NOVEL BENZIMIDAZOLONE COMPOUND AND PHARMACEUTICAL USE THEREOF
The present invention relates to a medicament for treating or preventing a disease involving Nav 1.7, specifically such neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, and multiple sclerosis, comprising a compound of formula (I) wherein R 1a , R 1b , R 1c , and R 1d are hydrogen, halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, etc., provided that at least one of R 1a , R 1b , R 1c and R 1d is the above C 6-10 aryl, C 6-10 aryloxy, etc., R 2 and R 3 are hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, etc., R 4 is hydrogen, C 1-6 alkyl, C 3-4 cycloalkyl, etc., m is 0, 1, 2, or 3, L is CR 7 R 8 , R 7 and R 8 are hydrogen, hydroxy group, C 1-4 alkyl, C 1-4 alkoxy, etc., or a pharmaceutically acceptable salt thereof.
1 . A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R 1a , R 1b , R 1c , and R 1d are independently hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy (wherein the alkyl and the alkyl moiety in the alkoxy may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, hydroxy group, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), C 3-7 cycloalkyl, C 3-7 cycloalkoxy (wherein the cycloalkyl and the cycloalkyl moiety in the cycloalkoxy may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, hydroxy group, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), C 6-10 aryl, C 6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (wherein the aryl and the aryl moiety in the aryloxy, and the heteroaryl and the heteroaryl moiety in the heteroaryloxy may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, cyano, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), provided that at least one of R 1a , R 1b , R 1c and R 1d is the above C 6-10 aryl, C 6-10 aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy,
R 2 and R 3 are independently hydrogen, C 1-6 alkyl (which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxy group, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), or C 3-10 cycloalkyl,
R 4 is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl wherein the C 1-4 alkyl and the C 3-4 cycloalkyl may be substituted with 1-5 the same or different halogen atoms,
m is 1, 2, or 3,
L is CR 7 R 8 provided that when m is 2 or 3, each CR 7 R 8 is independently the same or different,
R 7 and R 8 are independently hydrogen, hydroxy group, C 1-4 alkyl, C 1-4 alkoxy (wherein the alkyl and the alkyl moiety in the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy group, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), C 3-7 cycloalkyl, or C 3-7 cycloalkoxy (wherein the cycloalkyl and the cycloalkyl moiety in the cycloalkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy group, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), or
in R 2 , R 3 , and the hydroxy group bound to the carbon atom which is connected to R 2 and R 3 ,
R 2 and R 3 may be combined together with the carbon atom to which they are attached to form the following group of formula (II) with the hydroxy group
in formula (II),
e and f are independently 1, 2 or 3,
V is single bond or oxygen atom,
R 5a , R 5b , R 5c , and R 5d are independently hydrogen, halogen, hydroxy group, C 1-4 alkyl, or C 1-4 alkoxy, wherein the alkyl and the alkyl moiety in the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy group, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, or
in R 2 , R 3 , the hydroxy group bound to the carbon atom which is connected to R 2 and R 3 , and CR 7 R 8 in L,
R 2 and R 7 may be combined together with the carbon atom to which they are attached to form the following group of formula (III) with R 3 , the hydroxy group and R 8
in formula (III),
m 1 is 0 or 1,
m 2 is 0 or 1 and j is 1, 2, 3 or 4 when m 1 is 1, or
m 2 is 0, 1 or 2 and j is 1, 2, 3 or 4 when m 1 is 0,
R 8 and L are as defined above,
R 6a , R 6b , R 6c , and R 6d are independently hydrogen, halogen, hydroxy group, C 1-4 alkyl, or C 1-4 alkoxy, wherein the alkyl and the alkyl moiety in the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy group, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B,
Substituent-group A is independently halogen, hydroxy group, C 1-4 alkoxy, C 3-7 cycloalkyl, or C 3-7 cycloalkoxy, Substituent-group B is independently halogen, hydroxy group, C 1-4 alkyl, C 1-4 alkoxy, C 3-7 cycloalkyl, or C 3-7 cycloalkoxy,
provided that the following compounds are excluded:
5-(2-butyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-6-yl)-1-(2-hydroxyethyl)-1,3-dihydro-2H-benzimidazol-2-one,
3-[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile, and
3-[3-methyl-2-oxo-1-(3,3,3-trifluoro-2-hydroxy-2-methylpropyl)-2,3-dihydro-1H-benzimidazol-5-yl]pyridine-4-carbonitrile.
2 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1a , R 1b , R 1c , and R 1d are independently, hydrogen, halogen, C 1-4 alkyl, C 1-4 alkoxy (wherein the alkyl and the alkyl moiety in the alkoxy may be independently substituted with 1 to 3, the same or different halogen atoms), C 6-10 aryl, C 6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (wherein the aryl and the aryl moiety in the aryloxy, and the heteroaryl and the heteroaryl moiety in the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A).
3 . The compound of claim 1 or 2 or a pharmaceutically, acceptable salt thereof, wherein
R 1a , R 1b , R 1c , and R 1d are independently, hydrogen, C 6-10 aryl, C 6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein the aryl and the aryl moiety in the aryloxy, and the heteroaryl and the heteroaryl moiety in the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A.
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.
5 . The compound of any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein
R 1b or R 1c is C 6-10 aryl, C 6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein the aryl and the aryl moiety in the aryloxy, and the heteroaryl and the heteroaryl moiety in the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A.
6 . The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein
R 2 and R 3 are independently hydrogen or C 1-6 alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, hydroxy group, and C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, or
in R 2 , R 3 , and the hydroxy group bound to the carbon atom which is connected to R 2 and R 3 ,
R 2 and R 3 may be combined together with the carbon atom to which they are attached to form the following group of formula (IIa) with the hydroxy group
in formula (IIa),
e and f are independently 1 or 2,
V is as defined in claim 1 , and
R 5a , R 5b , R 5b , and R 5d are independently hydrogen or halogen, or
in R 2 , R 3 , the hydroxy group bound to the carbon atom which is connected to R 2 and R 3 , and CR 7 R 8 in L,
R 2 and R 7 may be combined together with the carbon atom to which they are attached to form the following group of formula (IIIa) with R 3 , the hydroxy group and R 8
in formula (IIIa),
m 1 is 0,
m 2 is 1 or 2, j is 1 or 2,
R 8 is hydrogen,
L is as defined in claim 1 , R 6a , R 6b , R 6c , and R 6d are independently hydrogen or halogen.
7 . The compound of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein
R 7 and R 8 are independently hydrogen or C 1-4 alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxy group, C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C 3-7 cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C 3-7 cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and
m is 1 or 2.
8 . The compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are hydrogen, and m is 1.
9 . The compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen or C 1-4 alkyl optionally-substituted with 1 to 5 the same or different halogen atoms.
10 . The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein
R 1b aryloxy, 5- to 12-membered is C 6-10 aryl, C 6-10 heteroaryl, or 5- to 12-membered heteroaryloxy, wherein the aryl and the aryl moiety in the aryloxy, and the heteroaryl and the heteroaryl moiety in the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A.
11 . The compound of any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein
R 1c is C 6-10 aryl, C 6-10 aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein the aryl and the aryl moiety in the aryloxy, and the heteroaryl and the heteroaryl moiety in the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, C 1-4 alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and C 1-4 alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A.
12 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:
1-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
1-[(3-hydroxyoxetan-3-yl)methyl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
1-[(3-hydroxyoxetan-3-yl)methyl]-6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
1-(cis-4-hydroxycyclohexyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
1-[(3-hydroxyoxetan-3-yl)methyl]-6-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-fluorophenoxy)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-fluorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-chlorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one,
1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-fluorophenoxy)-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-fluorophenoxy)-1-(cis-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-ethyl-3-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
3-(2-hydroxy-2-methylpropyl)-1-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
5-(4-fluorophenoxy)-3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one,
3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,
5-(4-chlorophenoxy)-3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-6-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-6-[5-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one,
5-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
1-[(3-hydroxyoxetan-3-yl)methyl]-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one, and
1-[(3-hydroxyoxetan-3-yl)methyl]-3-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one.
13 . The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:
1-(2-hydroxy-2-methylpropyl)-6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one,
1-[(3-hydroxyoxetan-3-yl)methyl]-6-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-chlorophenoxy)-1-[(3-hydroxyoxetan-3-yl)methyl]-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-fluorophenoxy)-1-[(2S)-3-hydroxy-3-methylbutan-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,
6-(4-fluorophenoxy)-1-(cis-4-hydroxycyclohexyl)-1,3-dihydro-2H-benzimidazol-2-one,
3-[(3-hydroxyoxetan-3-yl)methyl]-1-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-6-[5-(trifluoromethyl)pyridin-2-yl]-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-6-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3-dihydro-2H-benzimidazol-2-one,
5-(4-fluorophenyl)-1-(2-hydroxy-2-methylpropyl)-1,3-dihydro-2H-benzimidazol-2-one,
1-(2-hydroxy-2-methylpropyl)-5-{[5-(trifluoromethyl)pyridin-2-yl]oxy}-1,3-dihydro-2H-benzimidazol-2-one, and
1-[(3-hydroxyoxetan-3-yl)methyl]-3-methyl-5-[4-(trifluoromethoxy)phenoxy]-1,3-dihydro-2H-benzimidazol-2-one.
14 . A pharmaceutical combination comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.
15 . A medicament for treating a disease involving Nav 1.7 (SCN9A), comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.
16 . A medicament for treating neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, or multiple sclerosis, which comprises the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof as an active ingredient.
17 . A pharmaceutical combination comprising the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and at least one drug selected from the group consisting of an antiepileptic agent, an antidepressive agent, a narcotic analgesic, an anti-inflammatory agent, a reductase inhibitor, and a prostaglandin derivative drug.
18 . Use of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, or multiple sclerosis.
19 . A method for treating neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, or multiple sclerosis, which comprises administering a therapeutically effective amount of the compound of any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.