T-type calcium channel blocker

Abstract

The present invention provides a compound that has a T-type calcium channel blocking effect and that is represented by formula (I) [in the formula, R1, R2, R3, R4, k, l, m, and n are as defined in the description] or a pharmacologically acceptable salt thereof, and a drug that is useful in the treatment of diseases caused by activation of T-type calcium channels.

Description

T-type calcium channel inhibitors

[0001] The present invention relates to a T-type calcium channel inhibitor. More specifically, the present invention relates to a novel compound having a 1,3-dihydro-2H-benzimidazol-2-one skeleton and having T-type calcium channel inhibitory activity, and a pharmaceutical composition containing the same. The present invention also relates to a dopamine D ２ receptor (hereinafter referred to as D ２ The present invention may also be useful as a therapeutic agent for diseases caused by T-type calcium channel activation, such as pain and pruritus, by attenuating the inhibitory action of T-type calcium channels (sometimes referred to as T-type calcium channel receptors) and thereby reducing the risk of side effects.

[0002] Ion channels are transmembrane channels and are broadly divided into two types: ligand-gated channels and voltage-gated channels. In recent years, voltage-gated sodium channels and voltage-gated calcium channels have been identified as targets of one type of neuropathic pain mechanism. Drugs that target voltage-gated sodium channels include, for example, lidocaine, carbamazepine, lamotrigine, and mexiletine. Drugs that target voltage-gated calcium channels include, for example, gabapentin, pregabalin, and ziconotide.

[0003] Neuropathic pain is difficult to treat and responds poorly to existing analgesics. Even with established drug therapies, it is difficult to reliably predict their effectiveness, and other medications often must be used in combination. The Japan Society of Pain Clinicians' guidelines for neuropathic pain medication recommend high-voltage-activated calcium channel inhibitors as the first-line treatment, but these drugs often fail to provide sufficient therapeutic benefit. These inhibitors also have side effects, such as dizziness.

[0004] Voltage-gated calcium channels are classified into two types: high-voltage activated and low-voltage activated, depending on the activation and inactivation potentials. L-type, N-type, P / Q-type, and R-type calcium channels are activated by large depolarizations and are therefore classified as high-voltage activated calcium channels. In contrast, T-type calcium channels are activated by small depolarizations and are therefore classified as low-voltage activated calcium channels.

[0005] Recently, it has been reported that T-type calcium channels are involved in the onset and progression of neuropathic pain, suggesting the possibility that T-type calcium channel inhibitors could be therapeutic drugs for neuropathic pain. Known compounds with T-type calcium channel inhibitory activity include mibefradil (e.g., Non-Patent Document 1), ethosuximide, and (1S,2S)-2-[2-[[3-(1H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4-tetrahydro-1-(1-methylethyl)-2-naphthalenyl-cyclopropanecarboxylate hydrochloride (NNC55-0396) (e.g., Non-Patent Document 2).

[0006] Furthermore, T-type calcium channels are known to be involved in pathologies associated with various diseases and disorders, including pain such as neuropathic pain, inflammatory pain, and cancer pain, as well as epilepsy, essential tremor, schizophrenia, Parkinson's disease, depression, anxiety, sleep disorders, psychosis, schizophrenia, cardiac arrhythmia, hypertension, cancer, diabetes, overactive bladder, chronic kidney disease, infertility, and sexual dysfunction (Patent Document 1).

[0007] Currently, 1-{1-[4,4-bis(4-fluorophenyl)butyl]piperidin-4-yl}-1,3-dihydro-2H-benzimidazol-2-one (hereinafter sometimes referred to as pimozide) is known as a compound having a 1,3-dihydro-2H-benzimidazol-2-one skeleton that has T-type calcium channel inhibitory activity. However, this compound has a stronger D-type calcium channel inhibitory activity than the T-type calcium channel inhibitory activity. ２ Pimozide has strong D receptor inhibitory activity. ２The receptor inhibitory effect has the problem of causing extrapyramidal symptoms, and therefore T-type calcium channel inhibitory activity could not be applied to the treatment of diseases. ２ There are no known compounds having a 1,3-dihydro-2H-benzimidazol-2-one skeleton that can attenuate receptor inhibitory activity and effectively reduce the risk of side effects.

[0008] Although several compounds that can be used as T-type calcium channel inhibitors have already been found, there is a need to investigate further compounds that can be used as new T-type calcium channel inhibitors from the viewpoint of side effects and the like.

[0009] International Publication No. 2015-050212

[0010] Todorovic, Neuron, 2001, 31(1), p.75-85Huang, J Pharmacol Exp Ther., 309(1), p.193-199

[0011] The present invention investigates novel compounds having T-type calcium channel inhibitory activity and ２ The object of the present invention is to provide a pharmaceutical (e.g., a T-type calcium channel inhibitor) that is useful for treating diseases caused by activation of T-type calcium channels (e.g., pain, pruritus), which can attenuate receptor inhibitory action and reduce the risk of side effects.

[0012] As a result of intensive research aimed at solving the above problems, the present inventors have found that a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "the compound of the present invention") has a T-type calcium channel inhibitory effect. ２ The present invention was completed based on the discovery that the risk of side effects can be reduced by attenuating the receptor inhibitory effect.

[0013] That is, the present invention provides the following aspects: [1] A compound represented by formula (I): [In the formula: R １ is C １－１０ Alkyl, C(O)-C １－１０ Alkyl, C１－６ Alkylene-R １ａ , C(O)-C １－６ Alkylene-R １ａ , C １－６ Alkylene -CHR １ｂ R １ｂ or C(O)-C １－６ Alkylene -CHR １ｂ R １ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R ２ is hydrogen, C １－１０ Alkyl, C(O)-C １－１０ Alkyl, C １－６ Alkylene-R ２ａ , C(O)-C １－６ Alkylene-R ２ａ , C １－６ Alkylene -CHR ２ｂ R ２ｂ or C(O)-C １－６ Alkylene -CHR ２ｂ R ２ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ are each independently C １－６ Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ aryloxy, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 5- to 10-membered heteroaryloxy; R １ｂ and R ２ｂ Each independently represents an optionally substituted C ３－８Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０ R is selected from the group consisting of aryl and optionally substituted 5-10 membered heteroaryl; ３ are each independently a halogen, C １－６ Alkyl, C １－６ selected from the group consisting of haloalkyl, amino and hydroxy; R ４ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ alkenyl or C ２－６ alkynyl; k is 0 or 1; l is 0 to 2; m is 0 or 1, provided that when k is 1 and m is 1, R ４ and the carbon atom bonded to N together form a 4- to 6-membered nitrogen-containing heterocycle (the ring may be substituted with halogen, hydroxy, C １－６ Alkyl and C １－６ and n is 0 to 4, ... [2] Formula (I) is a compound represented by the formula (Ia): [In the formula: R １ , R ２ , R ３and n has the same meaning as in [1]. [3] The compound according to [1], wherein formula (I) is formula (Ib): [In the formula: R １ , R ２ , R ３ and n has the same meaning as in [1], or a pharmaceutically acceptable salt thereof. １ But C １－６ Alkyl, C(O)-C １－６ Alkyl, C １－６ Alkylene-R １ａ , C(O)-C １－６ Alkylene-R １ａ , C １－４ Alkylene -CHR １ｂ R １ｂ or C(O)-C １－４ Alkylene -CHR １ｂ R １ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R ２ But C １－６ Alkyl, C(O)-C １－６ Alkyl, C １－６ Alkylene-R ２ａ , C(O)-C １－６ Alkylene-R ２ａ , C １－４ Alkylene -CHR ２ｂ R ２ｂ or C(O)-C １－４ Alkylene -CHR ２ｂ R ２ｂ and the C １－６ The alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ are each independently C ３－８ Cycloalkyl, C ３－８ Cycloalkoxy, C ６－１０ Aryl and C ６－１０aryloxy, each of which may be selected at any available position from halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ R may be substituted with one or more of the same or different groups selected from the group consisting of haloalkyl, amino and hydroxy; １ｂ and R ２ｂ are each independently C ３－８ Cycloalkyl and C ６－１０ aryl, each of which may be selected at any available position from the group consisting of halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ R may be substituted with one or more of the same or different groups selected from the group consisting of haloalkyl, amino and hydroxy; ３ [5] The compound according to any one of [1] to [3], or a pharmaceutically acceptable salt thereof, wherein R is independently selected from the group consisting of halogen, amino, and hydroxy; and n is 0 or 1. １ But C １－６ Alkyl, C １－６ Alkylene-R １ａ , C(O)-C １－６ Alkylene-R １ａ or C １－４ Alkylene -CHR １ｂ R １ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ But C ３－６ Cycloalkyl, C ３－６ cycloalkyloxy, phenyl or phenoxy, each of which may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl; and R １ｂ However, each independently, C ３－６cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ [6] The compound according to any one of [1] to [4], or a pharmaceutically acceptable salt thereof, optionally substituted with one or two or more identical or different groups selected from the group consisting of haloalkyl. １ But C １－６ Alkyl, C １－６ Alkylene-R １ａ , C(O)-C １－６ Alkylene-R １ａ or C １－４ Alkylene -CHR １ｂ R １ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ But C ５－６ Cycloalkyl, C ５－６ cycloalkyloxy, phenyl, and phenoxy, each of which may be selected at any substitutable position from halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl; and R １ｂ However, each independently, C ５－６ cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ [7] The compound according to any one of [1] to [5], or a pharmaceutically acceptable salt thereof, optionally substituted with one or two or more identical or different groups selected from the group consisting of haloalkyl. １ But C １－６ Alkyl, C １－６ Alkylene-R １ａ , C(O)-C １－６ Alkylene-R １ａ , C１－４ Alkylene -CHR １ｂ R １ｂ and R １ａ is cyclohexyl, phenyl or phenoxy, and each group is optionally substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl; and R １ｂ are each independently selected from the group consisting of cyclohexyl and phenyl, and each group may be selected at any available position from halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ [8] The compound according to any one of [1] to [6], or a pharmaceutically acceptable salt thereof, optionally substituted with one or two or more identical or different groups selected from the group consisting of haloalkyl. １ But C １－５ Alkyl, wherein p is 1 to 4 and q is 1 to 5, and each group is selected from the group consisting of halogen and C １－６ The compound according to any one of [1] to [7], or a pharmaceutically acceptable salt thereof, optionally substituted with one or two or more identical or different groups selected from the group consisting of alkoxy. [9] R １ But butyl, [In the formula, R ５ is hydrogen, halogen or methoxy, and R ６

[10] The compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof, wherein R is a group selected from the group consisting of: ２ But C １－６ Alkyl, C １－６ Alkylene-R ２ａ , C(O)-C １－６ Alkylene-R ２ａ or C １－４ Alkylene -CHR ２ｂ R ２ｂ and R２ａ But C ３－６ Cycloalkyl, C ３－６ cycloalkyloxy, phenyl, and phenoxy, each of which may be selected at any substitutable position from halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl; and R ２ｂ However, each independently, C ３－６ cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６

[11] The compound according to any one of [1] to [9], or a pharmaceutically acceptable salt thereof, optionally substituted with one or two or more identical or different groups selected from the group consisting of haloalkyl. ２ But C １－６ Alkyl, C １－６ Alkylene-R ２ａ or C １－４ Alkylene -CHR ２ｂ R ２ｂ Yes; R ２ａ But C ５－６ Cycloalkyl, C ５－６ cycloalkyloxy, phenyl, and phenoxy, each of which may be substituted with halogen or C １－６ optionally substituted with alkoxy; and R ２ｂ However, each independently, C ５－６ cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen or C １－６

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

[10] , or a pharmaceutically acceptable salt thereof, optionally substituted by alkoxy. ２ But C １－６ Alkyl, C １－６ Alkylene-R ２ａ or C １－４ Alkylene -CHR ２ｂ R ２ｂ Yes; R２ａ is cyclohexyl, phenyl or phenoxy, and each group is selected from the group consisting of halogen and C １－６ optionally substituted with alkoxy; and R ２ｂ are each independently selected from the group consisting of cyclohexyl and phenyl, and each group is selected at any available position from halogen or C １－６

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

[11] , which is optionally substituted by alkoxy, or a pharmaceutically acceptable salt thereof. ２ But C １－５ Alkyl, [wherein p and q are as defined in [8]], and each group is selected from the group consisting of halogen and C at substitutable positions. １－６

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

[12] , or a pharmaceutically acceptable salt thereof, optionally substituted with one or two or more identical or different groups selected from the group consisting of alkoxy. ２ But butyl, [In the formula, R ５is hydrogen, halogen, or methoxy, and r is 1 to 5.

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

[13] , or a pharmaceutically acceptable salt thereof, including 1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 5), 1-butyl-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 6), 1-(4-cyclohexylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 7), 1-(1-(4-cyclohexylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 8), 1-(4-cyclohexylbutyl)-3-(1-(4-cyclohexylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 9), 1,3-bis(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 10), 1-(4-cyclohexylbutyl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 11), 1-(1-(4-cyclohexylbutyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 12), 1-(1-butylpiperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 13), 1-(4-phenylbutyl)-3-(1-(3-phenylpropyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 14), 1-(1-(4-phenylbutanoyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 15), 1-(4-phenylbutyl)-3-(1-(5-phenylpentyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 16),1-(1-(4-phenylbutyl)piperidin-4-yl)-3-(3-phenylpropyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 17), 1-(1-(4-phenylbutyl)piperidin-4-yl)-3-(5-phenylpentyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 18), 1-(1-benzylpiperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 19), 1-benzyl-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 20), 1-(1-(3-phenoxypropyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 21), 1-(3-phenoxypropyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 22), 1-(3-phenoxypropyl)-3-(1-(3-phenoxypropyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 23), 1-(1-(4-(2-methoxyphenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 24), 1-(4-(2-methoxyphenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 25), 1-(4-(2-methoxyphenyl)butyl)-3-(1-(4-(2-methoxyphenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 26), 1-(1-(4-(2-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 27), 1-(4-(2-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 28),1-(4-(2-chlorophenyl)butyl)-3-(1-(4-(2-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 29), 1-(1-(4-(2-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 30), 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 31), 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-(2-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 32), 1-(1-(4-(3-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 33), 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 34), 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-(3-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 35), 1-(1-(4-(3-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 36), 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 37), 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-(3-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 38), 1-(1-(4-(4-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 39),1-(4-(4-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 40), 1-(4-(4-chlorophenyl)butyl)-3-(1-(4-(4-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 41), 1-(1-(4-(4-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 42), 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 43), 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-(4-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 44), 5-fluoro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 45), 5-chloro-3-(4-phenylbutyl)-1-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 46), 5-chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 47), The compound according to [1], or a pharmaceutically acceptable salt thereof, selected from 4-chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (compound 48), 1-(1-(4,4-diphenylbutyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (compound 49), or 1-(1-(4,4-bis(4-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (compound 50).

[16] A compound of formula (I): [In the formula: R１ is C １－１０ Alkyl, C(O)-C １－１０ Alkyl, C １－６ Alkylene-R １ａ , C(O)-C １－６ Alkylene-R １ａ , C １－６ Alkylene -CHR １ｂ R １ｂ or C(O)-C １－６ Alkylene -CHR １ｂ R １ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R ２ is hydrogen, C １－１０ Alkyl, C(O)-C １－１０ Alkyl, C １－６ Alkylene-R ２ａ , C(O)-C １－６ Alkylene-R ２ａ , C １－６ Alkylene -CHR ２ｂ R ２ｂ or C(O)-C １－６ Alkylene -CHR ２ｂ R ２ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ are each independently C １－６ Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ aryloxy, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 5- to 10-membered heteroaryloxy; R １ｂ and R２ｂ Each independently represents an optionally substituted C ３－８ Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０ R is selected from the group consisting of aryl and optionally substituted 5-10 membered heteroaryl; ３ are each independently a halogen, C １－６ Alkyl, C １－６ selected from the group consisting of haloalkyl, amino and hydroxy; R ４ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ alkenyl or C ２－６ alkynyl; k is 0 or 1; l is 0 to 2; m is 0 or 1, provided that when k is 1 and m is 1, R ４ and the carbon atom bonded to N together form a 4- to 6-membered nitrogen-containing heterocycle (the ring may be substituted with halogen, hydroxy, C １－６ Alkyl and C １－６and n is 0 to 4] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[17] The pharmaceutical composition according to

[16] , for treating a disease caused by T-type calcium channel activation.

[18] The pharmaceutical composition according to

[17] , wherein the disease is selected from pain, epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic depression, bipolar disorder, depression, anxiety, dementia, Huntington's disease, sleep disorder, stroke, pruritus, atopic dermatitis, hyperaldosteronism, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes, infertility, sexual dysfunction, arrhythmia, hypertension, kidney disease, and overactive bladder.

[19] The pharmaceutical composition according to

[17] or

[18] , wherein the disease is pain.

[20] The pharmaceutical composition according to

[17] or

[18] , wherein the disease is pruritus.

[21] A compound represented by Formula (I): [In the formula: R １ is C １－１０ Alkyl, C(O)-C １－１０ Alkyl, C １－６ Alkylene-R １ａ , C(O)-C １－６ Alkylene-R １ａ , C １－６ Alkylene -CHR １ｂ R １ｂ or C(O)-C １－６ Alkylene -CHR １ｂ R １ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R ２ is hydrogen, C １－１０ Alkyl, C(O)-C １－１０ Alkyl, C １－６ Alkylene-R ２ａ , C(O)-C １－６ Alkylene-R ２ａ, C １－６ Alkylene -CHR ２ｂ R ２ｂ or C(O)-C １－６ Alkylene -CHR ２ｂ R ２ｂ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ are each independently C １－６ Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ aryloxy, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 5- to 10-membered heteroaryloxy; R １ｂ and R ２ｂ Each independently represents an optionally substituted C ３－８ Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０ R is selected from the group consisting of aryl and optionally substituted 5-10 membered heteroaryl; ３ are each independently a halogen, C １－６ Alkyl, C １－６ selected from the group consisting of haloalkyl, amino and hydroxy; R ４ is C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ alkenyl or C ２－６ alkynyl; k is 0 or 1; l is 0 to 2; m is 0 or 1, provided that when k is 1 and m is 1, R ４and the carbon atom bonded to N together form a 4- to 6-membered nitrogen-containing heterocycle (the ring may be substituted with halogen, hydroxy, C １－６ Alkyl and C １－６ and n is 0 to 4] (excluding 1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one) or a pharmaceutically acceptable salt thereof.

[0014] The present invention further provides the following aspects.

[22] A method for treating a disease caused by T-type calcium channel activation, comprising administering to a patient in need of such treatment a therapeutically effective amount of the compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to

[16] .

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

[15] or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease caused by T-type calcium channel activation.

[24] Use of the compound according to any one of [1] to

[15] or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic agent for a disease caused by T-type calcium channel activation.

[25] The method for treatment according to

[22] , the compound according to

[23] or a pharmaceutically acceptable salt thereof, or the use according to

[24] , wherein the disease is pain.

[26] The method for treatment according to

[22] , the compound according to

[23] or a pharmaceutically acceptable salt thereof, or the use according to

[24] , wherein the disease is pruritus.

[27] The pharmaceutical composition according to

[18] or

[19] , or the method of treatment, compound or a pharmaceutically acceptable salt thereof, or use according to

[25] , wherein the pain is visceral pain or somatic pain.

[28] The pharmaceutical composition according to

[18] or

[19] , the method of treatment according to

[25] , the compound or a pharmaceutically acceptable salt thereof, or use according to

[25] , wherein the pain is visceral pain, acute pain, chronic pain, or neuropathic pain.

[29] The pharmaceutical composition according to

[18] or

[19] , the method of treatment according to

[25] , the compound or a pharmaceutically acceptable salt thereof, or use according to

[25] , wherein the pain is acute pain or chronic pain.

[30] The pharmaceutical composition according to

[18] or

[19] , the method of treatment according to

[25] , the compound or a pharmaceutically acceptable salt thereof, or use according to

[25] , wherein the pain is neuropathic pain.

[31] The pharmaceutical composition according to

[18] or

[20] , the treatment method according to

[26] , the compound according to

[26] or a pharmaceutically acceptable salt thereof, or the use according to

[26] , wherein the pruritus is intractable pruritus.

[0015] According to the present invention, a novel benzimidazolone compound having excellent T-type calcium channel inhibitory activity can be provided. ２ The present invention may be useful as a novel therapeutic agent for diseases caused by activation of T-type calcium channels, such as pain and pruritus, which can attenuate receptor inhibitory action and reduce the risk of side effects.

[0016] The figures show the ratios (%) of T channel current values ​​after addition of pimozide and the compounds of the present invention (3 μM and 1 μM) to the T channel current values ​​after addition of the vehicle (solvent, control group) (n=3-10). (a) shows data obtained by directly adding the test compound at a concentration of 3 μM, and (b) shows data obtained by directly adding the test compound at a concentration of 1 μM. The figures show the rate of change in T channel current values ​​before addition of the vehicle and the compounds of the present invention and after perfusion addition of the vehicle and the compounds of the present invention (0.3 μM) (n=3-8). Dopamine D ２ Receptor and ３ (a) shows the inhibition rate of [H]-spiperone binding at a concentration of 1 μM by pimozide and compounds 4 to 7 (n=3). ３ H]-spiperone dopamine D ２ (b) shows the inhibition rate of receptor-specific binding at concentrations of 1 μM and 10 μM for pimozide, Compound 25, Compound 28, and Compound 30. ３ H]-spiperone dopamine D ２ (c) shows the inhibition rate of receptor-specific binding in pimozide, Compound 26, Compound 36 and Compound 38 at concentrations of 1 μM and 10 μM. ３ H]-spiperone dopamine D ２ The inhibition rate of each compound is shown as a ratio of each compound to the inhibition rate of pimozide, which is set to 100%. ３ H]-spiperone dopamine D ２ The receptor-specific binding amount is shown (n=3). (a) shows the [ ３ H]-spiperone dopamine D ２Receptor specific binding amount, after addition of pimozide, Compound 25, Compound 28 and Compound 30 at concentrations of 1 μM and 10 μM [ ３ H]-spiperone dopamine D ２ The receptor specific binding amount and the [ ３ H]-spiperone dopamine D ２ (b) shows the amount of receptor-specific binding when the solvent was added (total binding amount) ３ H]-spiperone dopamine D ２ Receptor specific binding amount, after addition of pimozide, Compound 26, Compound 36 and Compound 38 at concentrations of 1 μM and 10 μM [ ３ H]-spiperone dopamine D ２ The receptor specific binding amount and the [ ３ H]-spiperone dopamine D ２The amount of receptor-specific binding is shown. The duration of catalepsy (seconds) at 30, 60, 90, 120, 150, and 180 minutes after vehicle and test compound administration is shown. The mean ± standard error of scratching and wiping counts at 10, 20, 30, 40, 50, and 60 minutes after right cheek intradermal administration, as well as the mean ± standard error of total counts over 60 minutes, are shown. The mean ± standard error of pain thresholds (g) before, immediately after, and 15 to 60 minutes after hind paw intraplantar administration are shown. A graph of the mean ± standard error (n=6-7) of total scratching counts by the hind paw at the intradermal administration site 60 minutes after right cheek intradermal administration is shown for the group administered with saline containing 1% DMSO and 5% Tween 80 (solvent 1) + saline (solvent 2) (control group), the group administered with solvent 1 + histamine, and the group administered with compound 5 (10 mg / kg) + histamine.

[0049] Figure 1 shows a graph of the mean ± standard error (n=10) of the total number of scratching counts with the hind paws at the intradermal injection site 60 minutes after intradermal administration on the right cheek in the group (control group) administered with saline containing 1% DMSO and 5% Tween 80 (solvent 1) + saline (solvent 2), the group administered with solvent 1 + chloroquine, and the group administered with Compound 5 (10 mg / kg) + chloroquine. Figure 2 shows a graph of the mean ± standard error (n=6-8) of the total number of scratching counts with the hind paws at the intradermal injection site 60 minutes after intradermal administration on the right cheek in the group (control group) administered with saline containing 1% DMSO and 5% Tween 80 (solvent 1) + saline (solvent 2) (solvent group), the group administered with solvent 1 + chloroquine, the group administered with Compound 38 (1 mg / kg) + chloroquine, the group administered with Compound 38 (3 mg / kg) + chloroquine, and the group administered with Compound 38 (10 mg / kg) + chloroquine.

[0017] The terms used in this specification will be explained below.

[0018] As used herein, "halogen" means fluorine, chlorine, bromine or iodine.

[0019] In this specification, "C １－１０ "Alkyl" means a straight or branched chain saturated hydrocarbon group having from 1 to 10 carbon atoms. １－６ Alkyl" and "C １－４"Alkyl" means alkyl having 1 to 6 carbon atoms and alkyl having 1 to 4 carbon atoms, respectively. １－１０ Examples of "alkyl" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, and the like. They may be substituted at substitutable positions with one or more substituents included in the present invention.

[0020] In this specification, "C １－６ "Alkylene" means a divalent saturated hydrocarbon group having from 1 to 6 carbon atoms, which may be straight or branched, or a divalent saturated hydrocarbon group containing a cyclic structure having from 3 to 6 carbon atoms. １－４ "Alkylene" means an alkylene having 1 to 4 carbon atoms. １－６ Examples of "alkylene" include methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene, 2-methylethylene, 1-ethylethylene, etc. They may be substituted at substitutable positions with one or more substituents included in the present invention.

[0021] In this specification, "C ２－６ "Alkenyl" means a straight or branched chain unsaturated hydrocarbon group having from 2 to 6 carbon atoms and having one or more carbon-carbon double bonds at any position. ２－６ Alkenyl is preferably C ２－４ "C alkenyl". ２－６ Examples of "alkenyl" include ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc., which may be substituted at substitutable positions with one or more substituents included in the present invention.

[0022] In this specification, "C ２－６"Alkynyl" means a straight or branched chain unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or more carbon-carbon triple bonds at any position. ２－６ Alkynyl is preferably C ２－６ "Alkynyl". ２－６ Examples of "alkynyl" include ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc., which may be substituted at substitutable positions with one or more substituents included in the present invention.

[0023] In this specification, "C １－６ "Haloalkyl" refers to an alkyl group as defined above having 1 to 6 carbon atoms in which one or more hydrogen atoms have been replaced by halogen atoms. The number of replaced hydrogen atoms can range from 1 up to the total number of other hydrogen atoms present in the parent alkyl group. When there are multiple halogen atoms, they may be replaced by the same or different halogen atoms. １－６ Examples of "haloalkyl" include fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, and the like.

[0024] In this specification, "C １－６ "Alkoxy" means a group in which the above alkyl group having 1 to 6 carbon atoms is bonded via an oxygen atom. １－６ Examples of "alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butyloxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc. The alkyl portion thereof may be substituted with one or more substituents included in the present invention at substitutable positions.

[0025] In this specification, "C ３－８ "Cycloalkyl" means a monocyclic or polycyclic saturated or partially unsaturated hydrocarbon group having 3 to 8 carbon atoms. ３－８ "Cycloalkyl" is preferably "C ３－６ "Cycloalkyl". ３－８Examples of "cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyladamantyl, norbornyl, cyclopropylene, cyclobutylene, etc., which may be substituted at substitutable positions with one or more substituents included in the present invention.

[0026] In this specification, "C ３－８ "Cycloalkoxy" means the above C ３－８ It means an oxy group substituted by cycloalkyl. ３－８ Examples of "cycloalkoxy" include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and the like. They may be substituted at available positions with one or more substituents included in the present invention. The cycloalkyl portion thereof may be substituted at available positions with one or more substituents included in the present invention.

[0027] As used herein, "3- to 10-membered heterocycloalkyl" refers to a 3- to 10-membered monocyclic or bicyclic non-aromatic heterocyclic group containing one or more (e.g., 1 to 4) heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. The nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen atom may be optionally quaternized. Bicyclic heterocycloalkyl groups also include monocyclic heterocycloalkyl groups fused with an aromatic ring (e.g., benzene, pyridine) or a non-aromatic ring (e.g., cyclohexyl, piperidine). "3- to 10-membered heterocycloalkyl" is preferably a 5- or 6-membered heterocycloalkyl. Examples of "3- to 10-membered heterocycloalkyl" include aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, tetrahydrofuranyl, tetrahydropyranyl, and the like. They may be substituted, at substitutable positions, with one or more substituents encompassed by the present invention.

[0028] As used herein, "3- to 10-membered heterocycloalkoxy" refers to an oxy group substituted by the above-mentioned 3- to 10-membered heterocycloalkyl. Examples of "3- to 10-membered heterocycloalkoxy" include aziridinyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, morpholinyloxy, homopiperidinyloxy, tetrahydrofuranyloxy, and tetrahydropyranyloxy. The heterocycloalkyl moiety may be substituted with one or more substituents included in the present invention at substitutable positions.

[0029] In this specification, "C ６－１０ "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. ６－１０ "Aryl" is preferably "C ６ aryl(phenyl)". ６－１０ Examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc., which may be substituted at substitutable positions with one or more substituents included in the present invention.

[0030] In this specification, "C ６－１０ "Aryloxy" means the above C ６－１０ It means an oxy group substituted by an aryl. ６－１０ "Aryloxy" is preferably C ６ It is aryloxy. ６－１０ Examples of "aryloxy" include phenoxy, 1-naphthyloxy, 2-naphthyloxy, etc. The aryl moiety may be substituted with one or more substituents included in the present invention at substitutable positions.

[0031] As used herein, "5- to 10-membered heteroaryl" refers to a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic group containing one or more (e.g., 1 to 4) heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Bicyclic heteroaryl groups also include those in which a monocyclic heteroaryl group is fused with an aromatic ring (e.g., benzene, pyridine) or a non-aromatic ring (e.g., cyclohexyl, piperidine). The "5- to 10-membered heteroaryl" is preferably a 5- or 6-membered heteroaryl. Examples of "5- to 10-membered heteroaryl" include pyridyl, pyridazinyl, isothiazolyl, pyrrolyl, furyl, thienyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrazinyl, triazinyl, triazolyl, imidazolidinyl, oxadiazolyl, tetrazolyl, indolyl, indazolyl, quinolyl, isoquinolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, benzimidazolyl, etc. These may be substituted at substitutable positions with one or more substituents included in the present invention.

[0032] As used herein, "5- to 10-membered heteroaryloxy" refers to an oxy group substituted by the above-mentioned 5- to 10-membered heteroaryl. The "5- to 10-membered heteroaryloxy" is preferably a 5- or 6-membered heteroaryloxy. Examples of the "5- to 10-membered heteroaryloxy" include pyridyloxy, pyridazinyloxy, pyrrolyloxy, furyloxy, thienyloxy, thiazolyloxy, pyrimidinyloxy, pyrazolyloxy, and isoquinolyloxy. The heteroaryl moiety may be substituted with one or more substituents included in the present invention at substitutable positions.

[0033] As used herein, "4- to 6-membered nitrogen-containing heterocycle" refers to a saturated or partially unsaturated 4- to 6-membered ring having one nitrogen atom. Examples of "4- to 6-membered nitrogen-containing heterocycle" include azetidine, pyrrolidine, pyrroline, piperidine, and piperidine. These may be substituted at substitutable positions with one or more substituents included in the present invention.

[0034] In this specification, "optionally substituted" includes cases where the substitutable positions of the group are not substituted (unsubstituted) and cases where they are substituted. "Unsubstituted" means that all substitutable positions of the group are hydrogen atoms. When substituted, the group may be substituted with multiple substituents, if possible, and the substituents may be the same or different. In this specification, "optionally substituted C ３－８ "cycloalkyl," "optionally substituted C ３－８ "cycloalkoxy", "optionally substituted 3- to 10-membered heterocycloalkyl", "optionally substituted 3- to 10-membered heterocycloalkoxy", "optionally substituted C ６－１０ aryl," "optionally substituted C ６－１０ Substituents in "aryloxy," "optionally substituted 5- to 10-membered heteroaryl," and "optionally substituted 5- to 10-membered heteroaryloxy" include, for example, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, haloalkyl, alkoxy, haloalkoxy, amino, nitro, cyano, hydroxy, mono- or di-alkylamino, carbamoyl, carboxyl, morpholinyl, formyl, acetyl, mesyl, benzoyl, acylamino, benzyl, aryl, heteroaryl, and the like. Such substituents are preferably halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ haloalkyl, amino and hydroxy.

[0035] R in the compounds of the present invention represented by formula (I), formula (Ia) and formula (Ib) １ , R ２ , R ３ , R４ With regard to k, l, m and n, the preferred ones are as follows, but the technical scope of the present invention is not limited to the range of the compounds listed below.

[0036] R １ As for the following, (1) C １－１０ Alkyl; (2) C(O)-C １－１０ alkyl; (3) C １－６ Alkylene-R １ａ (R １ａ is C １－６ Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ (4) C(O)-C(aryloxy), optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 5- to 10-membered heteroaryloxy); １－６ Alkylene-R １ａ (R １ａ is C １－６ Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ (5) C is an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted 5- to 10-membered heteroaryloxy, or an optionally substituted 5- to 10-membered heteroaryloxy; １－６ Alkylene -CHR １ｂ R １ｂ (R １ｂ Each independently represents an optionally substituted C ３－８ Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０(6) C(O)—C １－６ Alkylene -CHR １ｂ R １ｂ (R １ｂ Each independently represents an optionally substituted C ３－８ Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０ aryl and optionally substituted 5- to 10-membered heteroaryl), and the alkyl and alkylene may be substituted, at substitutable positions, with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy.

[0037] R １ is preferably: (1) C １－６ Alkyl; (2) C(O)-C １－６ alkyl; (3) C １－６ Alkylene-R １ａ (R １ａ is C ３－８ Cycloalkyl, C ３－８ Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C ６－１０ Aryl, C ６－１０ aryloxy, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryloxy, each of which may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (4) C(O)-C １－６ Alkylene-R １ａ (R １ａ is C ３－８ Cycloalkyl, C ３－８ Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C ６－１０ Aryl, C ６－１０aryloxy, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryloxy, and the cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aryloxy, heteroaryl, and heteroaryloxy may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (5) C may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino and hydroxy; １－４ Alkylene -CHR １ｂ R １ｂ (R １ｂ are each independently C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６－１０ aryl and 5-10 membered heteroaryl, each of which may be selected at any available position from halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (6) C(O)—C １－４ Alkylene -CHR １ｂ R １ｂ (R １ｂ are each independently C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６－１０ aryl and 5-10 membered heteroaryl, each of which may be selected at any available position from halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (1) C may be substituted with one or more of the same or different groups selected from the group consisting of haloalkyl, amino, and hydroxy; １－６ alkyl; (2) C １－６ Alkylene-R １ａ (R １ａ is C ３－６ Cycloalkyl, C ３－６cycloalkyloxy, phenyl or phenoxy, each of which may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ (3) C(O)-C １－６ Alkylene-R １ａ (R １ａ is C ３－６ Cycloalkyl, C ３－６ cycloalkyloxy, phenyl or phenoxy, each of which may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl); or (4) C １－４ Alkylene -CHR １ｂ R １ｂ (R １ｂ are each independently C ３－６ cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ (1) C １－６ alkyl; (2) C １－６ Alkylene-R １ａ (R １ａ is C ５－６ Cycloalkyl, C ５－６ cycloalkyloxy, phenyl or phenoxy, each of which may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ (3) C(O)-C １－６ Alkylene-R １ａ (R １ａ is C ５－６Cycloalkyl, C ５－６ cycloalkyloxy, phenyl or phenoxy, each of which may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl); or (4) C １－４ Alkylene -CHR １ｂ R １ｂ (R １ｂ are each independently C ５－６ cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ (1) optionally substituted with one or two or more identical or different groups selected from the group consisting of haloalkyl; and even more preferably, １－６ alkyl; (2) C １－６ Alkylene-R １ａ (R １ａ is cyclohexyl, phenyl or phenoxy, and each group may be selected at any substitutable position from halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ (3) C(O)-C １－６ Alkylene-R １ａ (R １ａ is cyclohexyl, phenyl or phenoxy, and each group may be selected at any substitutable position from halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl); or (4) C １－４ Alkylene -CHR １ｂ R １ｂ (R １ｂ are each independently selected from the group consisting of cyclohexyl and phenyl, and each group may be selected at any available position from halogen, C１－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl), and particularly preferably C １－５ Alkyl, wherein p is 1 to 4 and q is 1 to 5, each of which is selected from the group consisting of halogen and C １－６ alkoxy), most preferably butyl, [In the formula, R ５ is hydrogen, halogen or methoxy, and R ６ are each independently hydrogen or halogen, and r is 1 to 5. １ The alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy.

[0038] R ２ (1) hydrogen; (2) C １－１０ Alkyl; (3) C(O)-C １－１０ alkyl; (4) C １－６ Alkylene-R ２ａ (R ２ａ is C １－６ Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ (4) C(O)-C(aryloxy), optionally substituted 5- to 10-membered heteroaryl, or optionally substituted 5- to 10-membered heteroaryloxy); １－６ Alkylene-R ２ａ (R ２ａ is C １－６Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ (5) C is an optionally substituted 5- to 10-membered heteroaryl, an optionally substituted 5- to 10-membered heteroaryloxy, or an optionally substituted 5- to 10-membered heteroaryloxy; １－６ Alkylene -CHR ２ｂ R ２ｂ (R ２ｂ Each independently represents an optionally substituted C ３－８ Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０ (6) C(O)—C １－６ Alkylene -CHR ２ｂ R ２ｂ (R ２ｂ Each independently represents an optionally substituted C ３－８ Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０ aryl and optionally substituted 5- to 10-membered heteroaryl), and the alkyl and alkylene may be substituted, at substitutable positions, with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy.

[0039] R ２ is preferably: (1) C １－６ Alkyl; (2) C(O)-C １－６ alkyl; (3) C １－６ Alkylene-R ２ａ (R ２ａ is C ３－８ Cycloalkyl, C ３－８ Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C６－１０ Aryl, C ６－１０ aryloxy, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryloxy, each of which may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (4) C(O)-C １－６ Alkylene-R ２ａ (R ２ａ is C ３－８ Cycloalkyl, C ３－８ Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C ６－１０ Aryl, C ６－１０ aryloxy, 5- to 10-membered heteroaryl, or 5- to 10-membered heteroaryloxy, and the cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aryloxy, heteroaryl, and heteroaryloxy may be substituted with halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (5) C may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino and hydroxy; １－４ Alkylene -CHR ２ｂ R ２ｂ (R ２ｂ are each independently C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６－１０ aryl and 5-10 membered heteroaryl, each of which may be selected at any available position from halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (6) C(O)—C １－４ Alkylene -CHR ２ｂ R ２ｂ (R２ｂ are each independently C ３－８ cycloalkyl, 3- to 8-membered heterocycloalkyl, C ６－１０ aryl and 5-10 membered heteroaryl, each of which may be selected at any available position from halogen, C １－６ Alkyl, C １－６ Alkoxy, C １－６ (1) C may be substituted with one or more of the same or different groups selected from the group consisting of haloalkyl, amino, and hydroxy; １－６ alkyl; (2) C １－６ Alkylene-R ２ａ (R ２ａ is C ３－６ Cycloalkyl, C ３－６ cycloalkyloxy, phenyl, and phenoxy, each of which may be selected at any substitutable position from halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ (3) C(O)-C １－６ Alkylene-R ２ａ (R ２ａ is C ３－６ Cycloalkyl, C ３－６ cycloalkyloxy, phenyl, and phenoxy, each of which may be selected at any substitutable position from halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６ haloalkyl); or (4) C １－４ Alkylene -CHR ２ｂ R ２ｂ (R ２ｂ are each independently C ３－６ cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen, C １－６ Alkyl, C １－６ Alkoxy and C １－６(1) C １－６ alkyl; (2) C １－６ Alkylene-R ２ａ (R ２ａ is C ５－６ Cycloalkyl, C ５－６ cycloalkyloxy, phenyl, and phenoxy, each of which may be substituted with halogen or C １－６ (3) C １－４ Alkylene -CHR ２ｂ R ２ｂ (R ２ｂ are each independently C ５－６ cycloalkyl and phenyl, each of which may be selected at any available position from the group consisting of halogen or C １－６ (1) C １－６ alkyl; (2) C １－６ Alkylene-R ２ａ (R ２ａ is cyclohexyl, phenyl or phenoxy, each group being optionally substituted with halogen or C １－６ (3) C １－４ Alkylene -CHR ２ｂ R ２ｂ (R ２ｂ are each independently selected from the group consisting of cyclohexyl and phenyl, and each group is selected at any available position from halogen or C １－６ and optionally substituted with alkoxy, and particularly preferably C １－５ Alkyl, [wherein p and q are the same as those in R １ and each of the groups selected from the group consisting of halogen and C １－６ alkoxy), most preferably butyl, [In the formula, R ５is hydrogen, halogen or methoxy, and r is 1 to 5.

[0040] R ３ Examples of the halogen include C. １－６ Alkyl, C １－６ Examples include haloalkyl, amino and hydroxy. Among these, halogen is preferred, and fluoro and chloro are more preferred.

[0041] R ４ As for C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenyl and C ２－６ Among them, C is preferably alkynyl. １－６ It is preferably alkyl, and more preferably methyl.

[0042] k is 0 or 1, l is 0 to 2, preferably 0 or 2, m is 0 or 1, and n is 0 to 4, preferably 0 or 1. When k is 1 and m is 1, R ４ and the carbon atom bonded to N together form a 4- to 6-membered nitrogen-containing heterocycle (the ring may be substituted with halogen, hydroxy, C １－６ Alkyl and C １－６ Preferably, k is 1, l is 2, m is 1, R ４ is methyl, then R ４ and the carbon atom bonded to N together form a piperidine ring. １ is also preferably directly bonded to

[0043] As used herein, "pharmaceutically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. Examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, etc. Examples of salts with organic acids include salts with acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptoic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, sulfosalicylic acid, etc.

[0044] The compound of the present invention may exist in the form of a hydrate and / or a solvate, and therefore, these hydrates or solvates such as ethanol solvates are also included in the compound of the present invention. Furthermore, the compound of the present invention also includes all crystalline forms.

[0045] The compounds of the present invention may exist as tautomers, and these tautomers are also encompassed in the compounds of the present invention.

[0046] The compounds of the present invention may have at least one asymmetric carbon atom, and therefore include not only the racemic compounds of the compounds represented by formula (I), formula (Ia), and formula (Ib), but also the optically active compounds of these compounds. When the compounds of formula (I), (Ia), and (Ib) have two or more asymmetric carbon atoms, stereoisomerism may occur. Therefore, the compounds of the present invention also include stereoisomers of these compounds, as well as mixtures and isolated forms thereof. In addition, any one or more of the compounds represented by formula (I), formula (Ia), and formula (Ib) may be used. １ H ２ Deuterium-converted derivatives converted to H(D) are also encompassed in the compounds of the present invention.

[0047] The production method of the compound of the present invention will be explained below with reference to examples, but the present invention is not limited to these.

[0048] The compounds used as starting compounds may be used as their respective salts. Note that these reactions are merely illustrative, and the compounds of the present invention may also be produced by other appropriate methods based on the knowledge of those skilled in organic synthesis.

[0049] In each of the production methods described below, even if the use of a protecting group is not specifically specified, if a functional group that requires protection is present, the functional group may be protected as necessary, and the target product may be obtained by deprotecting the functional group after completion of the reaction or after performing a series of reactions.

[0050] As the protecting group, a conventional protecting group described in the literature (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, Inc., New York (1999)) can be used. More specifically, examples of the protecting group for an amino group include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl, and examples of the protecting group for a hydroxy group include trialkylsilyl, acetyl, and benzyl.

[0051] Introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (e.g., the method described in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, Inc., New York (1999)) or a method similar thereto.

[0052] Among the compounds represented by formula (I), the compounds represented by formula (I-a) and formula (I-b) can be produced, for example, by the following production method. The starting compound, tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1), can be produced according to a known method, for example, the method described in J. Med. Chem., 2018, 61, 8895-8907. [In the formula: R １ has the same meaning as [1] above]

[0053] Production Method 2 Among the compounds represented by formula (I), the compound represented by formula (Ic) can be produced, for example, by the following production method. [In the formula: R １ is the same as the above [1], and R is R in the above [1]. １ is equivalent to

[0054] Of the compounds represented by formula (I), the compounds represented by formula (I-d) and formula (I-e) can be produced, for example, by the following production method: o-Phenylenediamine, the starting compound, is a commercially available product or can be produced according to known methods. [In the formula: R １ is the same as the above [1], and R is R in the above [1]. １ is equivalent to

[0055] Production Method 4 Among the compounds represented by formula (I), the compounds represented by formula (If) and formula (Ig) can be produced, for example, by the following production method. [In the formula: R １ is the same as the above [1], and R is R in the above [1]. １ is equivalent to

[0056] Production Method 5 Among the compounds represented by formula (I), the compound represented by formula (Ih) can be produced, for example, by the following production method. [Wherein: R is R in [1] above] １ and R' is C １－６Alkylene-R １ａ or C １－６ Alkylene -CHR １ｂ R １ｂ The alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ is C １－６ Alkoxy, optionally substituted C ３－８ Cycloalkyl, optionally substituted C ３－８ Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C ６－１０ aryl, optionally substituted C ６－１０ aryloxy, optionally substituted 5- to 10-membered heteroaryl, and optionally substituted 5- to 10-membered heteroaryloxy; R １ｂ Each independently represents an optionally substituted C ３－８ Cycloalkyl, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted C ６－１０ aryl and optionally substituted 5- to 10-membered heteroaryl.

[0057] Of the compounds represented by formula (I), the compounds represented by formula (I-j) and formula (I-k) can be produced, for example, by the following production method: The compound represented by formula (I-i) can be produced by a known method. [In the formula: R １ and R ３ is the same as the above [1], and R is R in the above [1]. １ is equivalent to

[0058] The solvent, acid and base used in the above production method can be appropriately changed depending on the types of raw material compounds, etc. Furthermore, conditions such as reaction temperature can also be appropriately changed.

[0059] The compound of the present invention or an intermediate thereof can be separated and purified by methods known to those skilled in the art. Examples of suitable methods include extraction, distribution, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion exchange column chromatography, or preparative liquid chromatography), and recrystallization. Examples of suitable recrystallization solvents include alcoholic solvents such as methanol, ethanol, and 2-propanol; etheric solvents such as diethyl ether; esteric solvents such as ethyl acetate; aromatic hydrocarbon solvents such as benzene and toluene; ketone solvents such as acetone; halogenated solvents such as dichloromethane and chloroform; hydrocarbon solvents such as hexane; aprotic solvents such as dimethylformamide and acetonitrile; water; and mixed solvents of two or more of the above solvents. Other purification methods include those described in Volume 1 of "Experimental Chemistry Lectures" (edited by the Chemical Society of Japan, Maruzen).

[0060] In the present invention, "diseases caused by T-type calcium channel activation" refers to diseases or symptoms thereof caused by activation of T-type calcium channels. Examples include, but are not limited to, pain, epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic-depressive illness, bipolar disorder, depression, anxiety, dementia, Huntington's disease, sleep disorders, stroke, pruritus, atopic dermatitis, hyperaldosteronism, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes, infertility, sexual dysfunction, arrhythmia, hypertension, kidney disease, and overactive bladder. In the present invention, preferred diseases include pain and pruritus, more preferably visceral pain, somatic pain, and pruritus, and even more preferably visceral pain, acute pain, chronic pain, neuropathic pain, and pruritus. Neuropathic pain is particularly preferred as pain.

[0061] In the present invention, "treatment" refers to any treatment (e.g., amelioration, alleviation, inhibition of progression, etc.) of a disease and its symptoms in a patient, particularly a human. It also includes prevention of the onset and / or progression of the disease.

[0062] In the present invention, the term "patient" refers to humans and animals, such as dogs, cats, horses, etc. Among these, humans are preferred.

[0063] As used herein, a "therapeutically effective amount" refers to an amount that results in a treatment of a disease and its symptoms or delays the progression of a disease and its symptoms compared to an untreated subject. The term also includes within its scope an amount effective to promote normal physiological function. Such effective amounts include the amount of a compound of the present invention alone, the amount of a combination of compounds of the present invention, and / or the amount of a compound of the present invention in combination with other active ingredients useful in treating a disease.

[0064] The compound of the present invention can be used in the form of a pharmaceutical composition. The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier.

[0065] Since the compound of the present invention has a T-type calcium channel inhibitory activity, the pharmaceutical composition of the present invention can be a novel therapeutic agent for pain (e.g., visceral pain, somatic pain), epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic-depressive illness, bipolar disorder, depression, anxiety, dementia, Huntington's disease, sleep disorder, stroke, pruritus (e.g., intractable pruritus observed in chronic kidney disease and chronic liver disease), atopic dermatitis, hyperaldosteronism, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes, infertility, sexual dysfunction, arrhythmia, hypertension, kidney disease, overactive bladder, etc. The pharmaceutical composition of the present invention can be preferably a therapeutic agent for visceral pain, somatic pain, and pruritus, more preferably a therapeutic agent for visceral pain, acute pain, chronic pain, neuropathic pain, and pruritus, and even more preferably a therapeutic agent for neuropathic pain and pruritus.

[0066] The compounds and pharmaceutical compositions of the present invention can be administered orally or parenterally by being formulated into appropriate dosage forms.

[0067] The dosage forms of the compound and pharmaceutical composition of the present invention include, for example, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolving tablets), capsules, granules (effervescent granules), powders, oral liquids (elixirs, suspensions, emulsions, lemonades), syrups (syrup preparations), oral jellies, oral tablets (troches, sublingual tablets, buccal tablets, adhesive tablets, gums), oral sprays, oral semisolid preparations, mouthwashes, injections (infusions, implantable injections, sustained-release injections), dialysis preparations ( Examples of the pharmaceutical composition include, but are not limited to, peritoneal dialysis agents, hemodialysis agents), inhalants (inhalation powders, inhalation liquids, inhalation aerosols), suppositories, rectal semisolid preparations, enemas, eye drops, eye ointments, ear drops, nasal preparations (nasal powders, nasal liquids), vaginal tablets, vaginal suppositories, solid preparations for external application (external powders), liquid preparations for external application (liniments, lotions), sprays (external aerosols, pump sprays), ointments, creams, gels, patches (tapes, poultices), etc. The formulations of the present invention can be produced by known methods using the compounds of the present invention and pharmaceutically acceptable additives.

[0068] Pharmaceutically acceptable additives (carriers) include stabilizers, surfactants, solubilizers, buffers, suspending agents, antioxidants, coating agents, wetting agents, moisturizing agents, cooling agents, colorants, flavoring agents, isotonicity agents, emulsifiers, pH adjusters, skin protective agents, dispersants, propellants, fragrances, preservatives, and solvents, and these additives (carriers) can be used depending on the purpose.

[0069] The compound of the present invention may be used in combination with other drugs as long as the therapeutic effects on diseases such as pain and pruritus are not impaired.

[0070] The dosage will vary depending on the individual compound, the patient's disease, age, weight, sex, symptoms, administration route, etc., but typically, for an adult (body weight 60 kg), the compound of the present invention is administered at a dose of 0.1 to 1000 mg / day, preferably 0.1 to 300 mg / day, once a day or in two or three divided doses. It can also be administered once every few days to every few weeks.

[0071] The present invention will be explained in more detail below with reference to Reference Examples, Examples, and Test Examples, but these examples are not intended to limit the scope of the present invention. The names of compounds shown in the following Reference Examples and Examples do not necessarily conform to the IUPAC nomenclature, and the compounds were identified by NMR spectroscopy.

[0072] To simplify the description in the specification, the following abbreviations may be used in the examples: Symbols used in NMR include s, singlet, d, doublet, dd, double doublet, ddd, double double doublet, t, triplet, td, triple doublet, tt, triple triplet, q, quartet, qd, quadruplet, quintet, sext, sext, m, multiplet, br, broad, brs, broad singlet, and J, coupling constant.

[0073] Reference Example 1 1-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (2) Under an Ar atmosphere, 4-phenylbutyl bromide (432 mg, 2.04 mmol) and potassium carbonate (141 mg, 2.04 mmol) were sequentially added to a solution of o-phenylenediamine (200 mg, 1.85 mmol) in N,N-dimethylformamide (5 mL), followed by stirring at room temperature for 16 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. N,N-dimethylformamide (5 mL) was added to the resulting residue. Carbonyldiimidazole (600 mg, 0.37 mmol) was then sequentially added at room temperature, followed by stirring at room temperature for 15 hours. After completion of the reaction, the solvent was removed using a rotary evaporator, and the resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (163 mg, 33% over two steps, 0.61 mmol).

[0074] 1H-NMR (400 MHz, CDCl3) δ: 1.74 (2H, quin, J = 7.2 Hz), 1.83 (2H, quin, J = 7.2 Hz), 2.68 (2H, t, J = 7.2 Hz), 3.91 (2H, t, J = 7.2 Hz), 6.96-6.97 (1H, m), 7.06-7.11 (3H, m), 7.16-7.20 (3H, m), 7.27-7.29 (2H, m), 8.73 (1H, br).

[0075] Reference Example 2 tert-Butyl 4-(2-oxo-3-(4-phenylbutyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (3) Under an Ar atmosphere, sodium hydride (11 mg, 60%, 0.46 mmol) was added to a solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1) (98 mg, 0.31 mmol) in N,N-dimethylformamide (1.5 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. Subsequently, 4-phenylbutyl bromide (78 mg, 0.37 mmol) was added under ice-cooling, followed by stirring at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) ​​to obtain the title compound (113 mg, 82%, 0.25 mmol).

[0076] 1H-NMR (400 MHz, CDCl3) δ: 1.50 (9H, s), 1.66-1.82 (6H, m), 2.31 (2H, qd, J = 12.8, 4.4 Hz), 2.66 (2H, t, J = 8.0 Hz), 2.86 (2H, br), 3.88 (2H, t, J = 8.0 Hz), 4.31 (2H, br), 4.49 (1H, tt, J = 12.8, 4.4 Hz), 6.95-6.97 (1H, m), 7.05 (2H, ddd, J = 6.8, 4.4, 2.0 Hz), 7.11-7.19 (4H, m), 7.25-7.28 (2H, m).

[0077] Reference Example 3 tert-Butyl 4-(2-oxo-3-(3-phenylpropyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (4) Under an Ar atmosphere, sodium hydride (11 mg, 60%, 0.46 mmol) was added to a solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1) (98 mg, 0.31 mmol) in N,N-dimethylformamide (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 3-phenylpropyl bromide (0.37 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to obtain the title compound (yield 95%).

[0078] 1H-NMR (400 MHz, CDCl3) δ: 1.50 (9H, s), 1.81 (2H, d, J = 11.2 Hz), 2.09 (2H, quin, J = 7.6 Hz), 2.31 (2H, qd, J = 12.8, 4.4 Hz), 2.72 (2H, t, J = 7.6 Hz), 2.86 (2H, br), 3.91 (2H, t, J = 7.6 Hz), 4.31 (2H, br), 4.49 (1H, tt, J = 12.8, 4.4 Hz), 6.90-6.92 (1H, m), 7.04-7.06 (2H, m), 7.11-7.14 (1H, m), 7.20 (3H, d, J = 7.2 Hz), 7.28-7.30 (2H, m).

[0079] Reference examples 4 to 13 The compounds of Reference Examples 4 to 13 were obtained according to the method described in Reference Example 3, except that the corresponding alkyl bromide was used in place of 3-phenylpropyl bromide.

[0080] Reference Example 14 tert-Butyl 4-(6-fluoro-2-oxo-3-(4-phenylbutyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (19) Under an Ar atmosphere, sodium hydride (11 mg, 60%, 0.46 mmol) was added to a solution of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (15) (0.31 mmol) in N,N-dimethylformamide (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 4-phenylbutyl bromide (79 mg, 0.37 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to obtain the title compound (yield 45%).

[0081] 1 H-NMR (500 MHz, CDCl3) δ: 1.50 (9H, s), 1.67-1.80 (6H, m), 2.24 (2H, dq, J = 8.0, 4.5 Hz), 2.65 (2H, t, J = 8.0 Hz), 2.85 (2H, br), 3.85 (2H, t, J = 8.0 Hz), 4.32 (2H, br), 4.44 (1H, m), 6.76 (1H, dt, J = 9.0, 2.0 Hz), 6.82 (1H, q, J = 4.5 Hz), 6.86 (1H, dd, J = 9.0, 2.0 Hz), 7.16 (2H, d, J = 7.5 Hz), 7.18 (1H, t, J = 7.5 Hz) 7.25 (2H, m).

[0082] Reference Example 15 tert-Butyl 4-(5-chloro-2-oxo-3-(4-phenylbutyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (20) The compound of Reference Example 15 (yield 58%) was obtained according to the method described in Reference Example 14, except that tert-butyl 4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (16) was used instead of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (15).

[0083] 1 H-NMR (400 MHz, CDCl3) δ: 1.56 (9H, s), 1.75-1.86 (6H, m), 2.30 (2H, dq, J = 6.0, 3.2 Hz), 2.72 (2H, t, J = 6.0 Hz), 2.90 (2H, br), 3.89 (2H, t, J = 6.0 Hz), 4.36 (2H, br), 4.50 (1H, tt, J = 10.0, 3.2 Hz), 6.99 (1H, s), 7.06 (2H, s), 7.21-7.33 (5H, m).

[0084] Reference Example 16 tert-Butyl 4-(6-chloro-2-oxo-3-(4-phenylbutyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (21) The compound of Reference Example 16 (yield 35%) was obtained according to the method described in Reference Example 14, except that tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (17) was used instead of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (15).

[0085] 1H-NMR (400 MHz, CDCl3) δ: 1.51 (9H, s), 1.66-1.81 (6H, m), 2.22-2.33 (2H, m), 2.65 (2H, t, J = 7.2 Hz), 2.85 (2H, br), 3.84-3.90 (2H, m), 4.31 (2H, br), 4.41-4.47 (1H, m), 6.84 (1H, d, J = 8.0 Hz), 7.02-7.20 (5H, m), 7.25-7.28 (2H, m).

[0086] Reference Example 17 tert-Butyl 4-(7-chloro-2-oxo-3-(4-phenylbutyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (22) The compound of Reference Example 17 (yield 69%) was obtained according to the method described in Reference Example 14, except that tert-butyl 4-(7-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (18) was used instead of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (15).

[0087] 1 H-NMR (400 MHz, CDCl3) δ: 1.48 (9H, s), 1.64-1.82 (7H, m), 2.65 (4H, t, J = 6.4 Hz), 2.79 (2H, br), 3.84 (2H, t, J = 6.4 Hz), 4.33 (2H, br), 5.14 (1H, br), 6.82 (1H, d, J = 7.6 Hz), 6.95-7.02 (2H, m), 7.14-7.19 (3H, m), 7.25-7.28 (2H, m).

[0088] Example 1 1-(1-benzylpiperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 1) Under an Ar atmosphere, trifluoroacetic acid (0.24 mL, 3.15 mmol) was added to a dichloromethane (1.5 mL) solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1) (100 mg, 0.32 mmol) under ice-cooling, followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and N,N-dimethylformamide (1.5 mL) was added to the resulting residue. Next, benzyl bromide (0.35 mmol) and potassium carbonate (221 mg, 1.60 mmol) were added sequentially at room temperature, followed by stirring at room temperature for 22 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 1:5) to obtain the title compound (yield 81%, two steps).

[0089] The product was analyzed by NMR, and the NMR results were in complete agreement with those described in J. Med. Chem., 2018, 61, 8895-8907.

[0090] Example 2 1-(1-(2-phenylethyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 2) The title compound was obtained according to the method described in Example 1, except that 2-phenylethyl bromide was used instead of benzyl bromide (yield 53%, two steps).

[0091] The product was analyzed by NMR, and the NMR results were in perfect agreement with those of the commercially available compound (No. AQ303831) from Aquila Pharmatech LLC.

[0092] Example 3 1-(1-(3-phenylpropyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 3) The title compound was obtained according to the method described in Example 1, except that 3-phenylpropyl bromide was used instead of benzyl bromide (yield 78%, two steps).

[0093] The product was analyzed by NMR, and the NMR results were in complete agreement with those described in J. Med. Chem., 2018, 61, 8895-8907.

[0094] Examples 4 and 5 1-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 4) and 1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 5) The title compounds (Compounds 4 and 5) were obtained according to the method described in Example 1, except that 4-phenylbutyl bromide was used instead of benzyl bromide.

[0095] Compound 4 (25% yield, 2 steps) was analyzed by NMR, and the NMR results were completely consistent with those of the commercially available compound (No. CB0902185) from Chemieliva Pharmaceutical Co., Ltd.

[0096] The NMR data of compound 5 (yield 11%, 2 steps) is as follows: 1 H-NMR (400 MHz, CDCl3) δ: 1.53-1.80 (10H, m), 2.10 (2H, t, J = 11.6 Hz), 2.39-2.47 (4H, m), 2.65 (4H, t, J = 7.6 Hz), 3.06 (2H, d, J = 11.6 Hz), 3.88 (2H, t, J = 6.4 Hz), 4.39 (1H, tt, J = 12.4, 4.4 Hz), 6.93-6.95 (1H, m), 7.00-7.07 (2H, m), 7.14-7.20 (6H, m), 7.24-7.31 (5H, m).

[0097] Example 6 1-butyl-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 6) Under an Ar atmosphere, sodium hydride (4 mg, 60%, 0.10 mmol) was added to a solution of compound 4 (29 mg, 0.07 mmol) in N,N-dimethylformamide (1.5 mL) under ice-cooling, followed by stirring at room temperature for 30 minutes. Subsequently, butyl bromide (0.10 mmol) was added under ice-cooling, followed by stirring at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (dichloromethane:methanol = 20:1 to 10:1) to obtain the title compound (yield 57%).

[0098] 1 H-NMR (400 MHz, CDCl3) δ: 0.95 (3H, t, J = 7.2 Hz), 1.39 (2H, sext, J = 7.2 Hz), 1.57-1.87 (10H, m), 2.11 (2H, t, J = 11.2 Hz), 2.42 (4H, br), 2.65 (2H, t, J = 8.0 Hz), 3.07 (2H, d, J = 11.2 Hz), 3.87 (2H, t, J = 7.2 Hz), 4.41 (1H, tt, J = 12.0, 4.0 Hz), 6.98-7.09 (3H, m), 7.14-7.20 (3H, m), 7.25-7.32 (3H, m).

[0099] Example 7 1-(4-cyclohexylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 7) The title compound (yield 36%) was obtained according to the method described in Example 6, except that 4-cyclohexylbutyl bromide was used instead of butyl bromide.

[0100] 1H-NMR (400 MHz, CDCl3) δ: 0.79-0.87 (2H, m), 1.12-1.22 (7H, m), 1.32-1.39 (2H, m), 1.52-1.74 (12H, m), 1.78 (2H, dd, J = 11.6, 1.6 Hz), 2.10 (2H, t, J = 11.6 Hz), 2.38-2.46 (3H, m), 2.64 (2H, t, J = 7.6 Hz), 3.05 (2H, d, J = 11.6 Hz), 3.84 (2H, t, J = 7.6 Hz), 4.39 (1H, tt, J = 12.4, 4.4 Hz), 6.98 (1H, dd, J = 7.6, 1.6 Hz), 7.02 (1H, td, J = 7.6, 1.6 Hz), 7.06 (1H, td, J = 7.6, 1.6 Hz), 7.14-7.19 (3H, m), 7.25-7.30 (3H, m).

[0101] Examples 8 and 9 1-(1-(4-cyclohexylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 8) and 1-(4-cyclohexylbutyl)-3-(1-(4-cyclohexylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 9) Under an Ar atmosphere, trifluoroacetic acid (0.24 mL, 3.15 mmol) was added to a dichloromethane (1.5 mL) solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidine-1-carboxylate (1) (100 mg, 0.32 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and N,N-dimethylformamide (1.5 mL) was added to the resulting residue. Furthermore, (4-bromobutyl)cyclohexane (77 mg, 0.35 mmol) and potassium carbonate (221 mg, 1.60 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:3) to obtain the title compound.

[0102] Compound 8 (28% yield, 2 steps): 1 H-NMR (400 MHz, CDCl3) δ: 0.83-0.91 (2H, m), 1.09-1.30 (9H, m), 1.51 (2H, br), 1.63-1.71 (5H, m), 1.83 (2H, d, J = 10.0 Hz), 2.14 (2H, br), 2.40 (2H, br), 2.49 (1H, d, J = 10.0 Hz), 3.12 (2H, d, J = 8.8 Hz), 4.39 (1H, t, J = 12.0 Hz), 7.02-7.11 (4H, m).

[0103] Compound 9 (16% yield, 2 steps): 1H-NMR (400 MHz, CDCl3) δ: 0.83-0.90 (4H, m), 1.10-1.23 (12H, m), 1.30-1.40 (4H, m), 1.46-1.53 ​​(2H, m), 1.65-1.73 (12H, m), 1.80 (2H, d, J = 9.6 Hz), 2.11 (2H, t, J = 11.2 Hz), 2.35-2.39 (2H, m), 2.44 (2H, qd, J = 12.4, 4.0 Hz), 3.08 (2H, d, J = 11.2 Hz), 3.85 (2H, t, J = 6.8 Hz), 4.41 (1H, tt, J = 12.4, 4.0 Hz), 6.99 (1H, dd, J = 6.8, 1.2 Hz), 7.03 (1H, td, J = 6.8, 1.2 Hz), 7.07 (1H, td, J = 6.8, 0.8 Hz), 7.32 (1H, dd, J = 6.8, 0.8 Hz).

[0104] Example 10 1,3-bis(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 10) Under an Ar atmosphere, sodium hydride (7 mg, 60%, 0.28 mmol) was added to a solution of the compound of Reference Example 1 (50 mg, 0.19 mmol) in N,N-dimethylformamide (1.5 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, 4-phenylbutyl bromide (0.23 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate = 1:1) to obtain the title compound (yield: 54%).

[0105] 1H-NMR (400 MHz, CDCl3) δ: 1.64-1.72 (4H, m), 1.75-1.82 (4H, m), 2.65 (4H, t, J = 7.6 Hz), 3.89 (4H, t, J = 7.6 Hz), 6.92-6.96 (2H, m), 7.03-7.07 (2H, m).

[0106] Example 11 1-(4-cyclohexylbutyl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 11) The title compound (yield 79%) was obtained according to the method described in Example 10, except that 4-cyclohexylbutyl bromide was used instead of 4-phenylbutyl bromide.

[0107] 1 H-NMR (400 MHz, CDCl3) δ: 0.80-0.88 (2H, m), 1.10-1.24 (6H, m), 1.33-1.40 (2H, m), 1.65-1.83 (11H, m), 2.66 (2H, t, J = 7.6 Hz), 3.87 (2H, J = 7.6 Hz), 3.90 (2H, t, J = 7.6 Hz), 6.94-7.00 (2H, m), 7.05-7.08 (2H, m), 7.15-7.19 (3H, m), 7.24-7.28 (2H, m).

[0108] Example 12 1-(1-(4-cyclohexylbutyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 12) Under an Ar atmosphere, trifluoroacetic acid (0.11 mL, 1.45 mmol) was added to a dichloromethane (1.5 mL) solution of the compound of Reference Example 2 (65 mg, 0.15 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and N,N-dimethylformamide (1.5 mL) was added to the resulting residue. Furthermore, 4-cyclohexylbutyl bromide (0.16 mmol) and potassium carbonate (100 mg, 0.73 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1 to 1:5) to obtain the title compound (yield 44%, two steps).

[0109] 1 H-NMR (400 MHz, CDCl3) δ: 0.83-0.91 (2H, m), 1.12-1.36 (8H, m), 1.46-1.53 ​​(2H, m), 1.63-1.81 (11H, m), 2.11 (2H, td, J = 10.8, 2.0 Hz), 2.37 (2H, t, J = 7.6 Hz), 2.44 (2H, qd, J = 12.0, 4.0 Hz), 2.65 (2H, t, J = 7.6 Hz), 3.08 (2H, d, J = 12.0 Hz), 4.40 (1H, tt, J = 12.0, 4.0 Hz), 6.94-6.96 (1H, m), 7.01-7.07 (2H, m), 7.15-7.19 (3H, m), 2.24-7.28 (2H, m), 7.30-7.33 (1H, m).

[0110] Example 13 1-(1-butylpiperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 13) The title compound was obtained (yield 67%, two steps) according to the method described in Example 12, except that butyl bromide was used instead of 4-cyclohexylbutyl bromide.

[0111] 1 H-NMR (400 MHz, CDCl3) δ: 1.02 (3H, t, J = 7.6 Hz), 1.43 (2H, sext, J = 7.6 Hz), 1.55-1.63 (2H, m), 1.74-1.89 (6H, m), 2.19 (2H, t, J = 10.0 Hz), 2.44-2.48 (2H, m), 2.52 (2H, qd, J = 12.0, 3.6 Hz), 2.73 (2H, t, J = 7.6 Hz), 3.16 (2H, d, J = 12.0 Hz), 4.48 (1H, tt, J = 12.0, 3.6 Hz), 7.01-7.04 (1H, m), 7.08-7.15 (2H, m), 7.22-7.26 (3H, m), 7.32-7.35 (2H, m), 7.38-7.40 (1H, m).

[0112] Example 14 1-(4-phenylbutyl)-3-(1-(3-phenylpropyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 14) The title compound was obtained (74% yield, two steps) according to the method described in Example 12, except that 3-phenylpropyl bromide was used instead of 4-cyclohexylbutyl bromide.

[0113] 1H-NMR (400 MHz, CDCl3) δ: 1.76-1.99 (8H, m), 2.21 (2H, t, J = 11.6 Hz), 2.48-2.58 (4H, m), 2.75 (2H, t, J = 7.6 Hz), 2.77 (2H, t, J = 7.6 Hz), 3.17 (2H, d, J = 12.4 Hz), 3.98 (2H, t, J = 7.6 Hz), 4.49 (1H, tt, J = 12.4, 4.4 Hz), 7.03-7.07 (1H, m), 7.11-7.17 (2H, m), 7.24-7.41 (11H, m).

[0114] Example 15 1-(1-(4-phenylbutanoyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 15) Under an Ar atmosphere, trifluoroacetic acid (0.67 mL, 8.78 mmol) was added to a dichloromethane (5 mL) solution of the compound of Reference Example 2 (394 mg, 0.88 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and dichloromethane (5 mL) was added to the resulting residue. Further, 4-phenylbutyric acid (216 mg, 1.32 mmol), 4-dimethylaminopyridine (161 mg, 1.32 mmol), triethylamine (0.19 mL, 1.32 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (252 mg, 1.32 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, 10% aqueous hydrochloric acid (3 mL) was added. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (2 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain the title compound (353 mg, 81%, two steps, 0.72 mmol).

[0115] 1H-NMR (400 MHz, CDCl3) δ: 1.65-1.87 (7H, m), 1.98-2.06 (3H, m), 2.21-2.33 (2H, m), 2.39 (2H, t, J = 8.0 Hz), 2.65 (2H, t, J = 6.8 Hz), 2.71 (2H, t, J = 6.8 Hz), 3.12 (1H, t, J = 12.4 Hz), 3.87 (2H, t, J = 6.8 Hz), 4.53 (1H, tt, J = 12.4, 4.4 Hz), 4.87 (1H, d, J = 12.4 Hz), 6.94-6.97 (1H, m), 7.01-7.09 (3H, m) 7.14-7.31 (10H, m).

[0116] Example 16 1-(4-phenylbutyl)-3-(1-(5-phenylpentyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 16) Under an Ar atmosphere, trifluoroacetic acid (0.16 mL, 2.14 mmol) was added to a dichloromethane (1 mL) solution of the compound of Reference Example 2 (0.21 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and N,N-dimethylformamide (1 mL) was added to the resulting residue. Furthermore, 5-phenylpentyl bromide (0.43 mmol) and potassium carbonate (147 mg, 1.07 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was then removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:2) to obtain the title compound (yield 33%, two steps).

[0117] 1H-NMR (400 MHz, CDCl3) δ: 1.34-1.42 (2H, m), 1.53-1.81 (10H, m), 2.12 (2H, t, J = 11.6 Hz), 2.37-2.50 (4H, m), 2.64 (2H, t, J = 8.0 Hz), 2.66 (2H, t, J = 8.0 Hz), 3.09 (2H, d, J = 10.8 Hz), 3.89 (2H, t, J = 8.0 Hz), 4.41 (1H, tt, J = 13.2, 4.0 Hz), 6.94-6.96 (1H, m), 7.02-7.08 (2H, m), 7,15-7.20 (6H, m), 7.25-7.32 (5H, m).

[0118] Example 17 1-(1-(4-phenylbutyl)piperidin-4-yl)-3-(3-phenylpropyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 17) The title compound (yield 16%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 3 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0119] 1 H-NMR (400 MHz, CDCl3) δ: 1.59-1.76 (4H, m), 1.85 (2H, d, J = 10.8 Hz), 2.12-2.20 (4H, m), 2.45-2.53 (4H, m), 2.70 (2H, t, J = 7.6 Hz), 2.76 (2H, t, J = 7.6 Hz), 3.12 (2H, d, J = 10.8 Hz), 3.96 (2H, t, J = 7.6 Hz), 4.46 (1H, tt, J = 12.4, 4.0 Hz), 6.94-6.96 (1H, m), 7.06-7.12 (2H, m), 7.22-7.25 (5H, m), 7.30-7.37 (6H, m).

[0120] Example 18 1-(1-(4-phenylbutyl)piperidin-4-yl)-3-(5-phenylpentyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 18) The title compound (yield 28%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 4 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0121] 1 H-NMR (400 MHz, CDCl3) δ: 1.40-1.48 (2H, m), 1.56-1.63 (2H, m), 1.65-1.73 (4H, m), 1.76-1.83 (4H, m), 2.13 (2H, t, J = 11.6 Hz), 2.42-2.50 (4H, m), 2.62 (2H, t, J = 8.0 Hz), 2.68 (2H, t, J = 8.0 Hz), 3.09 (2H, d, J = 11.6 Hz), 3.88 (2H, t, J = 8.0 Hz), 4.42 (1H, tt, J = 11.6, 4.4 Hz), 6.98-7.01 (1H, m), 7.04-7.11 (2H, m), 7.15-7.23 (6H, m), 7.27-7.34 (5H, m).

[0122] Example 19 1-(1-benzylpiperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 19) The title compound was obtained (yield 82%, 2 steps) according to the method described in Example 16, using the compound of Reference Example 4 instead of the compound of Reference Example 2 and benzyl bromide instead of 5-phenylpentyl bromide.

[0123] 1H-NMR (400 MHz, CDCl3) δ: 1.66-1.82 (6H, m), 2.17 (2H, td, J = 12.0, 2.0 Hz), 2.46 (2H, qd, J = 12.0, 4.0 Hz), 2.66 (2H, t, J = 7.2 Hz), 3.03 (2H, d, J = 12.0 Hz), 3.88 (2H, t, J = 7.2 Hz), 4.39 (1H, tt, J = 12.0, 4.0 Hz), 6.93-6.97 (1H, m), 7.03-7.08 (2H, m), 7.15-7.19 (3H, m), 7.24-7.39 (7H, m).

[0124] Example 20 1-benzyl-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 20) The title compound was obtained (yield 42%, 2 steps) according to the method described in Example 16, using the compound of Reference Example 5 instead of the compound of Reference Example 2 and benzyl bromide instead of 5-phenylpentyl bromide.

[0125] 1 H-NMR (400 MHz, CDCl3) δ: 1.46-1.56 (2H, m), 1.59-1.67 (2H, m), 1.79 (2H, dd, J = 12.0, 2.0 Hz), 2.07 (2H, t, J = 12.0 Hz), 2.37 (2H, t, J = 7.2 Hz), 2.41 (2H, qd, J = 12.0, 3.6 Hz), 2.61 (2H, t, J = 7.2 Hz), 3.03 (2H, d, J = 12.0 Hz), 4.40 (1H, tt, J = 12.0, 3.6 Hz), 6.88 (1H, dd, J = 8.0, 1.6 Hz), 6.93 (1H, td, J = 8.0, 1.6 Hz), 6.97 (1H, td, J = 8.0, 1.6 Hz), 7.12-7.16 (3H, m), 7.19-7.27 (8H, m).

[0126] Example 21 1-(1-(3-phenoxypropyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 21) The title compound was obtained (yield 68%, two steps) according to the method described in Example 16, except that 3-phenoxypropyl bromide was used instead of 5-phenylpentyl bromide.

[0127] 1 H-NMR (400 MHz, CDCl3) δ: 1.63-1.83 (8H, m), 2.03 (2H, br), 2.17 (2H, br), 2.46 (2H, br), 2.60 (2H, br), 2.66 (2H, t, J = 7.6 Hz), 3.11 (1H, br), 3.88 (2H, t, J = 7.6 Hz), 4.06 (2H, t, J = 6.4 Hz), 6.91-6.97 (4H, m), 7.05-0.06 (2H, m), 7.15-7.19 (3H, m), 7.25-7.32 (5H, m).

[0128] Example 22 1-(3-phenoxypropyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 22) The title compound (yield 26%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 6 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0129] 1H-NMR (400 MHz, CDCl3) δ: 1.25-1.29 (2H, m), 1.60-1.70 (4H, m), 1.79 (2H, d, J = 10.8 Hz), 2.15 (1H, br), 2.23 (2H, quin, J = 6.4 Hz), 2.44 (3H, br), 2.65 (2H, t, J = 7.6 Hz), 3.09 (2H, br), 4.01 (2H, t, J = 6.4 Hz), 4.08 (2H, t, J = 6.4 Hz), 4.41 (1H, t, J = 12.4 Hz), 6.87 (2H, d, J = 8.4 Hz), 6.94 (1H, t, J = 7.6 Hz), 6.98-7.05 (3H, m), 7.19 (3H, J = 7.6 Hz), 7.24-7.32 (5H, m).

[0130] Example 23 1-(3-phenoxypropyl)-3-(1-(3-phenoxypropyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 23) The title compound (yield 66%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 6 instead of the compound of Reference Example 2 and 3-phenoxypropyl bromide instead of 5-phenylpentyl bromide.

[0131] 1 H-NMR (400 MHz, CDCl3) δ: 2.05 (2H, d, J = 11.6 Hz), 2.27 (2H, br), 2.48 (4H, quin, J = 6.4 Hz), 2.71 (2H, br), 2.85 (2H, m), 3.36 (2H, br), 4.25 (2H, t, J = 6.4 Hz), 4.29 (2H, t, J = 6.4 Hz), 4.33 (2H, t, J = 6.4 Hz), 4.66 (1H, br), 7.11-7.20 (6H, m), 7.25-7.30 (3H, m), 7.49-7.55 (5H, m).

[0132] Example 24 1-(1-(4-(2-methoxyphenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 24) The title compound was obtained (yield 49%, two steps) according to the method described in Example 16, except that 4-(2-methoxyphenyl)butyl bromide was used instead of 5-phenylpentyl bromide.

[0133] 1 H-NMR (400 MHz, CDCl3) δ: 1.61-1.82 (12H, m), 2.14 (2H, br), 2.44 (3H, br), 2.64-2.68 (3H, m), 3.09 (2H, br), 3.83 (3H, s), 3.88 (2H, t, J = 7.2 Hz), 4.41 (1H, t, J = 12.0 Hz), 6.85 (1H, d, J = 7.2 Hz), 6.90 (1H, td, J = 7.2, 0.8 Hz), 6.94-6.96 (1H, m), 7.04-7.05 (2H, m), 7.13-7.20 (5H, m), 7.24-7.28 (3H, m).

[0134] Example 25 1-(4-(2-methoxyphenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 25) The title compound (35% yield, 2 steps) was obtained according to the method described in Example 16, using the compound of Reference Example 7 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0135] 1H-NMR (400 MHz, CDCl3) δ: 1.23-1.28 (2H, m), 1.66-1.82 (10H, m), 2.14 (2H, br), 2.44 (3H, br), 2.66 (3H, t, J = 7.6 Hz), 3.09 (2H, br), 3.78 (3H, s), 3.88 (2H, t, J = 7.6 Hz), 4.41 (1H, br), 6.82-6.88 (2H, m), 6.96-6.98 (1H, m), 7.04-7.11 (3H, m), 7.14-7.20 (4H, m), 7.29-7.31 (2H, m).

[0136] Example 26 1-(4-(2-methoxyphenyl)butyl)-3-(1-(4-(2-methoxyphenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 26) The title compound (33% yield, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 7 instead of the compound of Reference Example 2 and 4-(2-methoxyphenyl)butyl bromide instead of 5-phenylpentyl bromide.

[0137] 1 H-NMR (400 MHz, CDCl3) δ: 1.61-1.81 (10H, m), 2.14 (2H, t, J = 11.6 Hz), 2.42-2.48 (4H, m), 2.64-2.68 (4H, m), 3.10 (2H, d, J = 11.6 Hz), 3.80 (3H, s), 3.83 (3H, s), 3.88 (2H, t, J = 7.2 Hz), 4.41 (1H, tt, J = 11.6, 4.8 Hz), 6.82-6.91 (4H, m), 6.96-7.20 (7H, m), 7.32-7.34 (1H, m).

[0138] Example 27 1-(1-(4-(2-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 27) The title compound was obtained (yield 54%, two steps) according to the method described in Example 16, except that 4-(2-chlorophenyl)butyl bromide was used instead of 5-phenylpentyl bromide.

[0139] 1 H-NMR (400 MHz, CDCl3) δ: 1.67-1.84 (11H, m), 2.16 (2H, br), 2.46 (3H, br), 2.66 (2H, t, J = 7.2 Hz), 2.78 (2H, t, J = 7.2 Hz), 3.11 (2H, br), 3.88 (2H, t, J = 7.2 Hz), 4.42 (1H, br), 6.94-6.97 (1H, m), 7.02-7.07 (2H, m), 7.11-7.28 (8H, m), 7.34 (2H, dd, J = 8.0, 1.6 Hz).

[0140] Example 28 1-(4-(2-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 28) The title compound (yield 32%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 8 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0141] 1 H-NMR (400 MHz, CDCl3) δ: 1.26-1.49 (2H, m), 1.67-1.87 (12H, m), 2.17 (1H, br), 2.46 (2H, br), 2.66 (2H, m), 2.77 (2H, t, J = 7.6 Hz), 3.11 (1H, br), 3.90 (2H, t, J = 7.6 Hz), 4.45 (1H, m), 6.96-6.99 (1H, m), 7.06-7.20 (9H, m), 7.27-7.33 (3H, m).

[0142] Example 29 1-(4-(2-chlorophenyl)butyl)-3-(1-(4-(2-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 29) The title compound (70% yield, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 8 instead of the compound of Reference Example 2 and 4-(2-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide.

[0143] 1 H-NMR (400 MHz, CDCl3) δ: 1.66-1.83 (14H, m), 2.17 (1H, br), 2.46 (2H, br), 2.76 (4H, t, J = 7.6 Hz), 3.11 (1H, br), 3.89 (2H, t, J = 7.6 Hz), 4.43 (1H, br), 6.95-6.98 (1H, m), 7.03-7.08 (2H, m), 7.08-7.23 (7H, m), 7.29-7.34 (2H, m).

[0144] Example 30 1-(1-(4-(2-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 30) The title compound was obtained (73% yield, two steps) according to the method described in Example 16, except that 4-(2-fluorophenyl)butyl bromide was used instead of 5-phenylpentyl bromide.

[0145] 1 H-NMR (400 MHz, CDCl3) δ: 1.60-1.81 (10H, m), 2.14 (2H, br), 2.44 (4H, br), 2.64-2.71 (4H, m), 3.08 (2H, br), 3.88 (2H, t, J = 6.8 Hz), 4.41 (1H, br), 6.94-7.08 (5H, m), 7.15-7.21 (5H, m), 7.24-7.28 (3H, m), 7.32 (1H, br).

[0146] Example 31 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 31) The title compound (yield 51%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 9 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0147] 1 H-NMR (400 MHz, CDCl3) δ: 1.60-1.74 (9H, m), 1.75-1.84 (5H, m), 2.17 (1H, br), 2.46 (2H, br), 2.64-2.71 (4H, m), 3.11 (1H, br), 3.89 (2H, t, J = 7.6 Hz), 4.42 (1H, br), 6.95-7.80 (5H, m), 7.13-7.20 (6H, m), 7.27-7.31 (3H, m).

[0148] Example 32 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-(2-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 32) The title compound (73% yield, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 9 instead of the compound of Reference Example 2 and 4-(2-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide.

[0149] 1 H-NMR (400 MHz, CDCl3) δ: 1.65-1.81 (12H, m), 2.17 (1H, br), 2.46 (3H, br), 2.69 (4H, t, J = 7.2 Hz), 3.10 (2H, br), 3.89 (2H, t, J = 7.2 Hz), 4.42 (1H, t, J = 12.4 Hz), 6.95-7.08 (8H, m), 7.12-7.22 (4H, m).

[0150] Example 33 1-(1-(4-(3-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 33) The title compound was obtained (yield 67%, two steps) according to the method described in Example 16, except that 4-(3-chlorophenyl)butyl bromide was used instead of 5-phenylpentyl bromide.

[0151] 1 H-NMR (400 MHz, CDCl3) δ: 1.56-1.82 (11H, m), 2.14 (2H, br), 2.43 (3H, br), 2.63 (2H, t, J = 7.2 Hz), 2.66 (2H, t, J = 7.2 Hz), 3.08 (2H, d, J = 7.2 Hz), 3.88 (2H, t, J = 7.2 Hz), 4.41 (1H, t, J = 12.0 Hz), 6.94-6.97 (1H, m), 7.02-7.08 (3H, m), 7.15-7.21 (6H, m), 7.23-7.32 (3H, m).

[0152] Example 34 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 34) The title compound (yield 57%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 10 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0153] 1H-NMR (400 MHz, CDCl3) δ: 1.62-1.87 (10H, m), 2.19 (2H, br), 2.49 (4H, m), 2.69-2.73 (4H, m), 3.14 (2H, d, J = 7.2 Hz), 3.94 (2H, t, J = 7.2 Hz), 4.46 (1H, t, J = 12.4 Hz), 7.00-7.02 (1H, m), 7.07-7.14 (3H, m), 7.19-7.24 (6H, m), 7.32-7.38 (3H, m).

[0154] Example 35 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-(3-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 35) The title compound (yield 64%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 10 instead of the compound of Reference Example 2 and 4-(3-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide.

[0155] 1 H-NMR (400 MHz, CDCl3) δ: 1.51-1.58 (2H, m), 1.62-1.71 (4H, m), 1.74-1.81 (4H, m), 2.10 (2H, t, J = 10.8 Hz), 2.38-2.42 (2H, m), 2.43 (2H, qd, J = 12.4, 4.0 Hz), 2.63 (4H, t, J = 7.6 Hz), 3.39 (2H, t, J = 7.6 Hz), 4.29 (1H, tt, J = 12.4, 4.0 Hz), 6.94-6.96 (1H, m), 7.01-7.08 (4H, m), 7.13-7.21 (6H, m), 7.29-7.31 (1H, m).

[0156] Example 36 1-(1-(4-(3-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 36) The title compound was obtained (yield 80%, two steps) according to the method described in Example 16, except that 4-(3-fluorophenyl)butyl bromide was used instead of 5-phenylpentyl bromide.

[0157] 1 H-NMR (400 MHz, CDCl3) δ: 1.50-1.80 (10H, m), 2.10 (2H, t, J = 10.0 Hz), 2.37-2.41 (2H, m), 2.43 (2H, qd, J = 11.6, 4.4 Hz), 2.64 (2H, td, J = 7.2, 2.0 Hz), 3.04 (2H, d, J = 11.6 Hz), 3.87 (2H, t, J = 7.2 Hz), 4.38 (1H, tt, J = 11.6, 4.4 Hz), 6.82-6.97 (4H, m), 7.00-7.07 (2H, m), 7.14-7.31 (8H, m).

[0158] Example 37 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 37) The title compound (yield 55%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 11 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0159] 1 H-NMR (400 MHz, CDCl3) δ: 1.55-1.81 (11H, m), 2.13 (2H, t, J = 12.0 Hz), 2.41-2.47 (3H, m), 2.65 (4H, t, J = 7.6 Hz), 3.08 (2H, d, J = 10.4 Hz), 3.89 (2H, t, J = 7.6 Hz), 4.40 (1H, tt, J = 12.0, 4.4 Hz), 6.84-6.88 (2H, m), 6.91-6.96 (2H, m), 7.02-7.08 (2H, m), 7.17-7.22 (4H, m), 7.27-7.31 (3H, m).

[0160] Example 38 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-(3-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 38) The title compound (77% yield, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 11 instead of the compound of Reference Example 2 and 4-(3-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide.

[0161] 1 H-NMR (400 MHz, CDCl3) δ: 1.52-1.58 (2H, m), 1.64-1.72 (4H, m), 1.75-1.81 (4H, m), 2.10 (2H, t, J = 8.4 Hz), 2.38-2.42 (2H, m), 2.42 (2H, qd, J = 10.0, 3.6 Hz), 2.65 (4H, t, J = 6.0 Hz), 3.05 (2H, d, J = 8.4 Hz), 3.89 (2H, t, J = 6.0 Hz), 4.39 (1H, tt, J = 10.0, 3.6 Hz), 6.84-6.97 (7H, m), 7.02-7.08 (2H, m), 7.18-7.25 (2H, m), 7.29-7.31 (1H, m).

[0162] Example 39 1-(1-(4-(4-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 39) The title compound was obtained (yield 35%, two steps) according to the method described in Example 16, except that 4-(4-chlorophenyl)butyl bromide was used instead of 5-phenylpentyl bromide.

[0163] 1H-NMR (400 MHz, CDCl3) δ: 1.52-1.81 (10H, m), 2.10 (2H, t, J = 10.0 Hz), 2.37-2.41 (2H, m), 2.43 (2H, qd, J = 12.4, 4.0 Hz), 2.62 (2H, t, J = 7.6 Hz), 2.65 (2H, t, J = 7.6 Hz), 3.05 (2H, d, J = 10.0 Hz), 3.88 (2H, t, J = 7.6 Hz), 4.39 (1H, tt, J = 12.4, 4.0 Hz), 6.94-6.96 (1H, m), 7.01-7.07 (2H, m), 7.11-7.19 (5H, m), 7.23-7.30 (5H, m).

[0164] Example 40 1-(4-(4-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 40) The title compound (yield 56%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 12 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0165] 1 H-NMR (400 MHz, CDCl3) δ: 1.52-1.80 (10H, m), 2.11 (2H, t, J = 11.2 Hz), 2.39-2.47 (4H, m), 2.62 (2H, t, J = 7.2 Hz), 2.65 (2H, t, J = 7.2 Hz), 3.06 (2H, d, J = 11.2 Hz), 3.88 (2H, t, J = 6.8 Hz), 4.39 (1H, tt, J = 12.4, 4.4 Hz), 6.93-6.95 (1H, m), 7.01-7.08 (4H, m), 7.17-7.23 (4H, m), 7.27-7.32 (4H, m).

[0166] Example 41 1-(4-(4-chlorophenyl)butyl)-3-(1-(4-(4-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 41) The title compound (yield 54%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 12 instead of the compound of Reference Example 2 and 4-(4-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide.

[0167] 1 H-NMR (400 MHz, CDCl3) δ: 1.50-1.60 (2H, m), 1.60-1.71 (6H, m), 1.72-1.80 (4H, m), 2.10 (2H, t, J = 11.6 Hz), 2.37- (3H, m), 2.62 (3H, t, J = 7.2 Hz), 3.05 (2H, d, J = 11.6 Hz), 3.88 (2H, t, J = 7.2 Hz), 4.38 (1H, tt, J = 12.4, 4.4 Hz), 6.93-6.97 (1H, m), 7.03-7.13 (6H, m), 7.21-7.30 (5H, m).

[0168] Example 42 1-(1-(4-(4-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 42) The title compound was obtained (yield 64%, two steps) according to the method described in Example 16, except that 4-(4-fluorophenyl)butyl bromide was used instead of 5-phenylpentyl bromide.

[0169] 1H-NMR (400 MHz, CDCl3) δ: 1.51-1.81 (10H, m), 2.10 (2H, t, J = 11.6 Hz), 2.38-2.47 (4H, m), 2.62 (2H, t, J = 7.6 Hz), 2.65 (2H, t, J = 7.6 Hz), 3.05 (2H, d, J = 11.6 Hz), 3.88 (2H, t, J = 7.6 Hz), 4.39 (1H, tt, J = 11.6, 4.0 Hz), 6.94-7.08 (5H, m), 7.12-7.19 (5H, m), 7.24-7.30 (3H, m).

[0170] Example 43 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 43) The title compound (yield 56%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 13 instead of the compound of Reference Example 2 and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide.

[0171] 1 H-NMR (400 MHz, CDCl3) δ: 1.60-1.71 (6H, m), 1.74-1.81 (4H, m), 2.17 (2H, br), 2.45-2.51 (4H, m), 2.62 (2H, t, J = 6.4 Hz), 2.66 (2H, t, J = 6.4 Hz), 3.11 (2H, d, J = 8.0 Hz), 3.88 (2H, t, J = 6.4 Hz), 4.42 (1H, t, J = 10.4 Hz), 6.91-6.96 (3H, m), 7.05-7.11 (4H, m), 7.17-7.20 (3H, m), 7.25-7.30 (2H, m), 7.35 (1H, br).

[0172] Example 44 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-(4-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 44) The title compound (yield 59%, two steps) was obtained according to the method described in Example 16, using the compound of Reference Example 13 instead of the compound of Reference Example 2 and 4-(4-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide.

[0173] 1 H-NMR (400 MHz, CDCl3) δ: 1.51-1.80 (10H, m), 2.10 (2H, t, J = 11.6 Hz), 2.38-2.41 (2H, m), 2.42 (2H, qd, J = 12.4, 3.6 Hz), 2.62 (4H, t, J = 7.6 Hz), 3.05 (2H, d, J = 11.6 Hz), 3.88 (2H, t, J = 7.6 Hz), 4.39 (1H, tt, J = 12.4, 3.6 Hz), 6.91-6.99 (5H, m), 7.03-7.06 (2H, m), 7.08-7.16 (4H, m), 7.28-7.31 (1H, m).

[0174] Example 45 5-fluoro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 45) Under an Ar atmosphere, trifluoroacetic acid (0.16 mL, 2.14 mmol) was added to a dichloromethane (1 mL) solution of the compound of Reference Example 14 (0.21 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and N,N-dimethylformamide (1 mL) was added to the resulting residue. Further, 4-phenylbutyl bromide (92 mg, 0.43 mmol) and potassium carbonate (147 mg, 1.07 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 22 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:2) to obtain the title compound (yield 42%, 2 steps).

[0175] 1 H-NMR (400 MHz, CDCl3) δ: 1.58-1.76 (8H, m), 2.09 (2H, t, J = 11.6 Hz), 2.33-2.42 (3H, m), 2.65 (3H, t, J = 7.2 Hz), 3.06 (2H, d, J = 11.6 Hz), 3.85 (2H, t, J = 7.2 Hz), 4.36 (1H, m), 6.73-6.83 (2H, m), 7.05-7.30 (11H, m).

[0176] Example 46 5-chloro-3-(4-phenylbutyl)-1-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 46) The procedure of Example 45 was repeated, except that the compound of Reference Example 15 was used instead of the compound of Reference Example 14, to give the title compound (yield 60%, 2 steps).

[0177] 1H-NMR (500 MHz, CDCl3) δ: 1.57-1.63 (2H, m), 1.68-1.83 (8H, m), 2.14 (2H, t, J = 11.0 Hz), 2.38-2.46 (4H, m), 2.70 (4H, d, J = 4.5 Hz), 3.10 (2H, d, J = 11.0 Hz), 3.87 (2H, t, J = 7.0 Hz), 4.38-4.44 (1H, m), 6.96 (1H, s), 7.03 (1H, d, J = 8.0 Hz), 7.20-7.33 (11H, m).

[0178] Example 47 5-chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 47) The same procedure as in Example 45 was followed, except that the compound of Reference Example 16 was used instead of the compound of Reference Example 14, to give the title compound (yield 25%, 2 steps).

[0179] 1 H-NMR (400 MHz, CDCl3) δ: 1.57-1.80 (11H, m), 2.10 (2H, t, J = 11.2 Hz), 2.32-2.43 (3H, m), 2.63-2.67 (4H, m), 3.80 (2H, d, J = 11.2 Hz), 3.85 (2H, t, J = 6.8 Hz), 4.33-4.40 (1H, m), 6.82 (1H, d, J = 8.4 Hz), 7.01 (1H, dd, J = 8.4, 1.6 Hz), 7.14-7.31 (11H, m).

[0180] Example 48 4-chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 48) The same procedure as in Example 45 was followed, except that the compound of Reference Example 17 was used instead of the compound of Reference Example 14, to give the title compound (yield 50%, 2 steps).

[0181] 1H-NMR (400 MHz, CDCl3) δ: 1.51-1.80 (10H, m), 2.05 (2H, t, J = 12.0 Hz), 2.39 (2H, t, J = 7.2 Hz), 2.61-2.66 (4H, m), 2.78 (2H, qd, J = 12.0, 3.6 Hz), 3.05 (2H, d, J = 12.0 Hz), 3.83 (2H, t, J = 7.2 Hz), 4.96 (1H, t, J = 12.0 Hz), 6.79 (1H, dd, J = 7.6, 1.2 Hz), 6.92-6.99 (2H, m), 7.14-7.19 (6H, m), 7.24-7.29 (4H, m).

[0182] Example 49 1-(1-(4,4-diphenylbutyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 49) Under an Ar atmosphere, trifluoroacetic acid (0.11 mL, 1.40 mmol) was added to a dichloromethane (1.5 mL) solution of the compound of Reference Example 2 (63 mg, 0.14 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off using a rotary evaporator, and N,N-dimethylformamide (1.5 mL) was added to the resulting residue. Furthermore, 4,4-diphenylbutylbromide (0.28 mmol) and potassium carbonate (97 mg, 0.70 mmol) were added sequentially at room temperature, and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. The organic layer was separated, and the aqueous layer was extracted with diethyl ether (1.5 mL × 3) and combined with the previous organic layer. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was removed using a rotary evaporator. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:1) to obtain the title compound (yield 100%, two steps).

[0183] 1H-NMR (400 MHz, CDCl3) δ: 1.45-1.53 ​​(2H, m), 1.65-1.80 (6H, m), 2.01-2.12 (2H, m), 2.19-2.31 (2H, m), 2.36-2.42 (2H, m), 2.65 (2H, t, J = 7.2 Hz), 2.99 (2H, d, J = 12.0 Hz), 3.87 (2H, t, J = 7.2 Hz), 3.92 (1H, t, J = 7.2 Hz), 4.37 (1H, tt, J = 12.0, 4.8 Hz), 6.93-6.95 (1H, m), 7.00-7.05 (2H, m), 7.14-7.19 (5H, m), 7.24-7.30 (11H, m).

[0184] Example 50 1-(1-(4,4-bis(4-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 50) The title compound was obtained (yield 58%, two steps) according to the same method as in Example 49, except for using 4,4-bis(4-fluorophenyl)butyl bromide instead of 4,4-diphenylbutyl bromide.

[0185] 1 H-NMR (500 MHz, CDCl3) δ: 1.43-1.52 (2H, m), 1.68-1.74 (2H, m), 1.76-1.83 (4H, m), 2.03-2.10 (4H, m), 2.40-2.45 (4H, m), 2.67 (2H, t, J = 7.5 Hz), 3.00 (2H, d, J = 12.0 Hz), 3.89 (2H, t, J = 7.5 Hz), 3.91 (1H, t, J = 7.5 Hz), 4.38 (1H, tt, J = 12.0, 4.0 Hz), 6.95-7.08 (7H, m), 7.16-7.21 (7H, m), 7.26-7.29 (3H, m).

[0186] Test Example 1: Examination of the T-type calcium channel inhibitory effect of the compound of the present invention (1) Using the whole-cell patch clamp method,ｖ 3.2 The effect of the compounds of the present invention on T-type calcium channels was evaluated. DMSO solution was used as a control (vehicle). ｖ 3.2 HEK293 cells, a human kidney cell-derived cell line in which T-type calcium channels were overexpressed, were seeded on a cell culture dish using DMEM medium containing 10% fetal bovine serum and incubated at 37°C and 5% CO ２ The whole-cell patch assay was performed using the following solutions as extracellular and intracellular solutions. The holding potential was set at -80 mV, and the inward barium current was measured using a patch clamp amplifier and an AD converter (Axon Instruments) during a potential jump from -80 mV to -20 mV. To eliminate the influence of high-threshold activated calcium channels, the peak current minus the current 150 ms after the onset of stimulation was used as the T-channel current (T-current). Data analysis was performed using pClamp8 (Axon Instruments). Test compounds were added to the dish either directly (direct addition method) or by perfusion (perfusion addition method) in the extracellular solution.

[0187] Extracellular solution: 97 mM N-methyl-D-glucamine (NMDG) 10 mM BaCl ２ 10 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) 40 mM tetraethylammonium chloride (TEA-Cl) 5 mM glucose (pH 7.4)

[0188] Intracellular fluid: 4mM MgCl ２ 140 mM CsCl, 10 mM HEPES, 5 mM glycol ether diamine tetraacetic acid (EGTA) (pH 7.2)

[0189] The test results are shown in Figure 1 for the data obtained by the direct addition method, and in Figure 2 for the data obtained by the perfusion addition method. Figure 1 shows the ratio (%) of the T channel current value after addition of pimozide and the compounds of the present invention (3 μM and 1 μM) to the T channel current value after addition of the vehicle (solvent, control group) (n = 3-10). Figure 2 shows the rate of change in the T channel current value after addition of the vehicle and the test compound (0.3 μM) compared to the T channel current value before addition of the vehicle and the test compound (n = 3-8).

[0190] Test Example 2: Examination of the T-type calcium channel inhibitory effect of the compound of the present invention (2) ｖ The effects of the compounds of the present invention on 3.2 T-type channels were evaluated. The test compounds, pimozide, Compound 5, Compound 14, and Compound 15, were added by perfusion at concentrations of 0.01 μM, 0.1 μM, 0.3 μM, 1.0 μM, and 3.0 μM.

[0191] The test results are shown in Table 2. Table 2 shows the IC values ​​calculated by analyzing the rate of change in T channel current value before and after the addition of the test compound using Prism (GraphPad Software). ５０ Values ​​(μM) are shown (n=3-17).

[0192] The above test results demonstrate that the compounds of the present invention have excellent T-type calcium channel inhibitory activity.

[0193] Test Example 3: Dopamine D, a compound of the present invention ２ In this test, the compounds of the present invention bind to dopamine D receptors. ２ The binding ability of each compound to the dopamine D receptor was examined. ２The inhibitory effect on receptor binding was evaluated. Compounds 4 to 7, 25, 26, 28, 30, 36, and 38 were used as the compounds of the present invention, and pimozide and sulperide were used as comparative controls. 5 μL of the compounds of the present invention, sulperide, and pimozide were added to a reaction solution containing the rat brain striatum homogenate shown below so that the final concentration was 1 or 10 μM, and the reaction was carried out at room temperature for 90 minutes. After the reaction was completed, the reaction solution was filtered through a glass fiber filter, and the filter was washed and dried, after which the radioactivity was measured. The dopamine D ２ The binding ability to the receptor is the dopamine D2 receptor and ３ H]-spiperone binding inhibition rate and [ ３ Reaction solution: Rat brain striatum homogenate (200 μg protein / mL) 50 μL (final concentration: 10 μg protein / tube) [ ３ H]-spiperone (10nM) 5μL (final concentration: 0.5nM) Assay buffer 40μL (composition: NaCl: 120mM, KCl: 5mM, MgCl ２ : 1 mM CaCl ２ : 1mM, Tris-Cl: 50mM (pH 7.4))

[0194] The test results are shown in Figures 3 and 4. Figure 3 shows the dopamine D ２ Receptor and ３ 4 shows the inhibition rate of [H]-spiperone binding (n=3). The inhibition rate of each compound is expressed as a ratio to that of pimozide, assuming that the inhibition rate of pimozide is 100%. Figure 4 shows the inhibition rate of [H]-spiperone binding after the addition of the solvent (total binding amount) and the test compound (1 μM and 10 μM). ３ H]-spiperone dopamine D ２ The amount of receptor-specific binding is shown (n=3).

[0195] As shown by the results of this test, the compounds of the present invention have a higher dopamine D than pimozide and sulpiride. ２ Receptor and ３ Therefore, the compounds of the present invention did not inhibit the binding of dopamine D ２It has no inhibitory effect on dopamine D receptor binding. ２ It was shown that the receptor binding activity can be attenuated.

[0196] Test Example 4: Dopamine D in the compounds of the present invention in in vivo test ２ In this test, the catalepsy-inducing effect of the compound of the present invention was examined, and the dopamine D receptor blockade ２ The suppression of side effects caused by receptor inhibition was evaluated. Compounds 5 and 12 were used as the compounds of the present invention, and 2% DMSO solution was used as the vehicle. Pimozide was used as a control drug. Sixteen male ddY mice were randomly assigned to four groups: a compound 5 group, a compound 12 group, a pimozide group, and a vehicle group. Each group received intracerebroventricular administration of 8 nmol (0.8 mM / 10 μL) of compound 5, compound 12, or pimozide, along with 10 μL of vehicle. The mice were then forced to place both forelimbs on a horizontally placed iron bar (height: 5 cm). The time they maintained this position (catalepsy) was measured to evaluate the induction of catalepsy. The measurement was terminated when the forelimbs touched the floor or when the mice stepped onto the bar.

[0197] The test results are shown in Figure 5. Figure 5 shows the duration of catalepsy (seconds) at 30, 60, 90, 120, 150 and 180 minutes after administration of the vehicle and the test compound.

[0198] As shown in Figure 5, in the pimozide-administered group, the duration of catalepsy was prolonged, peaking at 120 minutes after administration, whereas catalepsy was not induced in the compound 5 and compound 12-administered groups. ２ It has been shown that it can attenuate receptor blockade and suppress the resulting effects.

[0199] Test Example 5: Na ２ Examination of the effect of the compound of the present invention on S-induced itching. ２The antipruritic and analgesic effects of the compound of the present invention were investigated in an itch model using intradermal injection of Na. Compound 5 was used as the compound of the present invention, and physiological saline containing 1% DMSO and 5% Tween 80 was used as the vehicle. 3.8 μmol (300 μg / 10 μL) Na was injected intradermally into the cheek of male ICR mice. ２ S was injected to induce T-type calcium channel-dependent pain in mice. ２ A cheek intradermal injection of S was used to create an itch model. Eighteen mice were divided into a vehicle + saline administration group (control group), a vehicle + Na ２ S administration group and Compound 5 (10 mg / kg) + Na ２ Six mice were randomly assigned to each S administration group. The mice were anesthetized with isoflurane, and the right cheek was shaved the day before or several days before the experiment. On the day of the experiment, the mice were placed in an acrylic observation cage with mirrors on all four sides and allowed to acclimate for 30 minutes or more. After acclimatization, Na was injected into the shaved cheek of the mice without anesthesia. ２ S was administered intradermally, and the subsequent behavior was videotaped. Compound 5 (10 mg / kg) or vehicle (V, 10 mL / kg) ２ The compound was intraperitoneally administered 30 minutes before injection of S. Later, the video was played back, and the number of scratching bouts with the hind paws at the injection site was counted as an itching response, and the number of wiping bouts with the forepaws was counted as a pain response for 60 minutes to evaluate the antipruritic and analgesic effects of the compound of the present invention.

[0200] The test results are shown in Table 3 and Figure 6. Table 3 shows the mean ± standard error of the total number of scratching and wiping behavior counts 60 minutes after right cheek intradermal administration, and Figure 6 shows a graph of the mean ± standard error of the scratching and wiping behavior counts 10, 20, 30, 40, 50, and 60 minutes after right cheek intradermal administration, as well as the mean ± standard error of the total number of counts over 60 minutes.

[0201] As shown in the results of this study, vehicle + Na ２ Itching and pain were not suppressed in the group administered with S, but were significantly suppressed in the group administered with Compound 5. Therefore, it was demonstrated that the compound of the present invention has antipruritic and analgesic effects.

[0202] Test Example 6: Na ２ Examination of the effect of the compound of the present invention on S-induced pain. ２ The analgesic effect of the compound of the present invention was investigated in an S intraplantar injection pain model. Compound 5 was used as the compound of the present invention, and physiological saline containing 1% DMSO and 5% Tween 80 was used as the vehicle. 10 pmol / paw / 10 μL of NaCl was injected into the plantar of ICR male mice. ２ S was injected to induce T-type calcium channel-dependent pain in mice. ２ A pain model was created using intraplantar injection of S. Mice were divided into a vehicle + vehicle administration group (control group), a vehicle + Na ２ S administration group, Compound 5 (1 mg / kg) + Na ２ S administration group, Compound 5 (3 mg / kg) + Na ２ S administration group and Compound 5 (10 mg / kg) + Na ２ The rats were randomly assigned to one of the following treatment groups (n=7-11): Vehicle (V, 10 mL / kg) or 1, 3, or 10 mg / kg of Compound 5. ２ The pain threshold was measured by the von Frey method using the NaCl injection 30 minutes before the intraplantar injection of S into the hind paw of the mice. ２ Measurements were made every 15 minutes up to 60 minutes after administration of S to evaluate the analgesic effect of the compound of the present invention.

[0203] The test results are shown in Table 4 and Figure 7. Table 4 shows the mean ± standard error of the pain threshold (g) for each group at 15 and 30 minutes after hind paw intraplantar administration, and Figure 7 shows a graph of the mean ± standard error of the pain threshold (g) before, immediately after, and 15, 30, 45, and 60 minutes after hind paw intraplantar administration.

[0204] As shown in the results of this study, vehicle + Na ２ Pain was not suppressed in the group administered with S, but was suppressed in the group administered with Compound 5. Therefore, it was demonstrated that the compound of the present invention has an analgesic effect.

[0205] Test Example 7: Examination of the Antipruritic Effect of Compounds of the Present Invention In this test, the antipruritic effect of the compounds of the present invention was examined in a mouse cheek intradermal injection pruritus model in which histamine or chloroquine was intradermally administered as a pruritic substance. Compounds 5 and 38 were used as the compounds of the present invention, and physiological saline containing 1% DMSO and 5% Tween 80 was used as a control. Compounds 5 and 38 were dissolved in physiological saline containing 1% DMSO and 5% Tween 80 to adjust their concentrations. Male ICR mice weighing 23-40 g were used as experimental animals. These mice were allowed to drink tap water and solid feed ad libitum and were housed at a room temperature of approximately 24°C under a 12-hour light-dark cycle. A mouse intradermal injection pruritus model was established in ICR male mice by injecting the pruritic substances histamine or chloroquine dissolved in saline into the cheek skin to induce pruritus, according to the method described in Shimada SG & LaMotte RH (2008) Behavioral differentiation between itch and pain in mice. Pain 139 (3): 681-687. Mice were randomly assigned (n = 6-10) to the following groups: a control group (a saline containing 1% DMSO and 5% Tween 80 (solvent 1) + saline (solvent 2) treatment group, a solvent 1 + histamine treatment group, a compound 5 (10 mg / kg) + histamine treatment group, a solvent 1 + chloroquine treatment group, a compound 5 (10 mg / kg) + chloroquine treatment group, a compound 38 (1 mg / kg) + chloroquine treatment group, a compound 38 (3 mg / kg) + chloroquine treatment group, and a compound 38 (10 mg / kg) + chloroquine treatment group. Mice in each group were anesthetized with isoflurane, and their right cheeks were shaved several days before the experiment. On the day of the experiment, the mice were placed in an acrylic observation cage (10 x 14 x 30 cm) with mirrors on all four sides and allowed to acclimate for at least 30 minutes. After acclimatization, 10 μL / site of saline, 300 μL / site of histamine, or 100 μL / site of chloroquine was administered intradermally to the shaved cheek of each mouse without anesthesia, and their subsequent behavior was videotaped for 60 minutes.Compound 5 (10 mg / kg), Compound 38 (1 mg / kg, 3 mg / kg, or 10 mg / kg), or Vehicle 1 (10 mL / kg) was intraperitoneally administered 30 minutes before the administration of saline or the pruritic substance. Later, the video was played back, and the number of scratching bouts with the hind paws at the intradermal injection site was counted as an itch response for 60 minutes to evaluate the antipruritic effect of the compound of the present invention.

[0206] The test results are shown in Tables 5 to 7 and Figures 8 to 10. Table 5 and Figure 8 show the mean ± standard error (total number (n)) of the total number of counts of scratching behavior with the hind paws at the intradermal administration site 60 minutes after right cheek intradermal administration in the control group, the solvent 1 + histamine administration group, and the compound 5 (10 mg / kg) + histamine administration group, and a graph thereof. Table 6 and Figure 9 show the mean ± standard error (total number (n)) of the total number of counts of scratching behavior with the hind paws at the intradermal administration site 60 minutes after right cheek intradermal administration in the control group, the solvent 1 + chloroquine administration group, and the compound 5 (10 mg / kg) + chloroquine administration group. Table 7 and Figure 10 show the mean ± standard error (total number (n)) of the total counts of scratching behavior by the hind paws toward the intradermal administration site 60 minutes after intradermal administration on the right cheek in the control group, solvent 1 + chloroquine administration group, compound 38 (1 mg / kg) + chloroquine administration group, compound 38 (3 mg / kg) + chloroquine administration group, and compound 38 (10 mg / kg) + chloroquine administration group, and a graph thereof.

[0207] As shown in the test results, compound 5 (10 mg / kg) potently suppressed histamine-dependent itch behavior and non-histamine-induced itch behavior (Tables 5-6 and Figures 8-9), and compound 38 potently suppressed non-histamine-induced itch behavior at a dose of 10 mg / kg (Table 7 and Figure 10). Therefore, it was demonstrated that the compounds of the present invention have antipruritic effects. Since the compounds of the present invention potently suppress both histamine-induced and non-histamine-induced itch, it is suggested that they may be useful therapeutic agents for intractable itch.

[0208] According to the present invention, a novel benzimidazolone compound having excellent T-type calcium channel inhibitory activity can be provided. ２ The present invention may be useful as a novel therapeutic agent for diseases caused by activation of T-type calcium channels, such as pain and pruritus, which can attenuate receptor inhibitory action and reduce the risk of side effects.

Claims

1. Formula (I): 【Chemical 1】 [wherein: R １ is C １－１０ alkyl, C(O)-C １－１０ alkyl, C １－６ alkylene-R １ａ or C(O)-C １－６ alkylene-R １ａ and the alkyl and alkylene may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, amino and hydroxy; R ２ is C(O)-C １－１０ alkyl, C3-6 alkylene-R2a or C(O)-C １－６ alkylene-R ２ａ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ each independently is selected from the group consisting of C １－６ alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, C6-10 aryl and C6-10 aryloxy, and each group may be substituted at a substitutable position with one or the same or different two or more groups selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, amino and hydroxy; R ３ each independently represents a halogen, C １－６ alkyl, C １－６ haloalkyl, amino or hydroxy, and is selected from the group consisting of; R ４ is C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C ２－６ alkenyl or C ２－６ alkynyl; k is 0 or 1; l is from 0 to 2; m is 0 or 1, provided that when k is 1 and m is 1, the carbon atom at the end of R ４ and the carbon atom bonded to N combine together to form a 6-membered nitrogen-containing heterocycle (the ring may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, hydroxy, C １－６ alkyl and C １－６ alkoxy); and n is from 0 to 4] A compound represented by the formula or a pharmaceutically acceptable salt thereof.

2. The compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein Formula (I) is Formula (Ia): 【Chemical 2】 [where: R １ , R ２ , R ３ and n have the same meanings as in claim 1]

3. The compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein Formula (I) is Formula (Ib):

4. [Chemical Formula 3] [where: R １ , R ２ , R ３ and n have the same meanings as in claim 1] The compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein n is 0 or 1.

5. R １ is C １－６ alkyl, C(O)-C １－６ alkyl, C １－６ alkylene-R １ａ or C(O)-C １－６ alkylene-R １ａ and the alkyl and alkylene may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, amino and hydroxy; R ２ is C(O)-C １－６ alkyl, C １－６ alkylene-R ２ａ or C(O)-C １－６ alkylene-R ２ａ wherein the alkyl and alkylene may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ each independently is selected from the group consisting of C ３－８ cycloalkyl, C ３－８ cycloalkoxy, C ６－１０ aryl and C ６－１０ aryloxy, and each group may be substituted at a substitutable position with one or the same or different two or more groups selected from the group consisting of halogen, C １－６ alkyl, C １－６ alkoxy, C １－６ haloalkyl, amino and hydroxy; R ３ each independently selected from the group consisting of halogen, amino and hydroxy; and

6.

7. R １ is C １－６ alkyl, C １－６ alkylene-R １ａ or C(O)-C １－６ alkylene-R １ａ wherein the alkyl and alkylene may be substituted at replaceable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino, and hydroxy; and R １ａ is C ３－６ cycloalkyl, C ３－６ cycloalkyloxy, phenyl or phenoxy, and each group may be substituted at a substitutable position with one or the same or different two or more groups selected from the group consisting of halogen, C １－６ alkyl, C １－６ alkoxy and C １－６ haloalkyl, or a pharmaceutically acceptable salt thereof, the compound according to claim 1.

8. R １ is C １－６ alkyl, C １－６ alkylene-R １ａ or C(O)-C １－６ alkylene-R １ａ wherein the alkyl and alkylene may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, amino and hydroxy; and R １ａ is selected from the group consisting of C ５－６ cycloalkyl, C ５－６ cycloalkyloxy, phenyl and phenoxy, and each group may be substituted at a substitutable position with halogen, C １－６ alkyl, C １－６ alkoxy and C １－６ haloalkyl by one or two or more identical or different groups selected from the group consisting of, the compound according to claim 1 or a pharmaceutically acceptable salt thereof. [wherein: q is from 1 to 5] R １ is C １－６ alkyl, C １－６ alkylene-R １ａ or C(O)-C １－６ alkylene-R １ａ and; and R １ａ is cyclohexyl, phenyl or phenoxy, and each group is, at a substitutable position, halogen, C １－６ alkyl, C １－６ alkoxy and C １－６ haloalkyl, and the compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted by one or two or more identical or different groups selected from the group consisting of

9. R １ is C １－５ alkyl, [Chemical Formula 4] The compound or a pharmaceutically acceptable salt thereof according to Claim 1, which is a group selected from the group consisting of a group selected from the group consisting of, each group being, at a substitutable position, halogen and C １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one or two or more identical or different groups selected from the group consisting of alkoxy.

10. R １ is butyl, 【Chemical Formula 5】 [wherein, R ５ is hydrogen, halogen or methoxy, and r is from 1 to 5]

11.

12. R ２ is C ３－６ alkylene-R ２ａ or C(O)-C １－６ alkylene-R ２ａ and; and R ２ａ is selected from the group consisting of C ３－６ cycloalkyl, C ３－６ cycloalkyloxy, phenyl and phenoxy, and each group may be substituted at a substitutable position with halogen, C １－６ alkyl, C １－６ alkoxy and C １－６ haloalkyl by one or two or more identical or different groups selected from the group consisting of, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R ２ is C3-6 alkylene-R2a; and R ２ａ is selected from the group consisting of C ５－６ cycloalkyl, C ５－６ cycloalkyloxy, phenyl and phenoxy, and each group may be substituted at a substitutable position with halogen or C １－６ alkoxy, and the compound according to claim 1 or a pharmaceutically acceptable salt thereof. [wherein, q is from 3 to 5] R ２ is C3-6 alkylene-R2a; and R ２ａ is cyclohexyl, phenyl or phenoxy, and each group may be substituted at a substitutable position with halogen or C １－６ alkoxy, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. R ２ is 【Chemical Formula 6】 The compound or a pharmaceutically acceptable salt thereof according to Claim 1, which is a group selected from the group consisting of, each group being, at a substitutable position, halogen and C １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one or two or more identical or different groups selected from the group consisting of alkoxy.

15. R ２ is 【Chemical Formula 7】 [wherein, R ５ is hydrogen, halogen or methoxy, and r is 3 to 5] 1-(4-Phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 5), 1-Butyl-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 6), 1-(4-Cyclohexylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 7), 1-(1-(4-Cyclohexylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 8), 1-(4-Cyclohexylbutyl)-3-(1-(4-cyclohexylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 9), 1,3-Bis(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 10), 1-(4-Cyclohexylbutyl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 11), 1-(1-(4-Cyclohexylbutyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 12), 1-(1-Butylpiperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 13), ​ ​ 1-(4-Phenylbutyl)-3-(1-(3-phenylpropyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 14), 1-(1-(4-Phenylbutanoyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 15), 1-(4-Phenylbutyl)-3-(1-(5-phenylpentyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 16), 1-(1-(4-Phenylbutyl)piperidin-4-yl)-3-(3-phenylpropyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 17), 1-(1-(4-Phenylbutyl)piperidin-4-yl)-3-(5-phenylpentyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 18), 1-(1-Benzylpiperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 19), 1-Benzyl-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 20), 1-(1-(3-Phenoxypropyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 21), 1-(3-Phenoxypropyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 22), 1-(3-Phenoxypropyl)-3-(1-(3-phenoxypropyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 23), 1-(1-(4-(2-Methoxyphenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 24), 1-(4-(2-Methoxyphenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 25), 1-(4-(2-Methoxyphenyl)butyl)-3-(1-(4-(2-methoxyphenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 26), 1-(1-(4-(2-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 27), 1-(4-(2-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 28), 1-(4-(2-chlorophenyl)butyl)-3-(1-(4-(2-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 29), 1-(1-(4-(2-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 30), 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 31), 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-(2-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 32), 1-(1-(4-(3-chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 33), 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 34), 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-(3-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 35), 1-(1-(4-(3-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 36), 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 37), 1-(4-(3-Fluorophenyl)butyl)-3-(1-(4-(3-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 38), 1-(1-(4-(4-Chlorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 39), 1-(4-(4-Chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 40), 1-(4-(4-Chlorophenyl)butyl)-3-(1-(4-(4-chlorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 41), 1-(1-(4-(4-Fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 42), 1-(4-(4-Fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 43), 1-(4-(4-Fluorophenyl)butyl)-3-(1-(4-(4-fluorophenyl)butyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 44), 5-Fluoro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 45), 5-Chloro-3-(4-phenylbutyl)-1-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 46), 5-Chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 47), 4-Chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one (Compound 48), 1-(1-(4,4-Diphenylbutyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 49), or 1-(1-(4,4-bis(4-fluorophenyl)butyl)piperidin-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazol-2(3H)-one (Compound 50) A compound or a pharmaceutically acceptable salt thereof selected from

16. Formula (I): 【Chemical Formula 8】 [Wherein: R １ is C １－１０ alkyl, C(O)-C １－１０ alkyl, C １－６ alkylene-R １ａ or C(O)-C １－６ alkylene-R １ａ and the alkyl and alkylene may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, amino and hydroxy; R ２ is C(O)-C １－１０ alkyl, C3-6 alkylene-R2a or C(O)-C １－６ alkylene-R ２ａ and the alkyl and alkylene may be substituted at replaceable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ each independently is selected from the group consisting of C １－６ alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, C6-10 aryl and C6-10 aryloxy, and each group may be substituted at a substitutable position with one or the same or different two or more groups selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, amino and hydroxy; R ３ each independently represents a halogen, C １－６ alkyl, C １－６ haloalkyl, amino or hydroxy, and is selected from the group consisting of; R ４ is C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C ２－６ alkenyl or C ２－６ alkynyl; k is 0 or 1; l is from 0 to 2; m is 0 or 1, provided that when k is 1 and m is 1, the carbon atom at the end of R ４ and the carbon atom bonded to N together form a 6-membered nitrogen-containing heterocycle (the ring may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, hydroxy, C １－６ alkyl and C １－６ alkoxy); and n is from 0 to 4] A pharmaceutical composition comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition according to claim 16 for treating a disease caused by T-type calcium channel activation.

18. The pharmaceutical composition according to claim 17, wherein the disease is selected from pain, epilepsy, essential tremor, schizophrenia, Parkinson's disease, mania, bipolar disorder, depression, anxiety disorder, dementia, Huntington's disease, sleep disorder, stroke, pruritus, atopic dermatitis, hyperaldosteronism, edema, ischemic heart disease, age-related macular degeneration, cancer, diabetes, infertility, sexual dysfunction, arrhythmia, hypertension, kidney disease or overactive bladder.

19. The pharmaceutical composition according to claim 17 or 18, wherein the disease is pain.

20. The pharmaceutical composition according to claim 17 or 18, wherein the disease is pruritus.

21. Formula (I): 【Chemical Formula 9】 [Wherein: R １ is C １－１０ alkyl, C(O)-C １－１０ alkyl, C １－６ alkylene-R １ａ or C(O)-C １－６ alkylene-R １ａ wherein the alkyl and alkylene may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, amino and hydroxy; R ２ is C(O)-C １－１０ alkyl, C3-6 alkylene-R2a or C(O)-C １－６ alkylene-R ２ａ wherein the alkyl and alkylene may be substituted at substitutable positions with one or two or more identical or different groups selected from the group consisting of halogen, amino and hydroxy; R １ａ and R ２ａ each independently is selected from the group consisting of C １－６ alkoxy, C3-8 cycloalkyl, C3-8 cycloalkoxy, C6-10 aryl and C6-10 aryloxy, and each group may be substituted at a substitutable position with one or the same or different two or more groups selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, amino and hydroxy; R ３ each independently represents a halogen, C １－６ alkyl, C １－６ haloalkyl, amino or hydroxy, and is selected from the group consisting thereof; R ４ is C １－６ alkyl, C １－６ haloalkyl, C １－６ alkoxy, C ２－６ alkenyl or C ２－６ alkynyl; k is 0 or 1; l is from 0 to 2; m is 0 or 1, provided that when k is 1 and m is 1, the carbon atom at the end of R ４ and the carbon atom bonded to N combine together to form a 6-membered nitrogen-containing heterocycle (the ring may be substituted at substitutable positions with one or the same or different two or more groups selected from the group consisting of halogen, hydroxy, C １－６ alkyl and C １－６ alkoxy); and n is from 0 to 4] A T-type calcium channel inhibitor comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof.

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