RU2804319C2 - Deuterized benzimidazole compound and its medical use - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, a pharmaceutical composition and a drug based on it for the treatment of a disease in which Nav 1.7 (SCN9A) is involved, selected from neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or multiple sclerosis, as well as a method of treating such diseases using it. In general formula (I), R^1a, R^1c and R^1d are hydrogen, R^1b is C₆ aryl, C₆ aryloxy or 6-membered heteroaryloxy, wherein the aryl and aryl group in aryloxy and the heteroaryl group in heteroaryloxy may be independently substituted with 1–2 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 substituents independently selected from Substituent Group A; R⁴ is hydrogen, m=0 or 1, L is CR⁷ R⁸, R⁷ and R⁸ are hydrogen; or R² and R³ are methyl or together with the carbon atom to which they are attached form a group of formula (II) with -OR⁴ ; in formula (II), e and f are 1, R⁴ is as defined above, V is an oxygen atom, R^5a, R^5b, R^5c and R^5d are hydrogen, Substituent Group A is independently halogen, and any 1–6 atoms of hydrogen in the compound of formula (I) may be replaced by deuterium atoms.

EFFECT: obtaining a deuterized benzimidazole compound.

11 cl, 5 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 benzimidazole 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, Nav channel 1.7 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 the experiment with knockout (Non-Patent Literature 2).

[0004]

Patent Literature 1 discloses a benzimidazole derivative represented by the following formula (A), but the compound has 2-(4-cyclopropylpyridin-2-yl)amino)isonicotinonitrile as a significant partial structure different from the compound of the present invention. And the invention described in Patent Literature 1 is directed to a Syk tyrosine kinase inhibitor, so Patent Literature 1 does not disclose the present invention at all.

[0005]

Patent Literature 2 discloses a benzimidazole derivative represented by the following formula (B), which relates to Nav 1.7 inhibitors, but this compound has 2-(benzimidazol-1-yl)acetamide as a significant partial structure different from the compound of the present invention.

BACKGROUND OF THE ART

[Patent Literature]

[0006]

[Patent Literature 1] WO 2012/057262

[Patent Literature 2] WO 2016/117647

[Non-Patent Literature]

[0007]

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

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

The essence of the invention

[0008]

(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 .

[0009]

(The solution of the problem)

The inventors of the present invention have conducted intensive studies in an attempt to solve the above-mentioned problem and have found that a compound having the benzimidazole 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 cell expressing the Nav 1.7 gene, i.e. That is, 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 benzimidazole 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, or a benzimidazole 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 "the compound of the present invention").

[0010]

The present invention can be illustrated as follows.

(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, cyano, C _1–4 alkyl, C _1–4 alkoxy, C _1–4 alkylamino (and the alkyl and alkyl group in alkoxy and alkylamino can be independently substituted with 1-5 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 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 1–3 substituents selected independently from Substituent Group B), C _3–7 cycloalkyl, C _3–7 cycloalkoxy, C _3–7 cycloalkylamino (and the cycloalkyl and cycloalkyl group in cycloalkoxy and cycloalkylamino can be independently substituted by 1–5 substituents independently selected 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 independently selected 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 the heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted by 1–5 substituents chosen 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 the Group substituents 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, 3–7 -membered non-aromatic heterocyclyl, optionally substituted with 1-3 substituents independently selected from Substituent Group B, C _1-4 alkylthio, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkylsulfonyl, 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,

^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,

^R4 is hydrogen, _C1-6 alkyl (which may be substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl group, _C1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent groups 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) or C _3-7 cycloalkyl (which may 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, 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 independently selected from Substituent Group B),

m=0, 1 or 2,

L denotes CR ⁷ R ⁸ with the proviso that when m is 2, 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 R ² , R ³ and –OR ⁴ , R ² and R ³ can, together with the carbon atom to which they are attached, form the following group of formula (II) with –OR ⁴

in formula (II),

e and f independently represent 1, 2 or 3,

R ⁴ has the value defined above,

V stands for single bond or oxygen atom,

R ^5a , R ^5b , R ^5c , and R ^5d independently represent hydrogen, halogen, hydroxyl, C _1–4 alkyl, or C _1–4 alkoxy, wherein the alkyl and alkyl group in alkoxy may be independently substituted with 1–3 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 IN,

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, etc.

any 1 to 6 hydrogen atoms in a compound of formula (I) may be replaced by deuterium atoms.

[0011]

(Paragraph 1–1)

Compound of formula (I’):

or a pharmaceutically acceptable salt thereof, in which

E stands for hydrogen,

R ^1a , R ^1b , R ^1c and R ^1d independently denote hydrogen, halogen, cyano, C _1–4 alkyl, C _1–4 alkoxy, C _1–4 alkylamino (and the alkyl and alkyl group in alkoxy and alkylamino can be independently substituted 1-5 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 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 , selected independently from Group of substituents B), C _3–7 cycloalkyl, C _3–7 cycloalkoxy, C _3–7 cycloalkylamino (wherein the cycloalkyl and cycloalkyl group in cycloalkoxy and cycloalkylamino can be independently substituted by 1–5 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, 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 independently selected 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 the heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted by 1–5 substituents, independently selected from 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, 3–7– member non-aromatic heterocyclyl, optionally substituted with 1-3 substituents independently selected from Substituent Group B, C _1-4 alkylthio, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkylsulfonyl, in 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,

^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,

^R4 is hydrogen, _C1-6 alkyl (which may be substituted with 1-3 substituents independently selected from the group consisting of halogen, hydroxyl group, _C1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent groups 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) or C _3-7 cycloalkyl (which may 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, 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 independently selected from Substituent Group B),

m=0, 1 or 2,

L denotes CR ⁷ R ⁸ with the proviso that when m is 2, 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 R ² , R ³ and –OR ⁴ , R ² and R ³ can, together with the carbon atom to which they are attached, form the following group of formula (II) with –OR ⁴

in formula (II),

e and f independently represent 1, 2 or 3,

R ⁴ has the value defined above,

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 ,

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

any 1 to 8 hydrogen atoms in a compound of formula (I') are replaced by deuterium atoms.

[0012]

(Paragraph 1–2)

The compound of Clause 1 or Clause 1-1 or a pharmaceutically acceptable salt thereof, provided that the following compounds having a deuterium atom instead of a hydrogen atom as previously defined are excluded:

6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-methoxyethyl)-1H-benzimidazole,

2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-yl]ethanol,

2-{5-[5-(tetrahydrofuran-3-yl)-4H-1,2,4-triazol-3-yl]-1H-benzimidazol-1-yl}ethanol,

2-{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol ,

2-{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol,

2-butyl-6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,

6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one,

2-{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-1,2,4-triazol-1-yl}ethanol,

6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H-benzimidazole-7-carbonitrile,

2-chloro-6-{7-fluoro-1-[(1S,3S)-3-methoxycyclohexyl]-1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)-9H- purine, and

2-{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-benzimidazol-1-yl}ethanol.

[0013]

(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, cyano, 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, 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, and C _1-4 alkylsulfonyl, optionally substituted with 1-3 substituents selected independently from Substituent Group A).

[0014]

(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, 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.

[0015]

(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.

[0016]

(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).

[0017]

(Clause 6)

The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R ^1a , R ^1c and R ^1d are hydrogen.

[0018]

(Clause 7)

A compound according to any one of Claims 1 to 6, 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 (and 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, _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 Alternate Group A).

[0019]

(Clause 8)

A compound according to any one of Claims 1 to 7, 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 cyano, halogen, hydroxyl group and C _1-4 alkoxy, optionally substituted with 1 –3 substituents independently selected from Substituent Group A, provided that both ^R2 and ^R3 are not hydrogen, or

R ² and R ³ may, together with the carbon atom to which they are attached, form the following group of formula (IIa) with –OR ⁴

in formula (IIa),

e and f independently denote 1 or 2,

R ⁴ and V have the meanings defined in Clause 1, and

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

[0020]

(Clause 9)

A compound according to any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, in which

R ² and R ³ independently represent C _1–6 alkyl, optionally substituted with 1–5 identical or different halogen atoms, or

R ² and R ³ may, together with the carbon atom to which they are attached, form the following group of formula (IIb) with –OR ⁴

in formula (IIb),

e and f stand for 1,

R ⁴ is hydrogen,

V stands for oxygen atom,

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

[0021]

(Clause 10)

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

R ² and R ³ independently represent hydrogen or C _1-6 alkyl, optionally substituted with 1-5 identical or different halogen atoms, and R ² and R ³ together with the carbon atom to which they are attached do not form a ring.

[0022]

(Clause 11)

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

R ² and R ³ may, together with the carbon atom to which they are attached, form the following group of formula (IIb) with –OR ⁴

in formula (IIb),

e and f stand for 1,

R ⁴ is hydrogen,

V stands for oxygen atom,

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

[0023]

(Clause 12)

A compound according to any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, in which

R ⁴ is hydrogen, C _1-4 alkyl, optionally substituted with 1-3 identical or different halogen atoms, or C _3-7 cycloalkyl, which may be substituted with 1-3 substituents independently selected 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.

[0024]

(Clause 13)

The compound of any one of Clauses 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen.

[0025]

(Clause 14)

A compound according to any one of Claims 1 to 13, 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=0 or 1.

[0026]

(Clause 15)

The compound of any one of Clauses 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R ⁷ and R ⁸ are hydrogen and m=0 or 1.

[0027]

(Clause 16)

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

Example 1: 6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(1,1- ² H ₂ )propan-2-ol,

Example 2: 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)(1,1- ² H ₂ )propan-2-ol ,

Example 3: 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(4,4- ² H ₂ )butan-2-ol,

Example 4: 3-[{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}( ² H ₂ )methyl]oxetan-3-ol, and

Example 5: 3-[{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}( ^2H2 ₎ methyl]oxetan-3-ol.

[0028]

(Clause 17)

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

Example 1: 6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(1,1- ² H ₂ )propan-2-ol,

Example 2: 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)(1,1- ² H ₂ )propan-2-ol , And

Example 3: 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(4,4- ² H ₂ )butan-2-ol.

[0029]

(Clause 18)

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

Example 4: 3-[{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}( ² H ₂ )methyl]oxetan-3-ol, and

Example 5: 3-[{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}( ^2H2 ₎ methyl]oxetan-3-ol.

[0030]

(Clause 19)

A pharmaceutical combination comprising the Compound of any one of Clauses 1 to 18 or a pharmaceutically acceptable salt thereof.

[0031]

(Clause 20)

A medicament for the treatment of a disease involving Nav 1.7 (SCN9A), comprising the Compound of any one of Claims 1 to 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0032]

(Clause 21)

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 18 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0033]

(Clause 22)

A pharmaceutical combination comprising the Compound of any one of Clauses 1 to 18 or a pharmaceutically acceptable salt thereof and at least one drug selected from the group consisting of an antiepileptic drug, an antidepressant, a narcotic analgesic, an anti-inflammatory agent, a reductase inhibitor and a drug derivative prostaglandin.

[0034]

(Clause 23)

Use of a compound according to any of Clauses 1 to 18 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.

[0035]

(Clause 24)

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 18 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.

[0036]

(Clause 25)

Embodiments of Clauses 2-24, wherein the compounds defined in Clauses 2-24 do not include compounds excluded in Clauses 1-2.

[0037]

(Invention Effect)

The present invention relates to a Nav 1.7 blocker comprising a novel benzimidazole 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. Moreover, the present invention provides an excellent metabolically stable compound by introducing a deuterium atom at specific position(s) of the compound.

Description of Embodiments

[0038]

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".

[0039]

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.

[0040]

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

[0041]

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

[0042]

"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.

[0043]

"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".

[0044]

" _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.

[0045]

"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.

[0046]

"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.

[0047]

"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".

[0048]

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.

[0049]

“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.

[0050]

"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.

[0051]

"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.

[0052]

"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".

[0053]

"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.

[0054]

"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.

[0055]

"C _1-4 alkylamino" means an amino group substituted by one or two of the above "C _1-4 alkyl". "C _1-4 alkylamino" includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino and ethylmethylamino, and preferably methylamino and dimethylamino.

[0056]

"C _3-7 cycloalkylamino" means an amino group substituted with one or two of the above "C _3-7 cycloalkyl". "C _3-7 cycloalkylamino" includes, for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and dicyclopropylamino, and preferably cyclohexylamino.

[0057]

"C _1-4 alkylsulfonyl" means a sulfonyl group substituted by the above-mentioned "C _1-4 alkyl". "C _1-4 alkylsulfonyl" includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and butylsulfonyl, and preferably methylsulfonyl.

[0058]

"C _1-4 alkylthio" means a thio group substituted by the above "C _1-4 alkyl". "C _1-4 alkylthio" includes, for example, methylthio, ethylthio, propylthio, isopropylthio and butylthio, and preferably methylthio.

[0059]

"Any 1 to 6 hydrogen atoms in a compound of formula (I) can be replaced by deuterium atoms," or "any 1 to 8 hydrogen atoms in a compound of formula (I') are replaced by deuterium atoms" means that the hydrogen atoms in a compound of formula (I ) or (I') are replaced by deuterium atoms, as well as hydrogen atoms in the above C _1–6 alkyl, C _1–6 alkoxy, C _3–7 cycloalkyl, C _3–7 cycloalkoxy, 3–7-membered non-aromatic heterocyclyl, C _{6 –10} aryl, C _6–10 aryloxy, 5–12 membered heteroaryl, 5–12 membered heteroaryloxy, C _1–4 alkylthio or C _1–4 alkylsulfonyl are replaced by deuterium atoms. For example, this ^includes ( ^2H3 )methyl, ( ^{2H5 )} ethyl _{, (2H3)methoxy, (2H5 ) phenyl , (} ^2H5 )phenoxy, etc.

[0060]

For a more detailed disclosure of the compound of the invention of the above formula (I) or (I'), each symbol used in formula (I) or (I') is further explained below by way of preferred examples.

[0061]

In an embodiment, R ^1a , R ^1b , R ^1c and R ^1d are independently hydrogen, deuterium, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylamino (where alkyl and alkyl group in alkoxy and alkylamino may be independently substituted with 1-3 substituents independently selected from the group consisting of deuterium, 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, if necessary, substituted with 1–3 substituents selected independently from Substituent Group B), C _3–7 cycloalkyl, C _3–7 cycloalkoxy, C _3–7 cycloalkylamino (and the cycloalkyl and cycloalkyl group in cycloalkoxy and cycloalkylamino can be independently substituted with 1– 3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl group, C _1-4 alkyl, optionally substituted by 1-3 substituents independently selected from Substituent Group A, C _1-4 alkoxy, optionally substituted 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 (and aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy can be independently substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, cyano, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A and deuterium, C _1-4 alkoxy, in optionally substituted with 1–3 substituents selected independently from Substituent Group A and deuterium, C _3–7 cycloalkyl, optionally substituted with 1–3 substituents independently selected from Substituent Group B and deuterium, C _3–7 cycloalkoxy, optionally substituted with 1–3 substituents independently selected from Group B and deuterium, 3–7-membered non-aromatic heterocyclyl, optionally substituted with 1–3 substituents independently selected from Group B and deuterium, C _1–4 alkylthio, optional substituted with 1-3 substituents independently selected from Substituent Group A and deuterium, and C _1-4 alkylsulfonyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A and deuterium). 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.

[0062]

In another embodiment, R ^1a , R ^1b , R ^1c and R ^1d are independently hydrogen, halogen, cyano, C _1-4 alkyl, C _1-4 alkoxy (wherein the alkyl and alkyl group in alkoxy may be independently substituted 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 aryl and aryl group in aryloxy and heteroaryl and heteroaryl group in heteroaryloxy can 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, C _1-4 alkoxy, optionally substituted 1 -3 substituents independently selected from Substituent Group A, and C _1-4 alkylsulfonyl, 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.

[0063]

In another embodiment, among R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen; and R ^1b and R ^1c independently denote 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, _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 Substituent Group A). Provided that both R ^1b and R ^1c are not hydrogen.

[0064]

In another embodiment, among R ^1a , R ^1b , R ^1c and R ^1d , R ^1a and R ^1d are hydrogen; and any of R ^1b and R ^1c denotes C _6-10 aryl, C _6-10 aryloxy, 5-12-membered heteroaryl or 5-12-membered heteroaryloxy (wherein aryl and the aryl group in aryloxy and heteroaryl and the heteroaryl group in heteroaryloxy can be independently substituted with 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 1-3 substituents independently selected from Substituent Group A), and the other is hydrogen.

[0065]

In another embodiment, among R ^1a , R ^1b , R ^1c and R ^1d , R ^1a , R ^1c and R ^1d are hydrogen, and R ^1b is 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 selected independently from the group consisting of halogen, C _1–4 alkyl, if necessary substituted 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).

[0066]

Preferred examples of R ^1a , R ^1b _{, R 1c and R 1d include hydrogen, deuterium, fluorine, chlorine, methyl, (2H3 )} ^{methyl , ethyl} , ( ^2H5 )ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ( ^2H3 )methoxy, ethoxy, phenyl _, ( _2H5 )phenyl, ² -fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl, 4-(trifluoromethyl)-(2,3, 5,6- ² H ₄ )phenyl, 5-(trifluoromethyl)pyridin-2-yl, phenoxy, ( ² H ₅ )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, 4-(methylsulfonyl)phenoxy, (5-methylpyridin-2-yl)oxy, (5 –(trifluoromethyl)pyridin-2-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.

[0067]

More preferred examples of R ^1a , R ^1b , R ^1c and R ^1d include hydrogen, fluorine, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 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, 2-methoxy-4-(trifluoromethyl )phenyl, 4-(trifluoromethoxy)phenyl and (5-chloropyridin-2-yl)oxy.

[0068]

Even more preferred examples of R ^1a , R ^1b , R ^1c and R ^1d include hydrogen, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 4-fluorophenoxy, 4-chlorophenoxy, 4-(trifluoromethyl)phenoxy , 4-(trifluoromethoxy)phenoxy, (5-(trifluoromethyl)pyridin-2-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl and (5-chloropyridin-2-yl)oxy .

[0069]

As a preferred combination of R ^1a , R ^1b , R ^1c and R ^1d ; R ^1a , R ^1c and R ^1d are hydrogen; R ^1b is 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 4-fluorophenoxy, 4-chlorophenoxy, 4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy)phenoxy, (5-(trifluoromethyl)pyridine –2-yl)oxy, 2-methoxy-4-(trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl or (5-chloropyridin-2-yl)oxy.

[0070]

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

[0071]

Preferably, R ² and R ³ are, for example, hydrogen, deuterium, methyl, ( ² H ₃ )methyl, ethyl, ( ² H ₅ )ethyl, isopropyl, isobutyl, trifluoromethyl, cyclopropyl, cyclopentyl and cyclohexyl; more preferably hydrogen, methyl and ethyl.

[0072]

Additionally, in another preferred embodiment, R ² and R ³ comprise the following group of formula (II) with –OR ⁴ which is formed by combining R ² and R ³ together with the carbon atom to which they are attached to form a ring.

[0073]

In the said formula (II),

preferably e and f are independently 1 or 2,

preferably V represents a single bond or an oxygen atom.

[0074]

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

[0075]

Preferably, ^R4 includes hydrogen, deuterium, _C1-4 alkyl (which may be substituted with 1-3 substituents independently selected from the group consisting of the same or different halogen and deuterium atoms) and _C3-7 cycloalkyl (which may be independently substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl group and C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A); more preferably hydrogen.

[0076]

Preferably, R ⁴ includes, for example, hydrogen, deuterium _, methyl, ( ^2H3 )methyl, ethyl, ( ^2H5 )ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl _; more preferably hydrogen, isopropyl and cyclopentyl; even more preferably hydrogen.

[0077]

Preferably m=0 or 1, more preferably 0.

[0078]

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

[0079]

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

[0080]

Preferably, R ⁷ and R ⁸ include, _for example, hydrogen, deuterium, methyl, ( ^2H3 )methyl, ethyl and ( ^2H5 )ethyl _; more preferably hydrogen.

[0081]

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

[0082]

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

[0083]

As a preferred combination of the two E's in formula (I'), either or both are deuterium; more preferably both are deuterium.

[0084]

One embodiment of a compound of formula (I) or (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, deuterium, 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 deuterium, halogen, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A and deuterium , and C _1-4 alkoxy, optionally substituted with 1-3 substituents selected independently from Substituent Group A and deuterium, provided that at least one of R ^1a , R ^1b , R ^1c and R ^1d is said C _{6 –10} aryl, C _6–10 aryloxy, 5–12 membered heteroaryl or 5–12 membered heteroaryloxy,

R ² and R ³ independently represent hydrogen, deuterium or C _1-6 alkyl, which may be independently substituted with 1-5 substituents independently selected from the group consisting of deuterium, cyano, halogen, hydroxyl group and C _1-4 alkoxy, in optionally substituted with 1 to 3 substituents independently selected from Substituent Group A, provided that both ^R2 and ^R3 are not hydrogen, 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 –OR ⁴

in formula (IIa),

e and f independently denote 1 or 2,

^R4 is hydrogen, deuterium, _C1-6 alkyl (which may be substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl group, _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, 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 the group of substituents B) or C _3-7 cycloalkyl (which can be independently substituted with 1-3 substituents independently selected from the group consisting from deuterium, 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 independently selected from Substituent Group B),

V represents a single bond or oxygen atom, and

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

^R4 is hydrogen, deuterium, _C1-4 alkyl (which may be substituted with 1-3 substituents independently selected from the group consisting of halogen and deuterium) or _C3-7 cycloalkyl (which may be substituted with 1-3 substituents selected independently from the group consisting of deuterium, halogen, hydroxyl group and C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A),

m=0 or 1,

L stands for CR ⁷ R ⁸ ,

R ⁷ and R ⁸ independently represent hydrogen, deuterium or C _1-4 alkyl, which may be independently substituted with 1-3 substituents independently selected from the group consisting of deuterium, halogen, hydroxyl group, C _1-4 alkoxy, as appropriate 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 independently selected from Substituent Group B,

further, with respect to the compound of formula (I'), both or either of E is deuterium.

[0085]

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

compound or a pharmaceutically acceptable salt thereof, in which

R ^1a and R ^1d represent hydrogen,

at least one of R ^1b and R ^1c is 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, C _1-4 alkyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkoxy, in the case need to be substituted with 1–3 substituents selected independently from Substituent Group A,

R ² and R ³ independently represent C _1–6 alkyl, optionally substituted with 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 (IIb) with –OR ⁴

in formula (IIb),

e and f stand for 1,

R ⁴ is hydrogen,

V stands for oxygen atom,

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

R ⁴ is hydrogen,

m=0 or 1,

L stands for CR ⁷ R ⁸ ,

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,

further, with regard to the compound of formula (I), any 1-6 hydrogen atoms are replaced by deuterium,

for a compound of formula (I'), any 1 to 8 hydrogen atoms are replaced by deuterium.

[0086]

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

compound or a pharmaceutically acceptable salt thereof, in which

R ^1a and R ^1d are hydrogen, any of R ^1b and R ^1c is phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, phenoxy, 3-fluorophenoxy, 3,4-difluorophenoxy, 3,5-difluorophenoxy, 4-chlorophenoxy, 4-(trifluoromethyl)phenoxy, 4-(trifluoromethoxy)phenoxy, 4-cyanophenoxy, 4-(methylsulfonyl)phenoxy, (5-methylpyridine- 2-yl)oxy, (5-(trifluoromethyl)pyridin-2-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, and the other is hydrogen,

R ² and R ³ are both methyl, or

R ² and R ³ together with the carbon atom to which they are attached form the following group of formula (IIc) with –OR ⁴

in formula (IIc) e and f represent 1, R ⁴ represents hydrogen, V represents a single bond or an oxygen atom,

m=0,

further, with respect to the compound of formula (I'), E is deuterium.

[0087]

Methods for preparing the compounds of the present invention are described below. Compound (I) or (I') according to the present invention can be obtained, for example, according to Methods 1 to 5 shown below. In the following methods, any hydrogen atoms other than E in each compound may be optionally replaced with deuterium, if possible.

[0088]

Method 1:

A compound of formula (I) or (I') in which R ^1b is OR ^a , ie, Compound (S-5), or a pharmaceutically acceptable salt thereof, can be prepared, for example, according to the following method.

In the above scheme, E are the same or different and represent hydrogen or deuterium; R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m have the meanings defined in Clause 1; R ^a O– denotes R ^1b , which is selected from C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A, C _3-7 cycloalkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group B, C _6–10 aryloxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, or 5–12-membered heteroaryloxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B ; and X ¹ and X ² independently represent a leaving group such as halogen, trifluoromethanesulfonyloxy and methanesulfonyloxy.

[0089]

Stage (1–1):

This step is a method of producing a nitroaniline compound (s–2) by the reaction of a nitrobenzene compound (s–1) and an amine compound (s–A). The base used herein includes an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate and cesium carbonate, and an organic base such as triethylamine and diisopropylethylamine. When the amine compound is used in large excess, there is no need to use such a base. The solvent used herein includes ethers such as THF, 1,2-dimethoxyethane, and 1,4-dioxane; DMF; NMP; acetonitrile; and so on. 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.

[0090]

Stage (1–2):

This step is a method for producing nitroaniline compound (s–3) by reacting compound (s–2) and a compound having a hydroxyl group. The base used herein includes sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate, sodium hydride and the like. The solvent used herein includes ethers such as THF, 1,2-dimethoxyethane and 1,4-dioxane; DMF; NMP; and acetonitrile. 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.

[0091]

Stage (1–3):

This step is a method for preparing the phenylenediamine compound (s–4) by reducing the compound (s–3). The reaction conditions in this step include those commonly used for reduction of the nitro group, such as catalytic reduction under hydrogenating conditions with palladium on carbon, etc.; metal reduction with zinc, iron, etc.; and reduction of hydride with lithium-aluminum hydride, etc. The solvent used in this reduction includes various solvents commonly used under 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 10 minutes to 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0092]

Stage (1–4):

This step is a method for preparing Compound (S–5) by reacting Compound (s–4) and formic acid or formic acid equivalent for cyclization. Formic acid equivalents include orthoformates such as methyl orthoformate and ethyl orthoformate. A catalyst may be used in this step which includes an organic acid such as formic acid and acetic acid and a Lewis acid such as ytterbium triflate. The solvent used here includes alcohols such as methanol and ethanol. It is also possible to use formic acid, orthoformate, etc., which are mentioned above as reagents, as a solvent. The reaction time is generally from 10 minutes to 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0093]

Stage (1-1) and Stage (1-2) can be carried out sequentially; for example, to a mixture after completion of the reaction of Step (1–1), the reagents to be used in Step (1–2) can be added to produce compound (s–3), to which two substituents are introduced in one step. Reaction times for sequential reactions typically range from 20 minutes to 20 hours.

[0094]

Method 2:

The nitroaniline compound of formula (s-3) can also be prepared, for example, according to the following method.

In the above scheme, E are the same or different and represent hydrogen or deuterium; R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m have the meanings defined in Clause 1; R ^a O– denotes R ^1b , which is selected from C _1-4 alkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group A, C _3-7 cycloalkoxy, optionally substituted with 1-3 substituents independently selected from Substituent Group B, C _6–10 aryloxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B, or 5–12-membered heteroaryloxy, optionally substituted with 1–3 substituents independently selected from Substituent Group B ; and X ¹ and X ³ independently represent a leaving group such as halogen, trifluoromethanesulfonyloxy and methanesulfonyloxy.

[0095]

Stage (2–1):

This step is a method of preparing an aminophenol compound of formula (s-7) from a phenol compound of formula (s-6) in the same manner as in Step (1-1).

[0096]

Stage (2–2):

This step is a process for preparing a nitroaniline compound of formula (s–3) by reacting a compound of formula (s–7) with R ^a –X ³ . The base used herein includes sodium hydroxide, potassium hydroxide, potassium carbonate, cesium carbonate and sodium hydride. The solvent used herein includes ethers such as THF, 1,2-dimethoxyethane and 1,4-dioxane; DMF; NMP; acetonitrile; and so on. 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.

[0097]

Stage (2-1) and Stage (2-2) can be carried out sequentially; for example, to a mixture after completion of the reaction of Step (2–1), the reagents to be used in Step (2–2) can be added to produce compound (s–3), to which two substituents are introduced in one step. Reaction times for sequential reactions typically range from 20 minutes to 20 hours.

[0098]

Method 3:

The compound of formula (I) or (I') in which R ^1b is OR ^a , ie, Compound (S-5), or a pharmaceutically acceptable salt thereof, can also be prepared, for example, according to the following method.

In the above scheme, E are the same or different and represent hydrogen or deuterium; R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m have the meanings defined in Clause 1; R ^a has the meaning defined above; X ¹ and X ⁴ independently represent a leaving group such as halogen, trifluoromethanesulfonyloxy and methanesulfonyloxy. Bn denotes a benzyl group, which may include a protecting group that may be removed, such as a benzyl group, for example, a substituted benzyl group disclosed in Protective Groups in Organic Synthesis.

[0099]

Stage (3–1):

This step is a process for preparing an ether compound of formula (s–9) by reacting a phenol compound of formula (s–8) with Bn–X ⁴ , for example, in the presence of a base. The base used herein includes sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride. Bn–X ⁴ includes benzyl chloride and benzyl bromide. If necessary, sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, etc. can 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, the compound of formula (s-9) can be prepared from the compound of formula (s-8) according to the method (conditions) described in Protective Groups in Organic Synthesis and the like.

[0100]

Stage (3–2):

This step is a method of preparing a nitroaniline compound of formula (s-10) from a compound of formula (s-9) in the same manner as in Step (1-1).

[0101]

Stage (3–3):

This step is a method of preparing a phenylenediamine compound of formula (s–11) by selectively reducing the nitro group in the compound of formula (s–10). Reaction conditions at this stage include catalytic reduction with sulfur-toxic platinum-carbon, etc. under hydrogenating 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 10 minutes to 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0102]

Stage (3–4):

This step is a method of preparing a benzimidazole compound of formula (s-12) from a compound of formula (s-11) in the same manner as in Step (1-4).

[0103]

Stage (3–5):

This step is a method of preparing a hydroxybenzimidazole compound of formula (s-13) by removing the protecting group of the hydroxyl group in the compound of formula (s-12), for example, by catalytic reduction under hydrogenating conditions. The catalyst used herein includes heterogeneous catalysts such as palladium on carbon. Hydrogenating 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 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, the compound of formula (s-13) can be prepared from the compound of formula (s-12) under the method (conditions) described in Protective Groups in Organic Synthesis, etc.

[0104]

Stage (3–6):

This step is a process for preparing a compound of formula (s-5) from a compound of formula (s-13), which includes, but is not limited to, two reaction conditions.

1) The reaction conditions using a base include the following step: a compound of formula (s-5) is prepared by reacting a compound of formula (s-13) and R ^a –X ⁵ (where R ^a is 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 Substituent Group B, C _6–10 aryl, optionally substituted with 1–3 substituents independently selected from Substituent Group B, or a 5-12 membered heteroaryl, optionally substituted with 1-3 substituents independently selected from Substituent Group B as defined in R ^1b , and X ⁵ has the meanings defined in said X ¹ ) in the same manner , as in Stage (2–2).

2) The reaction conditions using a catalyst and a base include a 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, DMSO 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.

[0105]

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

[0106]

Method 4:

A compound of formula (I) or (I') in which R ^1b is R ^b (aryl or heteroaryl), ie, Compound (S-16) or a pharmaceutically acceptable salt thereof can be prepared, for example, according to the following method.

In the above scheme, E are the same or different and represent hydrogen or deuterium; R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m have the meanings defined in Clause 1; X ² has the meaning 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, 3–7-membered non-aromatic heterocyclyl, optionally substituted with 1–3 substituents independently selected from Group substituents B, C _1-4 alkylthio, optionally substituted with 1-3 substituents independently selected from Substituent Group A, and C _1-4 alkylsulfonyl, optionally substituted with 1-3 substituents independently selected from Substituent Group A.

[0107]

Stage (4–1):

This step is a method of preparing a phenylenediamine compound of formula (s–14) by selective reduction of the nitro group in a nitroaniline compound of formula (s–2). Reaction conditions at this stage include catalytic reduction with sulfur-toxic platinum-carbon, etc. under hydrogenating 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 10 minutes to 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0108]

Stage (4–2):

This step is a method of preparing a benzimidazole compound of formula (s-15) from a compound of formula (s-14) in the same manner as in Step (1-4).

[0109]

Stage (4–3):

This step is a process for preparing a compound of formula (S-16) by reacting a compound of formula (s-15) 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 usually from 30 minutes to 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0110]

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.

[0111]

Method 5:

A compound of formula (I) or (I') in which R ^1b is R ^b , ie, Compound (S-16) or a pharmaceutically acceptable salt thereof can also be prepared, for example, according to the following method.

In the above scheme, E are the same or different and represent hydrogen or deuterium; R ^1a , R ^1c , R ^1d , R ² , R ³ , R ⁴ , L and m have the meanings defined in Clause 1; R ^b and X ² have the meanings defined above; and R ¹⁰ and R ¹¹ independently represent, if necessary, substituted C _1–4 alkyl, if necessary, substituted C _1–4 alkoxy, if necessary, substituted C _1–4 dialkylamino, if necessary, substituted C _6–10 aryl, if necessary optionally 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.

[0112]

Stage (5–1):

This step is a method of preparing a boronate compound of formula (s-17) by reacting a compound of formula (s-15) and diborons 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 generally from 1 hour to 48 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0113]

Stage (5–2):

This step is a process for preparing a compound of formula (S–16) by reacting a boronate compound of formula (s–17) and a halide or triflate compound having an R ^b group (R ^b –X ⁶ (X ⁶ : halogen atom) or CF ₃ SO ₂ O–R ^b, etc.) in the 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 generally from 30 minutes to 48 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0114]

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.

[0115]

Method 6:

A compound of formula (I) or (I') in which R ⁴ is R ^4a (alkyl or cycloalkyl), ie, Compound (S-19) or a pharmaceutically acceptable salt thereof can be prepared, for example, according to the following method.

In the above scheme, E are the same or different and represent hydrogen or deuterium; R ^1a , R ^1b , R ^1c , R ^1d , R ² , R ³ , L and m have the meanings defined in Clause 1; X ⁷ has the same definition as the specified X ¹ ; and R ^4a is the same as R ⁴ , provided that hydrogen is excluded.

[0116]

Stage (6–1):

This step is a method of preparing a compound of formula (S-19) by reacting an alcohol compound (s-18), which is a compound of formula (I) in which R ⁴ is hydrogen, and for example, a compound R ^4a X ⁷ in the presence of a base. The base used here includes sodium hydride, potassium hydride, lithium hydride, n-butyllithium and potassium tert-butoxide. The solvent used herein includes ethers such as diethyl ether and THF, DMF, NMP and DMSO. The reaction time is usually from 10 minutes to 24 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

[0117]

The indicated reduction of the nitro group (Step (1–3), Step (3–3), Step (4–1)) and subsequent cyclization (Step (1–4), Step (3–4), Step (4–2)) can be carried out sequentially to cyclize in one step, for example formic acid or a formic acid equivalent such as orthoformate can be added to the reduction reaction (s–3), (s–10) or (s–2) to give (S –5), (s–12) or (s–15). The reaction time of the sequential reactions is usually from 10 minutes to 12 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0118]

Method 7:

In these amine compounds (s–A), a compound (s–B) in which both E are deuterium, or a chemically acceptable salt, can be prepared, for example, according to the following method.

In the above scheme, R ² , R ³ , R ⁴ , L and m have the meanings defined in Item 1, Z represents a cyano group, a carbamoyl group and the like.

[0119]

Stage (7–1):

This step is a method of preparing an amine compound of formula (s–B) by the reductive addition of deuterium to a compound of formula (s–20), which includes, but is not limited to, two reaction conditions.

1) The reaction conditions using a reducing agent include the step of reacting a compound of formula (s–20) with a deuterated reducing agent. The deuterated reducing agent includes sodium borondeuteride and lithium aluminum deuteride. The solvent used here includes methanol, ether and THF. The reaction time is usually from 30 minutes to 10 hours, and the reaction temperature is from 0ºC to the boiling point of the solvent used here.

2) The reaction conditions using a catalyst include the stage of catalytic reduction of the compound of formula (s–20) under deuteration conditions. Deuteration conditions mean “in a deuterium atmosphere”, “in a deuterium atmosphere under pressure”, etc. The catalyst used here includes palladium hydroxide on carbon and platinum oxide. The solvent used herein includes methanol, ethanol, THF and ethyl acetate. The reaction time is generally from 1 hour to 24 hours, and the reaction temperature is from room temperature to the boiling point of the solvent used here.

[0120]

In addition, the amine compound of formula (s-B) can also be prepared, for example, using a deuterated starting material. Such _deuterated starting material includes lycine- ^2,2-2H2 .

[0121]

Room temperature in these methods means more specifically from 10ºC to 30ºC.

[0122]

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.

[0123]

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.

[0124]

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)).

[0125]

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.

[0126]

The compounds of the present invention may also include a compound of formula (I) or (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 forms of crystals and compounds in which some or all of the atoms constituting the compounds are replaced by another isotope (eg, replacing ¹² C with ¹⁴ C).

[0127]

The term "prodrug of a compound of formula (I) or (I')" as used herein means a compound that can be converted to a compound of formula (I) or (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) or (I'), and a compound that can be hydrolyzed by gastric juice, etc. converting into a compound of formula (I) or (I’).

[0128]

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)].

[0129]

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.

[0130]

The compound of formula (I) or (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.

[0131]

The novel compounds of the present invention or their pharmaceutically acceptable salts having a benzimidazole ring have Nav 1.7 inhibition property and thus can be used as a drug 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.

[0132]

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.

[0133]

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.

[0134]

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

[0135]

The present invention is explained in more detail in the following section through Reference Examples, Comparative Examples, Examples and 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 Reference Example, Comparative Examples and Examples is silica gel column chromatography or amino silica gel column chromatography manufactured by YAMAZEN CORPORATION. Each compound was identified with a proton nuclear magnetic resonance ( ^1H -NMR) spectrum. ¹ H-NMR was measured using a JNM-ECS400 (JEOL).

[0136]

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

[0137]

In the Methods, Reference Examples, Comparative Examples, Examples and Tests, the abbreviations shown below may sometimes be used to simplify the present description. Me: methyl, 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, NADPH: nicotinamide adenine dinucleotide phosphate, LC: liquid chromatography, MS: mass spectrography, NMR: nuclear magnetic resonance, D: deuterium, ² H: deuterium, J: coupling constant, s: singlet, d: doublet, t: triplet, dd: doublet of doublets, m: multiplet, broad: broadened.

[0138]

Reference Example 1: Preparation of 1-amino-2-methyl(1,1- ² H ₂ )propan-2-ol monohydrochloride (Compound 5)

[0139]

Stage (i):

Thionyl chloride (7.4 ml) was added to a mixture of glycine- ^2,2-2H2 (Compound 1, 5.0 g) and methanol (75 ml) at 0° _C and the mixture was stirred at 50°C for 4 hours . The reaction solution was cooled to room temperature and concentrated in vacuo, and the residue was azeotropically dried with methanol. The resulting residue was washed from the suspension with ethyl acetate to give Compound 2 (8.2 g).

[0140]

Stage (ii):

To a mixture of Compound 2 (8.0 g) and THF (75 ml) were added triethylamine (19.2 ml) and di-tert-butyl bicarbonate (13.7 g), and the mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with aqueous sodium bicarbonate and water. The organic layer was dried over sodium sulfate and then concentrated in vacuo to give Compound 3 as a crude product (11.3 g).

[0141]

Stage (iii):

To a solution of the crude product of Compound 3 (11.2 g) in THF (78 ml), a solution of methylmagnesium bromide/diethyl ether (3.0 mol/L, 78 ml) was added dropwise at 0°C over 3 hours, and the mixture was stirred at room temperature for another 3 hours. An aqueous ammonium chloride solution and ethyl acetate were added to the reaction mixture to separate the layers. The organic layer was washed with water and dried over sodium sulfate and then concentrated in vacuo to give Compound 4 as a crude product (10.7 g).

[0142]

Stage (iv):

To a solution of the crude product of Compound 4 (10.6 g) in ethyl acetate (25 ml) was added a solution of 4 mol/L hydrochloric acid/ethyl acetate (50 ml), and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated in vacuo and the residue was azeotropically dried with methanol to give 1-amino-2-methyl( ^1,1-2H2 ₎ propan-2-ol (Compound 5) as crude product (7.0 g).

[0143]

Reference Example 2: Preparation of 1-amino-2-methyl(1,1- ² H ₂ )propan-2-ol (Compound 7)

[0144]

Stage (i):

To a mixture of lithium aluminum deuteride (1.0 g) and THF (20 ml), a solution of acetone cyanohydrin (Compound 6, 1.0 g) in THF (10 ml) was added dropwise at 0°C over 30 minutes, and the mixture was stirred at room temperature for 3 hours. Sodium sulfate decahydrate (6.0 g) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite and the filtrate was then concentrated in vacuo to give 1-amino-2-methyl( ^1,1-2H2 ₎ propan-2-ol (Compound 7) as crude product (0.9 g).

[0145]

Also, Compound 7 can be prepared with 2-methyl-2-hydroxypropionamide (Compound 8) and lithium aluminum deuteride in a similar manner.

[0146]

Reference Example 3: Preparation of 4-amino-2-methyl(4,4- ² H ₂ )butan-2-ol (Compound 11)

Stage (i):

Sodium cyanide (283 mg) was added to a mixture of 1-chloro-2-methyl-propan-2-ol (Compound 9, 523 mg), ethanol (10 ml) and distilled water (2.0 ml), and the mixture was stirred while heating reflux for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was dried over sodium sulfate and concentrated in vacuo to give Compound 10 (250 mg).

[0147]

Stage (ii):

To a mixture of lithium aluminum deuteride (159 mg) and THF (10 ml), a solution of Compound 10 (1.0 g) in THF (5.0 ml) was added dropwise at 0°C, and the mixture was stirred at room temperature for another 3 hours. Sodium sulfate decahydrate (6.0 g) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite and the filtrate was then concentrated in vacuo to give 4-amino-2-methyl( ^4,4-2H2 ₎ butan-2-ol (Compound 11) as a crude product (240 mg).

[0148]

Reference Example 4: Preparation of 3-[amino( ^2H2 )methyl]oxetan-3-ol (Compound 14 ₎

Stage (i):

A mixture of oxetan-3-one (Compound 12, 464 mg), lithium perchlorate (685 mg) and trimethylsilyl cyanide (1.0 ml) was stirred at room temperature for 2 hours. Chloroform was added to the reaction mixture, and the mixture was filtered. The organic layer was then washed with water, dried over sodium sulfate and then concentrated in vacuo to give Compound 13 as a crude product (808 mg).

[0149]

Stage (ii):

To a suspension of lithium aluminum deuteride (297 mg) and THF (10 ml), a solution of Compound 13 (808 mg) in THF (10 ml) was added dropwise at 0°C, and the mixture was stirred at room temperature for 5 hours. Sodium sulfate decahydrate (2.0 g) was added to the reaction solution, and the mixture was stirred at room temperature overnight. The reaction mixture was _filtered through Celite and the filtrate was concentrated in vacuo to give 3-[amino( ^2H2 )methyl]oxetan-3-ol (Compound 14) as crude product (632 mg).

[0150]

Reference Example 5: Preparation of 6-(4-fluorophenoxy)-1H-benzimidazole (Compound 18)

[0151]

Stage (i):

A mixture of 5-fluoro-2-nitroaniline (Compound 15, 100 mg), cesium carbonate (313 mg), 4-fluorophenol (86 mg), and NMP (1.0 ml) was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=1/1) to obtain Compound 16 (124 mg).

[0152]

Stage (ii):

A mixture of Compound 16 (124 mg), palladium-carbon (120 mg) and THF (5.0 ml) was stirred under a hydrogen atmosphere at room temperature for 2 hours. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo to give Compound 17 (106 mg).

[0153]

Stage (iii):

A mixture of Compound 17 (106 mg), p-toluenesulfonic acid monohydrate (10 mg), trimethyl orthoformate (0.3 ml) and methanol (5.0 ml) was stirred at room temperature for 2 hours and then at 50°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain 6-(4-fluorophenoxy)-1H-benzimidazole (Compound 18, 82 mg).

[0154]

Reference Example 6: Preparation of 6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazole (Compound 21)

[0155]

Stage (i):

A mixture of 4-amino-3-nitrophenol (Compound 19, 200 mg), cesium carbonate (458 mg), 2-fluoro-5-(trifluoromethyl)pyridine (130 μl) and NMP (2.0 ml) was stirred at room temperature in within 6 hours. Ethyl acetate and water were added to the reaction mixture to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain Compound 20 (320 mg).

[0156]

Stage (ii):

To a solution of Compound 20 (320 mg) in methanol (6.0 ml) was added formic acid (0.4 ml), trimethyl orthoformate (3.0 ml) and zinc powder (354 mg), and the mixture was stirred at 60°C in within 2 hours. The reaction mixture was cooled to room temperature and aqueous sodium bicarbonate and ethyl acetate were added. The mixture was filtered through Celite and the filtrate was separated into layers. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=30/1) to obtain 6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazole (Compound 21, 135 mg).

[0157]

Reference Example 7: Preparation of 6-(4-chlorophenoxy)-1H-benzimidazole (Compound 24)

[0158]

Stage (i):

A mixture of 5-fluoro-2-nitroaniline (Compound 15, 100 mg), cesium carbonate (313 mg), 4-chlorophenol (99 mg) and NMP (1.0 ml) was stirred at 100°C for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=1/1) to obtain Compound 22 (136 mg).

[0159]

Stage (ii):

A mixture of Compound 22 (136 mg), platinum sulfide on carbon (130 mg) and THF (5.0 ml) was stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction solution was filtered through Celite and concentrated in vacuo to give Compound 23 (120 mg).

[0160]

Stage (iii):

A mixture of Compound 23 (120 mg), p-toluenesulfonic acid monohydrate (10 mg), trimethyl orthoformate (0.3 ml) and methanol (5.0 ml) was stirred at room temperature for 2 hours and then at 50°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain 6-(4-chlorophenoxy)-1H-benzimidazole (Compound 24, 88 mg).

[0161]

Reference Example 8: Preparation of 6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazole (Compound 27)

[0162]

Stage (i):

A mixture of 5-fluoro-2-nitroaniline (Compound 15, 100 mg), cesium carbonate (313 mg), 4-(trifluoromethoxy)phenol (99 µl) and NMP (1.0 ml) was stirred at 100°C for 1 hour . The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=1/1) to obtain Compound 25 (175 mg).

[0163]

Stage (ii):

A mixture of Compound 25 (175 mg), palladium-carbon (150 mg) and THF (5.0 ml) was stirred under a hydrogen atmosphere at room temperature for 6 hours. The reaction solution was filtered through Celite and concentrated in vacuo to give Compound 26 (152 mg).

[0164]

Stage (iii):

A mixture of Compound 26 (120 mg), p-toluenesulfonic acid monohydrate (10 mg), trimethyl orthoformate (0.3 ml) and methanol (5.0 ml) was stirred at room temperature for 2 hours and then at 50°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain 6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazole (Compound 27, 124 mg).

[0165]

Reference Example 9: Preparation of 6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazole (Compound 29)

[0166]

Stage (i):

Mixture of 6-bromobenzimidazole (Compound 28, 100 mg), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (167 mg), tetrakis(triphenylphosphine) palladium (26 mg), potassium carbonate (210 mg), 1,4-dioxane (2.0 ml) and distilled water (0.5 ml) were stirred at 100°C for 1 hour. The reaction solution was cooled to room temperature, loaded onto silica gel and purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain 6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazole (Compound 29.86 mg).

[0167]

Comparative Example 1: Preparation of 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol

[0168]

Stage (i):

A mixture of 2,4-difluoro-1-nitrobenzene (Compound 30, 1.6 g), 1-amino-2-methylpropan-2-ol (1.0 g), diisopropylethylamine (5.2 ml), and DMF (50 ml) was stirred at 60°C for 2 hours. The reaction mixture was cooled to room temperature and water, ethyl acetate and hexane were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo to give Compound 31 as a crude product.

[0169]

Stage (ii):

A mixture of the crude product of Compound 31, 4-fluorophenol (1.7 g), cesium carbonate (6.5 g) and NMP (25 ml) was stirred at 100°C for 2 hours. The reaction mixture was cooled to room temperature and water, ethyl acetate and hexane were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=3/1) to obtain Compound 32 (3.1 g).

[0170]

Stage (iii):

A mixture of Compound 32 (3.1 g), ammonium formate (3.0 g), palladium carbon (0.30 g) and methanol (47 ml) was stirred at 50°C for 2 hours. The reaction mixture was cooled to room temperature, filtered through Celite and concentrated in vacuo. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the residue to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=99/1) to obtain Compound 33 (2.7 g).

[0171]

Stage (iv):

A mixture of Compound 33 (600 mg), trimethyl orthoformate (1.7 ml) and p-toluenesulfonic acid monohydrate (79 mg) was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and saturated aqueous sodium bicarbonate and ethyl acetate were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=95/5) to obtain 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methylpropan-2-ol (410 mg).

¹ H–NMR (DMSO–d6) δ: 1.06 (6H, s), 4.08 (2H, s), 4.72 (1H, s), 6.87 (1H, m), 6.96 –6.99 (2H, m), 7.17 (2H, m), 7.39 (1H, m), 7.62 (1H, m), 8.09 (1H, s).

[0172]

Comparative Example 2: Preparation of 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol

[0173]

Stage (i):

A mixture of 3-fluoro-4-nitrophenol (Compound 34, 1.0 g), diisopropylethylamine (2.1 g), 1-amino-2-methylpropan-2-ol (0.7 g) and NMP (16 ml) was stirred at 100°C for 4 hours. Cesium carbonate (3.1 g) and 2-fluoro-5-(trifluoromethyl)pyridine (1.4 g) were added to the reaction mixture, and the mixture was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and water, ethyl acetate and hexane were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was washed from the suspension with hexane/ethyl acetate (=9/1) to give Compound 35 (1.5 g).

[0174]

Stage (ii):

To a solution of Compound 35 (500 mg) in methanol (7.0 ml) was added formic acid (0.5 ml), trimethyl orthoformate (3.7 ml) and zinc (440 mg), and the mixture was stirred at 70°C for 2 hours. The reaction solution was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo, and ethyl acetate and an aqueous solution of Rochelle's salt were added to the residue to separate the layers. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting residue was recrystallized with hexane/ethyl acetate (= 1:5), obtaining 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)propan-2 –ol (330 mg).

¹ H–NMR (DMSO–d6) δ: 1.07 (6H, s), 4.11 (2H, s), 4.73 (1H, s), 7.00 (1H, m), 7.18 (1H, m), 7.56 (1H, m), 7.66 (1H, m), 8.13 (1H, s), 8.20 (1H, m), 8.54 (1H, m) .

[0175]

Comparative Example 3: Preparation of 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol

[0176]

Stage (i):

A mixture of 2,4-difluoro-1-nitrobenzene (Compound 30, 200 mg), 4-amino-2-methylbutan-2-ol (136 mg), diisopropylethylamine (263 μl) and NMP (2.0 ml) was stirred at 110 °C for 30 minutes. Cesium carbonate (819 mg) and 4-chlorophenol (186 mg) were added to the reaction mixture, and the mixture was stirred at 150°C for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=1/1) to obtain Compound 36 (350 mg).

[0177]

Stage (ii):

To a solution of Compound 36 (350 mg) in methanol (5.0 ml) was added formic acid (0.4 ml), trimethyl orthoformate (2.8 ml) and zinc powder (326 mg), and the mixture was stirred at 60°C in within 3 hours. The reaction solution was cooled to room temperature and filtered through Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1).

The resulting crude product was recrystallized with hexane/ethyl acetate (= 1:1) to give 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methylbutan-2-ol (237 mg).

¹ H–NMR (CDCl3) δ: 1.30 (6H, s), 1.99–2.03 (2H, m), 4.28–4.32 (2H, m), 6.90–6, 91 (2H, m), 6.98 (1H, dd, J=8.5, 2.4 Hz), 7.07 (1H, d, J=2.4 Hz), 7.26–7.27 (2H, m), 7.75 (1H, d, J=9.2 Hz), 8.12 (1H, br).

[0178]

Comparative Example 4: Preparation of 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl} methyl)oxetan-3-ol

[0179]

Stage (i):

Mixture of 2,4-difluoro-1-nitrobenzene (Compound 30, 17.1 g), 3-(aminomethyl)oxetan-3-ol (11.7 g), diisopropylethylamine (24.2 ml) and NMP (110 ml) stirred at room temperature for 2 hours. Cesium carbonate (45.6 g) and 4-(trifluoromethoxy)phenol (14.6 ml) were added to the reaction mixture, and the mixture was stirred at 120°C for 4 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: ethyl acetate). The crude product was washed from the suspension with hexane/ethyl acetate (=3/1) to give Compound 37 (10.2 g).

[0180]

Stage (ii):

To a solution of Compound 37 (659 mg) in methanol (8.0 ml) was added formic acid (0.6 ml), trimethyl orthoformate (4.5 ml) and zinc powder (538 mg), and the mixture was stirred at 60°C in within 2 hours. The reaction solution was cooled to room temperature, filtered through Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1). The crude product was washed from the suspension with hexane/ethyl acetate (= 1:1) to give 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl} methyl)oxetan-3-ol (306 mg) .

¹ H–NMR (CDCl3) δ: 3.82 (1H, br), 4.49 (2H, s), 4.55–4.63 (4th, m), 6.92–6, 96 (3H, m), 7.14 (2H, d, J=8.6 Hz), 7.20 (1H, d, J=1.8 Hz), 7.62 (1H, d, J=8 .6 Hz), 7.94 (1H, s).

[0181]

Comparative Example 5: Preparation of 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetan-3-ol

[0182]

Stage (i):

A mixture of 4-bromo-2-fluoro-1-nitrobenzene (Compound 38, 26.2 g), 3-(aminomethyl)oxetan-3-ol (12.3 g), diisopropylethylamine (31.2 ml) and NMP (180 ml) was stirred at 100°C for 3 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was washed from the slurry with hexane/chloroform (=3/2) to give Compound 39 (29.8 g).

[0183]

Stage (ii):

To a solution of Compound 39 (22.0 g) in methanol (200 ml) was added formic acid (27.8 ml), trimethyl orthoformate (120 ml) and zinc powder (15.7 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite and concentrated in vacuo. Ethyl acetate and an aqueous Rochelle salt solution were added to the resulting residue to separate the layers. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting residue was washed from a heptane/2-propanol (=4/3) slurry to give Compound 40 (19.1 g).

[0184]

Stage (iii):

Mixture of Compound 40 (13.9 g), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (16.2 g), tetrakis(triphenylphosphine)palladium (5.7 g), potassium carbonate (20.4 g), 1 ,2-dimethoxyethane (180 ml) and distilled water (60 ml), stirred at 80°C for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1). The resulting crude product was recrystallized with heptane/2-propanol (= 2/1) to give 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}methyl)oxetane-3 -ola (10.60 g).

¹ H–NMR (DMSO–d6) δ: 3.84 (3H, s), 4.42 (2H, d, J=6.7 Hz), 4.54 (2H, d, J=6.7 Hz ), 4.59 (2H, s), 6.22 (1H, s), 7.33 (1H, dd, J=8.2, 1.5 Hz), 7.37–7.41 (2H, m), 7.55 (1H, d, J=7.9 Hz), 7.66 (1H, d, J=8.5 Hz), 7.84 (1H, s), 8.28 (1H, With).

[0185]

Example 1: preparation of 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(1,1- ² H ₂ )propan–2–ol

[0186]

Stage (i):

A mixture of 2,4-difluoro-1-nitrobenzene (Compound 30, 1.1 g), crude product of Compound 5 (Reference Example 1) (1.2 g), diisopropylethylamine (2.8 ml) and NMP (12 ml) was stirred at room temperature for 1 hour. Cesium carbonate (3.2 grams) and 4-fluorophenol (1.0 g) were added to the reaction mixture, and the mixture was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=1/1) to obtain Compound 41 as a crude product (2.7 g).

[0187]

Stage (ii):

To a solution of the crude product of Compound 41 (2.7 g) in methanol (30 ml) was added formic acid (2.5 ml), trimethyl orthoformate (14.6 ml) and zinc powder (2.2 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1). The crude product was washed from the suspension with hexane/ethyl acetate (= 1:1) to give 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl] _-2 -methyl( ^1,1-2H2 )propane- 2-ol (960 mg).

¹ H–NMR (DMSO–d6) δ: 1.06 (6H, s), 4.72 (1H, s), 6.87 (1H, dd, J=8.5, 2.4 Hz), 6 .96–7.00 (2H, m), 7.14–7.20 (2H, m), 7.39 (1H, d, J=2.4 Hz), 7.62 (1H, d, J =8.5 Hz), 8.08 (1H, s).

[0188]

Example 2: preparation of 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)(1,1- ² H ₂ )propan-2-ol

[0189]

Stage (i):

A mixture of 3-fluoro-4-nitrophenol (Compound 34, 2.1 g), crude product of Compound 5 (Reference Example 1) (2.0 g), diisopropylethylamine (8.0 ml) and NMP (25 ml) was stirred at 110 °C for 4 hours. Cesium carbonate (6.4 g) and 2-fluoro-5-(trifluoromethyl)pyridine (2.0 ml) were added to the reaction solution, and the mixture was stirred at 110°C for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=1/1) to obtain Compound 42 (3.7 g).

[0190]

Stage (ii):

To a solution of Compound 42 (1.5 g) in methanol (20 ml), formic acid (1.5 ml), trimethyl orthoformate (11.0 ml) and zinc powder (1.3 g) were added and the mixture was stirred at room temperature within 1 hour. The reaction solution was filtered through Celite and concentrated in vacuo. Ethyl acetate and an aqueous Rochelle salt solution were added to the residue to separate the layers. The organic layer was washed with water, dried over sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1). The resulting crude product was recrystallized with heptane/2-propanol (= 1/1) to give 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl )(1,1- ² H ₂ )propan-2-ol (650 mg).

¹ H–NMR (DMSO–d6) δ: 1.07 (6H, s), 4.72 (1H, s), 7.00 (1H, dd, J=8.5, 2.4 Hz), 7 .17 (1H, d, J=9.2 Hz), 7.56 (1H, d, J=2.4 Hz), 7.65 (1H, d, J=8.5 Hz), 8.13 (1H, s), 8.20 (1H, dd, J=9.2, 2.4 Hz), 8.55 (1H, d, J=2.4 Hz).

[0191]

Example 3: preparation of 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(4,4- ² H ₂ )butan-2-ol

[0192]

Stage (i):

A mixture of 2,4-difluoro-1-nitrobenzene (Compound 30, 149 mg), crude product of Compound 11 (Reference Example 3) (235 mg), diisopropylethylamine (212 μl) and NMP (2.0 ml) was stirred at room temperature in within 1 hour. Cesium carbonate (457 mg) and 4-chlorophenol (156 mg) were added to the reaction mixture, and the mixture was stirred at 150°C for 1 hour. The reaction mixture was cooled to room temperature and ethyl acetate and water were added to separate the layers. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: hexane/ethyl acetate=1/1) to obtain Compound 43 (276 mg).

[0193]

Stage (ii):

To a solution of Compound 43 (276 mg) in methanol (4.0 ml) was added formic acid (0.3 ml), trimethyl orthoformate (1.7 ml) and zinc powder (256 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1). The crude product was washed from the suspension with hexane/ethyl acetate (= 1:1) to give 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl] _-2 -methyl( ^4,4-2H2 )butane- 2-ol (186 mg).

¹ H–NMR (DMSO–d6) δ: 1.13 (6H, s), 1.84 (2H, s), 4.47 (1H, s), 6.91 (1H, dd, J=8, 5, 2.4 Hz), 6.95–6.99 (2H, m), 7.33 (1H, d, J=2.4 Hz), 7.36–7.41 (2H, m), 7.66 (1H, d, J=8.5 Hz), 8.23 (1H, s).

[0194]

Example 4: preparation of 3-[{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}( ² H ₂ )methyl]oxetan-3-ol

[0195]

Stage (i):

A mixture of 2,4-difluoro-1-nitrobenzene (Compound 30, 261 mg), crude product of Compound 14 (Reference Example 4) (632 mg), diisopropylethylamine (372 μl) and NMP (3.0 ml) was stirred at room temperature in within 2 hours. Cesium carbonate (801 mg) and 4-(trifluoromethoxy)phenol (317 μL) were added to the reaction mixture, and the mixture was stirred at 120°C for 2 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain Compound 44 (353 mg).

[0196]

Stage (ii):

To a solution of Compound 44 (353 mg) in methanol (4.0 ml) was added formic acid (0.3 ml), trimethyl orthoformate (1.9 ml) and zinc powder (287 mg), and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1). _The crude product was washed from the suspension with hexane/ethyl acetate (= 1:1) to give 3-[{6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1-yl}( ^2H2 )methyl]oxetane-3- ol (206 mg).

¹ H–NMR (DMSO–d6) δ: 4.37–4.49 (4H, m), 6.18 (1H, s), 6.94 (1H, dd, J=8.5, 2.4 Hz), 7.02–7.06 (2H, m), 7.34 (2H, d, J=9.1 Hz), 7.48 (1H, d, J=2.4 Hz), 7, 65 (1H, d, J=8.5 Hz), 8.26 (1H, s).

[0197]

Example 5: preparation of 3-[{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}( ² H ₂ )methyl]oxetan-3-ol

[0198]

Stage (i):

A mixture of 4-bromo-2-fluoro-1-nitrobenzene (Compound 38, 228 mg), crude product of Compound 14 (Reference Example 4) (770 mg), diisopropylethylamine (272 μl) and NMP (2.0 ml) was stirred at room temperature for 3 hours. Ethyl acetate and water were added to the reaction mixture to separate the layers. The organic layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain Compound 45 (275 mg).

[0199]

Stage (ii):

To a solution of Compound 45 (275 mg) in methanol (9.0 ml) was added formic acid (0.3 ml), trimethyl orthoformate (2.0 ml) and zinc powder (295 mg), and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered through Celite and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1) to obtain Compound 46 (184 mg).

[0200]

Stage (iii):

Mixture of Compound 46 (184 mg), 2-methoxy-4-(trifluoromethyl)phenylboronic acid (213 mg), tetrakis(triphenylphosphine)palladium (75 mg), potassium carbonate (268 mg), 1,4-dioxane (4.5 ml) and distilled water (1.5 ml), stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, loaded onto silica gel and purified by silica gel column chromatography (elution solution: chloroform/methanol=20/1). The resulting crude product was washed from the suspension with hexane/ethyl acetate ₍ = 1/1) to give 3-[{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}( ^2H2 )methyl ]oxetan-3-ol (153 mg).

¹ H–NMR (DMSO–d6) δ: 3.84 (3H, s), 4.41–4.55 (4H, m), 6.22 (1H, s), 7.33 (1H, dd, J=8.5, 1.8 Hz), 7.37–7.41 (2H, m), 7.55 (1H, d, J=7.9 Hz), 7.66 (1H, d, J =8.5 Hz), 7.84 (1H, d, J=1.2 Hz), 8.28 (1H, s).

[0201]

Test 1: 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.

[0202]

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 0.4 mg/ml zeocin. The day before the measurement, the medium was replaced with Ham's F-12 medium containing 1 μg/ml tetracycline, 100 μmol/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.

[0203]

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.

[0204]

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

[0205]

Intracellular solution (mmol/l): CsF 120, EGTA 10, NaCl 15, HEPES 10, (pH 7.2 with CsOH)

[0206]

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 3 kHz. All measurements were carried out at room temperature. The baseline potential was set to the 50% Nav 1.7 channel-inactivating potential (approximately −60 mV), and a 20-millisecond depolarizing pulse (+10 mV) was given once. The degree of inhibition of test compounds was calculated based on the results of cells whose maximum current was 500 Pa or more when applying a depolarization pulse 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 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)

[0207]

Result:

The degree of inhibition of the Na ion current for compounds from Examples 1–5 was assessed. 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.

[0208]

Analysis 2: Evaluation of analgesic effect in a model of streptozotocin-induced diabetic peripheral neuropathic pain

Using some representative compounds among the compounds of the present invention, the inhibitory effect on neuropathic pain was determined by evaluating the analgesic effect in a rat model of streptozotocin (STZ)-induced diabetic peripheral neuropathy.

An animal model of the disease was obtained by partially modifying the method of Fox et al . (Pain 81, 307–316, 1999). STZ was administered intraperitoneally to 9-week-old male Wistar rats at 45 mg/kg body weight to establish an animal model of diabetic peripheral neuropathy.

The analgesic effect was assessed using the von Frey test. Specifically, mechanical sensitivity was measured by applying filaments (von Frey filaments) to the plantar surface of the animal's hind paw, and then response thresholds (50% paw withdrawal thresholds) to mechanical stimulation were determined using a formula based on Chaplan et al . (Journal of Neuroscience Methods 53, 55–63, 1994).

In a preliminary study, it was already confirmed that the animal's hind paw response thresholds decreased markedly on or after day 21 after STZ administration, therefore, assessment of analgesic effect with test compounds was made on any day between day 21 and day 30 after STZ administration. One and two days before evaluation of test compounds, response thresholds were measured to obtain an average number, and the average value was used as the reference value obtained before administration of test compounds.

To reduce the variability of the average values among the tested groups and the measured values in each group, the animals were divided into 4–5 groups.

In the test to assess the quality of test compounds, response thresholds were measured after administration of each test compound. One hour before measuring response thresholds, each test compound was administered orally at 3 mg/kg body weight. The strength of the analgesic effect of each test compound is expressed as the increase in the width (g) of the response thresholds, which is obtained by the calculation formula (response threshold obtained after administration of the test compound) - (response threshold obtained before administration of the test compound).

[0209]

Result:

The increase in threshold width for the compound of Example 2 was 5.0 g. The increase in width in the solvent injection group in the present test was 0.1 g.

This result shows that the compounds of the present invention exhibit good analgesic effects when the compounds are orally administered in a rat model of diabetic peripheral neuropathy.

[0210]

Assay 3: Testing Metabolic Stability in the Liver Microsome

To a solution prepared by mixing 4 μl of human or rat liver microsome (manufactured by Xenotech, 20 mg/ml), 100 μl of 100 mM phosphate buffer solution (pH 7.4) and 74 μl of ultrapure water was added 2 μl of 1 μM solution of the test compound in DMSO and an additional 40 μl of 10 mM NADPH aqueous solution (manufactured by Oriental Yeast Co., ltd.), and then the mixture was incubated at 37°C for 30 minutes. After incubation, 50 μL of the reaction solution was added to methanol to stop the metabolic reaction. After stopping the reaction, the solution was centrifuged at 4°C and 4500 rpm for 5 minutes, and the supernatant was filtered. 100 μL of the supernatant was mixed with 100 μL of 10 mM ammonium acetate aqueous solution, and the mixture was analyzed by LC (Shimadzu, NexeraX2)–MS (AB Sciex, TripleTOF5600) to determine the amount of the corresponding metabolite product in the mixture.

[0211]

Result:

Regarding the compounds obtained in Comparative Examples 1-3 and Examples 1-3, the corresponding metabolite products (Reference Example 5-7) were tested. The results showed that the metabolite product generation rate of the compound of each Example was lower than that of the compound of each Comparative Example. Each generation rate of each metabolite product (pmol/min/mg protein) is shown in the following table.

Comparative Example/Example Metabolite product generation rate (pmol/min/mg protein) Human rat 1/1 0.045/n.d. 0.262/n.d. 2/2 0.204/0.026 2.52/0.260 3/3 0.756/0.069 3.30/0.40 n.d.: no dealkylated metabolite product detected

[0212]

Assay 4: Rat pharmacokinetic study

The test compound was suspended in a 0.5% aqueous solution of methylcellulose, which was administered to a male rat (Crl: CD (SD)) at a dose of 3 mg/5 ml/kg. Blood collection was carried out at 0.25, 0.5, 1, 2, 4, 6 and 24 hours after administration. Blood was drawn (0.4 ml each time) with a syringe containing 4 μl of HEPARIN NOVO. The collected blood was transferred to a cold centrifugation tube and centrifuged at 4°C at 3000 rpm x 10 minutes to obtain plasma. Methanol was added to 50 μl of the resulting plasma and the mixture was mixed with a Vortex mixer and then centrifuged at 4°C at approximately 9100 x g for 5 minutes. 150 μl of the supernatant was mixed with 300 μl of water, and the mixture was centrifuged at 4°C at approximately 1800 x g for 5 minutes. The supernatant was analyzed by LC (Shimadzu, series)–MS (AB Sciex, API4000) to determine the amount of the corresponding metabolite product.

[0213]

Result:

For the compounds obtained in Comparative Examples 2 and 3 and Examples 2 and 3, each concentration of the metabolite products was tested after administration to a male rat. The results showed that the exposure of the corresponding metabolite product (Reference Example 6 and 7) of the compound of each Example was less than that of the compound of each Comparative Example. Each pharmacokinetic parameter of the metabolite products is shown in the following table, in which _Cmax denotes the maximum plasma concentration, and AUC denotes the area under the plasma concentration-time curve from 0 to 24 hours.

Comparative Example/Example _Cmax
(ng/mL) AUC
(ng/h/mL) 2/2 52.0/4.8 131/19.0 3/3 12.4/7.0 56.1/32.2

Industrial applicability

[0214]

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 (44)

1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^1a , R ^1c and R ^1d represent hydrogen, R ^1b means C ₆ aryl, C ₆ aryloxy or 6-membered heteroaryloxy, wherein the aryl and aryl group in aryloxy and the heteroaryl group in heteroaryloxy can be independently substituted by 1-2 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 substituents independently selected from Substituent Group A; R ⁴ is hydrogen, m=0 or 1, L stands for CR ⁷ R ⁸ , R ⁷ and R ⁸ are hydrogen, or R ² and R ³ are methyl or, together with the carbon atom to which they are attached, form the following group of formula (II) with –OR ⁴ in formula (II) e and f denote 1, R ⁴ has the value defined above, V stands for oxygen atom, R ^5a , R ^5b , R ^5c and R ^5d are hydrogen, Substituent group A is independently halogen, and any 1 to 6 hydrogen atoms in the compound of formula (I) may be replaced by deuterium atoms. 2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ² and R ³ are methyl. 3. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, where R ² and R ³ together with the carbon atom to which they are attached form the following group of formula (IIb) with –OR ⁴ in formula (IIb) e and f denote 1, R ⁴ is hydrogen, V stands for oxygen atom, R ^5a , R ^5b , R ^5c and R ^5d are hydrogen. 4. A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(1,1- ² H ₂ )propan-2-ol, 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)(1,1- ² H ₂ )propan-2-ol, 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(4,4- ² H ₂ )butan-2-ol, 3–[{6–[4–(trifluoromethoxy)phenoxy]–1H–benzimidazol–1–yl}( ² H ₂ )methyl]oxetan–3–ol and 3-[{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}( ² H ₂ )methyl]oxetan-3-ol. 5. A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(1,1- ² H ₂ )propan-2-ol, 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)(1,1- ² H ₂ )propan-2-ol and 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1-yl]-2-methyl(4,4- ² H ₂ )butan-2-ol. 6. A compound according to claim 1 or a pharmaceutically acceptable salt thereof selected from the following compounds: 3–[{6–[4–(trifluoromethoxy)phenoxy]–1H–benzimidazol–1–yl}( ² H ₂ )methyl]oxetan–3–ol and 3-[{6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}( ² H ₂ )methyl]oxetan-3-ol. 7. 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. 1-6 or its pharmaceutically acceptable salts and pharmaceutically acceptable additives. 8. A medicament for the treatment of a disease involving Nav 1.7 (SCN9A), containing a therapeutically effective amount of a compound according to any one of claims. 1-6 or a pharmaceutically acceptable salt thereof as the active ingredient. 9. A medicament for the treatment of 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, containing a therapeutically effective amount of a compound of any of paragraphs. 1-6 or a pharmaceutically acceptable salt thereof as the active ingredient. 10. Use of the compound according to any one of paragraphs. 1-6 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 neuropathic pain, nociceptive pain, inflammatory pain, small fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria or dissipation sclerosis. 11. 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. 1-6 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.