T-type calcium channel inhibitors

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

[Technical Field]

[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-benzimidazole-2-one skeleton having T-type calcium channel inhibitory activity and a pharmaceutical composition containing the same. Furthermore, the present invention may also be useful as a therapeutic agent for diseases caused by T-type calcium channel activation, such as pain and itching, by reducing the inhibitory effect on dopamine D2 receptors (hereinafter sometimes referred to as D2 receptors) and thereby reducing the risk of side effects. [Background technology]

[0002] Ion channels are channels that transcend the cell membrane and are broadly classified 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 in one of the mechanisms of neuropathic pain. 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 diconotide.

[0003] Neuropathic pain is often difficult to treat and presents problems with insufficient response to existing analgesics. Furthermore, even with established drug therapies, predicting their effectiveness is often difficult, and concomitant use of other medications is frequently necessary. The Japanese Society of Pain Clinics' guidelines for neuropathic pain drug therapy list high-potential activated calcium channel inhibitors as the first-line treatment, but these often fail to achieve sufficient therapeutic effects. These inhibitors also pose problems due to side effects such as dizziness.

[0004] Voltage-gated calcium channels are classified into two types based on their activation and inactivation potentials: high-potential activated and low-potential activated. L-type, N-type, P / Q-type, and R-type calcium channels are activated by large depolarization and are therefore classified as high-potential activated calcium channels. In contrast, T-type calcium channels are activated by small depolarization and are therefore classified as low-potential 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 that T-type calcium channel inhibitors may be potential therapeutic agents for neuropathic pain. Examples of 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-naphthalenylcyclopropanecarboxylate hydrochloride (NNC55-0396) (e.g., Non-Patent Document 2).

[0006] Furthermore, T-type calcium channels are known to be involved in 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, cardiac arrhythmias, hypertension, cancer, diabetes, overactive bladder, chronic kidney disease, infertility, and sexual dysfunction (Patent Document 1).

[0007] Currently, the only known compound with a 1,3-dihydro-2H-benzimidazole-2-one skeleton that exhibits T-type calcium channel inhibitory activity is 1-{1-[4,4-bis(4-fluorophenyl)butyl]piperidine-4-yl}-1,3-dihydro-2H-benzimidazole-2-one (hereinafter sometimes referred to as pimozide). However, this compound exhibits stronger D2 receptor inhibitory activity compared to its T-type calcium channel inhibitory activity. Due to its strong D2 receptor inhibitory effect, pimozide has the problem of causing extrapyramidal symptoms, and its T-type calcium channel inhibitory activity has not been applicable to the treatment of diseases. To date, no compound with a 1,3-dihydro-2H-benzimidazole-2-one skeleton that can attenuate D2 receptor inhibitory activity and effectively suppress the risk of side effects is known.

[0008] Although several compounds that can be used as T-type calcium channel inhibitors have already been identified, further investigation into new compounds that can be used as T-type calcium channel inhibitors is needed, particularly from the perspective of side effects. [Prior art documents] [Patent Documents]

[0009] [Patent Document 1] International Publication No. 2015-050212 [Non-patent literature]

[0010] [Non-Patent Document 1] Todorovic, Neuron, 2001, 31(1), p.75-85 [Non-Patent Document 2] Huang, J Pharmacol Exp Ther., 309(1), p.193-199 [Overview of the Initiative] [Problems that the invention aims to solve]

[0011] The present invention examines novel compounds having a T-type calcium channel inhibitory action, and can reduce the D2 receptor inhibitory action to suppress the risk of side effects, and is useful for treating diseases caused by the activation of T-type calcium channels (for example, pain, pruritus), such as pharmaceuticals (for example, T-type calcium channel inhibitors). The purpose is to provide.

Means for Solving the Problems

[0012] As a result of intensive studies to solve the above problems, the 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 action. Furthermore, it was found that the D2 receptor inhibitory action was attenuated to suppress the risk of side effects, and the present invention was completed.

[0013] That is, the present invention provides the following aspects. [1] Formula (I):

Chemical formula

[10] R 2 However, C 1-6 Alkyl, C 1-6 Alkilen-R 2a , C(O)-C 1-6 Alkilen-R 2a or C 1-4 Alkylene-CHR 2b R 2b and; R 2a However, C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of cycloalkyloxy, phenyl, and phenoxy, each group is a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 They may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups; and R 2b However, each is independent of C 3-6 Selected from the group consisting of cycloalkyl and phenyl, each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 A compound or a pharmaceutically acceptable salt thereof according to any of [1] to [9], which may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups.

[11] R 2 However, C 1-6 Alkyl, C 1-6 Alkilen-R 2a or C 1-4 Alkylene-CHR 2b R 2b can be; R 2a However, C 5-6 Cycloalkyl, C 5-6 Selected from the group consisting of cycloalkyloxy, phenyl, and phenoxy, each group is substituted with a halogen or C at a substituted position. 1-6It may also be substituted with an alkoxy; and R 2b However, each is independent of C 5-6 Selected from the group consisting of cycloalkyl and phenyl, each group is substituted with a halogen or C at a substituted position. 1-6 A compound or a pharmaceutically acceptable salt thereof described in any of [1] to

[10] , which may be substituted with an alkoxy.

[12] R 2 However, C 1-6 Alkyl, C 1-6 Alkilen-R 2a or C 1-4 Alkylene-CHR 2b R 2b can be; R 2a However, the group is cyclohexyl, phenyl, or phenoxy, and each group is substituted with a halogen or C at a substituted position. 1-6 It may also be substituted with an alkoxy; and R 2b However, each is independently selected from the group consisting of cyclohexyl and phenyl, and each group is substituted with a halogen or C at a substituted position. 1-6 A compound or a pharmaceutically acceptable salt thereof described in any of [1] to

[11] , which may be substituted with an alkoxy.

[13] R 2 However, C 1-5 Alkyl, [ka] [In the formula, p and q are synonymous with [8]] A group selected from the group consisting of the following, where each group is a halogen and C at a substituted position. 1-6 A compound or a pharmaceutically acceptable salt thereof described in any of [1] to

[12] , which may be substituted with one or more identical or different groups selected from the group consisting of alkoxys.

[14] R 2 But butyl, [ka] [In the formula, R 5[where r is hydrogen, halogen, or methoxy, and r is 1-5] The compound described in any of [1] to

[13] or a pharmaceutically acceptable salt thereof.

[15] 1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 5), 1-Butyl-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 6), 1-(4-cyclohexylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 7), 1-(1-(4-cyclohexylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 8), 1-(4-cyclohexylbutyl)-3-(1-(4-cyclohexylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 9), 1,3-bis(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 10), 1-(4-cyclohexylbutyl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 11), 1-(1-(4-cyclohexylbutyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 12), 1-(1-butylpiperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 13), 1-(4-phenylbutyl)-3-(1-(3-phenylpropyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 14), 1-(1-(4-phenylbutanoyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 37), 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-(3-fluorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 38), 1-(1-(4-(4-chlorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 39), 1-(4-(4-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 40), 1-(4-(4-chlorophenyl)butyl)-3-(1-(4-(4-chlorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 41), 1-(1-(4-(4-fluorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 42), 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 43), 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-(4-fluorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 44), 5-Fluoro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 45), 5-Chloro-3-(4-phenylbutyl)-1-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 46), 5-Chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 47), 4-Chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 48), 1-(1-(4,4-diphenylbutyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 49), or 1-(1-(4,4-bis(4-fluorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 50) A compound selected from [1] or a pharmaceutically acceptable salt thereof.

[16] Equation (I): [ka] [In formula: R 1 C 1-10 Alkyl, C(O)-C 1-10 Alkyl, C 1-6 Alkilen-R 1a , C(O)-C 1-6 Alkilen-R 1a , C 1-6 Alkylene-CHR 1b R 1b or C(O)-C 1-6 Alkylene-CHR 1b R 1b The alkyl and alkylene may be substituted at substituted positions with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls; R 2 is hydrogen, C 1-10 Alkyl, C(O)-C 1-10 Alkyl, C 1-6 Alkilen-R 2a , C(O)-C 1-6 Alkilen-R 2a , C1-6 Alkylene-CHR 2b R 2b or C(O)-C 1-6 Alkylene-CHR 2b R 2b The alkyl and alkylene may be substituted at substituted positions with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls; R 1a and R 2a Each of them is independent of C 1-6 Alkoxy, C may be substituted. 3-8 Cycloalkyl, may be 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, C may be substituted. 6-10 Selected from the group consisting of aryloxys, optionally substituted 5-10 membered heteroaryls, and optionally substituted 5-10 membered heteroaryloxys; R 1b and R 2b Each of these can be substituted independently of the others. 3-8 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10 Selected from the group consisting of aryls and optionally substituted 5- to 10-membered heteroaryls; R 3 These are, independently, halogen and C 1-6 Alkyl, C 1-6 Selected from the group consisting of haloalkyl, amino, and hydroxy; R 4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl or C 2-6 It is alkinyl; k is either 0 or 1; l is between 0 and 2; m is either 0 or 1, except when k is 1 and m is 1, R 4 The terminal carbon atom and the carbon atom bonded to N combine to form a 4- to 6-membered nitrogen-containing heteroring (the ring has a halogen, hydroxyl, and C at the substitutionable positions). 1-6 Alkyl and C 1-6 They may form (which may be substituted with one or more identical or different groups selected from the group consisting of alkoxys); and n is between 0 and 4. A pharmaceutical composition comprising a compound represented by (excluding 1-[1-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazole-2-one) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[17] The pharmaceutical composition according to

[16] for treating a disease caused by activation of T-type calcium channels.

[18] The pharmaceutical composition according to

[17] , wherein the disease is selected from pain, epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic-depressive illness, 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 mellitus, infertility, sexual dysfunction, arrhythmia, hypertension, renal disease, or 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] Equation (I): [ka] [In formula: R 1 C 1-10 Alkyl, C(O)-C 1-10 Alkyl, C 1-6 Alkilen-R 1a , C(O)-C 1-6 Alkilen-R 1a , C 1-6 Alkylene-CHR 1b R1b or C(O)-C 1-6 Alkylene-CHR 1b R 1b The alkyl and alkylene may be substituted at substituted positions with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls; R 2 is hydrogen, C 1-10 Alkyl, C(O)-C 1-10 Alkyl, C 1-6 Alkilen-R 2a , C(O)-C 1-6 Alkilen-R 2a , C 1-6 Alkylene-CHR 2b R 2b or C(O)-C 1-6 Alkylene-CHR 2b R 2b The alkyl and alkylene may be substituted at substituted positions with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls; R 1a and R 2a Each of them is independent of C 1-6 Alkoxy, C may be substituted. 3-8 Cycloalkyl, may be 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, C may be substituted. 6-10 Selected from the group consisting of aryloxys, optionally substituted 5-10 membered heteroaryls, and optionally substituted 5-10 membered heteroaryloxys; R 1b and R 2b Each of these can be substituted independently of the others. 3-8 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10selected from the group consisting of aryl and optionally substituted 5- to 10-membered heteroaryl; R 3 each independently is selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 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;<00​​​​​​​​​​​​​​​​​​​​​​

[24] Use of any of the compounds described in [1] to

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

[25] The treatment method 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 treatment method 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 according to

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

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

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

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

[30] The pharmaceutical composition according to

[18] or

[19] , the method of treatment according to

[25] , the compound according to

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

[25] , wherein the pain is neuropathic pain.

[31] The pharmaceutical composition according to

[18] or

[20] , the therapeutic 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 refractory pruritus. [Effects of the Invention]

[0015] According to the present invention, a novel benzimidazolon compound having excellent T-type calcium channel inhibitory activity can be provided. Furthermore, the compounds of the present invention may be useful as novel therapeutic agents for diseases caused by activation of T-type calcium channels, such as pain and pruritus, as they can reduce the risk of side effects by attenuating D2 receptor inhibitory activity. [Brief explanation of the drawing]

[0016] [Figure 1] The ratio (%) of the T-channel current value after adding pimozide and the compound of the present invention (3 μM and 1 μM) to the T-channel current value after adding the vehicle (solvent, control group) is shown (n=3-10). (a) shows the data obtained by directly adding the test compound at a concentration of 3 μM, and (b) shows the data obtained by directly adding the test compound at a concentration of 1 μM. [Figure 2] The percentage change in T-channel current values ​​before the addition of the vehicle and the compound of the present invention, and after the addition of the vehicle and the compound of the present invention by perfusion (0.3 μM), is shown (n=3-8). [Figure 3] The inhibition rates of the compounds of the present invention against the binding of [3H]-spiperone to the dopamine D2 receptor are shown (n=3). (a) shows the inhibition rates of [3H]-spiperone against dopamine D2 receptor-specific binding at a concentration of 1 μM pimozide and compounds 4-7, (b) shows the inhibition rates of [3H]-spiperone against dopamine D2 receptor-specific binding at concentrations of 1 μM and 10 μM pimozide, compound 25, compound 28 and compound 30, and (c) shows the inhibition rates of [3H]-spiperone against dopamine D2 receptor-specific binding at concentrations of 1 μM and 10 μM pimozide, compound 26, compound 36 and compound 38. The inhibition rate of each compound is expressed as the ratio of each compound to the inhibition rate of pimozide, which is set to 100%. [Figure 4]The dopamine D2 receptor-specific binding amount of [3H]-spiperone after solvent addition (total binding amount) and after addition of the test compound (1 μM and 10 μM) is shown (n=3). (a) shows the amount of [3H]-spiperone specifically binding to the dopamine D2 receptor after solvent addition (total binding amount), the amount of [3H]-spiperone specifically binding to the dopamine D2 receptor after addition of 1 μM and 10 μM concentrations of pimozide, compound 25, compound 28, and compound 30, and the amount of [3H]-spiperone specifically binding to the dopamine D2 receptor after addition of 10 μM concentration of sulpiride. (b) shows the amount of [3H]-spiperone specifically binding to the dopamine D2 receptor at the time of solvent addition (total binding amount), the amount of [3H]-spiperone specifically binding to the dopamine D2 receptor after addition of 1 μM and 10 μM concentrations of pimozide, compound 26, compound 36, and compound 38, and the amount of [3H]-spiperone specifically binding to the dopamine D2 receptor after addition of 10 μM concentration of sulpiride. [Figure 5] The duration of catalepsy (in seconds) at 30, 60, 90, 120, 150, and 180 minutes after administration of the vehicle and test compound is shown. [Figure 6] The mean ± standard error of the number of scratching and wiping behaviors at 10, 20, 30, 40, 50, and 60 minutes after intradermal administration to the right cheek, as well as the mean ± standard error of the total number of counts over 60 minutes, are shown. [Figure 7] The mean ± standard error of the pain threshold (g) is shown for before administration to the hind limb sole, immediately after administration, and 15-60 minutes after administration. [Figure 8] The graph shows the mean ± standard error (n=6-7) of the total number of hindlimb scratching behaviors at the intradermal injection site 60 minutes after intradermal administration of compound 5 (10 mg / kg) in the right cheek in the control group (administered with 1% DMSO and 5% Tween 80 in saline (solvent 1) + saline (solvent 2)), the solvent 1 + histamine group, and the compound 5 (10 mg / kg) + histamine group. [Figure 9]The graph shows the mean ± standard error (n=10) of the total number of hindlimb scratching behaviors at the intradermal injection site 60 minutes after intradermal administration of compound 5 (10 mg / kg) in the right cheek in the control group (administered with 1% DMSO and 5% Tween 80 in saline (solvent 1) + saline (solvent 2)), the solvent 1 + chloroquine group, and the compound 5 (10 mg / kg) + chloroquine group. [Figure 10] The graph shows the mean ± standard error (n=6-8) of the total number of hindlimb scratching behaviors at the intradermal injection site 60 minutes after intradermal injection of compound 38 (1 mg / kg) + chloroquine at right cheek in the following groups: control group (1% DMSO and 5% Tween 80 administered as saline (solvent 1) + saline (solvent 2)); control group (solvent 1 + chloroquine); compound 38 (1 mg / kg) + chloroquine; compound 38 (3 mg / kg) + chloroquine; and compound 38 (10 mg / kg) + chloroquine. [Modes for carrying out the invention]

[0017] The following is an explanation of the terms used in this specification.

[0018] In this specification, "halogen" means fluorine, chlorine, bromine, or iodine.

[0019] In this specification, "C 1-10 "Alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 10 carbon atoms. 1-6 "Alkyl" and "C 1-4 "Alkyl" refers to alkyl groups having 1 to 6 carbon atoms and alkyl groups having 1 to 4 carbon atoms, respectively. "C 1-10 Examples of alkyl groups 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, and 2-ethylbutyl. These may be substituted with one or more substituents included in the present invention at substitutable positions.

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

[0021] In this specification, "C 2-6 "Alkenyl" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and having one or more carbon-carbon double bonds at any position. 2-6 "Alkenil" is preferably "C 2-4 It is "Alkenil". "C 2-6 Examples of "alkenyls" include ethenyl, propenyl, butenyl, pentenyl, and hexenyl. These may be substituted with one or more substituents included in the present invention at substituted positions.

[0022] In this specification, "C 2-6 "Alkynyl" refers to a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and possessing one or more carbon-carbon triple bonds at any position. 2-6 "Alkinyl" is preferably "C 2-6 It is "Alkinil". "C 2-6 Examples of "alkynyl" include ethinyl, propynyl, butynyl, pentynyl, and hexynyl. These may be substituted with one or more substituents included in the present invention at substituted positions.

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

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

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

[0026] In this specification, "C 3-8 "Cycloalkoxy" refers to the above C 3-8 This refers to an oxy group substituted with a cycloalkyl group. "C 3-8 Examples of "cycloalkoxy" include cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and cycloheptyloxy. These may be substituted with one or more substituents included in the present invention at substituted positions. The cycloalkyl portions may be substituted with one or more substituents included in the present invention at substituted positions.

[0027] In this specification, "3- to 10-membered heterocycloalkyl" means 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 oxidized as desired, and the nitrogen atom may be quaternized as desired. Bicyclic heterocycloalkyl groups also include those formed by fusion of a monocyclic heterocycloalkyl group with an aromatic ring (such as benzene or pyridine) or a non-aromatic ring (such as cyclohexyl or piperidine). "3- to 10-membered heterocycloalkyl" is preferably a 5- to 6-membered heterocycloalkyl group. Examples of "3- to 10-membered heterocycloalkyl groups" include azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, tetrahydrofuranil, and tetrahydropyranil. These may be substituted with one or more substituents included in the present invention at substituted positions.

[0028] In this specification, "3- to 10-membered heterocycloalkoxy" means an oxy group substituted with the above-mentioned 3- to 10-membered heterocycloalkyl group. Examples of "3-10 member heterocycloalkoxys" include azilidinyloxy, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy, piperazinyloxy, morpholinyloxy, homopiperidinyloxy, tetrahydrofuranyloxy, and tetrahydropyranyloxy. The heterocycloalkyl portion of these may be substituted with one or more substituents included in the present invention at a substituted position.

[0029] In this specification, "C 6-10 "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. 6-10 The "aryl" is preferably "C6 aryl (phenyl)". "C 6-10 Examples of "aryl" include phenyl, 1-naphthyl, and 2-naphthyl. These may be substituted with one or more substituents included in the present invention at their substitutable positions.

[0030] In this specification, "C 6-10 "Aryloxy" refers to the above C 6-10 This refers to an oxy group substituted with an aryl group. 6-10 The "aryloxy" is preferably a C6 aryloxy. "C 6-10 Examples of "aryloxy" include phenoxy, 1-naphthyloxy, and 2-naphthyloxy. The aryl portion may be substituted with one or more substituents included in the present invention at a replaceable position.

[0031] In this specification, "5-10 membered heteroaryl" means a 5- to 10 membered monocyclic or bicyclic aromatic heterocyclic group containing one or more (e.g., 1-4) heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur atoms. Bicyclic heteroaryl groups also include those formed by fusion of a monocyclic heteroaryl group with an aromatic ring (such as benzene or pyridine) or a non-aromatic ring (such as cyclohexyl or piperidine). "5- to 10 membered heteroaryl" is preferably a 5- to 6 membered heteroaryl. Examples of "5-10 member heteroaryls" 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, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, and benzimidazolyl. These may be substituted with one or more substituents included in the present invention at substitutable positions.

[0032] In this specification, "5- to 10-membered heteroaryloxy" means an oxy group substituted with the above-mentioned 5- to 10-membered heteroaryl group. The "5- to 10-membered heteroaryloxy" is preferably a 5 or 6-membered heteroaryloxy. Examples of "5-10 member heteroaryloxys" include pyridyloxy, pyridadinyloxy, pyrrolyloxy, furyloxy, thienyloxy, thiazolyloxy, pyrimidinyloxy, pyrazolyloxy, and isoquinolyloxy. The heteroaryl portion of these heteroaryl groups may be substituted with one or more substituents included in the present invention at substitutable positions.

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

[0034] In this specification, “may be substituted” includes both cases where the substitutable positions of the group are not substituted (unsubstituted) and cases where they are substituted. “Unsubstituted” means that all the substitutable positions of the group are hydrogen atoms. If substituted, the group may be substituted with multiple substituents if possible, and these substituents may be the same or different. In this specification, "C which may be substituted" 3-8 Cycloalkyl, "C may be substituted" 3-8 Cycloalkoxy, optionally substituted 3- to 10-membered heterocycloalkyl, optionally substituted 3- to 10-membered heterocycloalkoxy, optionally substituted C 6-10 "Aryl", "C may be substituted" 6-10 Examples of substituents in "aryloxy," "a 5-10 member heteroaryl that may be substituted," and "a good 5-10 member heteroaryloxy that may be substituted" include halogens, alkyls, alkenyls, alkynyls, cycloalkyls, heterocycloalkyls, haloalkyls, alkoxys, haloalkoxys, aminos, nitros, cyanos, hydroxys, mono- or di-alkylaminos, carbamoyls, carboxyls, morpholinyls, formyls, acetyls, mesyls, benzoyls, acylaminos, benzyls, aryls, and heteroaryls. Such substituents are preferably halogens, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 These are haloalkyl, amino, and hydroxy types.

[0035] R in the compounds of the present invention represented by formula (I), formula (Ia), and formula (Ib) 1 , R 2 , R 3 , R 4 With respect to k, l, m, and n, the following are preferred, but the technical scope of the present invention is not limited to the range of compounds listed below.

[0036] R 1 As for, (1)C 1-10alkyl; (2) C(O)-C 1-10 alkyl; (3)C 1-6 Alkilen-R 1a (R 1a C 1-6 Alkoxy, C may be substituted. 3-8 Cycloalkyl, may be 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, C may be substituted. 6-10 An aryloxy, a substituted or possibly substituted 5-10 member heteroaryl, or a substituted or possibly substituted 5-10 member heteroaryloxy; (4) C(O)-C 1-6 Alkilen-R 1a (R 1a C 1-6 Alkoxy, C may be substituted. 3-8 Cycloalkyl, may be 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, C may be substituted. 6-10 An aryloxy, a substituted or possibly substituted 5-10 member heteroaryl, or a substituted or possibly substituted 5-10 member heteroaryloxy; (5)C 1-6 Alkylene-CHR 1b R 1b (R 1b Each of these can be substituted independently of the others. 3-8 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10 Selected from the group consisting of aryls and optionally substituted 5-10 member heteroaryls); and (6)C(O)-C 1-6 Alkylene-CHR 1b R 1b (R1b Each of these can be substituted independently of the others. 3-8 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10 Examples include aryls and substituted 5- to 10-membered heteroaryls, wherein the alkyls and alkylenes may be substituted at substitutable positions with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls.

[0037] R 1 Preferably, (1)C 1-6 alkyl; (2) C(O)-C 1-6 alkyl; (3)C 1-6 Alkilen-R 1a (R 1a C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C 6-10 Ariel, C 6-10 The aryloxy, 5-10 membered heteroaryl, or 5-10 membered heteroaryloxy, where each group is substituted with a halogen, C at a substitutable position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl; (4) C(O)-C 1-6 Alkilen-R 1a (R 1a C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C 6-10 Ariel, C 6-10The aryloxy, 5-10 membered heteroaryl, or 5-10 membered heteroaryloxy is a cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aryloxy, heteroaryl, and heteroaryloxy with a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl; (5)C 1-4 Alkylene-CHR 1b R 1b (R 1b Each of them is independent of C 3-8 Cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryl and 5-10 membered heteroaryl groups, each group is substituted with a halogen, C at a replaceable position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl; or (6)C(O)-C 1-4 Alkylene-CHR 1b R 1b (R 1b Each of them is independent of C 3-8 Cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryl and 5-10 membered heteroaryl groups, each group is substituted with a halogen, C at a replaceable position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 (It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl), more preferably, (1)C 1-6 alkyl; (2)C 1-6 Alkilen-R 1a (R 1a C 3-6Cycloalkyl, C 3-6 The group is cycloalkyloxy, phenyl, or phenoxy, and each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups. (3) C(O)-C 1-6 Alkilen-R 1a (R 1a C 3-6 Cycloalkyl, C 3-6 The group is cycloalkyloxy, phenyl, or phenoxy, and each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups); or (4)C 1-4 Alkylene-CHR 1b R 1b (R 1b Each of them is independent of C 3-6 Selected from the group consisting of cycloalkyl and phenyl, each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It is more preferably a group selected from the group consisting of haloalkyls, which may be substituted with one or more identical or different groups, (1)C 1-6 alkyl; (2)C 1-6 Alkilen-R 1a (R 1a C 5-6 Cycloalkyl, C 5-6 The group is cycloalkyloxy, phenyl, or phenoxy, and each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups. (3) C(O)-C 1-6 Alkilen-R 1a (R 1a C 5-6 Cycloalkyl, C 5-6 The group is cycloalkyloxy, phenyl, or phenoxy, and each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups); or (4)C 1-4 Alkylene-CHR 1b R 1b (R 1b Each of them is independent of C 5-6 Selected from the group consisting of cycloalkyl and phenyl, each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 (It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyls), and more preferably, (1)C 1-6 alkyl; (2)C 1-6 Alkilen-R 1a (R 1a The group is cyclohexyl, phenyl, or phenoxy, and each group is substituted with a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups. (3) C(O)-C 1-6 Alkilen-R 1a (R 1a The group is cyclohexyl, phenyl, or phenoxy, and each group is substituted with a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups); or (4)C 1-4 Alkylene-CHR 1b R 1b (R 1b Each is independently selected from the group consisting of cyclohexyl and phenyl, and each group is substituted with a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 (It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyls), and is particularly preferably C 1-5 Alkyl, [ka] [In the formula: p is between 1 and 4, and q is between 1 and 5] A group selected from the group consisting of (each group is a halogen and C at a substituted position) 1-6 It is substituted with one or more identical or different groups selected from the group consisting of alkoxys, most preferably butyl, [ka] [In the formula, R 5 is hydrogen, halogen, or methoxy, and R 6 Each of these is either hydrogen or a halogen, and r is between 1 and 5. It is a group selected from the group consisting of R. 1 The alkyl and alkylene groups may be substituted at their substituted positions with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls.

[0038] R 2 As for, (1) Hydrogen; (2)C 1-10 alkyl; (3) C(O)-C 1-10 alkyl; (4)C 1-6 Alkilen-R 2a (R 2a C 1-6Alkoxy, C may be substituted. 3-8 Cycloalkyl, may be 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, C may be substituted. 6-10 An aryloxy, a substituted or possibly substituted 5-10 member heteroaryl, or a substituted or possibly substituted 5-10 member heteroaryloxy; (4) C(O)-C 1-6 Alkilen-R 2a (R 2a C 1-6 Alkoxy, C may be substituted. 3-8 Cycloalkyl, may be 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, C may be substituted. 6-10 An aryloxy, a substituted or possibly substituted 5-10 member heteroaryl, or a substituted or possibly substituted 5-10 member heteroaryloxy; (5)C 1-6 Alkylene-CHR 2b R 2b (R 2b Each of these can be substituted independently of the others. 3-8 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10 Selected from the group consisting of aryls and optionally substituted 5-10 member heteroaryls); and (6)C(O)-C 1-6 Alkylene-CHR 2b R 2b (R 2b Each of these can be substituted independently of the others. 3-8 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10Examples include aryls and substituted 5- to 10-membered heteroaryls, wherein the alkyls and alkylenes may be substituted at substitutable positions with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls.

[0039] R 2 Preferably, (1)C 1-6 alkyl; (2) C(O)-C 1-6 alkyl; (3)C 1-6 Alkilen-R 2a (R 2a C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C 6-10 Ariel, C 6-10 The aryloxy, 5-10 membered heteroaryl, or 5-10 membered heteroaryloxy, where each group is substituted with a halogen, C at a substitutable position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl; (4) C(O)-C 1-6 Alkilen-R 2a (R 2a C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3- to 8-membered heterocycloalkyl, 3- to 8-membered heterocycloalkoxy, C 6-10 Ariel, C 6-10 The aryloxy, 5-10 membered heteroaryl, or 5-10 membered heteroaryloxy is a cycloalkyl, cycloalkoxy, heterocycloalkyl, heterocycloalkoxy, aryl, aryloxy, heteroaryl, and heteroaryloxy with a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl; (5)C 1-4 Alkylene-CHR 2b R 2b (R 2b Each of them is independent of C 3-8 Cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryl and 5-10 membered heteroaryl groups, each group is substituted with a halogen, C at a replaceable position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl; or (6)C(O)-C 1-4 Alkylene-CHR 2b R 2b (R 2b Each of them is independent of C 3-8 Cycloalkyl, 3-membered to 8-membered heterocycloalkyl, C 6-10 Selected from the group consisting of aryl and 5-10 membered heteroaryl groups, each group is substituted with a halogen, C at a replaceable position. 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 (It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl, amino, and hydroxyl), more preferably, (1)C 1-6 alkyl; (2)C 1-6 Alkilen-R 2a (R 2a C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of cycloalkyloxy, phenyl, and phenoxy, each group is a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups. (3) C(O)-C 1-6 Alkilen-R 2a (R 2a C 3-6 Cycloalkyl, C 3-6 Selected from the group consisting of cycloalkyloxy, phenyl, and phenoxy, each group is a halogen, C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups); or (4)C 1-4 Alkylene-CHR 2b R 2b (R 2b Each of them is independent of C 3-6 Selected from the group consisting of cycloalkyl and phenyl, each group is substituted with a halogen or C at a substituted position. 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 It is more preferably a group selected from the group consisting of haloalkyls, which may be substituted with one or more identical or different groups, (1)C 1-6 alkyl; (2)C 1-6 Alkilen-R 2a (R 2a C 5-6 Cycloalkyl, C 5-6 Selected from the group consisting of cycloalkyloxy, phenyl, and phenoxy, each group is substituted with a halogen or C at a substituted position. 1-6 It may be substituted with an alkoxy); or (3)C 1-4 Alkylene-CHR 2b R 2b (R 2b Each of them is independent of C 5-6 Selected from the group consisting of cycloalkyl and phenyl, each group is substituted with a halogen or C at a substituted position. 1-6 (which may be substituted with alkoxy), and more preferably, (1)C 1-6 alkyl; (2)C 1-6 Alkilen-R 2a (R 2a The group is cyclohexyl, phenyl, or phenoxy, and each group is substituted with a halogen or C at a substituted position. 1-6 It may be substituted with an alkoxy); or (3)C 1-4 Alkylene-CHR 2b R 2b (R 2b Each is independently selected from the group consisting of cyclohexyl and phenyl, and each group is substituted with a halogen or C at a substituted position. 1-6 (May be substituted with alkoxy), and particularly preferably C 1-5 Alkyl, [ka] [In the formula, p and q are R as above] 1 [Synonymous with "thing"] A group selected from the group consisting of (each group is a halogen and C at a substituted position) 1-6 It is substituted with one or more identical or different groups selected from the group consisting of alkoxys, most preferably butyl, [ka] [In the formula, R 5 [where r is hydrogen, halogen, or methoxy, and r is 1-5] That is the case.

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

[0041] R 4 C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6Alkenyl and C 2-6 Alkinyl is one example. Among them, C is preferred. 1-6 It is 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 The terminal carbon atom and the carbon atom bonded to N combine to form a 4- to 6-membered nitrogen-containing heteroring (the ring has a halogen, hydroxyl, and C at the substitutionable positions). 1-6 Alkyl and C 1-6 It may form one or more identical or different groups selected from the group consisting of alkoxys. Preferably, k is 1, l is 2, m is 1, R 4 When R is methyl, 4 The carbon atom and the carbon atom bonded to N combine to form a piperidine ring. Also, k, l and m are 0, and the N atom and R in the 1,3-dihydro-2H-benzimidazole-2-one skeleton. 1 It is also preferable that they bond directly.

[0043] In this specification, "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, and phosphoric acid. 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, glucoheptic 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, and sulfosalicylic acid.

[0044] Since the compounds of the present invention may also exist in the form of hydrates and / or solvates, these hydrates or solvates, such as ethanol solvates, are also included in the compounds of the present invention. Furthermore, the compounds of the present invention also include all crystalline forms.

[0045] Since the compounds of the present invention may also exist as tautomers, these tautomers are also included in the compounds of the present invention.

[0046] Since the compounds of the present invention may have at least one chiral carbon atom, the compounds of the present invention encompass not only racemates of the compounds represented by formulas (I), (Ia), and (Ib), but also optically active forms of these compounds. When the compounds represented by formulas (I), (Ia), and (Ib) have two or more chiral carbon atoms, stereoisomerism may occur. Therefore, the compounds of the present invention also encompass stereoisomers of these compounds, mixtures thereof, and isolated forms. Furthermore, one or more compounds represented by formula (I), formula (Ia), and formula (Ib) 1 H 2 Deuterium converters converted to H(D) are also included in the compounds of the present invention.

[0047] The following describes a method for producing the compounds of the present invention, with examples, but the present invention is not limited thereto.

[0048] The compounds used as starting materials may also be used as salts. These reactions are merely examples, and the compounds of the present invention can be produced by other methods as appropriate, based on the knowledge of those proficient in organic synthesis.

[0049] In each of the manufacturing methods described below, even if the use of protecting groups is not explicitly stated, if there are functional groups that require protection, those functional groups may be protected as necessary, and the target product may be obtained by deprotecting them after the reaction is complete or after a series of reactions have been carried out.

[0050] As protecting groups, ordinary protecting groups described in literature such as (TW Greene and PGMWuts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, inc., New York (1999)) can be used. More specifically, examples of protecting groups for amino groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl, while examples of protecting groups for hydroxyl groups include trialkylsilyl, acetyl, and benzyl.

[0051] The introduction and removal of protecting groups can be carried out by methods commonly used in organic synthesis (for example, the methods described in TW Greene and PGMWuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999)) or by similar methods.

[0052] Manufacturing method 1 Of the compounds represented by formula (I), the compounds represented by formula (Ia) and formula (Ib) can be produced, for example, by the following manufacturing method. The starting compound, tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (1), can be produced by known methods, for example, the method described in J. Med. Chem., 2018, 61, 8895-8907. [ka] [In the formula: R 1 This is synonymous with [1] above.

[0053] Manufacturing method 2 Of the compounds represented by formula (I), the compound represented by formula (Ic) can be produced, for example, by the following manufacturing method. [ka] [In the formula: R 1 is equivalent to the above [1], and R is the R of the above [1]. 1 [Synonymous with "thing"]

[0054] Manufacturing method 3 Of the compounds represented by formula (I), the compounds represented by formula (Id) and formula (Ie) can be produced, for example, by the following manufacturing method. The raw material compound, o-phenylenediamine, is commercially available or can be produced according to known methods. [ka] [In the formula: R 1 is equivalent to the above [1], and R is the R of the above [1]. 1 [Synonymous with "thing"]

[0055] Manufacturing 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 manufacturing method. [ka] [In the formula: R 1 is equivalent to the above [1], and R is the R of the above [1]. 1 [Synonymous with "thing"]

[0056] Manufacturing method 5 Of the compounds represented by formula (I), the compound represented by formula (Ih) can be produced, for example, by the following manufacturing method. [ka] [In the formula: R is the same as R in [1] above] 1It is synonymous with C 1-6 Alkilen-R 1a or C 1-6 Alkylene-CHR 1b R 1b The alkylene may be substituted at a substituted position with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls, R 1a C 1-6 Alkoxy, C may be substituted. 3-8 Cycloalkyl, may be 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, C may be substituted. 6-10 Selected from the group consisting of aryloxy, optionally substituted 5-10 member heteroaryls, and optionally substituted 5-10 member heteroaryloxys, R 1b Each of these can be substituted independently of the others. 3-8 Cycloalkyl groups, optionally substituted 3- to 10-membered heterocycloalkyl groups, optionally substituted C 6-10 [Selected from the group consisting of aryls and optionally substituted 5-10 member heteroaryls]

[0057] Manufacturing method 6 Of the compounds represented by formula (I), those represented by formula (Ij) and formula (Ik) can be produced, for example, by the following manufacturing method. The compound represented by formula (Ii) can be produced by known methods. [ka] [In the formula: R 1 and R 3 is equivalent to the above [1], and R is the R of the above [1]. 1 [Synonymous with "thing"]

[0058] The solvent, acid, and base used in the above manufacturing method can be changed as appropriate depending on the type of raw material compound. Furthermore, conditions such as reaction temperature can also be changed as appropriate.

[0059] The compounds or intermediates of the present invention can be separated and purified by methods known to those skilled in the art. Examples include extraction, partitioning, reprecipitation, column chromatography (e.g., silica gel column chromatography, ion exchange column chromatography, or preparative liquid chromatography), or recrystallization. Suitable recrystallization solvents include, for example, 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; or a mixture of two or more solvents selected from the above. Other purification methods include those described in Volume 1 of "Experimental Chemistry Series" (edited by the Chemical Society of Japan, Maruzen).

[0060] In the present invention, "diseases caused by T-type calcium channel activation" means diseases or symptoms caused by the 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, renal disease, and overactive bladder. In the present invention, pain and pruritus are preferred diseases, visceral pain, somatic pain, and pruritus are more preferred, and visceral pain, acute pain, chronic pain, neuropathic pain, and pruritus are even more preferred. Among pains, neuropathic pain is particularly preferred.

[0061] In this invention, “treatment” means any treatment of a disease and its symptoms in a patient, particularly in a human (e.g., improvement, alleviation, inhibition of progression, etc.). It also includes preventing the onset and / or progression of the disease.

[0062] In this invention, "patient" means humans and animals, such as dogs, cats, and horses. Among these, humans are preferred.

[0063] In this invention, "therapeutically effective dose" means an amount that, compared to an untreated subject, produces a therapeutic effect on the disease and its symptoms, or a dose that delays the progression of the disease and its symptoms. This term also includes, within its scope, an amount that is effective in promoting normal physiological function. Such effective amounts include amounts of the compound of the present invention alone, amounts of combinations of the compounds of the present invention, and / or amounts of the compound of the present invention combined with other active ingredients useful for treating diseases.

[0064] The compounds 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] Because the compounds of the present invention have T-type calcium channel inhibitory activity, the pharmaceutical compositions of the present invention can serve as novel therapeutic agents for pain (e.g., visceral pain, somatic pain), epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic-depressive illness, bipolar disorder, depression, anxiety disorders, dementia, Huntington's disease, sleep disorders, stroke, pruritus (e.g., intractable pruritus seen 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, and the like. The pharmaceutical compositions of the present invention can serve as therapeutic agents for visceral pain, somatic pain and pruritus, more preferably for visceral pain, acute pain, chronic pain, neuropathic pain and pruritus, and even more preferably for neuropathic pain and pruritus.

[0066] The compounds and pharmaceutical compositions of the present invention can be administered orally or parenterally in the form of a suitable dosage form.

[0067] The dosage forms of the compounds and pharmaceutical compositions of the present invention include, for example, tablets (orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets, dissolvable tablets), capsules, granules (effervescent granules), powders, oral solutions (elixirs, suspensions, emulsions, limonades), syrups (syrup preparations), oral jellies, oral tablets (lozenges, sublingual tablets, buccal tablets, adhesive tablets, gums), oral sprays, semi-solid oral preparations, gargles, injections (infusions, implantable injections, sustained-release injections), and dialysis preparations. Examples of formulations include, but are not limited to, those for peritoneal dialysis (for peritoneal dialysis, for hemodialysis), inhalants (inhalant powders, inhalant solutions, inhalant aerosols), suppositories, semi-solid rectal preparations, enema preparations, eye drops, eye ointments, ear drops, nasal drops (nasal powders, nasal solutions), vaginal tablets, vaginal suppositories, external solid preparations (external powders), external liquid preparations (liniments, lotions), sprays (external aerosols, pump sprays), ointments, creams, gels, and patches (tapes, poultices). The formulations in this invention can be manufactured by known methods using the compounds of this invention and pharmaceutically acceptable additives.

[0068] Examples of pharmaceutically acceptable additives (carriers) include stabilizers, surfactants, solubilizers, buffers, suspending agents, antioxidants, coating agents, wetting agents, wetting modifiers, cooling agents, colorants, fragrances, isotonic agents, emulsifiers, pH adjusters, skin protectants, dispersants, propellants, fragrances, preservatives, and solvents. These additives (carriers) can be used depending on the purpose.

[0069] The compounds of the present invention may be used in combination with other drugs, provided that they do not interfere with the therapeutic effects of treating diseases such as pain and itching.

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

[0071] The present invention will be described in more detail below with reference examples, examples, and test examples, but these are not intended to limit the present invention. Note that the compound names shown in the following reference examples and examples do not necessarily follow IUPAC nomenclature, and compound identification was performed by NMR spectroscopy.

[0072] To simplify the description in the specification, the following abbreviations may be used in the examples. In NMR, s represents a single line, d represents a double line, dd represents a double double line, ddd represents a double double double line, t represents a triple line, td represents a triple double line, tt represents a triple triple line, q represents a quadruple line, qd represents a quadruple double line, quin represents a quintuple line, sext represents a sextuple line, m represents a multiline, br represents a broad line, brs represents a broad single line, and J represents a coupling constant.

[0073] Reference example 1 1-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one(2) [ka] 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), and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried with anhydrous sodium sulfate, and the solvent was removed using a rotary evaporator. N,N-dimethylformamide (5 mL) was added to the resulting residue. Carbonyl diimidazole (600 mg, 0.37 mmol) was then sequentially added at room temperature, and the mixture was stirred at room temperature for 15 hours. After the reaction was complete, 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% 2 steps, 0.61 mmol).

[0074] 1 H-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]imidazole-1-yl)piperidine-1-carboxylate(3) [ka] Under an Ar atmosphere, a solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (1) (98 mg, 0.31 mmol) in N,N-dimethylformamide (1.5 mL) was cooled on ice, and sodium hydride (11 mg, 60%, 0.46 mmol) was added. The mixture was then stirred at room temperature for 30 minutes. Subsequently, 4-phenylbutyl bromide (78 mg, 0.37 mmol) was added under ice, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and then water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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 = 2:1) to obtain the title compound (113 mg, 82%, 0.25 mmol).

[0076] 1 H-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]imidazole-1-yl)piperidine-1-carboxylate(4) [ka] Under an Ar atmosphere, a solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (1) (98 mg, 0.31 mmol) in N,N-dimethylformamide (1.5 mL) was mixed with sodium hydride (11 mg, 60%, 0.46 mmol) under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Then, 3-phenylpropyl bromide (0.37 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and then water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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 1:1) to obtain the title compound (yield 95%).

[0078] 1 H-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 4~13 [ka] By using the corresponding alkyl bromide instead of 3-phenylpropyl bromide and following the method described in Reference Example 3, compounds of Reference Examples 4 to 13 were obtained. [Table 1-1] [Table 1-2] [Table 1-3]

[0080] Reference example 14 tert-butyl 4-(6-fluoro-2-oxo-3-(4-phenylbutyl)-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (19) [ka] Under an Ar atmosphere, a solution of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (15) (0.31 mmol) in N,N-dimethylformamide (1.5 mL) was cooled on ice, and sodium hydride (11 mg, 60%, 0.46 mmol) was added. The mixture was then stirred at room temperature for 30 minutes. Subsequently, 4-phenylbutyl bromide (79 mg, 0.37 mmol) was added under ice, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and then water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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 1:1) to obtain the title compound (yield 45%).

[0081] 1H-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]imidazole-1-yl)piperidine-1-carboxylate (20) [ka] By using tert-butyl 4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (16) instead of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (15), the compound of Reference Example 15 (yield 58%) was obtained according to the method described in Reference Example 14.

[0083] 1H-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]imidazole-1-yl)piperidine-1-carboxylate(21) [ka] Instead of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (15), tert-butyl 4-(6-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (17) was used, and the compound of Reference Example 16 (yield 35%) was obtained according to the method described in Reference Example 14.

[0085] 1 H-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]imidazole-1-yl)piperidine-1-carboxylate(22) [ka] By using tert-butyl 4-(7-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (18) instead of tert-butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (15), the compound of Reference Example 17 (yield 69%) was obtained according to the method described in Reference Example 14.

[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-benzylpiperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 1) [ka] Under an Ar atmosphere, a solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (1) (100 mg, 0.32 mmol) in dichloromethane (1.5 mL) was cooled on ice and trifluoroacetic acid (0.24 mL, 3.15 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was complete, the solvent was removed 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, and the mixture was stirred at room temperature for 22 hours. After the reaction was complete, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried with 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 = 1:1 to 1:5) to obtain the title compound (yield 81%, 2 steps).

[0089] The product was analyzed by NMR. 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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 2) [ka] The title compound was obtained by using 2-phenylethyl bromide instead of benzyl bromide, following the method described in Example 1 (yield 53%, 2 steps).

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

[0092] Example 3 1-(1-(3-phenylpropyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 3) [ka] The title compound was obtained by using 3-phenylpropyl bromide instead of benzyl bromide, following the method described in Example 1 (78% yield, 2 steps).

[0093] The product was analyzed by NMR. 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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 4) and 1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 5) [ka] Using 4-phenylbutyl bromide instead of benzyl bromide, the title compounds (compounds 4 and 5) were obtained according to the method described in Example 1.

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

[0096] The NMR data for compound 5 (11% yield, 2 steps) is as follows: 1H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 6) [ka] 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, and the mixture was stirred at room temperature for 30 minutes. Then, butyl bromide (0.10 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 20 hours. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried with 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] 1H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 7) [ka] Using 4-cyclohexylbutyl bromide instead of butyl bromide, the title compound (yield 36%) was obtained according to the method described in Example 6.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 8) and 1-(4-cyclohexylbutyl)-3-(1-(4-cyclohexylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 9) [ka] Under an Ar atmosphere, a solution of tert-butyl 4-(2-oxo-2,3-dihydro-1H-benzo[d]imidazole-1-yl)piperidine-1-carboxylate (1) (100 mg, 0.32 mmol) in dichloromethane (1.5 mL) was cooled on ice and trifluoroacetic acid (0.24 mL, 3.15 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and N,N-dimethylformamide (1.5 mL) was added to the resulting residue. (4-bromobutyl)cyclohexane (77 mg, 0.35 mmol) and potassium carbonate (221 mg, 1.60 mmol) were then added sequentially at room temperature, followed by stirring at room temperature for 22 hours. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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]imidazole-2(3H)-one (compound 10) [ka] Under an Ar atmosphere, sodium hydride (7 mg, 60%, 0.28 mmol) was added to a solution of the compound from 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. Then, 4-phenylbutyl bromide (0.23 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 24 hours. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried with 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 = 1:1) to obtain the title compound (yield: 54%).

[0105] 1 H-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]imidazole-2(3H)-one (compound 11) [ka] The title compound (yield 79%) was obtained by using 4-cyclohexylbutyl bromide instead of 4-phenylbutyl bromide, following the method described in Example 10.

[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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 12) [ka] Under an Ar atmosphere, a solution of the compound from Reference Example 2 (65 mg, 0.15 mmol) in dichloromethane (1.5 mL) was cooled on ice and trifluoroacetic acid (0.11 mL, 1.45 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and N,N-dimethylformamide (1.5 mL) was added to the resulting residue. Then, at room temperature, 4-cyclohexylbutyl bromide (0.16 mmol) and potassium carbonate (100 mg, 0.73 mmol) were added sequentially, followed by stirring at room temperature for 15 hours. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and then water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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 = 1:1 to 1:5) to obtain the title compound (yield 44%, 2 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-butylpiperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 13) [ka] The title compound (67% yield, 2 steps) was obtained by using butyl bromide instead of 4-cyclohexylbutyl bromide, following the method described in Example 12.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 14) [ka] Using 3-phenylpropyl bromide instead of 4-cyclohexylbutyl bromide, the title compound (74% yield, 2 steps) was obtained according to the method described in Example 12.

[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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 15) [ka] Under an Ar atmosphere, trifluoroacetic acid (0.67 mL, 8.78 mmol) was added to a 5 mL solution of the compound from Reference Example 2 (394 mg, 0.88 mmol) under ice cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and dichloromethane (5 mL) was added to the resulting residue. Further, at room temperature, 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, and the mixture was stirred at room temperature for 15 hours. After the reaction was complete, 10% hydrochloric acid aqueous solution (3 mL) was added. After separating the organic layer, the aqueous layer was extracted with dichloromethane (2 mL x 3) and combined with the previously prepared organic layer. The organic layer was dried using 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 = 1:1) to obtain the title compound (353 mg, 81%, 2 steps, 0.72 mmol).

[0115] 1 H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 16) [ka] Under an Ar atmosphere, a solution of the compound from Reference Example 2 (0.21 mmol) in dichloromethane (1 mL) was cooled on ice and trifluoroacetic acid (0.16 mL, 2.14 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and N,N-dimethylformamide (1 mL) was added to the resulting residue. Further, 5-phenylpentyl bromide (0.43 mmol) and potassium carbonate (147 mg, 1.07 mmol) were added sequentially at room temperature, followed by stirring at room temperature for 22 hours. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and then water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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 33%, 2 steps).

[0117] 1 H-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)piperidine-4-yl)-3-(3-phenylpropyl)-1H-benzo[d]imidazole-2(3H)-one (compound 17) [ka] The title compound (16% yield, 2 steps) was obtained by using the compound from Reference Example 3 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-3-(5-phenylpentyl)-1H-benzo[d]imidazole-2(3H)-one (compound 18) [ka] The title compound (yield 28%, 2 steps) was obtained by using the compound from Reference Example 4 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0121] 1H-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-benzylpiperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 19) [ka] The title compound (82% yield, 2 steps) was obtained by using the compound from Reference Example 4 instead of the compound from Reference Example 2, and benzyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 20) [ka] The title compound (42% yield, 2 steps) was obtained by using the compound from Reference Example 5 instead of the compound from Reference Example 2, and benzyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0125] 1H-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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 21) [ka] The title compound (68% yield, 2 steps) was obtained by using 3-phenoxypropyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0127] 1H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 22) [ka] The title compound (yield 26%, 2 steps) was obtained by using the compound from Reference Example 6 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 23) [ka] The title compound (66% yield, 2 steps) was obtained by using the compound from Reference Example 6 instead of the compound from Reference Example 2, and 3-phenoxypropyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0131] 1H-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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 24) [ka] The title compound (49% yield, 2 steps) was obtained by using 4-(2-methoxyphenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 25) [ka] The title compound (35% yield, 2 steps) was obtained by using the compound from Reference Example 7 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0135] 1 H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 26) [ka] The title compound (33% yield, 2 steps) was obtained by using the compound from Reference Example 7 instead of the compound from Reference Example 2, and 4-(2-methoxyphenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0137] 1H-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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 27) [ka] The title compound (yield 54%, 2 steps) was obtained by using 4-(2-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 28) [ka] The title compound (32% yield, 2 steps) was obtained by using the compound from Reference Example 8 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 29) [ka] The title compound (70% yield, 2 steps) was obtained by using the compound from Reference Example 8 instead of the compound from Reference Example 2, and 4-(2-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0143] 1H-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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 30) [ka] The title compound (73% yield, 2 steps) was obtained by using 4-(2-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 31) [ka] The title compound (yield 51%, 2 steps) was obtained by using the compound from Reference Example 9 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 32) [ka] The title compound (73% yield, 2 steps) was obtained by using the compound from Reference Example 9 instead of the compound from Reference Example 2, and 4-(2-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 33) [ka] Using 4-(3-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide, the title compound (67% yield, 2 steps) was obtained according to the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 34) [ka] The title compound (yield 57%, 2 steps) was obtained by using the compound from Reference Example 10 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 35) [ka] The title compound (64% yield, 2 steps) was obtained by using the compound from Reference Example 10 instead of the compound from Reference Example 2, and 4-(3-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 36) [ka] The title compound (80% yield, 2 steps) was obtained by using 4-(3-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 37) [ka] The title compound (55% yield, 2 steps) was obtained by using the compound from Reference Example 11 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0159] 1H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 38) [ka] The title compound (77% yield, 2 steps) was obtained by using the compound from Reference Example 11 instead of the compound from Reference Example 2, and 4-(3-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0161] 1H-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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 39) [ka] The title compound (35% yield, 2 steps) was obtained by using 4-(4-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 40) [ka] The title compound (yield 56%, 2 steps) was obtained by using the compound from Reference Example 12 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0165] 1H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 41) [ka] The title compound (yield 54%, 2 steps) was obtained by using the compound from Reference Example 12 instead of the compound from Reference Example 2, and 4-(4-chlorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 42) [ka] The title compound (64% yield, 2 steps) was obtained by using 4-(4-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0169] 1 H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 43) [ka] The title compound (yield 56%, 2 steps) was obtained by using the compound from Reference Example 13 instead of the compound from Reference Example 2, and 4-phenylbutyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0171] 1H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 44) [ka] The title compound (59% yield, 2 steps) was obtained by using the compound from Reference Example 13 instead of the compound from Reference Example 2, and 4-(4-fluorophenyl)butyl bromide instead of 5-phenylpentyl bromide, following the method described in Example 16.

[0173] 1H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 45) [ka] Under an Ar atmosphere, a solution of the compound from Reference Example 14 (0.21 mmol) in dichloromethane (1 mL) was cooled on ice and trifluoroacetic acid (0.16 mL, 2.14 mmol) was added, followed by stirring at room temperature for 3 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and N,N-dimethylformamide (1 mL) was added to the resulting residue. Then, at room temperature, 4-phenylbutyl bromide (92 mg, 0.43 mmol) and potassium carbonate (147 mg, 1.07 mmol) were added sequentially, followed by stirring at room temperature for 22 hours. After the reaction was complete, the reaction mixture was diluted with diethyl ether (1.5 mL), and then water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 46) [ka] The title compound (60% yield, 2 steps) was obtained by following the same method as in Example 45, except that the compound in Reference Example 15 was used instead of the compound in Reference Example 14.

[0177] 1 H-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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 47) [ka] The title compound (yield 25%, 2 steps) was obtained by following the same method as in Example 45, except that the compound in Reference Example 16 was used instead of the compound in Reference Example 14.

[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)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 48) [ka] The title compound (50% yield, 2 steps) was obtained by following the same method as in Example 45, except that the compound in Reference Example 17 was used instead of the compound in Reference Example 14.

[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 (4 hours, m).

[0182] Example 49 1-(1-(4,4-diphenylbutyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 49) [ka] Under an Ar atmosphere, a solution of the compound from Reference Example 2 (63 mg, 0.14 mmol) in dichloromethane (1.5 mL) was added to trifluoroacetic acid (0.11 mL, 1.40 mmol) under ice cooling, and the mixture was stirred at room temperature for 3 hours. After the reaction was complete, the solvent was removed using a rotary evaporator, and N,N-dimethylformamide (1.5 mL) was added to the resulting residue. Then, at room temperature, 4,4-diphenylbutylbromide (0.28 mmol) and potassium carbonate (97 mg, 0.70 mmol) were added sequentially, and the mixture was stirred at room temperature for 20 hours. After the reaction was complete, the reaction solution was diluted with diethyl ether (1.5 mL), and water (1.5 mL) was added. After separating the organic layer, the aqueous layer was extracted with diethyl ether (1.5 mL x 3) and combined with the organic layer. The organic layer was dried using 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 1:1) to obtain the title compound (100% yield, 2 steps).

[0183] 1 H-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)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 50) [ka] The title compound (58% yield, 2 steps) was obtained by following the same method as in Example 49, except that 4,4-bis(4-fluorophenyl)butyl bromide was used instead of 4,4-diphenylbutyl bromide.

[0185] 1H-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: Investigation of the T-type calcium channel inhibitory effect of the compound of the present invention (1) Using the whole-cell patch-clamp method, human Ca v The effect of the compound of the present invention on 3,2T type calcium channels was evaluated. DMSO solution was used as a control (vehicle). Human Ca v 3.2T-type calcium channel-force-expressing human kidney cell-derived cell line HEK293 cells were seeded in cell culture dishes using DMEM medium containing 10% fetal bovine serum and cultured at 37°C under 5% CO2 conditions. In the whole-cell patch method, the following solutions were used as extracellular and intracellular fluids, and the holding potential was set to -80mV. The barium current flowing as an inward current during the potential jump from -80mV to -20mV was measured using a patch-clamp amplifier and AD converter (Axon Instruments). Here, to eliminate the influence of high-threshold activated calcium channels, the value obtained by subtracting the current 150ms after the start of stimulation from the peak current was used as the T-channel current (T-current) for data analysis. Data analysis was performed using pClamp8 (Axon Instruments). The test compound was either added directly to the dish after being dissolved in extracellular fluid (direct addition method) or added by perfusion (perfusion addition method).

[0187] extracellular fluid 97 mM N-methyl-D-glucamine (NMDG) 10 mM BaCl2 10 mM 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) 40 mM Tetraethylammonium Chloride (TEA-Cl) 5 mM glucose (pH 7.4)

[0188] Intracellular fluid: 4 mM MgCl2 140 mM CsCl 10mM HEPES 5 mM Glycol Ether Diamine Tetraacetic Acid (EGTA) (pH 7.2)

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

[0190] Test Example 2: Investigation of the T-type calcium channel inhibitory effect of the compound of the present invention (2) Human Ca was added using the same method as in the perfusion addition method of Test Example 1. v The effects of the compounds of the present invention on 3.2T channel type channels were evaluated. Pimozide, compound 5, compound 14, and compound 15 were used as test compounds at concentrations of 0.01 μM, 0.1 μM, 0.3 μM, 1.0 μM, and 3.0 μM, and these test compounds were added by perfusion.

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

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

[0193] Test Example 3: Dopamine D of the compound of the present invention 2 Examination of receptor binding ability In this study, the binding ability of the compounds of the present invention to dopamine D2 receptors was investigated, and the inhibitory effect of each compound on dopamine D2 receptor binding was evaluated. Compounds 4-7, 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. Using a reaction solution containing rat striatal homogenate as described below, 5 μL of the present invention compound, sulperidone, and pimozide were added to a final concentration of 1 or 10 μM, and the reaction was allowed to proceed at room temperature for 90 minutes. After the reaction was complete, the reaction solution was filtered through glass fiber filter paper, the filter paper was washed and dried, and then the radioactivity was measured. The binding ability of each compound to the dopamine D2 receptor was determined to be [ 3 Inhibition rate on the binding of H]-spiperone and [ 3 The amount of [H]-spiperone bound was used for evaluation. Reaction solution Rat striatum homogenate (200 μg protein / mL) 50 μL (Final concentration: 10 μg protein / tube) [ 3 [H]-spiperone (10 nM) 5 μL (Final concentration: 0.5nM) 40 μL of assay buffer (Composition: NaCl: 120mM, KCl: 5mM, MgCl2: 1mM, CaCl2: 1mM, Tris-Cl: 50mM (pH 7.4))

[0194] The test results are shown in Figures 3 and 4. Figure 3 shows the dopamine D2 receptor and [ 3Figure 4 shows the inhibition rate against binding of [H]-spiperone (n=3). The inhibition rate of each compound is expressed as a ratio to pimozide, with the inhibition rate of pimozide being 100%. 3 This shows the dopamine D2 receptor-specific binding amount of [H]-spiperone (n=3).

[0195] As shown in the results of this test, the compound of the present invention has a greater effect on dopamine D2 receptors compared to pimozide and sulpiride. 3 It did not inhibit the binding of [H]-spiperone. Therefore, it was shown that the compound of the present invention does not have an inhibitory effect on dopamine D2 receptor binding, that is, it can attenuate the dopamine D2 receptor binding effect.

[0196] Test Example 4: Dopamine D in the compound of the present invention in an in vivo study 2 Investigation of the attenuating effect of receptor blockade This study investigated the catalepsy-inducing effect of the compounds of the present invention and evaluated whether they could suppress side effects caused by dopamine D2 receptor inhibition. Compounds 5 and 12 of the present invention were used, and a 2% DMSO solution was used as the vehicle. Pimozide was used as a control drug. Sixteen ddY male mice were randomly assigned to one of four groups: compound 5, compound 12, pimozide, and vehicle. Each group of mice received 8 nmol (0.8 mM / 10 μL) of compound 5, compound 12, or pimozide, along with 10 μL of vehicle, administered intraventricularly. The mice were then forced to rest their forelimbs on a horizontally positioned iron bar (5 cm high), and the time they maintained this position (catalepsy) was measured to assess the occurrence of catalepsy. Measurements were terminated when the forelimbs touched the floor or when the mouse was on the bar.

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

[0198] As shown in Figure 5, the duration of catalepsy was prolonged in the pimozide-administered group, peaking 120 minutes after administration, whereas catalepsy was not induced in the groups administered with compound 5 and compound 12. Therefore, it was demonstrated that the compounds of the present invention can attenuate dopamine D2 receptor blockade and suppress the resulting effects.

[0199] Test Example 5: Na 2 Investigation of the effects of the present invention compound on S-induced pruritus. In this study, the antipruritic and analgesic effects of the compound of the present invention were investigated in a mouse Na2S intradermal injection pruritus 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. A mouse model of Na2S intracutaneous injection pruritus was created by injecting 3.8 μmol (300 μg / 10 μL) of Na2S intracutaneously into the cheek skin of male ICR mice to induce T-type calcium channel-dependent pain. Eighteen mice were randomly assigned to three groups of six: a vehicle + saline administration group (control group), a vehicle + Na2S administration group, and a compound 5 (10 mg / kg) + Na2S administration group. The mice were anesthetized with isoflurane, and their right cheeks were 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 at least 30 minutes. After acclimatization, Na2S was administered intracutaneously into the shaved cheek of the mice without anesthesia, and their subsequent behavior was videotaped. Compound 5 (10 mg / kg) or vehicle (V, 10 mL / kg) was administered intraperitoneally 30 minutes before Na2S injection. Later, the antipruritic and analgesic effects of the compound of the present invention were evaluated by playing back video footage and counting the number of times scratching behaviors by the hind limbs at the administration site (as an itching response) and wiping behaviors by the forelimbs (as a pain response) occurred over a 60-minute period.

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

[0201] As shown in the results of this study, itching and pain were not suppressed in the vehicle + Na2S administration group, but they were significantly suppressed in the compound 5 administration group. Therefore, it was demonstrated that the compound of the present invention has antipruritic and analgesic effects.

[0202] Test Example 6: Na 2 Investigation of the effects of the present invention compound on S-induced pain In this study, the analgesic effect of the compound of the present invention was investigated in a mouse Na2S 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. A mouse model of Na2S intraplantar injection pain was created by inducing T-type calcium channel-dependent pain in the soles of the feet of male ICR mice by injecting 10 pmol / paw / 10 μL of Na2S. Mice were randomly assigned to one of the following groups (n=7-11): vehicle + vehicle (control group), vehicle + Na2S, compound 5 (1 mg / kg) + Na2S, compound 5 (3 mg / kg) + Na2S, or compound 5 (10 mg / kg) + Na2S. Vehicle (V, 10 mL / kg) or compound 5 at 1, 3, or 10 mg / kg was administered intraperitoneally 30 minutes before intraplantar injection of Na2S into the hind limbs of mice. The analgesic effect of the present invention compound was evaluated by measuring the pain threshold every 15 minutes using the von Frey method until 60 minutes after Na2S administration.

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

[0204] As shown in the results of this study, pain was not suppressed in the vehicle + Na2S administration group, but pain was suppressed in the compound 5 administration group. Therefore, it was demonstrated that the compound of the present invention has an analgesic effect.

[0205] Test Example 7: Investigation of the antipruritic effect of the compound of the present invention In this study, the antipruritic effect of the compounds of the present invention was investigated in a mouse intracutaneous injection pruritus model in the cheek, in which histamine or chloroquine was administered intracutaneously as the 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. In addition, male ICR mice weighing 23-40g were used as experimental animals. These mice were allowed to freely consume tap water and solid feed with water conservation, and were housed at room temperature of approximately 24°C under a 12-hour light-dark cycle. A mouse intracutaneous injection pruritus model was created by inducing pruritus in the cheek skin of male ICR mice by administering histamine or chloroquine, which are pruritic substances, dissolved in physiological saline, in accordance with the method described in Shimada SG & LaMotte RH (2008) Behavioral differentiation between itch and pain in mouse. Pain 139 (3): 681-687. Mice were randomly assigned to one of the following groups (n=6-10): a control group administered with physiological saline (solvent 1) + physiological saline (solvent 2) containing 1% DMSO and 5% Tween 80; a group administered with solvent 1 + histamine; a group administered with compound 5 (10 mg / kg) + histamine; a group administered with solvent 1 + chloroquine; a group administered with compound 5 (10 mg / kg) + chloroquine; a group administered with compound 38 (1 mg / kg) + chloroquine; a group administered with compound 38 (3 mg / kg) + chloroquine; and a group administered with compound 38 (10 mg / kg) + chloroquine. Each group of mice was anesthetized with isoflurane, and their right cheek was shaved several days prior to the experiment. On the day of the experiment, the mice were placed in an acrylic observation cage (10x14x30cm) 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 the mice 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 Solvent 1 (10 mL / kg) was administered intraperitoneally 30 minutes before administration of saline or an pruritic substance. Later, the video footage was played back, and the number of scratching bouts by the hind limbs at the intradermal administration site was counted for 60 minutes to evaluate the antipruritic effect of the compounds of the present invention.

[0206] The test results are shown in Tables 5-7 and Figures 8-10. Table 5 and Figure 8 show the mean ± standard error (total number (n)) of the total number of hind limb scratching behaviors at the intradermal injection site 60 minutes after intradermal administration of the right cheek in the control group, the solvent 1 + histamine administration group, and the compound 5 (10 mg / kg) + histamine administration group, and their graphs. Table 6 and Figure 9 show the hind limb scratching behaviors at the intradermal injection site 60 minutes after intradermal administration of the right cheek 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 and their graphs, respectively. For 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, the mean ± standard error (total number (n)) of the total counts of hind limb scratching behavior at the intradermal administration site 60 minutes after intradermal administration of the right cheek and their graphs. [Table 5] [Table 6] [Table 7]

[0207] As shown in the test results, compound 5 (10 mg / kg) strongly suppressed histamine-dependent and non-histamine-dependent itching behavior (Tables 5-6 and Figures 8-9), and compound 38 also strongly suppressed non-histamine-dependent itching 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 an antipruritic effect. The compound of the present invention strongly suppresses both histamine and nonhistamine-induced itching, suggesting its potential as a treatment for intractable pruritus. [Industrial applicability]

[0208] According to the present invention, a novel benzimidazolon compound having excellent T-type calcium channel inhibitory activity can be provided. Furthermore, the compounds of the present invention may be useful as novel therapeutic agents for diseases caused by activation of T-type calcium channels, such as pain and pruritus, as they can reduce the risk of side effects by attenuating D2 receptor inhibitory activity.

Claims

1. Equation (Ia): 【Chemistry 1】 [In the formula: R1 is C1-6 alkylene-R1a or C(O)-C1-6 alkylene-R1a, and the alkylene may be substituted at a substituted position with one or more identical or different groups selected from the group consisting of halogens, aminos, and hydroxyls; R2 is C3-6 alkylene-R2a or C(O)-C1-6 alkylene-R2a; R1a is a C3-6 cycloalkyl or phenyl group, and each group may be substituted at a substituted position with one or more identical or different groups selected from the group consisting of halogens, C1-6 alkyl groups, C1-6 alkoxy groups, and C1-6 haloalkyl groups; R 2a is a C3-6 cycloalkyl or phenyl group, and each group may be substituted at a substituted position with one or more identical or different groups selected from the group consisting of halogens, C1-6 alkyl groups, C1-6 alkoxy groups, and C1-6 haloalkyl groups; R3 is independently selected from the group consisting of halogens, C1-6 alkyls, C1-6 haloalkyls, aminos, and hydroxyls; and n is between 0 and 4. The compound indicated by or a pharmaceutically acceptable salt thereof.

2. R ３ However, each is independently selected from the group consisting of halogens, aminos, and hydroxyls; and The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is 0 or 1.

3. R １ａ However, C ５－６ It is a cycloalkyl or phenyl group, and each group is substituted with a halogen, C at a substituted position. １－６ Alkyl, C １－６ Alkoxy and C １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more identical or different groups selected from the group consisting of haloalkyl groups.

4. R １ａ is cyclohexyl or phenyl, and each group is, at a substitutable position, halogen, C １－６ alkyl, C １－６ alkoxy, and C １－６ haloalkyl, and may be substituted with 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.

5. R １ but, 【Chemistry 2】 [In the formula, q is between 1 and 5] A group selected from the group consisting of the following, where each group is a halogen and C at a substituted position. １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more identical or different groups selected from the group consisting of alkoxys.

6. R １ but, 【Transformation 3】 [In the formula, R ５ [where is hydrogen, halogen, or methoxy, and r is 1 to 5] A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the group is selected from the group consisting of the following.

7. R ２ However, C ３－６ Alkilen-R ２ａ and R ２ａ However, C ５－６ It is a cycloalkyl or phenyl group, and each group is substituted with a halogen or C at a substituted position. １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with an alkoxy.

8. R ２ However, C ３－６ Alkilen-R ２ａ and R ２ａ However, it is cyclohexyl or phenyl, and each group is a halogen or C at a substituted position. １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with an alkoxy.

9. R ２ but, 【Chemistry 4】 [In the formula, q is between 3 and 5.] A group selected from the group consisting of the following, where each group is a halogen and C at a substituted position. １－６ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which may be substituted with one or more identical or different groups selected from the group consisting of alkoxys.

10. R ２ but, 【Transformation 5】 [In the formula, R ５ [where r is hydrogen, halogen, or methoxy, and r is 3 to 5] The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. 1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 5), 1-(4-cyclohexylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 7), 1-(4-cyclohexylbutyl)-3-(1-(4-cyclohexylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 9), 1-(1-(4-cyclohexylbutyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 12), 1-(4-phenylbutyl)-3-(1-(3-phenylpropyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 14), 1-(1-(4-phenylbutanoyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 15), 1-(4-phenylbutyl)-3-(1-(5-phenylpentyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 16), 1-(1-(4-phenylbutyl)piperidine-4-yl)-3-(3-phenylpropyl)-1H-benzo[d]imidazole-2(3H)-one (compound 17), 1-(1-(4-phenylbutyl)piperidine-4-yl)-3-(5-phenylpentyl)-1H-benzo[d]imidazole-2(3H)-one (compound 18), 1-(1-benzylpiperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 19), 1-benzyl-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 20), 1-(1-(4-(2-methoxyphenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 24), 1-(4-(2-methoxyphenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 25), 1-(4-(2-methoxyphenyl)butyl)-3-(1-(4-(2-methoxyphenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 26), 1-(1-(4-(2-chlorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 27), 1-(4-(2-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 28), 1-(4-(2-chlorophenyl)butyl)-3-(1-(4-(2-chlorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 29), 1-(1-(4-(2-fluorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 30), 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 31), 1-(4-(2-fluorophenyl)butyl)-3-(1-(4-(2-fluorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 32), 1-(1-(4-(3-chlorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 33), 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 34), 1-(4-(3-chlorophenyl)butyl)-3-(1-(4-(3-chlorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 35), 1-(1-(4-(3-fluorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 36), 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 37), 1-(4-(3-fluorophenyl)butyl)-3-(1-(4-(3-fluorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 38), 1-(1-(4-(4-chlorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 39), 1-(4-(4-chlorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 40), 1-(4-(4-chlorophenyl)butyl)-3-(1-(4-(4-chlorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 41), 1-(1-(4-(4-fluorophenyl)butyl)piperidine-4-yl)-3-(4-phenylbutyl)-1H-benzo[d]imidazole-2(3H)-one (compound 42), 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 43), 1-(4-(4-fluorophenyl)butyl)-3-(1-(4-(4-fluorophenyl)butyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 44), 5-Fluoro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 45), 5-Chloro-3-(4-phenylbutyl)-1-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 46), 5-Chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 47), or 4-Chloro-1-(4-phenylbutyl)-3-(1-(4-phenylbutyl)piperidine-4-yl)-1H-benzo[d]imidazole-2(3H)-one (compound 48) A compound or a pharmaceutically acceptable salt thereof, selected from the above.

12. A pharmaceutical composition comprising the compound described in claim 1 or 11 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition according to claim 12 for treating a disease caused by activation of T-type calcium channels.

14. The pharmaceutical composition according to claim 13, wherein the disease is selected from pain, epilepsy, essential tremor, schizophrenia, Parkinson's disease, manic-depressive illness, 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, renal disease, or overactive bladder.

15. The pharmaceutical composition according to claim 13, wherein the disease is pain.

16. The pharmaceutical composition according to claim 13, wherein the disease is itching.

17. A T-type calcium channel inhibitor comprising the compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof.

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