RU2803938C2 - New compound of benzimidazolone and its pharmaceutical use - Google Patents

Abstract

FIELD: organic chemistry and pharmaceuticals.

SUBSTANCE: group of inventions is aimed at providing compounds for the treatment or prevention of a disease in which the Na channel is involved, in particular SCN9A (Nav 1.7). The following is disclosed: a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R^1a and R^1d are independently hydrogen, one of R^1b and R^1c is either C₆ aryl, C₆ aryloxy, 6-membered heteroaryl, or 6-membered heteroaryloxy, wherein aryl and aryl group in aryloxy; and heteroaryl and heteroaryl group in heteroaryloxy may be independently substituted with 1–3 substituents independently selected from the group consisting of halo, methyl optionally substituted with 1–3 substituents independently selected from Substituent Group A, and methoxy optionally substituted with 1–3 substituents independently selected from Substituent Group A; and the other R^1b or R^1c are hydrogen, R⁴ is either hydrogen, methyl or ethyl; m=1, L is CR⁷R⁸, R⁷ and R⁸ are independently hydrogen or methyl, R² and R³ are methyl, or in R², R³ and the hydroxyl group associated with the carbon atom associated with R² and R³, R² and R³ can, together with the carbon atom to which they are attached, form the following group of formula (II) with a hydroxyl group, in formula (II), e and f are 1, V is an oxygen atom, R^5a, R^5b, R^5c and R^5d are hydrogen, or in R², R³, the hydroxyl group associated with the carbon atom associated with R² and R³ and CR⁷ R⁸ in L, R² and R⁷ may together with the carbon atom to which they are attached to form the following group of formula (III) with R³, hydroxyl group and R⁸ in formula (III), m¹ =0, m² = 2, and j= 2, R⁸ and L have the meanings defined above, R^6a, R^6b, R^6c and R^6d are hydrogen, Substituent group A is independently halogen, provided that the following compounds are excluded: 5-(2-butyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-1-1,3-dihydro-2H-benzimidazol-2-one (2-hydroxyethyl), 3-[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile, and -[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile. Besides, the following is described: a pharmaceutical composition for the treatment of a disease in which Nav 1.7 (SCN9A) is involved, containing a therapeutically effective amount of the above compound, a drug for the treatment of a disease in which Nav 1.7 (SCN9A) is involved, the use of this compound or its pharmaceutically acceptable salts to produce a drug; and a method of treating a disease that involves Nav 1.7 (SCN9A).

EFFECT: group of inventions provides effective treatment of the disease using the involved Nav 1.7 (SCN9A).

10 cl, 1 tbl, 28 ex

Description

TECHNICAL FIELD

[0001]

The present invention relates to a medicament for the treatment or prevention of a disease involving a Na channel, in particular SCN9A (Nav 1,7), which includes a novel compound having a benzimidazolone skeleton, or a pharmaceutically acceptable salt thereof, as an active ingredient. More specifically, it relates to a medicament for the treatment or prevention of a disease such as neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria and multiple sclerosis.

BACKGROUND OF THE ART

[0002]

It is known that the pore-forming α subunit of the voltage-dependent Na channel currently includes 9 types. This subunit, in particular Nav 1.7, has recently been documented to be widely involved in acute and chronic pain signal transduction.

[0003]

SCN9A (Nav 1.7) is a tetrodotoxin (TTX)-sensitive Na channel located in the peripheral sensory nerve or sympathetic nerve, also referred to as NENA or PN1. Physiologically, the Nav 1.7 channel functions by amplifying the pain signal (i.e., generating a generator potential) at the end of the sensory nerve. In the field of gene research, it has been found that a person whose SCN9A gene is mutated to a loss of function exhibits a congenital insensitivity to pain. On the contrary, it has been observed that in patients suffering from severe orphan diseases such as erythromelalgia and paroxysmal extreme pain disorder, the SCN9A gene is mutated with a gain of function. In addition, it has been reported that approximately 30% of patients suffering from small fiber neuropathy have a Nav 1.7 gain-of-function genetic polymorphism (Non-Patent Literature 1). And it has been suggested that Nav 1.7 channel function is directly involved in the increased excitability of the DRG neuron in patients suffering from pain, since the expression level and activity of the DRG neuron are increased in an animal model suffering from chronic pain, and neuropathic pain and inflammatory pain are reduced in knockout experiment (Non-Patent Literature 2).

[0004]

Patent Literature 1 discloses a phenylene urea derivative represented by the following formula (A), but the invention described in Patent Literature 1 relates to an activated factor X inhibitor, so Patent Literature 1 does not disclose the present invention at all.

BACKGROUND OF THE ART

[Patent Literature]

[0005]

[Patent Literature 1] WO 2001/057019

[Non-proprietary literature]

[0006]

[Non-Patent Literature 1] Nat Rev Neurosci. 14:49, 2013

[Non-Patent Literature 2] Nat Commun. 3: 791, 2012

The essence of the invention

[0007]

(Technical problem)

An object of the present invention may be to provide a medicament for the treatment or prevention of a disease in which Nav 1,7 is involved, in particular, such as neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria and multiple sclerosis.

[0008]

(The solution of the problem)

The present inventors have conducted intensive studies in an attempt to solve the above-mentioned problem and have found that a compound having the benzimidazolone ring mentioned below, or a pharmaceutically acceptable salt thereof, can inhibit the change in membrane potential or the very current of Na ions through the Na channel in a Nav 1,7 gene expressing cell, those. this compound or a pharmaceutically acceptable salt thereof is a blocker having inhibitory activity against Nav 1,7. In addition, the inventors of the present invention have discovered that this derivative can be used as a drug for the treatment or prevention of a disease such as neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia and paroxysmal extreme pain disorder, having completed the present invention . Accordingly, the present invention can provide a benzimidazolone compound represented by the following formula (I) (hereinafter also referred to as “the compound represented by formula (I)” or “the compound of formula (I)”), or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “ compound according to the present invention").

The present invention can be illustrated as follows.

[0009]

(Paragraph 1)

Compound of formula (I):

or a pharmaceutically acceptable salt thereof, in which

R ^1a , R ^1b , R ^1c and R ^1d independently denote hydrogen, halogen, C _1–4 alkyl, C _1–4 alkoxy (wherein the alkyl and alkyl group in alkoxy can be independently substituted by 1–5 substituents selected independently from the group consisting of halogen, hydroxyl group, C _1–4 alkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B , C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and 3–7-membered non-aromatic heterocyclyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B), C _3–7 cycloalkyl, C _3–7 cycloalkoxy (wherein the cycloalkyl and cycloalkyl group in cycloalkoxy can be independently substituted with 1–5 substituents selected independently from the group consisting of halogen, hydroxyl group, C _1–4 alkyl, optionally substituted with 1 –3 substituents independently selected from Substituent Group A, C _1–4 alkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents selected independently from Substituent Group B), C _6–10 aryl, C _6–10 aryloxy, 5–12-membered heteroaryl or 5– 12-membered heteroaryloxy (wherein the aryl and aryl group in aryloxy and heteroaryl and the heteroaryl group in heteroaryloxy can be independently substituted with 1–5 substituents selected independently from the group consisting of halogen, cyano, C _1–4 alkyl, optionally substituted with 1 –3 substituents independently selected from Substituent Group A, C _1–4 alkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and 3–7-membered non-aromatic heterocyclyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B), provided that at least one of R ^1a , R ^1b , R ^1c and R ^1d is the above-mentioned C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy ,

^R2 and ^R3 are independently hydrogen, _C1-6 alkyl (which may be independently substituted with 1-5 substituents independently selected from the group consisting of cyano, halogen, hydroxyl, _C1-4 alkoxy, optionally substituted with 1 –3 substituents independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents selected regardless of Substituent Group B), or C _3–10 cycloalkyl,

R ⁴ is hydrogen, C _1–4 alkyl or C _3–4 cycloalkyl, wherein C _1–4 alkyl and C _3–4 cycloalkyl may be replaced by 1–5 identical or different halogen atoms,

m=1, 2, or 3,

L denotes CR ⁷ R ⁸ with the proviso that when m is 2 or 3, each CR ⁷ R ⁸ is independently the same or different,

R ⁷ and R ⁸ independently denote hydrogen, a hydroxyl group, C _1–4 alkyl, C _1–4 alkoxy (wherein the alkyl and alkyl group in alkoxy can be independently substituted by 1–3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _1–4 alkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, C _3–7 cycloalkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group B, and 3-7-membered non-aromatic heterocyclyl, optionally substituted with 1-3 substituents independently selected from Substituent Group B), C _3-7 cycloalkyl or C _3–7 cycloalkoxy (wherein the cycloalkyl and cycloalkyl group in cycloalkoxy can be independently substituted with 1–3 substituents selected independently from the group consisting of halogen, hydroxyl group, C _1–4 alkyl, optionally substituted with 1–3 substituents selected independently from Substituent Group A, C _1–4 alkoxy, optionally substituted with 1–3 substituents selected independently from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and C _3-7 cycloalkoxy, optionally substituted with 1-3 substituents selected independently from Substituent Group B), or

in ^R2 , ^R3 and the hydroxyl group bonded to the carbon atom bonded to ^R2 and ^R3 ,

R ² and R ³ can, together with the carbon atom to which they are attached, form the following group of formula (II) with a hydroxyl group

in formula (II),

e and f independently represent 1, 2 or 3,

V stands for single bond or oxygen atom,

R ^5a , R ^5b , R ^5c and R ^5d independently represent hydrogen, halogen, hydroxyl group, C _1–4 alkyl or C _1–4 alkoxy, wherein the alkyl and alkyl group in alkoxy may be independently substituted by 1–3 independently selected substituents from the group consisting of halogen, hydroxyl group, C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A, C _3-7 cycloalkyl, optionally substituted with 1-3 substituents independently selected from Substituent groups B, C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and 3–7-membered non-aromatic heterocyclyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B , or

in R ² , R ³ , a hydroxyl group bonded to the carbon atom bonded to R ² and R ³ , and CR ⁷ R ⁸ in L,

R ² and R ⁷ may, together with the carbon atom to which they are attached, form the following group of formula (III) with R ³ , a hydroxyl group and R ⁸

in formula (III),

m ¹ =0 or 1,

m ² =0 or 1, and j=1, 2, 3 or 4 when m ¹ =1, or

m ² =0, 1 or 2, and j=1, 2, 3 or 4 when m ¹ =0,

R ⁸ and L have the meanings defined above,

R ^6a , R ^6b , R ^6c and R ^6d independently represent hydrogen, halogen, hydroxyl group, C _1–4 alkyl or C _1–4 alkoxy, wherein the alkyl and alkyl group in alkoxy can be independently substituted with 1–3 independently selected substituents from the group consisting of halogen, hydroxyl group, C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A, C _3-7 cycloalkyl, optionally substituted with 1-3 substituents independently selected from Substituent groups B, C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and 3–7-membered non-aromatic heterocyclyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B ,

Substituent group A is independently halogen, hydroxyl, _C1-4 alkoxy, _C3-7 cycloalkyl or _C3-7 cycloalkoxy,

Substituent group B is independently halogen, hydroxyl, _C1-4 alkyl, _C1-4 alkoxy, _C3-7 cycloalkyl or _C3-7 cycloalkoxy,

provided that the following connections are excluded:

5-(2-butyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-1-(2-hydroxyethyl)-1,3-dihydro-2H- benzimidazol-2-one,

3-[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile, and

3-[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile .

[0010]

(Point 2)

The compound of Claim 1 or a pharmaceutically acceptable salt thereof, in which

R ^1a , R ^1b , R ^1c and R ^1d independently denote hydrogen, halogen, C _1–4 alkyl, C _1–4 alkoxy (and the alkyl and alkyl group in alkoxy can be independently substituted by 1–3 identical or different halogen atoms), C _6–10 aryl, C _6–10 aryloxy, 5–12-membered heteroaryl or 5–12-membered heteroaryloxy (wherein the aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted with 1–3 substituents selected independently from the group consisting of halogen, cyano, _C1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and _C1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Alternate Group A).

[0011]

(Point 3)

The compound according to Claim 1 or 2 or a pharmaceutically acceptable salt thereof, in which

R ^1a , R ^1b , R ^1c and R ^1d independently represent hydrogen, C _6–10 aryl, C _6–10 aryloxy, 5–12 membered heteroaryl or 5–12 membered heteroaryloxy, with aryl and aryl group in aryloxy and heteroaryl and the heteroaryl group in heteroaryloxy may be independently substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _{1 –4} alkoxy, optionally substituted with 1–3 substituents selected independently from Substituent Group A.

[0012]

(Point 4)

The compound of any one of Claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^1d are hydrogen.

[0013]

(Clause 5)

A compound according to any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, in which

R ^1b or R ^1c denotes C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy, wherein aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted 1-3 substituents independently selected from the group consisting of halogen, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkoxy, optionally substituted with 1-3 alternates selected independently from Alternate Group A.

[0014]

(Clause 6)

A compound according to any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, in which

R ² and R ³ independently represent hydrogen or C _1-6 alkyl, which may be independently substituted with 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group and C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A, or

in ^R2 , ^R3 and the hydroxyl group bonded to the carbon atom bonded to ^R2 and ^R3 ,

R ² and R ³ can, together with the carbon atom to which they are attached, form the following group of formula (IIa) with a hydroxyl group

in formula (IIa),

e and f independently denote 1 or 2,

V has the meanings defined in Clause 1, and

R ^5a , R ^5b , R ^5c and R ^5d are independently hydrogen or halogen, or

in R ² , R ³ the hydroxyl group bonded to the carbon atom bonded to R ² and R ³ , and CR ⁷ R ⁸ in L,

R ² and R ⁷ may, together with the carbon atom to which they are attached, form the following group of formula (IIIa) with R ³ , a hydroxyl group and R ⁸

in formula (IIIa),

m ¹ =0,

m ² =1 or 2, j=1 or 2,

R ⁸ denotes hydrogen,

L has the meanings defined in Clause 1,

R ^6a , R ^6b , R ^6c and R ^6d are independently hydrogen or halogen.

[0015]

(Clause 7)

A compound according to any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, in which

R ⁷ and R ⁸ independently represent hydrogen or C _1-4 alkyl, which may be substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _1-4 alkoxy, optionally substituted with 1-3 substituents , independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and a 3-7 membered non-aromatic heterocyclyl, optionally substituted with 1-3 substituents selected independently from Substituent Group B, and

m=1 or 2.

[0016]

(Clause 8)

The compound of any one of Clauses 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ are hydrogen and m=1.

[0017]

(Clause 9)

A compound according to any of Clauses 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen or C _1-4 alkyl, optionally substituted with 1 to 5 identical or different halogen atoms.

[0018]

(Clause 10)

A compound according to any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, in which

R ^1b denotes C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy, wherein aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted 1-3 substituents independently selected from the group consisting of halogen, cyano, _C1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and _C1-4 alkoxy, optionally substituted with 1-3 substituents , independently selected from Alternate Group A.

[0019]

(Clause 11)

A compound according to any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, in which

R ^1c denotes C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy, wherein aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted 1-3 substituents independently selected from the group consisting of halogen, cyano, _C1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and _C1-4 alkoxy, optionally substituted with 1-3 substituents , independently selected from Alternate Group A.

[0020]

(Clause 12)

The compound of Claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:

Example 1: 1-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,

Example 2: 1-[(3-hydroxyoxetan-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,

Example 3: 1-[(3-hydroxyoxetan-3-yl)methyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,

Example 4: 1-(cis-4-hydroxycyclohexyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,

Example 5: 1-[(3-hydroxyoxetan-3-yl)methyl]-6-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,

Example 6: 6-(4-fluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,

Example 7: 6-(4-fluorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 8: 6-(4-chlorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 9: 1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazole -2-he,

Example 10: 6-(4-fluorophenoxy)-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 11: 6-(4-fluorophenoxy)-1-(cis-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one,

Example 12: 1-ethyl-3-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one ,

Example 13: 3-(2-hydroxy-2-methylpropyl)-1-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one ,

Example 14: 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazole- 2–he,

Example 15: 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1,3-dihydro-2H-benzimidazole- 2–he,

Example 16: 5-(4-fluorophenoxy)-3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one,

Example 17: 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,

Example 18: 5-(4-chlorophenoxy)-3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one,

Example 19: 1-(2-hydroxy-2-methylpropyl)-6-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 20: 1-(2-hydroxy-2-methylpropyl)-6-[5-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 21: 1-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 22: 6-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,

Example 23: 1-(2-hydroxy-2-methylpropyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 24: 5-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,

Example 25: 1-(2-hydroxy-2-methylpropyl)-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,

Example 26: 1-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,

Example 27: 1-[(3-hydroxyoxetan-3-yl)methyl]-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, and

Example 28: 1-[(3-hydroxyoxetan-3-yl)methyl]-3-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one.

[0021]

(Clause 13)

The compound of Claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds:

Example 1: 1-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,

Example 5: 1-[(3-hydroxyoxetan-3-yl)methyl]-6-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,

Example 8: 6-(4-chlorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 10: 6-(4-fluorophenoxy)-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 11: 6-(4-fluorophenoxy)-1-(cis-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one,

Example 17: 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,

Example 20: 1-(2-hydroxy-2-methylpropyl)-6-[5-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 21: 1-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 23: 1-(2-hydroxy-2-methylpropyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one,

Example 24: 5-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,

Example 26: 1-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, and

Example 28: 1-[(3-hydroxyoxetan-3-yl)methyl]-3-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one.

[0022]

(Clause 14)

A pharmaceutical combination comprising the Compound of any one of Clauses 1 to 13 or a pharmaceutically acceptable salt thereof.

[0023]

(Clause 15)

A medicament for the treatment of a disease involving Nav 1,7 (SCN9A), comprising the Compound of any one of Claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0024]

(Clause 16)

A drug for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis, comprising the Compound of any of Claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0025]

(Clause 17)

A pharmaceutical combination comprising the Compound of any one of Clauses 1 to 13 or a pharmaceutically acceptable salt thereof and at least one drug selected from the group consisting of an antiepileptic agent, an antidepressant, a narcotic analgesic, an anti-inflammatory agent, a reductase inhibitor and a drug derivative prostaglandin.

[0026]

(Clause 18)

Use of a compound according to any of Clauses 1 to 13 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis.

[0027]

(Clause 19)

A method of treating neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis, comprising administering a therapeutically effective amount of a compound of any of Claims 1 to 13 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

[0028]

(Invention Effect)

The present invention relates to a Nav 1,7 blocker comprising a novel benzimidazolone compound or a pharmaceutically acceptable salt thereof. The compounds of the present invention can be used as a medicament for the treatment or prevention of a disease involving Nav 1,7 (SCN9A), namely, these compounds are applicable to a patient suffering from neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, etc.

Description of Embodiments

[0029]

In the following, the present invention is explained in detail. In the description, the number of carbon atoms in the definition of “substituents” may indicate, for example, “C _1–6 ”. The specific definition of "C _1-6 alkyl" means an alkyl group having from 1 to 6 carbon atoms. As used herein, a substituent group not accompanied by the words “optionally substituted” or “substituted” implies an “unsubstituted” substituent group. For example, " _C1-6 alkyl" means "unsubstituted _C1-6 alkyl".

[0030]

Groups of substituents in the present description may sometimes be expressed without the term "group". In the event that "optionally substituted" is used in the definition of substituent groups, the number of substituting groups is not limited, provided that substitutions are available, i.e., it is one or more. This means that the possible number of substituent groups is the number available for substitution on the carbon atoms or carbon-nitrogen atoms in the substituent group that are acceptable for substitution. Unless otherwise stated, the definition of each substituent group also applies to the case of partial inclusion of a substituent group or the case of a substituent group replacing another substituent group.

[0031]

Unless otherwise stated, the binding site of the substituent groups is not limited, provided that the site is accessible for binding.

[0032]

"Halogen" includes, for example, fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

[0033]

"C _1-2 alkyl" means a saturated hydrocarbon group having 1-2 carbon atoms, "C _1-3 alkyl" means a straight or branched chain saturated hydrocarbon group having 1-3 carbon atoms, "C _1-4 alkyl" means a straight or branched chain saturated hydrocarbon group having 1-4 carbon atoms, and "C _1-6 alkyl" means a straight or branched chain saturated hydrocarbon group having 1-6 carbon atoms. "C _1-2 alkyl" includes, for example, methyl and ethyl; "C _1-3 alkyl" includes, for example, propyl and isopropyl, in addition to the above-mentioned alkyl; "C _1-4 alkyl" includes, for example, butyl, isobutyl, sec-butyl and tert-butyl, in addition to the above alkyl; and “C _1-6 alkyl” includes, for example, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and a structural isomer thereof, in addition to the above-mentioned alkyl. Preferred examples of "C _1-6 alkyl" or "C _1-4 alkyl" include "C _1-3 alkyl", and more preferably methyl and ethyl.

[0034]

"C _3-7 cycloalkyl" means a non-aromatic cyclic hydrocarbon group (i.e., a saturated hydrocarbon group and a partially unsaturated hydrocarbon group) having from 3 to 7 carbon atoms, and "C _3-10 cycloalkyl" means a non-aromatic cyclic hydrocarbon group ( i.e., a saturated hydrocarbon group and a partially unsaturated hydrocarbon group) having from 3 to 10 carbon atoms. "C _3-7 cycloalkyl" and "C _3-10 cycloalkyl" also include bridged. "C _3-7 cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl and cycloheptyl. "C _3-10 cycloalkyl" includes, for example, cyclooctyl and adamantyl, in addition to the above, preferably "C _3-7 cycloalkyl".

[0035]

" _C3-7 cycloalkyl" and " _C3-10 cycloalkyl" also include a bicyclic fused ring in which " _C3-7 cycloalkyl" and " _C3-10 cycloalkyl" are fused with benzene or a 5- or 6-membered ring, having one heteroatom selected from nitrogen, sulfur or oxygen, or two or more (for example, 2 to 4) identical or different heteroatoms (for example, a “5- or 6-membered monocyclic heteroaryl” mentioned below, and 5- or 6-membered ring in the "3-7 membered non-aromatic heterocyclyl" mentioned below), respectively. Examples of the bicyclic fused ring include groups of the following formulas.

[0036]

"C _6-10 aryl" as used herein means an aromatic hydrocarbon group having from 6 to 10 carbon atoms, preferably phenyl. "C _6-10 aryl" includes, for example, phenyl, 1-naphthyl and 2-naphthyl.

[0037]

"C _6-10 aryl" also includes a fused ring in which "phenyl" is fused to a 5- or 6-membered ring having one heteroatom selected from nitrogen, sulfur or oxygen, or two or more (for example, 2 to 4) the same or different heteroatoms (for example, the “5- or 6-membered monocyclic heteroaryl” mentioned below, and the 5- or 6-membered ring in the “3-7-membered non-aromatic heterocyclyl” mentioned below), or 5-7 -membered cycloalkyl ring (for example, cyclopentane, cyclohexane and cycloheptane). Examples of a fused ring include groups of the following formulas.

[0038]

"5 to 12 membered heteroaryl" means a 5 to 12 membered mono- or polycyclic aromatic radical having one heteroatom selected from nitrogen, sulfur or oxygen, or two or more (for example, 2 to 4) of the same or different heteroatoms other than carbon atoms as ring atoms, preferably "5- or 6-membered monocyclic heteroaryl". "5- or 6-membered monocyclic heteroaryl" means a 5- or 6-membered monocyclic aromatic radical in a "5-12-membered heteroaryl".

[0039]

A multi-cyclic heteroaryl in "5-12 membered heteroaryl" includes, for example, a fused ring in which two identical or different monocyclic heteroaryls are fused, or a monocyclic heteroaryl and an aromatic ring (for example, benzene) or a non-aromatic ring (for example, cyclohexane) are fused .

"5-12 membered heteroaryl" includes, for example, the groups of formulas shown below. Preferably, "5-12 membered heteroaryl" includes pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. Another embodiment preferably includes benzofuranyl, in which the binding site is on a heteroaryl (furan) ring, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. Examples of "5- or 6-membered monocyclic heteroaryl" include monocyclic groups from the groups of the following formulas.

[0040]

“3 to 7 membered non-aromatic heterocyclyl” means a 3 to 7 membered cyclic group having one heteroatom selected from nitrogen, oxygen or sulfur, or two or more (for example, 2 to 4, preferably 2 to 3) of the same or various heteroatoms other than carbon atoms as ring atoms. Heterocyclyl is a non-aromatic which may be saturated or partially unsaturated. Preferred is a saturated heterocyclyl, more preferably a 5- or 6-membered saturated heterocyclyl. "3-7 membered non-aromatic heterocyclyl" includes, for example, oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethylene iminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxo-oxazolidinyl , dioxooxazolidinyl, dioxothiazolidinyl, tetrahydropyranyl and tetrahydropyridinyl, and preferably pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl and morpholinyl.

[0041]

"3-7 membered non-aromatic heterocyclyl" also includes a fused ring in which a 3-7 membered non-aromatic heterocyclyl is fused with benzene or a 6-membered heteroaryl (eg, pyridine, pyrimidine or pyridazine). Examples of this include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrolopyridinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl and tetrahydropyrido azepinil.

[0042]

"C _1-2 alkoxy" means a hydroxy group substituted by the above "C _1-2 alkyl", and "C _1-4 alkoxy" means a hydroxy group substituted by the above "C _1-4 alkyl". "C _1-2 alkoxy" includes, for example, methoxy and ethoxy, and "C _1-4 alkoxy" includes, for example, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, in addition to the above examples. Preferably, "C _1-4 alkoxy" includes methoxy, ethoxy and isopropoxy.

[0043]

"C _3-7 cycloalkoxy" means an oxy group substituted by the above-mentioned "C _3-7 cycloalkyl". "C _3-7 cycloalkoxy" includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy, and preferably cyclohexyloxy. "C _5-6 cycloalkoxy" means cycloalkoxy having 5 or 6 carbon atoms in "C _3-7 cycloalkoxy".

[0044]

"C _6-10 aryloxy" means an oxy group substituted by the above-mentioned "C _6-10 aryl". "C _6-10 aryloxy" includes, for example, phenyloxy and naphthyloxy, and preferably phenyloxy.

[0045]

"5-12 membered heteroaryloxy" means an oxy group substituted by the above-mentioned "5-12 membered heteroaryl". "5-12 membered heteroaryloxy" includes, for example, pyridyloxy, imidazolyloxy and furyloxy, and preferably pyridyloxy.

[0046]

To disclose the inventive compound of the above formula (I) in more detail, each symbol used in formula (I) is further explained below by way of preferred examples.

[0047]

Preferably, R ^1a , R ^1b , R ^1c and R ^1d independently represent hydrogen, halogen, C _1–4 alkyl, C _1–4 alkoxy (wherein the alkyl and alkyl group in alkoxy can be independently substituted by 1–3 substituents chosen independently from group consisting of a halogen, a hydroxyl group and a C _1–4 alkoxy, optionally substituted with 1–3 substituents selected independently from Substituent Group A), C _3–7 cycloalkyl, C _3–7 cycloalkoxy (with cycloalkyl and cycloalkyl group in The cycloalkoxy may be independently substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl group, _C1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and _C1-4 alkoxy , optionally substituted with 1–3 substituents selected independently from Substituent Group A), C _6–10 aryl, C _6–10 aryloxy, 5–12-membered heteroaryl or 5–12-membered heteroaryloxy (with aryl and aryl group in The aryloxy and heteroaryl and heteroaryl group in heteroaryloxy may be independently substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A). Provided that at least one of R ^1a , R ^1b , R ^1c and R ^1d is the above-mentioned C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy.

[0048]

More preferably, R ^1a , R ^1b , R ^1c and R ^1d independently represent hydrogen, halogen, C _1–4 alkyl, C _1–4 alkoxy (wherein the alkyl and alkyl group in alkoxy may be independently substituted by 1–3 independently selected substituents from the group consisting of halogen, hydroxyl group and C _1-4 alkoxy, optionally substituted with 1-3 substituents selected independently from Substituent Group A), C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12-membered heteroaryloxy (wherein the aryl and aryl group in aryloxy and heteroaryl and the heteroaryl group in heteroaryloxy can be independently substituted by 1-3 substituents independently selected from the group consisting of halogen, cyano, C _1-4 alkyl, in optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A). Provided that at least one of R ^1a , R ^1b , R ^1c and R ^1d is the above-mentioned C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy.

[0049]

Even more preferably, R ^1a , R ^1b , R ^1c and R ^1d independently represent hydrogen, halogen, C _1–4 alkyl, C _1–4 alkoxy (wherein the alkyl and alkyl group in alkoxy can be independently substituted with 1–3 identical or different halogen atoms), C _6–10 aryl, C _6–10 aryloxy, 5–12-membered heteroaryl or 5–12-membered heteroaryloxy (and the aryl and aryl group in aryloxy and heteroaryl and the heteroaryl group in heteroaryloxy can be independently substituted 1– 3 substituents independently selected from the group consisting of halogen, cyano, _C1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and _C1-4 alkoxy, optionally substituted with 1-3 alternates selected independently from Alternate Group A). Provided that at least one of R ^1a , R ^1b , R ^1c and R ^1d is the above-mentioned C _6-10 aryl, C _6-10 aryloxy, 5-12 membered heteroaryl or 5-12 membered heteroaryloxy.

[0050]

In another embodiment, R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen; and R ^1b and R ^1c independently represent hydrogen, C _6–10 aryl, C _6–10 aryloxy, 5–12 membered heteroaryl or 5–12 membered heteroaryloxy, with aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy may be independently substituted with 1-3 substituents independently selected from the group consisting of halogen and, if necessary, substituted C _1-4 alkyl. Provided that both R ^1b and R ^1c are not hydrogen.

[0051]

Preferred examples of R ^1a , R ^1b , R ^1c and R ^1d include hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3-chlorophenyl, 4-chlorophenyl, phenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 3 ,4-difluorophenoxy, 3,5-difluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, (5-methylpyridin-2-yl) oxy, (5-(trifluoromethyl)pyridin-2-yl)oxy, (6-(trifluoromethyl)pyridin-3-yl)oxy, (5-fluoropyridin-2-yl)oxy, 2-methoxy-4-(trifluoromethyl) phenyl, 2-fluoro-4-(trifluoromethyl)phenyl, 2-chloro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, (5-chloropyridin-2-yl)oxy, 2,4-dichlorophenyl, 2- chloro-4-fluorophenoxy, 4-chloro-2-fluorophenoxy and 2,4-dichlorophenoxy.

[0052]

More preferred examples of R ^1a , R ^1b , R ^1c and R ^1d include hydrogen, fluorine, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3- fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-fluorophenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy)phenoxy, (5-methylpyridin-2-yl)oxy , (5-(trifluoromethyl)pyridin-2-yl)oxy, (6-(trifluoromethyl)pyridin-3-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl and (5- chloropyridin-2-yl)oxy.

[0053]

Preferably, R ² and R ³ are independently hydrogen or C _1-6 alkyl, which may be independently substituted with 1-5 substituents independently selected from the group consisting of cyano, halogen, hydroxyl and C _1-4 alkoxy, as appropriate substituted with 1-3 substituents independently selected from Substituent Group A; more preferably hydrogen or C _1–6 alkyl, optionally substituted with 1–5 halogen atoms.

[0054]

Preferably, R ² and R ³ are, for example, hydrogen, methyl, ethyl, isopropyl, isobutyl, trifluoromethyl, cyclopropyl, cyclopentyl and cyclohexyl, more preferably hydrogen, methyl and ethyl.

[0055]

Additionally, in another preferred embodiment, R ² and R ³ may, together with the carbon atom to which they are attached, form a ring to form the following group of formula (II) with a hydroxyl group attached to the common carbon atom.

[0056]

In the above formula (II),

preferably e and f are independently 1 or 2,

preferably, R ^5a , R ^5b , R ^5c and R ^5d are independently hydrogen or halogen,

preferably R ⁴ is hydrogen,

preferably V represents an oxygen atom.

[0057]

Additionally, as another preferred embodiment, R ² and R ³ in R ² , R ³ , a hydroxyl group bonded to the carbon atom bonded to R ² and R ³ , and CR ⁷ R ⁸ in L,

R ² and R ⁷ can, together with the carbon atom to which they are attached, form the following group of formula (III) with R ³ , a hydroxyl group and R ⁸ .

[0058]

In the above formula (III),

preferably m ¹ =0,

preferably m ² =1 or 2,

preferably j=1 or 2,

L stands for CR ⁷ R ⁸ ,

preferably R ⁸ is hydrogen,

preferably R ^6a , R ^6b , R ^6c and R ^6d are independently hydrogen or halogen.

[0059]

Preferably m=1 or 2,

more preferably m=1.

[0060]

L denotes CR ⁷ R ⁸ with the proviso that when m=2 or 3, each CR ⁷ R ⁸ is independently the same or different.

[0061]

Preferably, R ⁴ is hydrogen or C _1-4 alkyl, which may be substituted by 1 to 5 identical or different halogen atoms; more preferably hydrogen or methyl.

[0062]

Preferably, R ⁷ and R ⁸ include hydrogen or C _1-4 alkyl, which may be independently substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _1-4 alkoxy, optionally substituted with 1- 3 substituents independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Group of substituents B, and 3-7-membered non-aromatic heterocyclyl, if necessary substituted with 1-3 substituents selected independently from Group of substituents B; more preferably hydrogen.

[0063]

Preferably, R ⁷ and R ⁸ include, for example, hydrogen, methyl and ethyl; more preferably hydrogen.

[0064]

Preferably, Substituent Group A includes fluorine, chlorine, hydroxyl group, C _1-2 alkoxy and C _5-6 cycloalkoxy; more preferably fluorine, hydroxyl group and C _1-2 alkoxy.

[0065]

Preferably, Substituent Group B includes fluorine, chlorine, hydroxyl, _C1-2 alkyl, _C1-2 alkoxy and _C5-6 cycloalkoxy; more preferably fluorine, hydroxyl group, C _1-2 alkyl and C _1-2 alkoxy.

[0066]

One embodiment of the compound of formula (I) includes the following:

compound or a pharmaceutically acceptable salt thereof, in which

R ^1a , R ^1b , R ^1c and R ^1d independently denote hydrogen, halogen, C _1–4 alkyl, C _1–4 alkoxy (wherein the alkyl and alkyl group in alkoxy can be independently substituted by 1–3 substituents selected independently from the group consisting of a halogen, a hydroxyl group and a C _1–4 alkoxy, optionally substituted with 1–3 substituents selected independently from Substituent Group A), C _3–7 cycloalkyl, C _3–7 cycloalkoxy (and the cycloalkyl and cycloalkyl group in cycloalkoxy can be independently substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl group, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkoxy, in if necessary, substituted with 1-3 substituents selected independently from Substituent Group A), C _6-10 aryl, C _6-10 aryloxy, 5-12-membered heteroaryl or 5-12-membered heteroaryloxy (with aryl and aryl group in aryloxy and The heteroaryl and heteroaryl group in heteroaryloxy may be independently substituted with 1-3 substituents independently selected from the group consisting of halogen, cyano, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkoxy, optionally substituted with 1-3 substituents selected independently from Substituent Group A),

R ² and R ³ independently represent hydrogen or C _1-6 alkyl, which may be independently substituted with 1-5 substituents independently selected from the group consisting of halogen, hydroxyl group and C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A, or

R ² and R ³ can, together with the carbon atom to which they are attached, form a ring, i.e., the following group of formula (IIa) with a hydroxyl group

in formula (IIa),

e and f independently denote 1 or 2,

V stands for single bond or oxygen atom,

R ^5a , R ^5b , R ^5c and R ^5d are independently hydrogen or halogen, or

in R ² , R ³ , a hydroxyl group bonded to the carbon atom bonded to R ² and R ³ , and CR ⁷ R ⁸ in L,

R ² and R ⁷ can, together with the carbon atom to which they are attached, form a ring, i.e., the following group of formula (IIIa) with R ³ , a hydroxyl group and R ⁸

in formula (IIIa),

m ¹ =0,

m ² =1 or 2,

j=1 or 2,

R ³ represents hydrogen or C _1–6 alkyl, which may be independently substituted by 1–3 identical or different halogen atoms,

R ⁸ denotes hydrogen,

L denotes CR ⁷ R ⁸ , with the proviso that when m ² =2, each CR ⁷ R ⁸ is independently the same or different,

R ^6a , R ^6b , R ^6c and R ^6d are independently hydrogen or halogen,

R ⁴ represents hydrogen or C _1–4 alkyl, which may be substituted by 1–5 identical or different halogen atoms,

m=1 or 2,

L denotes CR ⁷ R ⁸ , with the proviso that when m=2, each CR ⁷ R ⁸ is independently the same or different,

R ⁷ and R ⁸ independently represent hydrogen or C _1–4 alkyl, which may be substituted by 1–3 identical or different halogen atoms.

[0067]

Another embodiment of the compound of formula (I) includes the following:

compound or a pharmaceutically acceptable salt thereof, in which

R ^1a , R ^1b , R ^1c and R ^1d independently represent hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl , 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3-chlorophenyl, 4-chlorophenyl, phenoxy, 3-fluorophenoxy, 4-fluorophenoxy, 3, 4-difluorophenoxy, 3,5-difluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-methoxyphenoxy, 4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, (5-methylpyridin-2-yl)oxy , (5-(trifluoromethyl)pyridin-2-yl)oxy, (6-(trifluoromethyl)pyridin-3-yl)oxy, (5-fluoropyridin-2-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl , 2-fluoro-4-(trifluoromethyl)phenyl, 2-chloro-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, (5-chloropyridin-2-yl)oxy, 2,4-dichlorophenyl, 2-chloro –4-fluorophenoxy, 4-chloro-2-fluorophenoxy or 2,4-dichlorophenoxy,

R ² and R ³ independently represent hydrogen or C _1–6 alkyl, which may be independently substituted by 1–5 identical or different halogen atoms, or

R ² and R ³ can, together with the carbon atom to which they are attached, form a ring, i.e., the following group of formula (IIa) with a hydroxyl group

in formula (IIa),

e and f independently denote 1 or 2,

V stands for oxygen atom,

R ^5a , R ^5b , R ^5c and R ^5d are hydrogen, or

in R ² , R ³ , a hydroxyl group bonded to the carbon atom bonded to R ² and R ³ , and CR ⁷ R ⁸ in L,

R ² and R ⁷ can, together with the carbon atom to which they are attached, form a ring, i.e., the following group of formula (IIIa) with R ³ , a hydroxyl group and R ⁸

in formula (IIIa),

m ¹ =0,

m ² =1 or 2,

j=1 or 2,

R ³ is hydrogen or C _1–6 alkyl,

R ⁸ denotes hydrogen,

L denotes CR ⁷ R ⁸ , with the proviso that when m ² =2, each CR ⁷ R ⁸ is independently the same or different,

R ^6a , R ^6b , R ^6c and R ^6d are hydrogen,

R ⁴ is hydrogen or C _1–4 alkyl,

m=1 or 2,

L denotes CR ⁷ R ⁸ , with the proviso that when m=2, each CR ⁷ R ⁸ is independently the same or different,

R ⁷ and R ⁸ are independently hydrogen or C _1–4 alkyl.

[0068]

Another embodiment of the compound of formula (I) includes the following:

compound or a pharmaceutically acceptable salt thereof, in which

R ^1a , R ^1b , R ^1c and R ^1d independently represent hydrogen, fluorine, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 3-fluorophenoxy, 4-fluorophenoxy, 4-chlorophenoxy, 4-methylphenoxy, 4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy)phenoxy, (5-methylpyridin-2-yl)oxy, ( 5-(trifluoromethyl)pyridin-2-yl)oxy, (6-(trifluoromethyl)pyridin-3-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl or (5-chloropyridine- 2-yl)oxy,

R ² and R ³ are independently hydrogen or methyl, or

R ² and R ³ can, together with the carbon atom to which they are attached, form a ring, i.e., the following group of formula (IIa) with a hydroxyl group

in formula (IIa),

e and f stand for 1,

V stands for oxygen atom,

R ^5a , R ^5b , R ^5c and R ^5d are hydrogen, or

in R ² , R ³ , a hydroxyl group bonded to the carbon atom bonded to R ² and R ³ , and CR ⁷ R ⁸ in L,

R ² and R ⁷ can, together with the carbon atom to which they are attached, form a ring, i.e., the following group of formula (IIIa) with R ³ , a hydroxyl group and R ⁸

in formula (IIIa),

m ¹ =0,

m ² =2,

j=2,

R ³ is hydrogen,

R ⁸ denotes hydrogen,

L is CH ₂ and

R ^6a , R ^6b , R ^6c , and R ^6d are hydrogen,

R ⁴ is hydrogen or C _1–4 alkyl,

m=1,

L stands for CR ⁷ R ⁸ ,

R ⁷ and R ⁸ are independently hydrogen or methyl.

[0069]

Methods for preparing the compounds of the present invention are described below. Compound (I) according to the present invention can be obtained, for example, according to Methods 1 to 5 shown below.

[0070]

Method 1:

In the compounds of formula (I), the compound of formula (7) or (9) in which R ^1b is OR ^a or a pharmaceutically acceptable salt thereof can be prepared, for example, according to the following method.

In the above scheme, R ^1a , R ^1c , R ^1d , R ² , R ³ , L and m have the meanings defined in Clause 1; R ^a denotes R ^1b which is selected from C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, C _3-7 cycloalkyl, optionally substituted with 1-3 substituents independently selected from Group substituents B, C _6–10 aryl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, or 5–12-membered heteroaryl, optionally substituted with 1–3 substituents independently selected from Substituent Group B; X ¹ , X ² and X ³ independently represent a leaving group such as halogen, trifluoromethanesulfonyloxy and methanesulfonyloxy; and R ^4a is R ⁴ which is selected from C _1-4 alkyl or C _3-4 cycloalkyl (wherein C _1-4 alkyl and C _3-4 cycloalkyl may be substituted by 1-5 identical or different halogen atoms).

[0071]

Stage (1–1):

The nitroaniline compound (3) can be prepared by reacting the nitrobenzene compound (1) and the amine compound (2) in a suitable inert solvent in the presence of a base. The base used herein includes inorganic bases such as sodium hydroxide, potassium hydroxide, potassium carbonate and cesium carbonate; and organic bases such as triethylamine, diisopropylethylamine and DABCO. When the amine compound is used in large excess, there is no need to use such a base. The solvent used here includes ethers such as THF, 1,2-dimethoxyethane and 1,4-dioxane, DMF, NMP and acetonitrile. The reaction time is from about 10 minutes to about 10 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0072]

Stage 1–2:

Compound (5) can be prepared by reacting Compound (3) and Compound (4) in a suitable inert solvent in the presence of a base. The base used herein includes sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and sodium hydride. The solvent used here includes ethers such as THF, 1,2-dimethoxyethane and 1,4-dioxane, DMF, NMP and acetonitrile. The reaction time is from about 10 minutes to about 10 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0073]

Stage 1–3:

Compound (6) can be prepared by reducing Compound (5) in a suitable inert solvent under commonly used conditions for reducing the nitro group. Reaction conditions at this stage include catalytic reduction with palladium on carbon, etc. under hydrogenation conditions; metal reduction with zinc, iron, etc.; reduction of hydride with lithium-aluminum hydride, etc. The solvent used in this reduction includes various solvents commonly used in each reduction condition. In the case of catalytic reduction, it includes methanol, ethanol, THF and ethyl acetate; in the case of metal reduction, it includes THF, acetic acid, methanol and ethanol; and in the case of hydride reduction, it includes diethyl ether and THF. The reaction time is from about 10 minutes to about 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0074]

Stage 1–4:

Compound (7) can be prepared by reacting Compound (6) in a suitable inert solvent under commonly used conditions to form an imidazolone ring. Reaction conditions include, for example, cyclization conditions using 1,1'-carbonyldiimidazole, triphosgene or urea. If necessary, bases such as triethylamine and diisopropylethylamine can be added to the reaction. The solvent used herein includes ethers such as THF, 1,2-dimethoxyethane and 1,4-dioxane; aprotic polar solvents such as DMF, NMP and acetonitrile; and aromatic hydrocarbons such as benzene and toluene. The reaction time is from about 10 minutes to about 10 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0075]

Stage 1–5:

Compound (9) can be prepared by reacting Compound (7) and Compound (8) in a suitable inert solvent in the presence of a base. The base used herein includes sodium hydride, potassium carbonate, cesium carbonate and calcium carbonate. The solvent used here includes ethers such as THF, 1,2-dimethoxyethane and 1,4-dioxane, DMF, NMP and acetonitrile. The reaction time is from about 10 minutes to about 10 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0076]

Stage 1–4':

Compound (7') can be prepared by reacting Compound (6) and a corresponding aldehyde or ketone compound in a suitable inert solvent in the presence of a reducing agent. The reducing agent used herein includes sodium borohydride and sodium cyanotrihydroborate. The solvent used herein includes halogenated carbons such as chloroform and dichloromethane; ethers such as diethyl ether, THF and 1,4-dioxane; acetonitrile; and alcohols such as methanol and ethanol. The reaction time is usually from about 10 minutes to about 10 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here. Compound (7') can also be prepared from Compound (6) in the same manner as in Step (1-5).

[0077]

Stage 1–5':

Compound (9) can also be prepared from Compound (7') in the same manner as in Step (1-4).

[0078]

The above-described Step (1-1) and the subsequent Step (1-2) can be carried out sequentially, that is, Compound (5) can be obtained in one step from Compound (1). The reaction time of the sequential reactions is from 10 minutes to 12 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0079]

Method 2:

In the compounds of formula (I), the compound of formula (7) in which R ^1b is OR ^a or a pharmaceutically acceptable salt thereof can also be prepared, for example, according to the following method.

In the above diagram, R ^1a , R ^1c , R ^1d , R ² , R ³ , L and m have the meanings defined in Clause 1; R ^a and X ¹ have the meanings defined above; X ⁴ represents a leaving group such as halogen, trifluoromethanesulfonyloxy and methanesulfonyloxy. Bn denotes a benzyl group, which may include a protecting group that can be removed as a benzyl group, for example, a substituted benzyl group disclosed in Protective Groups in Organic Synthesis.

[0080]

Stage 2–1:

Compound (12) can be prepared, for example, by reacting Compound (10) and Compound (11) in a suitable inert solvent in the presence of a base. The base used herein includes sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride. Compound (11) includes benzyl chloride and benzyl bromide. If necessary, sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, etc. may be added to the reaction. The solvent used here includes acetone, acetonitrile, THF, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane, DMF and NMP. The reaction time is usually from 30 minutes to 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here. In addition, compound (12) can be prepared from compound (10) according to the method (conditions) described in Protective Groups in Organic Synthesis and the like.

[0081]

Stage 2–2:

Compound (13) can be prepared from Compound (12) in the same manner as in Step (1-1).

[0082]

Stage 2–3:

Compound (14) can be prepared by selectively reducing the nitro group in Compound (13). Reaction conditions at this stage include catalytic reduction with sulfur-toxic platinum-carbon, etc. under hydrogenation conditions; metal reduction with zinc, iron, tin, etc.; reduction of hydride with lithium-aluminum hydride, etc. The solvent used in this reduction includes various solvents commonly used in each reduction condition. In the case of catalytic reduction, it includes methanol, ethanol, THF and ethyl acetate; in the case of metal reduction, it includes THF, acetic acid, methanol and ethanol; and in the case of hydride reduction, it includes diethyl ether and THF. The reaction time is usually from about 10 minutes to about 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0083]

Stage 2–4:

Compound (15) can be prepared from Compound (14) in the same manner as in Step (1-4).

[0084]

Stage 2–5:

Compound (16) can be obtained, for example, by catalytic reduction of Compound (15) under hydrogenation conditions. The catalyst used herein includes heterogeneous catalysts such as palladium on carbon. Hydrogenation conditions mean "under an atmosphere of hydrogen" or "in the presence of formic acid, ammonium formate, etc." The solvent used herein includes methanol, ethanol, THF and ethyl acetate. The reaction time is from 30 minutes to 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here. In addition, compound (16) can be prepared from compound (15) according to the method (conditions) described in Protective Groups in Organic Synthesis and the like.

[0085]

Stage 2–6:

This step is a method for preparing Compound (7) from Compound (16), which includes but is not limited to two reaction conditions.

1) The reaction conditions here using a base include the following step: Compound (7) is prepared by reacting Compound (16) and R ^a –X ⁵ (wherein R ^a has the meanings defined above, X ⁵ denotes a leaving group such as halogen, trifluoromethanesulfonyloxy , and methanesulfonyloxy) in the same manner as in Step (2–1).

2) The reaction conditions here using a catalyst and a base include reaction with a boronate compound or a halogen compound having a R ^a group. The catalyst used herein includes copper(II) acetate, copper(I) iodide and copper(II) oxide. The base used herein includes potassium carbonate, cesium carbonate, potassium hydroxide and triethylamine. The solvent used here includes chloroform, 1,4-dioxane, DMF, dimethyl sulfoxide and NMP. The reaction time is usually from 30 minutes to 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0086]

The compound of formula (I) in which one or more of R ^1a , R ^1b , R ^1c and R ^1d is OR ^a , or a pharmaceutically acceptable salt thereof, can also be prepared in the same manner as described above.

[0087]

Method 3:

In the compounds of formula (I), the compound of formula (7) in which R ^1b is OR ^a , or a pharmaceutically acceptable salt thereof, can also be prepared, for example, according to the following method.

In the above diagram, R ^1a , R ^1c , R ^1d , R ² , R ³ , L and m have the meanings defined in Clause 1, and R ^a and X ¹ have the meanings defined above.

[0088]

Stage 3–1:

Compound (17) can be prepared from Compound (10) in the same manner as in Step (1-1).

[0089]

Stage 3–2:

Compound (18) can be prepared from Compound (17) in the same manner as in Step (2-6).

[0090]

Stage 3–3:

Compound (19) can be prepared from Compound (18) in the same manner as in Step (1-3).

[0091]

Stage 3–4:

Compound (7) can be prepared from Compound (19) in the same manner as in Step (1-4).

[0092]

The above Step (3-1) and the subsequent Step (3-2) can be carried out sequentially, that is, Compound (18) can be obtained in one step from Compound (10). The reaction time of the sequential reactions is from 10 minutes to 12 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0093]

Method 4:

In the compounds of formula (I), the compound of formula (22) or (23) in which R ^1b is R ^b , or a pharmaceutically acceptable salt thereof, can be prepared, for example, according to the following method.

In the above diagram, R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m have the meanings defined in Clause 1; X ² and X ³ have the meanings defined above; and R ^b is _C6-10 aryl or 5-12 membered heteroaryl (wherein aryl and heteroaryl may be independently substituted with 1-5 substituents independently selected from the group consisting of halogen, cyano, _C1-4 alkyl, as appropriate substituted with 1–3 substituents independently selected from Substituent Group A, C _1–4 alkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group A, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents, independently selected from Substituent Group B, C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, and 3–7 membered non-aromatic heterocyclyl, optionally substituted with 1–3 substituents independently selected from Groups of substituents B).

[0094]

Stage 4–1:

Compound (20) can be prepared from Compound (3) in the same manner as in Step (2–3) (selective reduction of nitro group).

[0095]

Stage 4–2:

Compound (21) can be prepared from Compound (20) in the same manner as in Step (1-4).

[0096]

Stage 4–3:

Compound (22) can be prepared by reacting Compound (21) and a boronic acid or boronate compound having an R ^b group in the presence of a base and a catalyst. For example, this stage is the Suzuki combination reaction. The base used herein includes sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate. The catalyst used herein includes palladium acetate, tetrakis(triphenylphosphine)palladium and tris(dibenzylideneacetone)dipalladium. The solvent used here includes 1,4-dioxane, toluene and 1,2-dimethoxyethane. The reaction time is from about 30 minutes to about 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0097]

Stage 4–4:

Compound (23) can be prepared from Compound (22) and Compound (8) in the same manner as in Step (1-5).

[0098]

The compound of formula (I) in which one or more of R ^1a , R ^1b , R ^1c and R ^1d is R ^b , or a pharmaceutically acceptable salt thereof, can also be prepared in the same manner as described above.

[0099]

Method 5:

In the compounds of formula (I), the compound of formula (22) in which R ^1b is R ^b , or a pharmaceutically acceptable salt thereof, can also be prepared, for example, according to the following method.

In the above diagram, R ^1a , R ^1c , R ^1d , R ² , R ³ , L and m have the meanings defined in Clause 1; R ^b and X ² have the meanings defined above; R ¹⁰ and R ¹¹ independently represent optionally substituted C _1–4 alkyl, optionally substituted C _1–4 alkoxy, optionally substituted C _1–4 dialkylamino, optionally substituted C 6–10 aryl, optionally substituted C _6–10 aryl. substituted C _6–10 aryloxy, optionally substituted 5–12 membered heteroaryl, optionally substituted 5–12 membered heteroaryloxy or hydroxyl group. Preferably, R ¹⁰ R ¹¹ B– includes, but is not limited to, the following structures.

[0100]

Stage 5–1:

Compound (24) can be prepared by reacting Compound (21) and diborones such as bis(pinacolate)diborone in the presence of a catalyst and a base. The catalyst used herein includes [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, tetrakis(triphenylphosphine)palladium, tris(dibenzylideneacetone)dipalladium and dichlorobis(triphenylphosphine)palladium. The base used herein includes potassium acetate, tripotassium phosphate and potassium carbonate. The solvent used here includes 1,4-dioxane, toluene and 1,2-dimethoxyethane. The reaction time is from about 1 hour to about 48 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0101]

Stage 5–2:

Compound (22) can be prepared by reacting Compound (24) and a halide or triflate compound having an R ^b group (R ^b –X (X: halogen atom) or CF ₃ SO ₂ O – R ^b , etc.) in presence of a catalyst and base. For example, this stage is the Suzuki combination reaction. The base used herein includes sodium carbonate, potassium carbonate, cesium carbonate and tripotassium phosphate. The catalyst used herein includes palladium acetate, tetrakis(triphenylphosphine)palladium and tris(dibenzylideneacetone)dipalladium. The solvent used here includes 1,4-dioxane, toluene and 1,2-dimethoxyethane. The reaction time is from about 30 minutes to 48 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0102]

The compound of formula (I) in which one or more of R ^1a , R ^1b , R ^1c and R ^1d is R ^b , or a pharmaceutically acceptable salt thereof, can also be prepared in the same manner as described above.

[0103]

Room temperature in the above methods specifically means 10ºC to 30ºC.

[0104]

The starting materials and intermediates in these methods are known compounds or can be prepared from known compounds according to a known method. In case any functional group other than the target reaction site may react or may be unsuitable in these methods, the functional group other than the target reaction site may be protected for the reaction and the protecting group may be cleaved off to obtain the desired connections after completion of the reaction. The protecting group used herein includes, for example, a standard protecting group disclosed in Protective Groups in Organic Synthesis and the like. In particular, the protecting group for the amino group includes, for example, ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like; and the protecting group for the hydroxyl group includes, for example, tri-lower alkylsilyl, acetyl, benzyl and the like.

[0105]

The introduction and removal of protective groups can be carried out by a standard method known in organic chemistry (for example, see the specified Protective Groups in Organic Synthesis), or a similar method.

[0106]

By suitable modification of the functional group(s) in the intermediate or final product in these methods, it is also possible to obtain the various compounds defined in the present invention. The transformation of the functional group(s) can be carried out according to a standard method (eg, Comprehensive Organic Transformations, R. C. Larock (1989)).

[0107]

Intermediates and desired compounds in these methods can be isolated/purified by purification commonly used in synthetic organic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. Some intermediates can be used in the next step without any purification.

The optical isomers of the present invention can be isolated using a known separation method at a suitable stage, for example, optically active column separation and fractional crystallization. And this is feasible using an optically active starting material.

The compounds of the present invention may sometimes be an optical isomer, a stereoisomer, a tautomer such as a keto-enol compound and/or a geometric isomer, and therefore includes all possible isomers, including said isomers and mixtures thereof.

[0108]

The compounds of the present invention may also include a compound of formula (I), a prodrug thereof and a pharmaceutically acceptable salt thereof, in addition to these isomers. And the compounds of the present invention or pharmaceutically acceptable salts thereof may be in the form of an adduct with water or each solvent, hence they also include such adducts. In addition, the compounds of the present invention may also include various variations of crystals and compounds in which some or all of the atoms constituting the compounds are replaced by another isotope (eg, replacing hydrogen with deuterium and replacing ¹² C with ¹⁴ C).

[0109]

The term “prodrug of a compound of formula (I)” as used herein means a compound that can be converted to a compound of formula (I) by reaction with an enzyme, gastric juice, etc. under physiological conditions, i.e., a compound that can be enzymatically oxidized, reduced, hydrolyzed or otherwise converted into a compound of formula (I), and a compound that can be hydrolyzed by gastric juice and the like. to convert into the compound of formula (I).

[0110]

A "pharmaceutically acceptable salt" as used herein includes, for example, a base addition salt or an acid addition salt. The base addition salt includes, for example, an alkali metal salt such as a potassium salt and a sodium salt; an alkaline earth metal salt such as a calcium salt and a magnesium salt; a water-soluble amine addition salt such as ammonium salt and N-methylglucamine (meglumine); and a lower alkanolammonium salt of an organic amine. The acid addition salt includes, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate[1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].

[0111]

Salts of the compounds of the invention can be prepared, for example, as follows. For example, when the compound of the invention is obtained in the form of a salt, its salt can be obtained by directly purifying it. the compound of the invention is obtained in free form, a salt thereof can be prepared by dissolving or suspending it in a suitable organic solvent, adding to it an optional acid or base and then treating the resulting mixture in the usual manner.

[0112]

The compound of formula (I) obtained by the above methods can be isolated/purified by standard methods such as extraction, column chromatography, recrystallization and reprecipitation. The extraction solvent used herein includes, for example, diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene and the like. Purification by column chromatography can be accomplished by treatment with acid, base, or various chemicals on silica gel, alumina, and the like. The eluent used herein includes, for example, hexane/ethyl acetate, hexane/chloroform, ethyl acetate/methanol, chloroform/methanol, acetonitrile/water, methanol/water and the like.

[0113]

The novel compounds of the present invention or their pharmaceutically acceptable salts having a benzimidazolone ring have Nav 1,7 inhibitory property and thus can be used as a medicament for the treatment or prevention of pain involving peripheral nerve such as C-fibers and Aδ fibers, spontaneous pain such as numbness, sharp pain, dull pain, stabbing pain and shooting pain, neuropathic pain accompanied by hyperalgesia such as mechanical stimulation and cold stimulation or allodynia, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, etc. Neuropathic pain includes, for example, diabetic neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathy, cancer pain, sensory nerve damage caused by viral infection in human immunodeficiency syndrome, trigeminal neuralgia, complex regional pain syndrome, sympathetic reflex dystrophy, neuralgia after lumbar surgery, phantom pain pain, pain after spinal cord injury, persistent postoperative pain, inflammatory demyelinating polyradiculopathy, alcoholic neuropathy, peripheral neuropathy associated with organ entrapment, iatrogenic neuropathy, sudden sensorineural disorder, neuropathy caused by poor nutrition, post-radiation neuropathy, radiculopathy, toxic peripheral neuropathy, traumatic peripheral neuropathy, brachial plexus rupture, glossopharyngeal neuralgia, autoimmune neuropathy and chronic cauda equina syndrome. Nociceptive pain or inflammatory pain includes lumbar pain, abdominal pain, chronic rheumatoid arthritis, pain caused by osteoarthritis, myalgia, acute postoperative pain, fracture pain, pain after burn injury, and the like. In addition, the compounds of the invention or pharmaceutically acceptable salts thereof may also be used as a medicament for the treatment or prevention of dysuria. Dysuria includes frequent urination, bladder pain caused by prostatic hyperplasia, etc. In addition, the compounds of the invention or pharmaceutically acceptable salts thereof may also be used as a medicament for the treatment or prevention of ataxia resulting from suppression of pathological nerve loss in the cerebellum in multiple sclerosis. In addition, the compounds of the invention or their pharmaceutically acceptable salts may be medicinal without the cardiac or central nervous system side effects that are a problem with existing treatments because they have selective inhibitory activity towards Nav 1,7.

[0114]

The compounds of the invention may be administered orally, parenterally or rectally, and the daily dose may vary depending on the compound, route of administration, condition/age of the patient, etc. For oral administration, for example, the compounds of the invention may generally be administered at a dosage of from about 0.01 to 1000 mg, preferably from about 0.1 to 500 mg per day per kilogram of human or mammal body weight and from one to several times. For parenteral administration, such as intravenous injection, for example, the compounds of the invention may generally be administered at a dosage of from about 0.01 to 300 mg, preferably from about 1 to 100 mg, per kilogram of body weight of a human or mammal.

[0115]

The compounds of the invention may be administered orally or parenterally, directly or in the form of a suitable formulation containing them. The composition may be, for example, but is not limited to, a tablet, capsule, powder, granule, liquid, suspension, injection, patch, gel patch, and the like. The composition can be prepared with pharmaceutically acceptable additives by known means. Additives may be selected for any purpose, including excipient, disintegrant, binder, fluidizing agent, lubricant, coating agent, fluidizing agent, solubilizing agent, thickener, dispersant, stabilizer, sweetener, flavoring agent, and the like. In particular, they include, for example, lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropylcellulose, corn starch, partially pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol , titanium oxide, talc, etc.

[0116]

The compounds of the invention and a pharmaceutically acceptable salt thereof may be used in combination with, for example, a non-steroidal anti-inflammatory drug such as celecoxib, voltaren, ibuprofen, loxoprofen, acetaminophen, diclofenac and dexamethasone, and an opioid analgesic such as tramadol, morphine and oxycodone to enhance his actions. In addition, the compounds of the invention and a pharmaceutically acceptable salt thereof may also be used in combination with an antiepileptic agent (such as pregabalin and carbamazepine), an aldose reductase inhibitor (such as epalrestat), a prostaglandin derivative drug (such as limaprost alfadex), an antidepressant (such as amitriptyline and duloxetine), an anticonvulsant agent, an anxiolytic agent, a dopamine receptor agonist, an antiparkinsonian agent, a hormonal drug, an anti-migraine drug, a β adrenergic receptor antagonist, a drug for treating dementia, a drug for treating a mood disorder, and the like. Preferred drugs used in combination with a compound of the invention and a pharmaceutically acceptable salt thereof include an antiepileptic agent such as pregabalin and carbamazepine, an antidepressant such as amitriptyline and duloxetine, a narcotic analgesic such as morphine, oxycodone and tramadol, an anti-inflammatory agent such as such as acetaminophen, diclofenac and dexamethasone, an aldose reductase inhibitor such as epalrestat, and a prostaglandin derivative such as limaprost alfadex. To reduce side effects, the compounds of the invention and their pharmaceutically acceptable salt can be used in combination with an antiemetic drug and a hypnotic drug. The interval of administration of the compound of the invention and its concomitant drug is not limited, ie, the concomitant drug can be administered at the same time as the compound of the invention, or at a suitable interval. Or, the compound of the invention and its concomitant drug may be formulated into a combination drug. The dose of the combination drug can be suitably determined based on its clinically used dose standard. The ratio of the combination of a compound of the invention and its concomitant drug can be suitably determined based on the subject patient, route of administration, disease, pathology, concomitant drug, etc. For example, when the patient in question is a human, the concomitant drug may be used in an amount of from 0.01 to 1000 parts by weight per part of the compound of the invention.

EXAMPLES

[0117]

The present invention is explained in more detail in the following section through Reference Examples, Examples and Pharmacological Tests; however, the technical scope of the present invention is not limited to such Examples and the like. The silica gel chromatography used in the Examples was silica gel column chromatography or amino silica gel column chromatography manufactured by YAMAZEN CORPORATION. Each compound was identified by proton nuclear magnetic resonance spectrum ( ^1H -NMR), high-performance liquid chromatography-mass spectrometry; LCMS, etc. ¹ H-NMR was measured using a JNM-ECS400 (JEOL).

[0118]

Measurement conditions using high performance liquid chromatography - mass spectrometry; LCMS are shown below and the mass spectrography detection value [MS (m/z)] is shown as M+H.

MS sensor: ACQITY SQD

HPLC: ACQITY UPLC

Column: ACQITY BEH C18 1.7 µm, 2.1x50 mm

Flow rate: 0.75 ml/min.

Wavelength: 254 nm

Mobile phase: A: 0.05% aqueous formic acid

B: Acetonitrile

Time program:

Stage time (min.)

1 0.0–1.3 A : B=90 : 10 => 1: 99

2 1.3–1.5 A : B=1 : 99

3 1.5–2.0 A : B=90 : 10

[0119]

Unless otherwise stated, the starting materials, reaction reagents and solvents used herein were commercially available products or were prepared according to known methods.

[0120]

In the Reference Examples, Examples and Pharmacological Examples, abbreviations shown below may sometimes be used to simplify the present description. Me: methyl, Et: ethyl, THF: tetrahydrofuran, DMF: N, N-dimethylformamide, NMP: N-methyl-2-pyrrolidinone, DMSO: dimethyl sulfoxide, HEPES: 2-[4-(2-hydroxyethyl)-1-piperazinyl ]ethanesulfonic acid, EGTA: O, O'-bis(2-aminoethyl)ethylene glycol-N, N,N',N'-tetraacetate, J: binding constant, c: singlet, d: doublet, t: triplet, q: quartet, dd: doublet of doublets, m: multiplet, wide: widened.

[0121]

Reference Example 1: 2-methyl-1-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]propan-2-ol

To a solution of 3-fluoro-4-nitrophenol (1.0 g) in NMP (15.9 ml) was added 1-amino-2-methylpropan-2-ol (0.74 g) and diisopropylethylamine (2.78 ml), and the mixture was stirred at 110°C for 3 hours. The reaction solution was cooled to room temperature, and 2-fluoro-5-(trifluoromethyl)pyridine (1.37 g) and cesium carbonate (3.11 g) were added to the reaction solution. The mixture was stirred at 110°C for 2 hours. The reaction solution was cooled to room temperature, and water and ethyl acetate/hexane (3/1) were added to the reaction solution. The desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Ethyl acetate (10 ml) and then hexane (100 ml) were added to the resulting residue. The mixture was sonicated to obtain a precipitated solid. The solid was collected on a filter, washed with hexane and dried in vacuo to give the title compound (1.53 g).

LCMS, m/z; 372 [M+H] ⁺

[0122]

Reference Example 2: 1-[(2-amino-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]-2-methylpropan-2-ol

Formic acid (0.52 ml) was added to a solution of the compound of Reference Example 1 (500 mg) in methanol (6.7 ml). And zinc (440 mg) was gradually added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite and concentrated in vacuo. A saturated aqueous solution of Rochelle salt and ethyl acetate were added to the resulting residue, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the target compound (146 mg).

LCMS, m/z; 342 [M+H] ⁺

[0123]

Reference examples 3, 4 and 5:

The compounds of Reference Examples 3–5 shown below were prepared with each respective starting material in the same manner as in Reference Example 1.

Reference example Structure LC–MS, m/z 3 386 [M+H] ⁺ 4 386 [M+H] ⁺ 5 398 [M+H] ⁺

[0124]

Reference Example 6: 3-{[(5-fluoro-2-nitrophenyl)amino]methyl}oxetan-3-ol

To a solution of 3-(aminomethyl)oxetan-3-ol (960 mg) in NMP (20 ml), 2,4-difluoronitrobenzene (1.48 g) and diisopropylethylamine (1.95 ml) were added and the mixture was stirred at room temperature in for 9 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the target compound (1.44 g).

LCMS, m/z; 243 [M+H] ⁺

[0125]

Reference Example 7: 3-[({2-nitro-5-[4-(trifluoromethoxy)phenoxy]phenyl}amino)methyl]oxetan-3-ol

To a solution of the compound of Reference Example 6 (529 mg) in NMP (10 ml), 4-(trifluoromethoxy)phenol (324 mg) and cesium carbonate (771 mg) were added, and the mixture was stirred at 100°C for 4 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the target compound (1.44 g).

LCMS, m/z; 401 [M+H] ⁺

[0126]

Reference Example 8: 1-[(5-fluoro-2-nitrophenyl)amino]-2-methylpropan-2-ol

The target compound (1.1 g) was prepared with 1-amino-2-methylpropan-2-ol (500 mg) in the same manner as Reference Example 6.

LCMS, m/z; 229 [M+H] ⁺

[0127]

Reference Example 9: 1-{[5-(4-fluorophenoxy)-2-nitrophenyl]amino}-2-methylpropan-2-ol

The target compound (1.33 g) was prepared with the compound of Reference Example 8 (1.1 g) and 4-fluorophenol (450 mg) in the same manner as Reference Example 7.

LCMS, m/z; 321 [M+H] ⁺

[0128]

Reference Example 10: 3-({[5-(4-fluorophenoxy)-2-nitrophenyl]amino}methyl)oxetan-3-ol

The target compound (354 mg) was prepared with 4-fluorophenol (116 mg) in the same manner as Reference Example 7.

LCMS, m/z; 335 [M+H] ⁺

[0129]

Reference Example 11: 3-({[5-(4-chlorophenoxy)-2-nitrophenyl]amino}methyl)oxetan-3-ol

The target compound (416 mg) was prepared with 4-chlorophenol (150 mg) in the same manner as Reference Example 7.

LCMS, m/z; 351 [M+H] ⁺

[0130]

Reference examples 12, 13, 14, 15, 16, 17 and 18:

The compounds of Reference Examples 12, 13, 14, 15, 16, 17 and 18 shown below were prepared with each respective starting material in the same manner as in Reference Example 2.

Reference example Structure Raw material LC–MS, m/z 12 Reference Example 3 356 [M+H] ⁺ 13 Reference Example 4 356 [M+H] ⁺ 14 Reference Example 5 368 [M+H] ⁺ 15 Reference Example 7 371 [M+H] ⁺ 16 Reference Example 9 291 [M+H] ⁺ 17 Reference Example 10 305 [M+H] ⁺ 18 Reference Example 11 321 [M+H] ⁺

[0131]

Reference Example 19: 1-[(5-bromo-2-nitrophenyl)amino]-2-methylpropan-2-ol

To a solution of 4-bromo-2-fluoronitrobenzene (5.0 g) in NMP (40 ml) was added 1-amino-2-methylpropan-2-ol (2.43 g) and diisopropylethylamine (5.95 ml), and the mixture stirred at 100°C for 3 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by trituration with hexane and ethyl acetate to give the title compound (5.18 g).

LCMS, m/z; 289 [M] ⁺ , 291 [M+2] ⁺

[0132]

Reference Example 20: 1-[(2-amino-5-bromophenyl)amino]-2-methylpropan-2-ol

To a solution of the compound of Reference Example 19 (2.65 g) in THF (30 ml) was added 3% Pt sulfide on carbon (1.3 g), and the mixture was stirred under a hydrogen atmosphere at room temperature for 10 hours. The reaction solution was filtered through Celite and concentrated in vacuo. The resulting residue was purified by trituration with hexane and ethyl acetate to give the title compound (2.09 g).

LCMS, m/z; 259 [M] ⁺ , 261 [M+2] ⁺

[0133]

Reference Example 21: 6-bromo-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one

To a solution of the compound of Reference Example 20 (1.51 g) in THF (60 ml) in an ice bath, N,N'-carbonyldiimidazole (1.13 g) was added, and the mixture was stirred for 8 hours, gradually warming to room temperature. The reaction solution was concentrated in vacuo, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain the target compound (1.16 g).

LCMS, m/z; 285 [M] ⁺ , 287 [M+2] ⁺

[0134]

Reference Example 22: 1-[(4-bromo-2-nitrophenyl)amino]-2-methylpropan-2-ol

The target compound (1.8 g) was prepared with 5-bromo-2-fluoronitrobenzene (2.06 g) in the same manner as Reference Example 19.

LCMS, m/z; 289 [M] ⁺ , 291 [M+2] ⁺

[0135]

Reference Example 23: 1-[(2-amino-4-bromophenyl)amino]-2-methylpropan-2-ol

The target compound (930 mg) was prepared with the compound of Reference Example 22 (416 mg) in the same manner as Reference Example 20.

LCMS, m/z; 259 [M] ⁺ , 261 [M+2] ⁺

[0136]

Reference Example 24: 1-{[4-(benzyloxy)-2-nitrophenyl]amino}-2-methylpropan-2-ol

To a solution of 4-(benzyloxy)-1-fluoro-2-nitrobenzene (1.1 g) in NMP (9 ml) was added 1-amino-2-methylpropan-2-ol (476 mg) and diisopropylethylamine (2.72 ml ), and the mixture was stirred at 110°C for 2 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the target compound (1.4 g).

LCMS, m/z; 317 [M+H] ⁺

[0137]

Reference Example 25: 1-{[2-amino-4-(benzyloxy)phenyl]amino}-2-methylpropan-2-ol

The target compound (0.92 g) was prepared with the compound of Reference Example 24 (1.4 g) in the same manner as Reference Example 2.

LCMS, m/z; 287 [M+H] ⁺

[0138]

Reference Example 26: 3-({[4-(benzyloxy)-2-nitrophenyl]amino}methyl)oxetan-3-ol

The target compound (2.95 g) was prepared with 3-(aminomethyl)oxetan-3-ol (1.25 g) in the same manner as Reference Example 24.

LCMS, m/z; 331 [M+H] ⁺

[0139]

Reference Example 27: 3-({[2-amino-4-(benzyloxy)phenyl]amino}methyl)oxetan-3-ol

The target compound (1.2 g) was prepared with the compound of Reference Example 26 (2.92 g) in the same manner as Reference Example 2.

LCMS, m/z; 301 [M+H] ⁺

[0140]

Reference examples 28, 29 and 30:

The compounds of Reference Examples 28, 29 and 30 shown below were prepared with each respective starting material in the same manner as in Reference Example 21.

Reference example Structure Raw material LC–MS, m/z 28 Reference Example 23 285[M] ⁺ ,
287 [M+2] ⁺ 29 Reference Example 25 313 [M+H] ⁺ thirty Reference Example 27 327 [M+H] ⁺

[0141]

Reference Example 31: 5-hydroxy-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one

To a solution of the compound of Reference Example 29 (750 mg) in methanol (6 ml) was added 10% palladium on carbon (375 mg), and the mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction solution was filtered through Celite and concentrated in vacuo to give the title compound (521 mg).

LCMS, m/z; 223 [M+H] ⁺

[0142]

Reference Example 32: 5-hydroxy-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one

The target compound (0.43 g) was prepared with the compound of Reference Example 30 (1.1 g) in the same manner as Reference Example 31.

LCMS, m/z; 237 [M+H] ⁺

[0143]

Reference Example 33: 1-(2-hydroxy-2-methylpropyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H- benzimidazol-2-one

To a solution of the compound of Reference Example 21 (124 mg) in dioxane (2 ml) was added bis(pinacolate)diborone (166 mg), potassium carbonate (85 mg) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II). chloride (35.5 mg), and the mixture was stirred at 110°C for 3 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (chloroform/methanol) to give the target compound (123 mg).

LCMS, m/z; 333 [M+H] ⁺

[0144]

Reference Example 34: (3S)-3-amino-2-methylbutan-2-ol hydrochloride

To a solution of N-α-tert-butoxycarbonyl-L-alanine methyl ester (5.0 g) in diethyl ether (80 ml) was added methylmagnesium bromide (29.5 ml, in diethyl ether (3 mol/l)) in a bath of ice and the mixture was stirred for 30 minutes. And then the reaction mixture was warmed to room temperature and stirred for 3 hours. Ethyl acetate and an aqueous ammonium chloride solution were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo.

The resulting compound (5.4 g) was dissolved in ethyl acetate (40 ml) and a solution of 4 mol/L hydrochloric acid/1,4-dioxane (7.5 ml) was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated in vacuo, and toluene was added to the residue. The toluene solution was concentrated in vacuo. The procedure was repeated 3 times. The resulting residue was purified by trituration with hexane and ethyl acetate to give the title compound (3.08 g).

¹ H–NMR (400 MHz, DMSO–D6) δ: 1.07 (3H, s), 1.11 (3H, d, J=6.8 Hz), 1.15 (3H, s), 2, 98 (1H, k, J=6.8, 14 Hz), 5.11 (1H, s), 7.76 (3H, br).

[0145]

Reference Example 35: (3S)-2-methyl-3-[(2-nitro-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]butan-2-ol

The target compound (500 mg) was prepared with the compound of Reference Example 34 (300 mg) and 2-fluoro-5-(trifluoromethyl)pyridine (0.337 ml) in the same manner as Reference Example 1.

LCMS, m/z; 386 [M+H] ⁺

[0146]

Reference Example 36: (3S)-3-[(2-amino-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)amino]-2-methylbutan-2-ol

To a solution of the compound of Reference Example 35 (26.1 g) in methanol (250 ml) was added hydrochloric acid (67.7 ml, 5 M). And zinc (440 mg) was gradually added at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite and concentrated in vacuo. A saturated aqueous solution of Rochelle salt and ethyl acetate were added to the resulting residue, and the desired product was extracted in an organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by aminosilica gel column chromatography (chloroform/methanol) to give the target compound (22.4 g).

LCMS, m/z; 356 [M+H] ⁺

[0147]

Reference Example 37: (3S)-3-{[5-(4-fluorophenoxy)-2-nitrophenyl]amino}-2-methylbutan-2-ol

To a solution of 2,4-difluoronitrobenzene (316 mg) in NMP (4 ml), the compound of Reference Example 34 (305 mg) and diisopropylethylamine (1.04 ml) were added, and the mixture was stirred at room temperature for 3 hours. 4-Fluorophenol (334 mg) and cesium carbonate (971 mg) were added to the reaction solution, and the mixture was stirred at 100°C for 8 hours. The reaction solution was cooled to room temperature, and water and ethyl acetate were added to the reaction solution. The desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the target compound (545 mg).

LCMS, m/z; 335 [M+H] ⁺

[0148]

Reference Example 38: (3S)-3-{[2-amino-5-(4-fluorophenoxy)phenyl]amino}-2-methylbutan-2-ol

To a solution of the compound of Reference Example 37 (545 mg) in methanol (8 ml) was added 10% palladium-carbon (100 mg), and the mixture was stirred under a hydrogen atmosphere for 6 hours. The reaction solution was filtered through Celite and concentrated in vacuo to give the title compound (485 mg).

LCMS, m/z; 305 [M+H] ⁺

[0149]

Reference Example 39: cis-4-{[5-(4-fluorophenoxy)-2-nitrophenyl]amino}cyclohexanol

The target compound (755 mg) was prepared with cis-4-aminocyclohexanol hydrochloride (415 mg) in the same manner as Reference Example 37.

LCMS, m/z; 347 [M+H] ⁺

[0150]

Reference Example 40: cis-4-{[2-amino-5-(4-fluorophenoxy)phenyl]amino}cyclohexanol

The target compound (625 mg) was prepared with the compound of Reference Example 39 (755 mg) in the same manner as Reference Example 38.

LCMS, m/z; 317 [M+H] ⁺

[0151]

Examples 1–11:

The compounds of Examples 1–11 shown below were prepared with each respective starting material in the same manner as in Reference Example 21.

Example R ^A – R ^B – Raw material Spectral data 1 Reference example 2 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.11 (6H, s), 3.64 (2H, s), 4.55 (1H, s), 6.77 (1H, dd, J=8.4, 2.4 Hz), 6.97 (1H, d, J=8.4 Hz), 7.13–7.15 (2H, m), 8.18 (1H, dd, J=9.2, 2.4 Hz), 8.54–8.55 (1H, m), 10.89 (1H, s). 2 Reference Example 12 ¹ H–NMR (400 MHz, DMSO–D6) δ: 4.11 (2H, s), 4.45 (2H, d, J=6.8 Hz), 4.62 (2H, d, J=6.8 Hz), 6.05 (1H, s ), 6.85–6.88 (1H, m), 7.06 (1H, d, J=8.4 Hz), 7.16 (1H, d, J=2.4 Hz), 7.22 (1H, d, J=8.4 Hz), 8.26 (1H , dd, J=9.2, 2.4 Hz), 8.61–8.62 (1H, m), 11.06 (1H, s). 3 Reference Example 13 ¹ H–NMR (400 MHz, DMSO–D6) δ: 4.06 (2H, s), 4.38 (2H, d, J=6.8 Hz), 4.54 (2H, d, J=6.8 Hz), 5.99 (1H, s ), 6.83 (1H, dd, J=8.0, 2.4 Hz), 7.02 (1H, d, J=8.4 Hz), 7.13 (1H, d, J=2.4 Hz), 7.42–7.45 (1H, m), 7.84 (1H, d, J=8.4 Hz), 8.49 (1H, d, J=2.4 Hz), 11.03 (1H, s). 4 Reference Example 14 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.39–1.42 (2H, m), 1.53–1.57 (2H, m), 1.74–1.77 (2H, m), 2.38–2.42 (2H, m), 3.83–3.86 (1H, m),4.13–4.20 (1H, m), 4.46 (1H, d, J=3.2 Hz), 6.78 (1H, dd, J=8.8, 2.4 Hz), 6.99 (1H, d, J=8.0 Hz), 7.08 (1H, d, J=2.4 Hz), 7.17 (1H, d, J=8.0 Hz), 8.19 (1H, dd, J=12.0, 2.8 Hz), 8.55–8.56 (1H, m), 10.89 (1H, s). 5 Reference Example 15 ¹ H–NMR (400 MHz, DMSO–D6) δ: 4.04 (2H, s), 4.38 (2H, d, J=6.8 Hz), 4.54 (2H, d, J=6.8 Hz), 5.97 (1H, s ), 6.69–6.72 (1H, m), 6.96–7.01 (3H, m), 7.04 (1H, d, J=2.4 Hz), 7.30–7.33 (2H, m), 10.95 (1H, s). 6 Reference Example 16 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.10 (6H, s), 3.63 (2H, s), 4.59 (1H, s), 6.62 (1H, dd, J=8.4, 2.4 Hz), 6.92 –6.96 (3H, m), 7.04 (1H, d, J=2.4 Hz), 7.12–7.19 (2H, m), 10.84 (1H, s). 7 Reference example17 ¹ H–NMR (400 MHz, DMSO–D6) δ: 4.02 (2H, s), 4.37 (2H, d, J=6.8 Hz), 4.54 (2H, d, J=6.8 Hz), 5.98 (1H, s ), 6.64 (1H, d, J=8.4, 2.4 Hz), 6.93–6.98 (4H, m), 7.14–7.18 (2H, m), 10.92 (1H, s). 8 Reference example18 ¹ H–NMR (400 MHz, DMSO–D6) δ: 4.03 (2H, s), 4.37 (2H, d, J=6.8 Hz), 4.54 (2H, d, J=6.8 Hz), 5.98 (1H, s ), 6.67–6.70 (1H, m), 6.91–6.95 (2H, m), 6.96 (1H, d, J=8.4 Hz), 7.00 (1H, d, J=2.4 Hz), 7.34–7.38 (2H, m), 10.94 (1H, s). 9 Reference example36 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.21 (3H, s), 1.33 (3H, s), 1.55 (3H, d, J=7.3 Hz), 4.05 (1H, br), 6.87 (1H, dd, J=8.5, 2.4 Hz), 6.96 (1H, s), 7.01 (1H, d, J=9.1 Hz), 7.09 (1H, d, J=8.5 Hz), 7.89 (1H, dd, J=8.5, 2.4 Hz), 8.41 (1H, d, J=2.4 Hz), 9.03 (1H, s). 10 Reference example38 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.19 (3H, s), 1.33 (3H, s), 1.54 (3H, d, J=7.3 Hz), 4.00 (1H, br), 6.71 (1H, dd, J=8.5, 2.4 Hz), 6.81 (1H, sb), 6.89–6.94 (2H, m), 6.97–7.03 (3H, m), 9.52 (1H, s). eleven Reference example40 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.42 (1H, d, J=3.0 Hz), 1.62–1.73 (4H, m), 1.94 (2H, d, J=13.4 Hz), 2.46–2.57 (2H, m), 4.12 (1H, d, J=2.4 Hz), 4.28–4.38 (1H, m), 6.64 (1H, dd, J=8.5, 2.4 Hz), 6.89–7.01 (5H, m), 7.02 (1H, d, J=2.4 Hz), 9.15 (1H, s).

[0152]

Example 12: 1-ethyl-3-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one

To a solution of the compound of Example 1 (100 mg) in DMSO (1 ml) was added sodium hydride (13.1 mg), and the mixture was stirred for 1 hour. Next, ethyl iodide (37 μL) was added to the reaction mixture, and the mixture was stirred at 60°C for 4 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the target compound (93 mg).

LCMS, m/z; 396 [M+H] ⁺ (RT 0.934 min.)

¹ H–NMR (400 MHz, DMSO–D6) δ: 1.10 (6H, s), 1.22 (3H, t, J=7.0 Hz), 3.68 (2H, s), 3, 89 (2H, k, J=14.0, 6.8 Hz), 4.57 (1H, s), 6.86 (1H, dd, J=8.4, 2.4 Hz), 7.15 –7.22 (3H, m), 8.19 (1H, dd, J=8.4, 2.4 Hz), 8.53–8.55 (1H, m).

[0153]

Example 13: 3-(2-hydroxy-2-methylpropyl)-1-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one

The target compound (133 mg) was prepared with the compound of Example 1 (180 mg) and methyl iodide (61 μl) in the same manner as Example 12.

LCMS, m/z; 382 [M+H] ⁺ (RT 0.803 min.)

¹ H–NMR (400 MHz, DMSO–D6) δ: 1.23 (6H, s), 3.44 (3H, s), 3.84 (2H, s), 6.88–6.91 (1H , m), 6.95 (1H, d, J=2.4 Hz), 6.99 (1H, d, J=2.8 Hz), 7.01 (1H, d, J=2.8 Hz ), 7.88 (1H, dd, J=8.8, 2.8 Hz), 8.38–8.39 (1H, m).

[0154]

Examples 14–18:

The compounds of Examples 14–18 shown below were prepared with each respective starting material in the same manner as in Example 13.

Example R ^A – R ^B – Raw material Spectral data 14 Example 2 ¹ H–NMR (400 MHz, DMSO–D6) δ: 3.36 (3H, s), 4.09 (2H, s), 4.38 (2H, d, J=6.8 Hz), 4.56 (2H, d, J=6.8 Hz ), 5.97 (1H, s), 6.89 (1H, dd, J=8.8, 2.4 Hz), 7.15 (1H, d, J=2.4 Hz), 7.17 (2H, d, J=8.8 Hz), 8.18 –8.21 (1H, m), 8.53–8.54 (1H, m). 15 Example 3 ¹ H–NMR (400 MHz, DMSO–D6) δ: 3.36 (3H, s), 4.11 (2H, s), 4.38 (2H, d, J=6.8 Hz), 4.55 (2H, d, J=6.8 Hz ), 5.99 (1H, s), 6.92–6.95 (1H, m), 7.19 (1H, d, J=2.4 Hz), 7.21 (1H, d, J=8.4 Hz), 7.44 (1H, dd, J= 8.8, 2.4 Hz), 7.85 (1H, d, J=8.4 Hz), 8.49 (1H, d, J=2.4 Hz). 16 Example 7 ¹ H–NMR (400 MHz, DMSO–D6) δ: 3.30 (3H, s), 4.08 (2H, s), 4.37 (2H, d, J=6.4 Hz), 4.54 (2H, d, J=6.4 Hz ), 5.97 (1H, s), 6.74 (1H, dd, J=8.4, 2.4 Hz), 6.93–6.97 (2H, m), 7.03–7.04 (1H, m), 7.12 (1H, d, J=8.4 Hz), 7.14–7.18 (2H, m). 17 Example 5 ¹ H–NMR (400 MHz, DMSO–D6) δ: 3.35 (3H, s), 4.09 (2H, s), 4.38 (2H, d, J=6.8 Hz), 4.55 (2H, d, J=6.8 Hz ), 5.97 (1H, s), 6.81 (1H, dd, J=8.0, 2.4 Hz), 6.98–7.02 (2H, m), 7.10 (1H, d, J=2.4 Hz), 7.16 (1H, d, J=8.4 Hz), 7.31–7.33 (2H, m). 18 Example 8 ¹ H–NMR (400 MHz, DMSO–D6) δ: 3.34 (3H, s), 4.09 (2H, s), 4.37 (2H, d, J=6.4 Hz), 4.54 (2H, d, J=6.4 Hz ), 5.97 (1H, s), 6.78 (1H, dd, J=8.8, 2.4 Hz), 6.92–6.94 (2H, m), 7.06 (1H, d, J=2.8 Hz), 7.14 (1H, d, J=8.8Hz), 7.35–7.38 (2H, m).

[0155]

Example 19: 1-(2-hydroxy-2-methylpropyl)-6-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one

The compound of Reference Example 21 (100 mg) was dissolved in a solvent of distilled water (0.5 ml) and 1,4-dioxane (1.5 ml) and tetrakis(triphenylphosphine) palladium (0) (40.5 mg) was added. 2-(trifluoromethyl)pyridin-5-ylboronic acid (100 mg) and potassium carbonate (145 mg). The mixture was stirred at 100°C for 6 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by aminosilica gel column chromatography (chloroform/methanol) and trituration with hexane and ethyl acetate to give the target compound (48 mg).

LCMS, m/z; 352 [M+H] ⁺ (RT 0.802 min.)

¹ H–NMR (400 MHz, DMSO–D6) δ: 1.15 (6H, s), 3.77 (2H, s), 4.67 (1H, s), 7.10 (1H, d, J =7.9 Hz), 7.42 (1H, dd, J=7.9, 1.8 Hz), 7.71 (1H, d, J=1.8 Hz), 7.95 (1H, d , J=8.5 Hz), 8.29 (1H, dd, J=8.5, 2.4 Hz), 9.05 (1H, d, J=2.4 Hz), 11.05 (1H , With).

[0156]

Example 20: 1-(2-hydroxy-2-methylpropyl)-6-[5-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one

The compound of Reference Example 33 (123 mg) was dissolved in a solvent of distilled water (1 ml) and 1,4-dioxane (3 ml) and tetrakis(triphenylphosphine) palladium (0) (42.8 mg), 2-bromo- 5-(trifluoromethyl)pyridine (126 mg) and potassium carbonate (154 mg). The mixture was stirred at 100°C for 6 hours. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by aminosilica gel column chromatography (chloroform/methanol) and trituration with hexane and ethyl acetate to give the target compound (64 mg).

LCMS, m/z; 352 [M+H] ⁺ (RT 0.848 min.)

¹ H–NMR (400 MHz, DMSO–D6) δ: 1.16 (6H, s), 3.76 (2H, s), 4.70 (1H, s), 7.08 (1H, d, J =8.2 Hz), 7.84 (1H, dd, J=8.2, 1.8 Hz), 8.05 (1H, d, J=1.8 Hz), 8.12 (1H, d , J=8.5 Hz), 8.22 (1H, dd, J=8.5, 1.8 Hz), 8.97 (1H, s), 11.09 (1H, s).

[0157]

Examples 21–24:

The compounds of Examples 21–24 shown below were prepared with each respective starting material in the same manner as in Example 19.

Example Structure Raw material Spectral data 21 Reference Example 21 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.15 (6H, s), 3.76 (2H, s), 4.68 (1H, s), 7.06 (1H, d, J=7.9 Hz), 7.34 (1H , dd, J=8.2, 1.5 Hz), 7.63 (1H, d, J=1.8 Hz), 7.77–7.85 (4H, m), 10.98 (1H, s). 22 Reference Example 21 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.15 (6H, s), 3.74 (2H, s), 4.67 (1H, s), 7.01 (1H, d, J=7.9 Hz), 7.20–7.29 (3H, m), 7.52 (1H, d, J=1.8 Hz), 7.61–7.65 (2H, m), 10.89 (1H, s). 23 Reference Example 28 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.14 (6H, s), 3.72 (2H, s), 4.67 (1H, s), 7.33–7.45 (3H, m), 7.92 (1H, d, J=8.5 Hz), 8.30 (1H, dd, J=8.5, 2.4 Hz), 9.04 (1H, d, J=1.8 Hz), 11.08 (1H, s). 24 Reference Example 28 ¹ H–NMR (400 MHz, DMSO–D6) δ: 1.14 (6H, s), 3.69 (2H, s), 4.65 (1H, s), 7.14 (1H, d, J=1.8 Hz), 7.22–7.30 (4H, m), 7.60–7.64 (2H, m), 10.93 (1H, s).

[0158]

Example 25: 1-(2-hydroxy-2-methylpropyl)-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one

The compound of Reference Example 31 (50 mg) was dissolved in DMF (1 ml) and (4-(trifluoromethoxy)phenyl)boronic acid (139 mg), triethylamine (94 μl) and copper acetate (12.3 mg) were added. The mixture was stirred at 80°C for 9 hours in the open air. Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the target compound (8 mg).

LCMS, m/z; 383 [M+H] ⁺ (RT 0.866 min.)

¹ H–NMR (400 MHz, DMSO–D6) δ: 1.16 (6H, s), 3.71 (2H, s), 4.65 (1H, s), 6.48 (1H, d, J =2.4 Hz), 6.52 (1H, dd, J=8.8, 2.4 Hz), 7.16 (1H, d, J=8.4 Hz), 7.29–7.31 (1H, m), 7.55–7.58 (2H, m), 7.66–7.68 (1H, m), 9.10 (1H, s).

[0159]

Example 26: 1-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one

To a solution of the compound of Reference Example 31 (50 mg) in NMP (1 ml), 2-fluoro-5-(trifluoromethyl)pyridine (45 mg) and cesium carbonate (110 mg) were added, and the mixture was stirred at 110°C for 4 hours. . Water and ethyl acetate were added to the reaction solution, and the desired product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the target compound (9.0 mg).

LCMS, m/z; 368 [M+H] ⁺ (RT 0.734 min.)

¹ H–NMR (400 MHz, DMSO–D6) δ: 1.14 (6H, s), 3.68 (2H, s), 4.66 (1H, s), 6.79–6.80 (2H , m), 7.16 (1H, d, J=8.4 Hz), 7.24–7.26 (1H, m), 8.18 (1H, dd, J=8.8, 2.4 Hz), 8.54–8.55 (1H, m), 10.93 (1H, s).

[0160]

Example 27: 1-[(3-hydroxyoxetan-3-yl)methyl]-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one

The target compound (31 mg) was prepared with the compound of Reference Example 32 (150 mg) in the same manner as Example 25.

LCMS, m/z; 397 [M+H] ⁺ (RT 0.893 min.)

¹ H–NMR (400 MHz, DMSO–D6) δ: 4.11 (2H, s), 4.43 (2H, d, J=6.8 Hz), 4.60 (2H, d, J=6 .8 Hz), 6.07 (1H, s), 6.48 (1H, d, J=2.4 Hz), 6.52–6.55 (1H, m), 7.13 (1H, d , J=8.4 Hz), 7.56–7.59 (2H, m), 7.67–7.69 (2H, m), 9.13 (1H, s).

[0161]

Example 28: 1-[(3-hydroxyoxetan-3-yl)methyl]-3-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one

The target compound (12 mg) was prepared with the compound of Example 27 (50 mg) in the same manner as Example 13.

LCMS, m/z; 411 [M+H] ⁺ (RT 1.068 min)

¹ H–NMR (400 MHz, DMSO–D6) δ: 3.70 (3H, s), 4.15 (2H, s), 4.44 (2H, d, J=6.8 Hz), 4.601 ( 2H, d, J=6.8 Hz), 6.09 (1H, s), 6.63 (1H, d, J=2.4 Hz), 6.73 (1H, dd, J=8.8 , 2.4 Hz), 7.26 (1H, d, J=8.8 Hz), 7.56 (2H, d, J=8.4 Hz), 7.70–7.72 (2H, m ).

[0162]

Pharmacological test

Measurement of Na ion current in a cell expressing the voltage-gated Na channel gene

Nav 1.7 current was measured in an automated voltage clamp test using cells stably expressing human SCN9A.

[0163]

Cells stably expressing human SCN9A

Tetracycline-induced cells stably expressing SCN9A were obtained from ChanTest Corporation. Cells were passaged in Ham's F-12 medium containing 10% fetal bovine serum, 100 units/ml penicillin-streptomycin, 0.01 mg/ml blasticidin and 400 μg/ml zeocin. Cells seeded on a glass plate were cultured in Ham's F-12 medium containing 1 µg/ml tetracycline, 1 µg/l sodium butyrate, 10% fetal bovine serum and 100 units/ml penicillin-streptomycin. The next day, Na ion current was measured by an automated voltage clamp test.

[0164]

Electrophysiological measurement of Na ion current

Na ion current was measured by an automated voltage clamp test using the following extracellular solution and intracellular solution.

[0165]

Extracellular solution (mmol/l): NaCl 130, MgCl2 2, CaCl2 2, CdCl2 0.1, NiCl2 0.1, Tetraethylammonium-Cl 18, 4-aminopyridine 1, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid) 10, (pH 7.4 with NaOH)

[0166]

Intracellular solution (mmol/L): CsF 120, EGTA (ethylene glycol tetraacetic acid) 10, NaCl 15, HEPES 10, (pH 7.2 with CsOH)

[0167]

Stimulus control and data acquisition were performed using an EPC10 amplifier and Patch Master Software (HEKA). Data were collected at 10 kHz and low-pass filtered at 2.9 kHz. All measurements were carried out at room temperature. The baseline potential was set at the 50% Nav 1.7 channel inactivating potential (approximately –60 mV), and a 20 millisecond depolarizing pulse (approximately 0 mV) was given at 10 Hz 30 times. The degree of inhibition of test compounds was calculated based on the results of cells whose maximum current was 500 Pa or more when the first stimulating pulse was applied and whose whole cell parameter did not vary significantly until the end of data acquisition. The degree of inhibition of the test compounds on Na ion current was calculated according to the following calculation formula with the peak current value generated based on the 30th depolarization pulse.

Na current inhibition rate (%) = 100 x [(Peak current value in the absence of the Test Compound) – (Peak current value in the presence of the Test Compound)] / (Peak current value in the absence of the Test Compound)

[0168]

Result:

The degree of inhibition of the Na ion current was assessed for the compounds of each of the Examples. The results showed that the compounds of the present invention exhibit an inhibitory effect on Nav 1.7. The degree of inhibition (%) at which the concentration of each compound is 10 μmol/L is shown in the following table.

Example Inhibition rate (%) Example Inhibition rate (%) Example Inhibition rate (%) 1 33 2 26 3 22 4 39 5 86 6 40 7 40 8 80 9 27 10 50 eleven 65 12 14 13 38 14 39 15 46 16 61 17 87 18 86 19 8 20 29 21 96 22 43 23 36 24 45 25 42 26 32 27 38 28 39

Industrial applicability

[0169]

The compounds of the present invention can be used as a medicament for the treatment of a disease involving Nav 1.7, for example, neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria and multiple sclerosis. Thus, the compounds of the present invention can be very useful pharmaceutical agents.

Claims (80)

1. Compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein R ^1a and R ^1d independently represent hydrogen, one of R ^1b and R ^1c denotes C ₆ aryl, C ₆ aryloxy, 6-membered heteroaryl or 6-membered heteroaryloxy, wherein the aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted with 1-3 substituents selected independently from the group consisting of halogen, methyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and methoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A; and the other R ^1b or R ^1c is hydrogen, R ⁴ is hydrogen, methyl or ethyl; m=1, L stands for CR ⁷ R ⁸ , R ⁷ and R ⁸ are independently hydrogen or methyl, R ² and R ³ are methyl, or in ^R2 , ^R3 and the hydroxyl group bonded to the carbon atom bonded to ^R2 and ^R3 , R ² and R ³ can, together with the carbon atom to which they are attached, form the following group of formula (II) with a hydroxyl group in formula (II), e and f stand for 1, V stands for oxygen atom, R ^5a , R ^5b , R ^5c and R ^5d are hydrogen, or in R ² , R ³ , a hydroxyl group bonded to the carbon atom bonded to R ² and R ³ , and CR ⁷ R ⁸ in L, R ² and R ⁷ may, together with the carbon atom to which they are attached, form the following group of formula (III) with R ³ , a hydroxyl group and R ⁸ in formula (III), m ¹ =0, m ² = 2, and j = 2, R ⁸ and L have the meanings defined above, R ^6a , R ^6b , R ^6c and R ^6d are hydrogen, Substituent group A is independently halogen, provided that the following compounds are excluded: 5-(2-butyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-1-1,3-dihydro-2H-benzimidazol-2-one ( 2-hydroxyethyl), 3-[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile, and 3-[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile . 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ^1b denotes C ₆ aryl, C ₆ aryloxy, 6-membered heteroaryl or 6-membered heteroaryloxy, wherein the aryl and aryl group in aryloxy and the heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted by 1-3 substituents independently selected from the group consisting from halogen, methyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and methoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A; and R ^1c is hydrogen. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ^1c denotes C ₆ aryl, C ₆ aryloxy, 6-membered heteroaryl or 6-membered heteroaryloxy, wherein the aryl and aryl group in aryloxy and the heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted by 1-3 substituents independently selected from the group consisting from halogen, methyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and methoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A; and R ^1b is hydrogen. 4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds: 1-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 1-[(3-hydroxyoxetan-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 1-[(3-hydroxyoxetan-3-yl)methyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 1-(cis-4-hydroxycyclohexyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 1-[(3-hydroxyoxetan-3-yl)methyl]-6-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-fluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-fluorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-chlorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one, 1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazole-2- He, 6-(4-fluorophenoxy)-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-fluorophenoxy)-1-(cis-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one, 1-ethyl-3-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 3-(2-hydroxy-2-methylpropyl)-1-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one , 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one , 5-(4-fluorophenoxy)-3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, 5-(4-chlorophenoxy)-3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-6-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-6-[5-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one, 5-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 1-[(3-hydroxyoxetan-3-yl)methyl]-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, and 1-[(3-hydroxyoxetan-3-yl)methyl]-3-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one. 5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds: 1-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, 1-[(3-hydroxyoxetan-3-yl)methyl]-6-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-chlorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-fluorophenoxy)-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-1,3-dihydro-2H-benzimidazol-2-one, 6-(4-fluorophenoxy)-1-(cis-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one, 3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-6-[5-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one, 5-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one, 1-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, and 1-[(3-hydroxyoxetan-3-yl)methyl]-3-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one. 6. A pharmaceutical composition for the treatment of a disease involving Nav 1.7 (SCN9A), containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-5 or its pharmaceutically acceptable salts and pharmaceutically acceptable additives. 7. A medicament for the treatment of a disease involving Nav 1.7 (SCN9A), comprising a therapeutically effective amount of a compound according to any one of claims. 1-5 or a pharmaceutically acceptable salt thereof as the active ingredient. 8. The drug according to claim 7, wherein the disease involving Nav 1.7 (SCN9A) is selected from the group consisting of neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or dissipation sclerosis. 9. Use of the connection according to any one of paragraphs. 1-5 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease involving Nav 1.7 (SCN9A) selected from the group consisting of neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder , dysuria or multiple sclerosis. 10. A method of treating a disease involving Nav 1.7 (SCN9A) selected from neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis, comprising administering a therapeutically effective amount of a compound of any from paragraphs. 1-5 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.