203 mg) in THF (5 mL) was added and stirred at room temperature for 1 hour. Water was added 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 obtain the target compound (39 mg).

[0185] Reference Example 156: Preparation of ethyl 5-(1-adamantyl)-7-pentylpyrazolo[1,5-a]pyrimidine-2-carboxylate A solution of 1-(1-adamantyl)-2-(triphenyl-λ5-phosphanylidene)ethanone (1.39 g) in toluene (40 ml) was added with hexane (0.761 ml) and heated to reflux for 3 hours. The reaction mixture was concentrated, and the residue was purified by medium-pressure column chromatography (Hexane / AcOEt) to give the intermediate (697 mg). This intermediate was dissolved in DMF (10.5 ml), and ethyl 5-amino-1H-pyrazole-3-carboxylate (0.492 g) and K2CO3 (0.876 g) were added, followed by stirring at 100 °C overnight. Saturated aqueous NH4Cl was added to the reaction mixture, which was then 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 (329 mg).

[0186] The compounds of Reference Examples 13, 14, 23-30, 32-42, 45-48, 50-83, 85, 87-92, 94-98, 102-107, 110-114, 116-131, 134-142, 147, 148, 150, 151, 153, 154 and 157-236 were produced in the same manner as in Reference Examples 1-12, 15-22, 31, 43, 44, 49, 84, 86, 93, 99-101, 108, 109, 115, 132, 133, 143-146, 149, 152, 155 and 156. The structural formulas and physical property data of the compounds of Reference Examples 1-236 are shown in Tables 1-1 to 1-32, respectively.

[0187] [Table 1-1] [Table 4] [Table 1-2] [Table 5] [Table 1-3] [Table 6] [Table 1-4] [Table 7] [Table 1-5]

Table 8

Table 9

Table 10

Table 11

Table 12

Table 13

Table 14

Table 15

Table 19

[0188] [Example] Example 1: Preparation of (5-adamantan-1-yl)-7-propylpyrazolo[1,5-a]pyrimidin-2-yl)(azepan-1-yl)methanone To a solution of 5-(1-adamantyl)-7-propylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (81.9 mg) in DCM (5 mL), hexamethyleneimine (0.041 mL), HATU (138 mg), and TEA (0.067 mL) were added at 0°C and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with DCM and concentrated. The residue was crystallized from AcOEt / Hexane to give the desired compound (44.4 mg).

[0189] Example 2: Preparation of (5-adamantan-1-yl)-7-isopropylpyrazolo[1,5-a]pyrimidin-2-yl)(2,2-dimethylpiperidin-1-yl)methanone To a solution of 5-(1-adamantyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (300 mg) and HATU (504 mg) in DCM (10 ml), TEA (0.370 ml) and 2,2-dimethylpiperidine hydrochloride (159 mg) were added and stirred overnight at room temperature. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with DCM and concentrated. The residue was purified by column chromatography (Hexane / AcOEt) and recrystallized from EtOH / water to give the desired compound (320 mg).

[0190] Example 3: Preparation of azepan-1-yl(5-(cyclohexylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone To a solution of 5-(cyclohexylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (60 mg) in DCM (3 ml), HATU (105 mg), TEA (0.038 ml), and hexamethyleneimine (0.031 ml) were added and stirred at room temperature overnight. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was extracted with DCM and concentrated. The residue was purified by column chromatography (Hexane / AcOEt) to give the desired compound (44 mg).

[0191] Example 4: Preparation of azepan-1-yl(5-(cyclopentylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone To a solution of 5-(cyclopentylmethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (250 mg) and hexamethyleneimine (0.135 ml) in DCM (5 ml), HATU (455 mg) and TEA (0.334 ml) were added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted with AcOEt. The organic layer was concentrated, and the residue was purified by medium-pressure column chromatography (Hexane / AcOEt). Crystallization from EtOH / water afforded the target compound (232 mg).

[0192] Example 6: Preparation of azepan-1-yl(5-(2-cyclopentylethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone To a solution of 5-(2-cyclopentylethyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carboxylic acid (500 mg) in NMP (10 ml), hexamethyleneimine (0.21 ml), HATU (871 mg), and TEA (0.32 ml) were added and stirred at room temperature for 3 hours. A saturated aqueous solution of Na2CO3 was added to the reaction mixture, which was extracted with AcOEt. The organic layer was concentrated. The residue was purified by column chromatography (Hexane / AcOEt) to obtain the target compound (530 mg).

[0193] Example 7: Preparation of azepan-1-yl(5-(cyclohexylmethyl)-7-isopropylpyrazolo[1,5-a]pyrimidin-2-yl)methanone To a solution of 5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (368 mg) in NMP (4 ml), WSC (281 mg) and HOBt (224 mg) were added and stirred at room temperature. After 10 minutes, hexamethyleneimine (0.165 ml) was added and stirred overnight. Water and saturated aqueous Na2CO3 were added, and the resulting mixture was extracted with AcOEt. The organic layer was concentrated. The residue was purified by column chromatography (Hexane / AcOEt) and recrystallized from EtOH / water to give the target compound (304 mg).

[0194] Example 8: Preparation of azepan-1-yl(7-cyclohexyl-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl)methanone A solution of azepan-1-yl-[7-(cyclohexen-1-yl)-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone (440 mg) in AcOEt (4 ml) was added with 10% Pd / C (50 mg) under a nitrogen atmosphere and stirred at room temperature under a hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography (Hexane / AcOEt) and recrystallized from EtOH / water to give the target compound (278 mg).

[0195] Example 9: Preparation of azepan-1-yl(5-(cyclohexylmethyl)-7-propylpyrazolo[1,5-a]pyrimidin-2-yl)methanone Azepan-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone (500 mg), n-propylboronic acid (234 mg), PdCl(dppf)DCM (109 mg), and KPO (849 mg) were dissolved in 1,4-dioxane (5 ml) and heated to reflux under a nitrogen atmosphere for 6 hours. Water was added to the reaction mixture, which was then extracted with AcOEt. The organic layer was concentrated, and the residue was purified by column chromatography (Hexane / AcOEt) to obtain the target compound (440 mg).

[0196] Example 15: Synthesis of azepan-1-yl-[5-(cyclopentylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]methanone To a solution of 5-(cyclopentylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidine-2-carboxylic acid (2.00 g) and hexamethyleneimine (1.177 ml) in DCM (20 ml) was added HATU (3.18 g) and TEA (2.91 ml), 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 obtain the target compound (2.24 g).

[0197] Example 28: Preparation of azepan-1-yl-[7-tert-butyl-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone A solution of azepan-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone (600 mg) in NMP (1.8 ml) was added with 0.5 M tert-butylzinc bromide in THF (4.81 ml), copper(I) iodide (91 mg), and lithium chloride (102 mg). The mixture was stirred at 50°C under a nitrogen atmosphere for 6 hours. 1N HCl was added to the reaction mixture, which was then extracted with AcOEt. 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 (363 mg).

[0198] Example 53: Preparation of [5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidin-2-yl]-(2,2-dimethylpiperazin-1-yl)methanone To a solution of tert-butyl 4-[5-(1-adamantyl)-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-2-carbonyl]-3,3-dimethylpiperazine-1-carboxylate (3.0 g) in DCM (30 ml), TFA (5 ml) was added under ice cooling and stirred at room temperature for 5 hours. Water was added under ice cooling, the mixture was made alkaline with aqueous Na2CO3, and extracted with DCM. The organic layer was concentrated, and the residue was purified by column chromatography (MeOH / AcOEt) and recrystallized from EtOH / water to obtain the target compound (1.65 g).

[0199] Example 87: Preparation of azepan-1-yl-[5-(cyclohexylmethyl)-7-ethylsulfanylpyrazolo[1,5-a]pyrimidin-2-yl]methanone A solution of azepan-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone (200 mg) in THF (2 ml) was added with sodium ethanethiol (53.8 mg) and 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).

[0200] Example 88: Preparation of azepan-1-yl-[5-(cyclohexylmethyl)-3-fluoro-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]methanone A solution of azepan-1-yl-[5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]methanone (419 mg) in CH3CN (10 ml) was added to selectfluor (970 mg) and stirred at 40 °C for 3 hours. The reaction mixture was concentrated, ice was added to the residue, neutralized with aqueous Na2CO3, and extracted with AcOEt. The organic layer was concentrated, and the residue was purified by basic column chromatography (Hexane / AcOEt) to obtain the target compound (95 mg).

[0201] Example 89: Preparation of azepan-1-yl-[5-(cyclohexylmethyl)-7-(dipropylamino)pyrazolo[1,5-a]pyrimidin-2-yl]methanone A solution of azepan-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone (200 mg) in IPA (2 ml) was added with dipropylamine (439 μl) and 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).

[0202] Example 90: Preparation of azepan-1-yl-[5-(cyclohexylmethyl)-7-cyclohexyloxypyrazolo[1,5-a]pyrimidin-2-yl]methanone A solution of azepan-1-yl-[7-chloro-5-(cyclohexylmethyl)pyrazolo[1,5-a]pyrimidin-2-yl]methanone (200 mg) and cyclohexanol (1113 μl) in THF (5 ml) was added with KOH (150 mg) and stirred at room temperature for 30 minutes. Water and aqueous NH4Cl were added to the reaction mixture, which was then 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).

[0203] Example 116: Preparation of [5-(cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]-[4-(2-methoxyethyl)-2,2-dimethylpiperazin-1-yl]methanone [5-(Cyclohexylmethyl)-7-propan-2-ylpyrazolo[1,5-a]pyrimidin-2-yl]-(2,2-dimethylpiperazin-1-yl)methanone (512 mg), 2-bromoethyl methyl ether (0.147 ml), and K2CO3 (267 mg) were dissolved in NMP (5 ml) and stirred at room temperature for 3 days. Saturated Na2CO3 aqueous solution was added, and the mixture was extracted with toluene. The organic layer was concentrated. The residue was purified by silica gel column chromatography (hexane / AcOEt) to obtain the target compound (314 mg).

[0204] 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 produced in the same manner as in Examples 1 to 4, 6 to 9, 15, 28, 53, 87 to 90, and 116. The structural formulas and physical property data of the compounds of Examples 1 to 162 are shown in Tables 2-1 to 2-23, respectively.

[0205] [Table 2-1] Table 36 [Table 2-2] Table 37 [Table 2-3] Table 38 [Table 2-4] Table 39 [Table 2-5] Table 40 [Table 2-6] Table 41 [Table 2-7] Table 42 [Table 2-8] Table 43 [Table 2-9] Table 44 [Table 2-10] Table 45 [Table 2-11] Table 46 [Table 2-12] Table 47 [Table 2-13] Table 48 [Table 2-14] Table 49 [Table 2-15]

Table 50

[0206] [Test example] Test Example 1: Measurement of intracellular calcium concentration 4 × 10 HEK293 cells, a human embryonic kidney-derived cell line, were cultured in MEM culture medium (Invitrogen) supplemented with 10% fetal bovine serum (10% FBS). 5 The cells were adjusted to a concentration of 1000 cells / mL in MEM medium supplemented with 1% FBS and seeded at 25 μL / well in a 384-well black plate (clear bottom) (Greiner) coated with Poly-D-Lysine. The plated cells were cultured for 2 days in a CO2 incubator. 20 μL of Fluo-8 No Wash Calcium Assay Kit (AAT Bioquest) prepared in 10 mM Hepes buffer (0.1% BSA-HHBS) supplemented with 0.1% bovine serum albumin was added to the cells. 5 μL of test compound solution prepared in 0.1% BSA-HHBS was then added to the cells and the cells were cultured for 30 minutes in a CO2 incubator. SLIGKV-NH2 (Sigma-Aldrich) diluted in 0.1% BSA-HHBS buffer was added to a 384-well polypropylene plate (Greiner) to prepare an agonist plate. The cell plate containing the test compound and the agonist plate were placed in the FDSS / μCELL (Hamamatsu Photonics), and 10 μL of SLIGKV-NH2 solution was added from the agonist plate using the built-in automatic dispenser (final concentration: 10 μM). The fluorescence change was detected by a CCD camera in the FDSS / μCELL at 37°C for 180 seconds immediately after addition, and the change in intracellular calcium was measured. I C 50 The values ​​(nM) are shown in Tables 3-1 and 3-2.

[0207] [Table 3-1] [Table 59] [Table 3-2] [Table 60]

[0208] Test Example 2: Scratching behavior test with PAR2 agonist peptide administration A scratching behavior measurement magnet (Neuroscience, Inc.) was implanted into both paws of 6-7 week-old female ICR mice under 3.5% isoflurane inhalation anesthesia. After about one week, the mice were allowed to acclimate overnight in a cylindrical cage for a scratching behavior measurement device (MicroAct, Neuroscience, Inc.). Under isoflurane inhalation anesthesia, the upper back was shaved to a size of approximately 2 x 3 cm with a shaver, and 40 μL of a 6% test compound solution was applied using a micropipette. The mice were then housed in dedicated cages for one 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 PAR2 agonist peptide (SLIGRL-NH2) dissolved in distilled water at 25 mg / mL was administered intradermally using a needle connected to a Hamilton syringe. The mice were then returned to their cages and the number of scratches was measured using a scratching behavior measuring device for 30 minutes, from 10 to 40 minutes after administration. The scratching inhibitory effect of the test compound was calculated as the inhibition rate relative to the number of scratchings in the solvent-applied and PAR2 agonist peptide-administered groups, and the results are shown in Table 4 as a percentage.

[0209] [Table 4] [Table 61]

[0210] Test Example 3: Scratching behavior test using atopic dermatitis model Magnets for measuring scratching behavior were implanted in both paws of 7-week-old female NC / Nga mice under anesthesia. Approximately one week later, an area of ​​approximately 2 x 3 cm on the upper back was shaved with a shaver and depilated with depilatory cream under isoflurane anesthesia. Next, 100 μL of 4% SDS was applied to the depilated area under anesthesia, and two hours later, an appropriate amount (approximately 100 μg) of mite antigen ointment (Biosta AD, Biosta Co., Ltd.) was applied. This SDS and mite ointment sensitization was performed a total of six times over 14 days. Before the final sensitization, the animals' skin symptoms were scored based on redness (7-point scale) and crusting (7-point scale) using the following criteria. Animals with a total score (dermatitis score) of 2 or higher were selected as test candidates. Transepidermal water loss (TEWL) was measured using a Tewameter TM300 (Courage+Khazaka). Subsequently, animals were divided into groups based on the dermatitis score and TEWL values, and the final sensitization was performed. After grouping, the animals were acclimatized overnight in cylindrical cages for a scratching behavior measurement device (MicroAct, Neuroscience Inc.). The following morning, under anesthesia, 60 μL of the test compound dissolved in the solvent (1%, 3%, or 6%) was applied to the animals. The number of scratches was measured using the scratching behavior measurement device 7 hours after application. 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 scratching incidents in the group of non-sensitized animals to which the solvent was applied was converted to an inhibition rate of 100%, and the number of scratching incidents in the group of sensitized animals to which the solvent was applied was converted to an inhibition rate of 0%, and the scratching inhibitory effect of the example compounds is shown in Table 5 as a percentage. [Table 62]

[0211] [Table 5] [Table 63]

[0212] Test Example 4: Rabbit skin cumulative irritation test Female NZW rabbits aged 18-20 weeks had their backs shaved with a shaver and were fitted with a collar (Natsume Seisakusho). A 2.5 cm x 2.5 cm frame was placed on the back of the rabbit, and 50 μL of 3% compound dissolved in 70% ethanol was applied to two or three rabbits. The next day (approximately 24 hours later), the drug applied the previous day was wiped away with absorbent cotton soaked in lukewarm water, and approximately 30 minutes later, erythema (scored on a 5-point scale) and edema (scored on a 5-point scale) were evaluated using the scoring scale shown below. After the score evaluation, the compound was applied again. This procedure was repeated for 7 days, and irritation was evaluated based on the total score of erythema and edema on the final evaluation day (Day 7) and the average maximum (total) score during the test period. The scoring criteria were as follows: [Table 64]

[0213] [Table 6] [Table 65]

Claims

1. General formula [I]: 【Chemical 1】 During the ceremony R 1 is C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-8 Cycloalkoxy, C 1-6 Alkylthio or mono or di C 1-6 alkylamino; R 2 is a halogen or C 1-6 C4-8 cycloalkyl optionally substituted with alkyl, halogen or C 1-6 C optionally substituted with alkyl 4-10 Bicycloalkyl, C 5-13 Spiroalkyl, C 6-12 Tricycloalkyl, halogen, C 1-6 Alkyl or C 1-6 C optionally substituted with haloalkyl 3-8 Cycloalkyl-C 1-6 Alkyl, C 3-8 Cycloalkoxy-C 1-6 Alkyl, halogen or C 1-6 C optionally substituted with alkyl 4-10 Bicycloalkyl-C 1-6 Alkyl, C 6-12 Tricycloalkyl-C 1-6 Alkyl, C 6-12 tricycloalkyl-amino or piperidinyl; R 3 is hydrogen, halogen or C 1-6 is alkyl; 【Chemistry 2】 is a halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkoxy-C 1-6 a 5- to 9-membered saturated or partially unsaturated heterocycle or its oxo derivative containing one nitrogen atom as a ring-constituting element, which may have alkyl, hydroxy or methylidene as a substituent, and which heterocycle may further have one nitrogen atom, one oxygen atom and / or one sulfur atom as ring-constituting elements; provided that R 2 is halogen or piperidinyl, and 【Chemistry 3】 except when it is piperidinyl; or a salt thereof.

2. In general formula [I], 【Chemistry 4】 is piperidinyl, azepanyl, azocanyl, azonanyl, azepinyl, 2,3,4,7-tetrahydroazepinyl, 2,3,6,7-tetrahydroazepinyl, diazepanyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazepanyl or oxo-forms thereof, and the heterocycle is 1-6 Alkyl, C 1-6 optionally having alkoxy or hydroxy as a substituent; 2. The compound according to claim 1, wherein:

3. In general formula [I], R 1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 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; R 2 is cyclopentyl, cyclohexyl, 1-methylcyclohexyl, 4-butylcyclohexyl, 4,4-difluorocyclohexyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]heptanylmethyl, bicyclo[4.1.0]heptanyl, bicyclo[2.2.2]octanyl, decahydronaphthyl, adamantyl (tricyclo[3.3.1.1]decanyl), spiro[2,5]octanyl, spiro[3,3]heptanylmethyl, 1-cyclohexylcyclopropyl, 1-methylcyclohexylmethyl, 2-methylcyclohexylmethyl, 3-methylcyclohexylmethyl, 4-methylcyclohexylmethyl, 3,5-dimethylcyclohexylmethyl, 4-ethylcyclohexylmethyl cyclohexyl, 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; R 3 is hydrogen; 【Chemistry 5】 are azepanil, azocanyl, azonanyl, 2,3,4,7-tetrahydroazepinyl, 2,3,6,7-tetrahydroazepinyl, 1,4-diazepanyl, oxazepanyl, 2,2-dimethylazepanyl, 3-hydroxyazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4,4-difluoroazepanyl, 4-methylpiperidinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-methylidenepiperidinyl, 2,2-dimethyl-4-hydroxypiperidinyl, 2,2-dimethyl-3-methoxypiperidinyl, 2,2-dimethyl-4-methoxypiperidinyl, 2,2,4,4-tetrahydroazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxy ...3-methylidenepiperidinyl, 2,2-dimethyl-4-hydroxypiperidinyl, 2,2-dimethyl-3-methoxypiperidinyl, 2,2-dimethyl-4-methoxypiperidinyl, 2,2,4,4-tetrahydroazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyazepanyl, 4-methylazepanyl, 4-hydroxyaze methylpiperidinyl, 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-dimethylpiperazinyl, 2,2-dimethyl-4-hydroxypiperazinyl, 2,2-dimethylmorpholinyl, 2,2-dimethyl-3-oxopiperidinyl, 2,2,4,4-tetramethyl-3-hydroxypiperidinyl, 2,2,4,4-tetramethyl-3-oxopiperidinyl, 2,2-dimethyl-4-thiomorpholinyl, 3,3-dimethyl-4-thiomorpholinyl, or oxazepanyl; 2. The compound according to claim 1, wherein:

4. In general formula [I], R 1 is ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 3-pentyl, cyclohexyl or trifluoromethyl; R 2 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]heptanylmethyl, spiro[3.3]heptanylmethyl or adamantylamino; R 3 is hydrogen; 【Chemistry 6】 is piperidinyl, azepanyl, azocanyl, 2,3,4,7-tetrahydroazepinyl, 2,2-dimethylpiperidinyl, 2,2-dimethyl-3-hydroxypiperidinyl, 2,2-dimethyl-3-oxopiperidinyl, 2,2,4,4-tetramethyl-3-oxopiperidinyl or 3,3-dimethyl-4-thiomorpholinyl; 2. The compound according to claim 1, wherein:

5. 2. The compound according to claim 1, selected from the following, or a salt thereof: 【Chemistry 7】 【Chemistry 8】

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