Benzimidazole compound and medical use thereof
Patent Information
- Application Number
- CA2989992
- Authority / Receiving Office
- CA · CA
- Patent Type
- Patents
- Current Assignee / Owner
- Priority Date
- 2015-09-11
- Filing Date
- 2016-09-09
- Publication Date
- 2026-10-13
- Estimated Expiration
- 2036-09-09
Abstract
Description
BENZIMIDAZOLE COMPOUND AND MEDICAL USE THEREOF Technical Field
[0001] The present invention may relate to a medicament for treating or preventing a disease involving Na channel, particularly SCN9A (Nav 1.7), which comprises a novel compound having a benzimidazole skeleton or a pharmaceutically-acceptable salt thereof as an active ingredient. In more detail, it relates to a medicament for treating or preventing a disease such as neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, and multiple sclerosis. Background Art
[0002] Voltage-dependent Na channel <com:Math><semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>< / com:Math> subunit that forms pore is known to include 9 kinds at present. Recently, it has been evidenced that the subunit, particularly Nav 1.7 is broadly concerned in the signal transduction of acute and chronic pain.
[0003] SCN9A (Nav 1.7) is tetrodotoxin (TTX)-sensitive Na channel localized in the peripheral sensory nerve or sympathetic nerve, which is also referred to as NENA or PN1. Physiologically, Nav 1.7 channel functions to amplify a pain signal (i.e., generate a generator potential) at the sensory nerve ending. In the field of genetic investigation, it has been getting evident that a human whose SCN9A gene mutates to result in loss-of-function shows congenital insensitivity to pain. Reversely, in patients suffering from a severe orphan disease such as erythromelalgia and paroxysmal extreme pain disorder, it is observed that SCN9A gene mutates to result in gain-of-function. Furthermore, it has been reported that approximately 30% of patients suffering from small fiber neuropathy have genetic polymorphism to enhance Nav 1.7 function (Non-Patent Literature 1). And, it is suggested that Nav 1.7 channel function is directly concerned in the hyperexcitability of DRG neuron in patients suffering from pain since the expression level and activity increase in DRG neuron of model animals suffering from chronic pain, and neuropathic pain and inflammatory pain decrease in a knockout experiment (Non-Patent Literature 2).
[0004] Patent Literature 1 discloses a benzimidazole derivative represented by the following formula (A), but the compound have 2-((4-cyclopropylpyridin-2- yl)amino)isonicotinonitrile as an essential partial structure, which is different from the compound of the present invention. And, the invention described in Patent Literature 1 is directed to a Syk tyrosine kinase inhibitor, thus Patent Literature 1 does not disclose the present invention at all. [Image disponible dans le document PDF, Image available in the PDF document] Citation List (Patent Literature)
[0005] 10 [Patent Literature 1] WO 2012 / 057262 (Non-Patent Literature)
[0006] [Non-Patent Literature 1] Nat Rev Neurosci. 14: 49, 2013 15 [Non-Patent Literature 2] Nat Commun. 3: 791, 2012 Summary [0006a] Certain exemplary embodiments provide a compound of 20 formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I) or a pharmaceutically acceptable salt thereof, wherein one of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12- membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein the heteroaryl or the heteroaryl moiety of the heteroaryloxy has the same or different 1 to 4 heteroatoms selected from nitrogen, sulfur atom, or oxygen, and each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and the other of R1b or R1c is hydrogen, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are each independently hydrogen or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different 1 to 3 halogens, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally substituted with 1 to 3 substituents selected independently from Substituent-group Α, m is 1, 2 or 3, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math>, wherein when m is 2 or 3, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are independently hydrogen or methyl, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (II) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (II) in formula (II), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, V is single bond or oxygen atom, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are hydrogen or halogen, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> in L, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atoms to which they are each attached to form the following group of formula (IV) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] in formula (IV), <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math>, the sum of <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> and j is 2 or 4, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is hydrogen or methyl, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, R<com:Sup>8< / com:Sup> is hydrogen, and L is as defined above, <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are hydrogen, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (III) with R<com:Sup>2< / com:Sup> [Image disponible dans le document PDF, Image available in the PDF document] (III) in formula (III), h is 2, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>R6a<annotation encoding="application / x-tex">R^{6a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6b<annotation encoding="application / x-tex">R^{6b}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6c<annotation encoding="application / x-tex">R^{6c}< / annotation>< / semantics>< / com:Math> are each hydrogen, and wherein not all of <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> are combined together to form a ring, Substituent-group A is independently halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, and provided that the following compounds are excluded: <com:Math><semantics>6−[6−chloro−2−(morpholin−4−yl)pyrimidin−4−yl]−1−(2−yl)<annotation encoding="application / x-tex">6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-yl)< / annotation>< / semantics>< / com:Math> methoxyethyl) -1H-benzimidazole, <com:Math><semantics>2−[5−(3,5−dimethyl−1,2−oxazol−4−yl)−1H−benzimidazol−1−<annotation encoding="application / x-tex">2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-< / annotation>< / semantics>< / com:Math> yl]ethanol, <com:Math><semantics>2−{5−[5−(tetrahydrofuran−3−y1)−4H−1,2,4−triazol−3−y1]−<annotation encoding="application / x-tex">2-\{5-[5-(tetrahydrofuran-3-y1)-4H-1,2,4-triazol-3-y1]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}ethanol, <com:Math><semantics>2−{5−[3−(2−methoxyethyl)−1−(2,2,2−trifluoroethyl)−1H−<annotation encoding="application / x-tex">2-\{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-< / annotation>< / semantics>< / com:Math> 1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol, <com:Math><semantics>2−{5−[3−methyl−1−(1−methylpiperidin−4−yl)−1H−1,2,4−<annotation encoding="application / x-tex">2-\{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-< / annotation>< / semantics>< / com:Math> 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, <com:Math><semantics>6−[1−(2−hydroxyethyl)−1H−benzimidazol−6−yl]−2−(3−<annotation encoding="application / x-tex">6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-< / annotation>< / semantics>< / com:Math> methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one, <com:Math><semantics>2−{5−[1−(2−hydroxyethyl)−1H−benzimidazol−5−yl]−1H−<annotation encoding="application / x-tex">2-\{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-< / annotation>< / semantics>< / com:Math> 1,2,4-triazol-1-yl}ethanol, 6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H- benzimidazole-7-carbonitrile, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] purine, and [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}ethanol.
[0007] (Technical Problem) The purpose of the present invention may be to provide a medicament for treating or preventing a disease involving Nav 1.7, specifically such as neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, and multiple sclerosis.
[0008] (Solution to Problem) The present inventors have conducted intensive studies in an attempt to solve the aforementioned problem and found that a compound having a benzimidazole ring mentioned below or a pharmaceutically acceptable salt thereof can inhibit the membrane potential change or the Na ion current itself via Na channel in Nav 1.7 gene expressing cell, i.e., the compound or a pharmaceutically acceptable salt thereof is a blocker having a inhibitory activity for Nav 1.7. In addition, the present inventors have found that the derivative is useful as a medicament for treating or preventing a disease such as neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, and paroxysmal extreme pain disorder, which resulted in the completion of the present invention. Accordingly, the present invention can provide a benzimidazole compound represented by the following formula (I) (hereinafter, also referred to as "compound represented by formula (I)" or "compound of formula (I)") or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as "compound of the present invention").
[0009] The present invention can show as follows. Term 1 A compound of formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I) or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylamino, (wherein each alkyl moiety of the alkyl, the alkoxy and the alkylamino may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 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), <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 7 cycloalkoxy, C<com:Sub>3-7< / com:Sub> cycloalkylamino, (wherein each cycloalkyl moiety of the cycloalkyl, the cycloalkoxy and the cycloalkylamino may be independently substituted with 1 to 15 5 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B), <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12- membered heteroaryl, or 5- to 12-membered heteroaryloxy, (wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylthio optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A), provided that at least one of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> is the above <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently hydrogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent- group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, or <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 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 C<com:Sub>3-7< / com:Sub> cycloalkyl which may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted 13 with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, m is 1, 2 or 3, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> provided that when m is 2 or 3, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are independently hydrogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, (wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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), <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, (wherein each cycloalkyl moiety of the cycloalkyl and the cycloalkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and C<com:Sub>3-7< / com:Sub> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (II) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (II) in formula (II), e and f are independently 1, 2 or 3, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is as defined above, V is single bond or oxygen atom, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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 <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> in L, <com:Math><semantics>ℝ2<annotation encoding="application / x-tex">\mathbb{R}^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>ℝ7<annotation encoding="application / x-tex">\mathbb{R}^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IV) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] (IV) in formula (IV), <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is 0 or 1, <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 0 or 1 and j is 1, 2, 3 or 4 when <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is 1, or <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 0, 1 or 2 and j is 1, 2, 3 or 4 when <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is 0, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> and L are as defined above, <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, 20 hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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 R<com:Sup>3< / com:Sup> and -OR<com:Sup>4< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (III) with R<com:Sup>2< / com:Sup> [Image disponible dans le document PDF, Image available in the PDF document] (III) in formula (III), h is 1, 2, 3, or 4, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is as defined above, <com:Math><semantics>R6a<annotation encoding="application / x-tex">R^{6a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6b<annotation encoding="application / x-tex">R^{6b}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6c<annotation encoding="application / x-tex">R^{6c}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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 В, provided that all of <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> are not combined together to form a ring, Substituent-group A is independently halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, and Substituent-group B is independently halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, provide that the following compounds are excluded: <com:Math><semantics>6−[6−chloro−2−(morpholin−4−yl)pyrimidin−4−yl]−1−(2−yl)<annotation encoding="application / x-tex">6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-yl)< / annotation>< / semantics>< / com:Math> methoxyethyl) -1H-benzimidazole, <com:Math><semantics>2−[5−(3,5−dimethyl−1,2−oxazol−4−yl)−1H−benzimidazol−1−<annotation encoding="application / x-tex">2-[5-(3,5-dimethyl-1,2-oxazol-4-yl)-1H-benzimidazol-1-< / annotation>< / semantics>< / com:Math> yl]ethanol, <com:Math><semantics>2−{5−[5−(tetrahydrofuran−3−y1)−4H−1,2,4−triazol−3−y1]−<annotation encoding="application / x-tex">2-\{5-[5-(tetrahydrofuran-3-y1)-4H-1,2,4-triazol-3-y1]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}ethanol, <com:Math><semantics>2−{5−[3−(2−methoxyethyl)−1−(2,2,2−trifluoroethyl)−1H−<annotation encoding="application / x-tex">2-\{5-[3-(2-methoxyethyl)-1-(2,2,2-trifluoroethyl)-1H-< / annotation>< / semantics>< / com:Math> 1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol, <com:Math><semantics>2−{5−[3−methyl−1−(1−methylpiperidin−4−yl)−1H−1,2,4−<annotation encoding="application / x-tex">2-\{5-[3-methyl-1-(1-methylpiperidin-4-yl)-1H-1,2,4-< / annotation>< / semantics>< / com:Math> 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, <com:Math><semantics>6−[1−(2−hydroxyethyl)−1H−benzimidazol−6−yl]−2−(3−<annotation encoding="application / x-tex">6-[1-(2-hydroxyethyl)-1H-benzimidazol-6-yl]-2-(3-< / annotation>< / semantics>< / com:Math> methylbutyl)-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one, <com:Math><semantics>2−{5−[1−(2−hydroxyethyl)−1H−benzimidazol−5−yl]−1H−<annotation encoding="application / x-tex">2-\{5-[1-(2-hydroxyethyl)-1H-benzimidazol-5-yl]-1H-< / annotation>< / semantics>< / com:Math> 1,2,4-triazol-1-yl}ethanol, 6-(2-chlorophenyl)-1-(2-hydroxyethyl)-1H- benzimidazole-7-carbonitrile, <com:Math><semantics>2−chloro−6−{7−fluoro−1−[(1S,3S)−3−methoxycyclohexyl]−1}<annotation encoding="application / x-tex">2-\text{chloro}-6-\{7-\text{fluoro}-1-[(1S,3S)-3-\text{methoxycyclohexyl}]-1\}< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-5-yl}-9-(tetrahydro-2H-pyran-2-yl)-9H- purine, and <com:Math><semantics>2−{5−[2−(tetrahydrofuran−3−yl)−1H−imidazol−1−yl]−1H−imidazol−1−yl]<annotation encoding="application / x-tex">2-\{5-[2-(tetrahydrofuran-3-yl)-1H-imidazol-1-yl]-1H-imidazol-1-yl]< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl}ethanol.
[0010] Term 2 The compound of Term 1 presented in formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I) or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylamino, (wherein each alkyl moiety of the alkyl, the alkoxy and the alkylamino may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Β, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), C<com:Sub>3-7< / com:Sub> cycloalkyl, C<com:Sub>3-< / com:Sub> <com:Math><semantics>7<annotation encoding="application / x-tex">_{7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkylamino, (wherein each cycloalkyl moiety of the cycloalkyl, the cycloalkoxy and the cycloalkylamino may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B), <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12- membered heteroaryl, or 5- to 12-membered heteroaryloxy, (wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylthio optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A), provided that at least one of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> is the above <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently hydrogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent- group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, or <com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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 C<com:Sub>3-7< / com:Sub> cycloalkyl which may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, m is 1, 2 or 3, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> provided that when m is 2 or 3, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are independently hydrogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, (wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group <com:Math><semantics>Ar<annotation encoding="application / x-tex">A_{r}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 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<com:Sub>3-7< / com:Sub> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, (wherein each cycloalkyl moiety of the cycloalkyl and the cycloalkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and C<com:Sub>3-7< / com:Sub> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (II) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (II) in formula (II), e and f are independently 1, 2 or 3, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is as defined above, V is single bond or oxygen atom, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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 <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (III) with R<com:Sup>2< / com:Sup> [Image disponible dans le document PDF, Image available in the PDF document] (III) in formula (III), h is 1, 2, 3, or 4, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is as defined above, <com:Math><semantics>R6a<annotation encoding="application / x-tex">R^{6a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6b<annotation encoding="application / x-tex">R^{6b}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6c<annotation encoding="application / x-tex">R^{6c}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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 В, provided that all of <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> are not combined together to form a ring, Substituent-group A is independently halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, and Substituent-group B is independently halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy.
[0011] Term 3 The compound of Term 1 or 2 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are independently, hydrogen, halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy (wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with the same or different and 1 to 3 halogens), <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy (wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A). 27
[0012] Term 4 The compound of any one of Terms 1 to 3 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are independently, hydrogen, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A.
[0013] Term 5 The compound of any one of Terms 1 to 4 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are hydrogen.
[0014] Term 6 The compound of any one of Terms 1 and 3 to 5 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, provided that both of <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are not hydrogen, or R<com:Sup>2< / com:Sup> and R<com:Sup>3< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIa) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (IIa) in formula (IIa), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> and V are as defined in Term 1, and <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> in L, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IVa) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] in formula (IVa), <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 1 or 2, j is 1, 2 or 3, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is as defined above, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> and L are as defined in Term 1, and <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen.
[0015] Term 7 The compound of any one of Terms 1 and 3 to 6 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with the same or different and 1 to 5 halogens, or <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIb) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (IIb) in formula (IIb), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>V<annotation encoding="application / x-tex">V< / annotation>< / semantics>< / com:Math> are as defined in Term 1, and <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> in L, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IVa) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] in formula (IVa), <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 1 or 2, j is 1, 2 or 3, R4 is hydrogen, <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> and L are as defined in Term 1, and <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen.
[0016] Term 8 The compound of any one of Terms 1 to 6 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, or <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIa) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (IIa) in formula (IIa), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> and V are as defined in Term 1, and <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen. 32
[0017] Term 9 The compound of any one of Terms 1 to 6 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 5 halogens, or <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIb) with <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] (IIb) in formula (IIb), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>V<annotation encoding="application / x-tex">V< / annotation>< / semantics>< / com:Math> are as defined in Term 1, and <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen.
[0018] Term 10 The compound of any one of Terms 1 to 9 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 5 halogens, and <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are not combined together with the carbon atom to which they are attached to form a ring.
[0019] Term 11 The compound of any one of Terms 1 to 5 and 10 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, or R<com:Sup>3< / com:Sup> and -OR<com:Sup>4< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIIa) with R<com:Sup>2< / com:Sup> [Image disponible dans le document PDF, Image available in the PDF document] (IIIa) in formula (IIIa), h is 1, 2, or 3, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is as defined in Term 1, <com:Math><semantics>R6a<annotation encoding="application / x-tex">R^{6a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6b<annotation encoding="application / x-tex">R^{6b}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6c<annotation encoding="application / x-tex">R^{6c}< / annotation>< / semantics>< / com:Math> are independently, hydrogen, halogen, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens.
[0020] Term 12 The compound of any one of Terms 1 to 11 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> are not combined together with the carbon atom to which they are attached to form a ring.
[0021] Term 13 The compound of any one of Terms 1 to 12 or a pharmaceutically acceptable salt thereof, wherein R4 is hydrogen.
[0022] Term 14 The compound of any one of Terms 1 to 13 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 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.
[0023] Term 15 The compound of any one of Terms 1 to 14 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are hydrogen, and m is 1.
[0024] Term 16 The compound of any one of Terms 1 to 15 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>1-4< / com:Sub> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Α.
[0025] Term 17 The compound of any one of Terms 1 to 16 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Α.
[0026] Term 18 The compound of any one of Terms 1 to 16 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Α.
[0027] Term 19 The compound of any one of Terms 1 to 16 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy or 5- to 12-membered heteroaryloxy wherein the aryl moiety of the aryloxy and the heteroaryl moiety of the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group <com:Math><semantics>Ar<annotation encoding="application / x-tex">A_{r}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Α.
[0028] Term 20 The compound of any one of Terms 1 to 16 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or 5- to 12-membered heteroaryl wherein the aryl and the heteroaryl may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Α.
[0029] Term 21 The compound of any one of Terms 1 to 20 or a pharmaceutically acceptable salt thereof, wherein <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 5 halogens.
[0030] Term 22 The compound of any one of Terms 1 and 3 to 20 or a pharmaceutically acceptable salt thereof, wherein R<com:Sup>2< / com:Sup> and R<com:Sup>3< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIb) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (IIb) in formula (IIb), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>V<annotation encoding="application / x-tex">V< / annotation>< / semantics>< / com:Math> are as defined in Term 1, and <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> in L, R<com:Sup>2< / com:Sup> and R<com:Sup>7< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IVa) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] in formula (IVa), <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 1 or 2, j is 1, 2 or 3, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> and L are as defined in Term 1, and <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen.
[0031] Term 23 The compound of Term 1 or 2, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: Example 1: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1- yl]-2-methylpropan-2-ol, Example 2: 6-(4-fluorophenoxy)-1-(tetrahydrofuran-2- ylmethyl) -1H-benzimidazole, Example 7: 1-(tetrahydrofuran-2-ylmethyl)-6-[4- (trifluoromethyl)phenyl]-1H-benzimidazole, Example 9: <com:Math><semantics>2−methyl−1−{6−[4−(trifluoromethyl)phenyl]−<annotation encoding="application / x-tex">2-\text{methyl}-1-\{6-[4-(\text{trifluoromethyl})\text{phenyl}]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}propan-2-ol, Example <com:Math><semantics>10:<annotation encoding="application / x-tex">10:< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1−[2−(cyclopentyloxy)ethyl]−6−[4−<annotation encoding="application / x-tex">1-[2-(cyclopentyloxy)ethyl]-6-[4-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)phenyl]-1H-benzimidazole, Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin- 2-yl]-1H-benzimidazol-1-yl}propan-2-ol, Example 12: <com:Math><semantics>1−[2−(cyclopentyloxy)ethyl]−6−[5−<annotation encoding="application / x-tex">1-[2-(cyclopentyloxy)ethyl]-6-[5-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyridin-2-yl]-1H-benzimidazole, Example 14: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-\text{methyl-1-}[6-(4-\text{methylphenoxy})-1H- benzimidazol-1-yl]propan-2-ol, Example 15: 2-methyl-1-{6-[4- (trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol, Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1- yl]-2-methylpropan-2-ol, Example 22: 2-methyl-1-{6-[4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl}propan-2-ol, Example 24: <com:Math><semantics>2−methyl−1−{6−[(6−methylpyridin−3−yl)oxy]−<annotation encoding="application / x-tex">2-\text{methyl}-1-\{6-[(6-\text{methylpyridin}-3-\text{yl})\text{oxy}]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 28: [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 51: [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 52: [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 53: [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2- methylpropan-2-ol, Example 54: 1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]- 1H-benzimidazol-1-yl}-2-methylpropan-2-ol, Example <com:Math><semantics>56<annotation encoding="application / x-tex">56< / annotation>< / semantics>< / com:Math>: <com:Math><semantics>3−[(6−{[5−(trifluoromethyl)pyridin−2−<annotation encoding="application / x-tex">3-[(6-\{[5-(trifluoromethyl)pyridin-2-< / annotation>< / semantics>< / com:Math> yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol, Example 58: <com:Math><semantics>1−[(6−{[5−(trifluoromethyl)pyridin−2−<annotation encoding="application / x-tex">1-[(6-\{[5-(trifluoromethyl)pyridin-2-< / annotation>< / semantics>< / com:Math> yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol, Example 59: [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> butan-2-ol, Example 60: [Image disponible dans le document PDF, Image available in the PDF document] trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 93: <com:Math><semantics>3−({6−[4−(trifluoromethyl)phenoxy]−1H−<annotation encoding="application / x-tex">3-(\{6-[4-(trifluoromethyl)phenoxy]-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl}methyl)oxetan-3-ol, Example 94: <com:Math><semantics>3−({6−[4−(trifluoromethoxy)phenoxy]−1H−<annotation encoding="application / x-tex">3-(\{6-[4-(trifluoromethoxy)phenoxy]-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl}methyl)oxetan-3-ol, Example 101: 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1- yl]-2-methylbutan-2-ol, Example <com:Math><semantics>3−{[6−(2−chloro−4−fluorophenoxy)−1H-}<annotation encoding="application / x-tex">3-\{[6-(2-\text{chloro}-4-\text{fluorophenoxy})-1\text{H-}\}< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl]methyl}oxetan-3-ol, Example 118: cis-4-(6-{[5-(trifluoromethyl)pyridin-2- yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol, Example 123: 1-{6-[2-fluoro-4- (trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2- methylpropan-2-ol, Example <com:Math><semantics>130:<annotation encoding="application / x-tex">130:< / annotation>< / semantics>< / com:Math> <com:Math><semantics>1−[6−(4−chloro−2−fluorophenyl)−1H−<annotation encoding="application / x-tex">1-[6-(4-chloro-2-fluorophenyl)-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl]-2-methylpropan-2-ol, Example 148: <com:Math><semantics>3−({6−[2−methoxy−4−<annotation encoding="application / x-tex">3-(\{6-[2-methoxy-4-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)phenyl]-1H-benzimidazol-1- yl}methyl)oxetan-3-ol, Example 173: <com:Math><semantics>4−{6−[2−methoxy−4−4]}<annotation encoding="application / x-tex">4 - \{6 - [2 - methoxy - 4 - 4]\}< / annotation>< / semantics>< / com:Math> (trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2- methylbutan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2- methylpropan-2-ol, Example 179: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-{5-[4- (trifluoromethoxy)phenyl]-1H-benzimidazol-1-yl}propan-2-ol, Example 181: 1-{5-[2-fluoro-4- (trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2- methylpropan-2-ol, Example 205: [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)phenyl]-1H-benzimidazol-1- yl}methyl)oxetan-3-ol, and Example 229: <com:Math><semantics>(3S)−2−methyl−3−(6−{[5−<annotation encoding="application / x-tex">(3S) - 2 - methyl - 3 - (6 - \{ [5 -< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> butan-2-ol.
[0032] Term 24 The compound of Term 1 or 2, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: Example 1: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1- yl]-2-methylpropan-2-ol, Example 2: 6-(4-fluorophenoxy)-1-(tetrahydrofuran-2- ylmethyl) -1H-benzimidazole, Example 7: 1-(tetrahydrofuran-2-ylmethyl)-6-[4- (trifluoromethyl)phenyl]-1H-benzimidazole, Example 9: <com:Math><semantics>2−methyl−1−{6−[4−(trifluoromethyl)phenyl]−<annotation encoding="application / x-tex">2-\text{methyl}-1-\{6-[4-(\text{trifluoromethyl})\text{phenyl}]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}propan-2-ol, Example 10: <com:Math><semantics>1−[2−(cyclopentyloxy)ethyl]−6−[4−<annotation encoding="application / x-tex">1-[2-(cyclopentyloxy)ethyl]-6-[4-< / annotation>< / semantics>< / com:Math> (trifluoromethyl) phenyl] -1H-benzimidazole, Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin- 2-yl]-1H-benzimidazol-1-yl}propan-2-ol, Example <com:Math><semantics>1−[2−(cyclopentyloxy)ethyl]−6−[5−<annotation encoding="application / x-tex">1-[2-(cyclopentyloxy)ethyl]-6-[5-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyridin-2-yl]-1H-benzimidazole, Example <com:Math><semantics>14:<annotation encoding="application / x-tex">14:< / annotation>< / semantics>< / com:Math> 2-methyl-1-[6-(4-methylphenoxy)-1H- benzimidazol-1-yl]propan-2-ol, Example 15: 2-methyl-1-{6-[4- (trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol, Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1- yl]-2-methylpropan-2-ol, Example 22: 2-methyl-1-{6-[4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl} propan-2-ol, Example 24: <com:Math><semantics>2−methyl−1−{6−[(6−methylpyridin−3−yl)oxy]−<annotation encoding="application / x-tex">2-\text{methyl}-1-\{6-[(6-\text{methylpyridin}-3-\text{yl})\text{oxy}]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}propan-2-ol, Example 25: <com:Math><semantics>2−methyl−1−(6−{[6−<annotation encoding="application / x-tex">2-methyl-1-(6-\{[6-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyridin-3-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 28: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-(6-{[5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> propan-2-o1, Example 51: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-(5-{5- (trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 52: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-(5-{[5- (trifluoromethyl)pyrimidin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> propan-2-o1, Example 53: 1-(5-{[3-fluoro-5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2- methylpropan-2-ol, Example 54: 1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]- 1H-benzimidazol-1-yl}-2-methylpropan-2-ol, Example 56: <com:Math><semantics>3−[(6−{[5−(trifluoromethyl)pyridin−2−<annotation encoding="application / x-tex">3-[(6-\{[5-(trifluoromethyl)pyridin-2-< / annotation>< / semantics>< / com:Math> yl]oxy}-1H-benzimidazol-1-yl)methyl]oxetan-3-ol, Example 58: <com:Math><semantics>1−[(6−{[5−(trifluoromethyl)pyridin−2−<annotation encoding="application / x-tex">1-[(6-\{[5-(trifluoromethyl)pyridin-2-< / annotation>< / semantics>< / com:Math> yl]oxy}-1H-benzimidazol-1-yl)methyl]cyclobutanol, Example 59: 2-methyl-4-(6-{[5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- yl)butan-2-ol, and Example 60: <com:Math><semantics>2−methyl−1−(6−{[5−(2,2,2−<annotation encoding="application / x-tex">2-methyl-1-(6-\{[5-(2,2,2-< / annotation>< / semantics>< / com:Math> trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol.
[0033] Term 25 The compound of Term 1 or 2, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: Example 1: <com:Math><semantics>1−[6−(4−fluorophenoxy)−1H−benzimidazol−1−<annotation encoding="application / x-tex">1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-< / annotation>< / semantics>< / com:Math> yl]-2-methylpropan-2-ol, Example 9: <com:Math><semantics>2−methyl−1−{6−[4−(trifluoromethyl)phenyl]−<annotation encoding="application / x-tex">2-\text{methyl}-1-\{6-[4-(\text{trifluoromethyl})\text{phenyl}]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}propan-2-ol, Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin- 2-yl]-1H-benzimidazol-1-yl}propan-2-ol, Example 15: <com:Math><semantics>2−methyl−1−{6−[4−<annotation encoding="application / x-tex">2-methyl-1-\{6-[4-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol, Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1- yl]-2-methylpropan-2-ol, Example 22: 2-methyl-1-{6-[4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl}propan-2-ol, Example 24: 2-methyl-1-{6-[(6-methylpyridin-3-yl)oxy]- 1H-benzimidazol-1-yl}propan-2-ol, Example 28: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-(6-{[5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 51: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-(5-{[5- (trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> propan-2-o1, Example 53: 1-(5-{[3-fluoro-5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2- methylpropan-2-ol, Example 59: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-4-(6-{[5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> butan-2-ol, Example 60: <com:Math><semantics>2−methyl−1−(6−{[5−(2,2,2−<annotation encoding="application / x-tex">2-methyl-1-(6-\{[5-(2,2,2-< / annotation>< / semantics>< / com:Math> trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 94: <com:Math><semantics>3−({6−[4−(trifluoromethoxy)phenoxy]−1H−<annotation encoding="application / x-tex">3-(\{6-[4-(trifluoromethoxy)phenoxy]-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl}methyl)oxetan-3-ol, Example 101: 4-[6-(4-chlorophenoxy)-1H-benzimidazol-1- yl]-2-methylbutan-2-ol, Example 118: cis-4-(6-{[5-(trifluoromethyl)pyridin-2- yl]oxy}-1H-benzimidazol-1-yl)cyclohexanol, Example 123: 1-{6-[2-fluoro-4- (trifluoromethyl)phenyl]-1H-benzimidazol-1-yl}-2- methylpropan-2-ol, Example 148: <com:Math><semantics>3−({6−[2−methoxy−4−<annotation encoding="application / x-tex">3-(\{6-[2-methoxy-4-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)phenyl]-1H-benzimidazol-1- yl}methyl)oxetan-3-ol, Example 205: <com:Math><semantics>3−({5−[2−methoxy−4−<annotation encoding="application / x-tex">3-(\{5-[2-methoxy-4-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)phenyl]-1H-benzimidazol-1- yl}methyl)oxetan-3-ol, and Example 229: <com:Math><semantics>(3S)−2−methyl−3−(6−{[5−<annotation encoding="application / x-tex">(3S) - 2 - methyl - 3 - (6 - \{ [5 -< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>yl)<annotation encoding="application / x-tex">yl)< / annotation>< / semantics>< / com:Math> butan-2-ol.
[0034] Term 26 The compound of Term 1 or 2, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: Example 1: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1- yl]-2-methylpropan-2-ol, Example 9: 2-methyl-1-{6-[4-(trifluoromethyl)phenyl]- 1H-benzimidazol-1-yl}propan-2-ol, Example 11: 2-methyl-1-{6-[5-(trifluoromethyl)pyridin- 2-yl]-1H-benzimidazol-1-yl}propan-2-ol, Example 15: 2-methyl-1-{6-[4- (trifluoromethyl)phenoxy]-1H-benzimidazol-1-yl}propan-2-ol, Example 20: 1-[6-(4-chlorophenoxy)-1H-benzimidazol-1- yl]-2-methylpropan-2-ol, Example 22: 2-methyl-1-{6-[4- (trifluoromethoxy) phenoxy] -1H-benzimidazol-1-yl}propan-2-ol, Example 24: <com:Math><semantics>2−methyl−1−{6−[(6−methylpyridin−3−yl)oxy]−<annotation encoding="application / x-tex">2-\text{methyl}-1-\{6-[(6-\text{methylpyridin}-3-\text{yl})\text{oxy}]-< / annotation>< / semantics>< / com:Math> 1H-benzimidazol-1-yl}propan-2-ol, Example 28: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-(6-{[5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> propan-2-o1, Example 51: <Formule mathématique disponible dans le document PDF, Math available in the PDF document>2-methyl-1-(5-{[5- (trifluoromethyl)pyrazin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol, Example 53: 1-(5-{[3-fluoro-5- (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1-yl)-2- methylpropan-2-ol, Example 59: <com:Math><semantics>2−methyl−4−(6−{[5−<annotation encoding="application / x-tex">2-methyl-4-(6-\{[5-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- <com:Math><semantics>y1)<annotation encoding="application / x-tex">y1)< / annotation>< / semantics>< / com:Math> butan-2-ol, and Example 60: <com:Math><semantics>2−methyl−1−(6−{[5−(2,2,2−<annotation encoding="application / x-tex">2-methyl-1-(6-\{[5-(2,2,2-< / annotation>< / semantics>< / com:Math> trifluoroethyl)pyridin-2-yl]oxy}-1H-benzimidazol-1- yl)propan-2-ol.
[0035] Term 27 A pharmaceutical composition comprising the compound of any one of Terms 1 to 26 or a pharmaceutically acceptable salt thereof.
[0036] Term 28 A medicament for treating a disease involving Nav 1.7 (SCN9A), comprising the compound of any one of Terms 1 to 26 or a pharmaceutically acceptable salt thereof as an active ingredient. Term 29 A compound of any one of Terms 1 to 26 or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of [Image disponible dans le document PDF, Image available in the PDF document] methoxyethyl) -1H-benzimidazole, [Image disponible dans le document PDF, Image available in the PDF document] yl]ethanol, [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzimidazol-1-yl}ethanol, [Image disponible dans le document PDF, Image available in the PDF document] 1,2,4-triazol-5-yl]-1H-benzimidazol-1-yl}ethanol, [Image disponible dans le document PDF, Image available in the PDF document] 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, [Image disponible dans le document PDF, Image available in the PDF document] 1,2,4-triazol-1-yl}ethanol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazole-7-carbonitrile, [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] purine, and [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}ethanol, or a pharmaceutically acceptable salt thereof. Term 30 A medicament for treating a disease involving Nav 1.7 (SCN9A), comprising the compound of Term 29 or a pharmaceutically acceptable salt thereof as an active ingredient.
[0037] Term 29 is the same as any one of Terms 1 to 26, provided that the 11 compounds excluded at the proviso in the end of Term 1 should not be excluded.
[0038] Term 31 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 Terms 1 to 26 or a pharmaceutically acceptable salt thereof as an active ingredient. Term 32 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 Term 29 or a pharmaceutically acceptable salt thereof as an active ingredient.
[0039] Term 33 A pharmaceutical combination comprising the compound of any one of Terms 1 to 26 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. Term 34 A pharmaceutical combination comprising the compound of Term 29 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.
[0040] Term 35 Use of the compound of any one of Terms 1 to 26 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. Term 36 Use of the compound of Term 29 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.
[0041] Term 37 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 Terms 1 to 26 or a pharmaceutically acceptable salt thereof to a mammal in need thereof. Term 38 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 Term 29 or a pharmaceutically acceptable salt thereof to a mammal in need thereof.
[0042] (Effect of Invention) The present invention provides a Nav 1.7 blocker comprising a novel benzimidazole compound or a pharmaceutically acceptable salt thereof. The compounds of the present invention are useful as a medicament for treating or preventing a disease involving Nav 1.7 (SCN9A), namely, the compounds are applicable to a patient suffering from neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, and the like. Description of Embodiments
[0043] Hereafter, the present invention is explained in more detail. The number of carbon atoms in the "substituent group" used herein can be sometimes expressed, for example, as "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math>". Specifically, the term "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" means an alkyl having 1 to 6 carbon atoms. In the present description, a substituent group which is not accompanied with "optionally- substituted" or "substituted" means an "unsubstituted" substituent group. For example, "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" means "unsubstituted <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl".
[0044] The substituent groups in the present description may be sometimes expressed without the term "group". In case that "optionally-substituted" is used in the definition of substituent groups, the number of the substituting groups is not limited as long as the substitutions are available, i.e., it is one or more. It means that the possible number of substituting groups is the substitution-available number on carbon atoms or carbon-nitrogen atoms in a substituent group which are acceptable for substitution. Unless otherwise specified, the definition of each substituent group also extends over the case of partially-including the substituent group or the case that the substituent group substituting another substituent groups.
[0045] Unless otherwise specified, the binding site of substituent groups is not limited as long as the site is available to be bound.
[0046] The "halogen" includes, for example, fluorine, chlorine, bromine, and iodine, preferably fluorine and chlorine.
[0047] The "<com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkyl" means a saturated hydrocarbon group having 1 to 2 carbon atoms, the "<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkyl" means a saturated straight or branched chain hydrocarbon group having 1 to 3 carbon atoms, the "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl" means a saturated straight or branched chain hydrocarbon group having 1 to 4 carbon atoms, and the "C<com:Sub>1-6< / com:Sub> alkyl" means a saturated straight or branched chain hydrocarbon group having 1 to 6 carbon atoms. The "<com:Math><semantics>C1−<annotation encoding="application / x-tex">C_{1-}< / annotation>< / semantics>< / com:Math> 2 alkyl" includes, for example, methyl and ethyl; the "<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkyl" includes, for example, propyl and isopropyl, besides the above alkyl; the "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl" includes, for example, butyl, isobutyl, sec-butyl, and tert-butyl, besides the above alkyl; and the "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" includes, for example, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, and a structural isomer thereof, besides the above alkyl. Preferred examples of the "<com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl" or "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl" include "<com:Math><semantics>C1−3<annotation encoding="application / x-tex">C_{1-3}< / annotation>< / semantics>< / com:Math> alkyl", and more preferably methyl and ethyl.
[0048] The "C<com:Sub>3-7< / com:Sub> cycloalkyl" means a non-aromatic cyclic hydrocarbon group (i.e., saturated hydrocarbon group) having 3 to 7 carbon atoms, and the "<com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl" means a non- aromatic cyclic hydrocarbon group (i.e., saturated hydrocarbon group) having 3 to 10 carbon atoms. The <com:Math><semantics>"C3−7<annotation encoding="application / x-tex">{}^{\text{"}}\text{C}_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl" and the "C<com:Sub>3-10< / com:Sub> cycloalkyl" also include a bridged one. The "C<com:Sub>3-7< / com:Sub> cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The "<com:Math><semantics>C3−10<annotation encoding="application / x-tex">C_{3-10}< / annotation>< / semantics>< / com:Math> cycloalkyl" includes, for example, cyclooctyl and adamantyl, besides the above, preferably, "C<com:Sub>3-7< / com:Sub> cycloalkyl".
[0049] The "C<com:Sub>6-10< / com:Sub> aryl" means an aromatic hydrocarbon group having 6 to 10 carbon atoms, preferably phenyl. The "<com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl" includes, for example, phenyl, 1-naphthyl and 2- naphthyl.
[0050] The "C<com:Sub>6-10< / com:Sub> aryl" also includes a condensed ring in which "phenyl" is fused with a 5- or 6-membered ring having one heteroatom selected from nitrogen, sulfur, or oxygen atom, or the same or different and two or more (for example, 2 to 4) heteroatoms thereof (for example, "5- or 6-membered mono- cyclic heteroaryl" mentioned below, and 5- or 6-membered ring in "3- to 7-membered non-aromatic heterocyclyl" mentioned below), or a 5- to 7-membered cycloalkyl ring (for example, cyclopentane, cyclohexane and cycloheptane). Examples of the condensed ring include groups of the following formulae. [Image disponible dans le document PDF, Image available in the PDF document]
[0051] The "5- to 12-membered heteroaryl" means a 5- to 12- membered mono- or multiple-cyclic aromatic group having one heteroatom selected from nitrogen, sulfur, or oxygen atom, or the same or different and two or more (for example, 2 to 4) heteroatoms thereof, besides carbon atoms as the ring atoms, preferably, "5- or 6-membered mono-cyclic heteroaryl". The "5- or 6-membered mono-cyclic heteroaryl" means a 5- or 6-membered mono-cyclic aromatic group within the "5- to 12- membered heteroaryl".
[0052] The multiple-cyclic heteroaryl in the "5- to 12- membered heteroaryl" includes, for example, a condensed ring in which the same or different two mono-cyclic heteroaryls are fused, or a mono-cyclic heteroaryl and an aromatic ring 60 (for example, benzene) or a non-aromatic ring (for example, cyclohexane) are fused. The "5- to 12-membered heteroaryl" includes, for example, groups of the formulae shown below. Preferably, the "5- to 12-membered heteroaryl" includes pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. Another embodiment includes, preferably, benzofuranyl in which the binding site is on the heteroaryl (furan) ring, pyridyl, pyrimidinyl, pyrazinyl, and pyridazinyl. Examples of the "5- or 6-membered mono-cyclic heteroaryl" include mono-cyclic groups out of the groups of the following formulae. [Image disponible dans le document PDF, Image available in the PDF document]
[0053] The "3- to 7-membered non-aromatic heterocyclyl" means 3- to 7-membered cyclic group having one heteroatom selected 5 from nitrogen, oxygen, or sulfur atom, or the same or different and two or more (for example, 2 to 4, preferably 2 to 3) heteroatoms thereof, besides carbon atoms as the ring atoms. The heterocyclyl is non-aromatic, which may be a saturated one or a partially-unsaturated one. Preferred one thereof is a saturated heterocyclyl, more preferably 5- or 6-membered saturated heterocyclyl. The "3- to 7-membered non-aromatic heterocyclyl" includes, for example, oxetanyl, azetidinyl, pyranyl, tetrahydrofuryl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxo-oxazolidinyl, dioxo-oxazolidinyl, dioxothiazolidinyl, tetrahydropyranyl, and tetrahydropyridinyl, and preferably pyranyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, and morpholinyl.
[0054] The "3- to 7-membered non-aromatic heterocyclyl" also includes a condensed ring in which the 3- to 7-membered non- aromatic heterocyclyl is fused with benzene or a 6-membered heteroaryl (for example, pyridine, pyrimidine or pyridazine). The examples thereof include dihydroindolyl, dihydroisoindolyl, dihydropurinyl, dihydrothiazolopyrimidinyl, dihydrobenzodioxanyl, isoindolinyl, indazolyl, pyrrolopyridinyl, tetrahydroquinolinyl, decahydroquinolinyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, tetrahydronaphthyridinyl, and tetrahydropyrido-azepinyl. 63
[0055] The "<com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkoxy" means oxy group substituted with the above "<com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkyl", and the "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy" means oxy group substituted with the above "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl". The "<com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkoxy" includes, for example, methoxy and ethoxy, and the <Formule mathématique disponible dans le document PDF, Math available in the PDF document>${}^{"}C_{1-4}$ alkoxy" includes, for example, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, and tert-butoxy, besides the above examples. Preferably, the "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy" includes methoxy, ethoxy, and isopropoxy.
[0056] The "C<com:Sub>3-7< / com:Sub> cycloalkoxy" means oxy group substituted with the above "<com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl". The "<com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy" includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy, and preferably cyclohexyloxy. The "<com:Math><semantics>C5−6<annotation encoding="application / x-tex">C_{5-6}< / annotation>< / semantics>< / com:Math> cycloalkoxy" means a cycloalkoxy having 5 or 6 carbon atoms within the "<com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy".
[0057] The "C<com:Sub>6-10< / com:Sub> aryloxy" means oxy group substituted with the above "<com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl". The "<com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy" includes, for example, phenyloxy and naphthyloxy, and preferably phenyloxy.
[0058] The "5- to 12-membered heteroaryloxy" means oxy group substituted with the above "5- to 12-membered heteroaryl". The "5- to 12-membered heteroaryloxy" includes, for example, pyridyloxy, imidazolyloxy and furyloxy, and preferably pyridyloxy.
[0059] The "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylamino" means amino group substituted with one or two of the above "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl". The "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylamino" includes, for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, dimethylamino, diethylamino, and ethylmethylamino, and preferably methylamino and dimethylamino.
[0060] The "C<com:Sub>3-7< / com:Sub> cycloalkylamino" means amino group substituted with one or two of the above "<com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl". The "<com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkylamino" includes, for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino and dicyclopropylamino, and preferably cyclohexylamino.
[0061] The "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl" means sulfonyl group substituted with the above "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl". The "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl" includes, for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and butylsulfonyl, and preferably methylsulfonyl.
[0062] The "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylthio" means thio group substituted with the above "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl". The "<com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylthio" includes, for 65 example, methylthio, ethylthio, propylthio, isopropylthio and butylthio, and preferably methylthio.
[0063] In order to disclose the present compound of the above formula (I) in more detail, each symbol used in the present invention is further explained below showing preferred examples.
[0064] Preferably, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> include independently hydrogen, halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylamino, (wherein each alkyl moiety of the alkyl, the alkoxy and the alkylamino may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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), <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkylamino, (wherein each cycloalkyl moiety of the cycloalkyl, the cycloalkoxy and the cycloalkylamino may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group <com:Math><semantics>A•<annotation encoding="application / x-tex">A_{\bullet}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and C<com:Sub>3-7< / com:Sub> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B), <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, and 5- to 12-membered heteroaryloxy, (wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylthio optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A), provided that at least one of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> is the above <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy.
[0065] More preferably, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> include independently hydrogen, halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, (wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with the same or different and 1 to 3 halogens), <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, and 5- to 12-membered heteroaryloxy, (wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A), provided that at least one of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> is the above <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy.
[0066] Even more preferably, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> include hydrogen, and <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> are independently hydrogen, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and optionally-substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, provided that both of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> are not hydrogen.
[0067] In another embodiment of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are hydrogen, and <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> are independently hydrogen, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, or 5- to 12-membered heteroaryloxy, wherein the aryl moiety of the aryloxy and the heteroaryl moiety of the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and optionally-substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, provided that both of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> are not hydrogen.
[0068] In another embodiment of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are hydrogen, and <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> are independently hydrogen, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and optionally-substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, provided that both of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> are not hydrogen.
[0069] In another embodiment of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are hydrogen, one of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy or 5- to 12-membered heteroaryloxy, wherein the aryl moiety of the aryloxy and the heteroaryl moiety of the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and optionally-substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, and the other is hydrogen.
[0070] In another embodiment of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are hydrogen, one of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and optionally- substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, and the other is hydrogen.
[0071] Preferred examples of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> include hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 4-(trifluoromethyl)phenyl, 5- (trifluoromethyl)pyridin-2-yl, 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, and (5- fluoropyridin-2-yl)oxy.
[0072] More preferred examples of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> include hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl, 5-(trifluoromethyl)pyridin-2-yl, 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, <com:Math><semantics>(5−<annotation encoding="application / x-tex">(5-< / annotation>< / semantics>< / com:Math> (trifluoromethyl)pyridin-2-yl)oxy, and (5-fluoropyridin-2- yl) oxy.
[0073] Even more preferred examples of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> 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, and (5-(trifluoromethyl)pyridin-2- yl)oxy.
[0074] Other embodiments of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> include hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, phenyl, 2-fluorophenyl, 3-fluorophenyl, 4- fluorophenyl, 4-(trifluoromethyl)phenyl, 5- (trifluoromethyl)pyridin-2-yl, 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.
[0075] Other embodiments of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> 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.
[0076] Preferably, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> include hydrogen and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and more preferably hydrogen and <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 5 halogens.
[0077] Preferred examples of <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> include hydrogen, methyl, ethyl, isopropyl, isobutyl, trifluoromethyl, cyclopropyl, cyclopentyl, and cyclohexyl, and more preferably hydrogen, methyl, and ethyl.
[0078] And, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (II) with <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document] (II)
[0079] In the above formula (II), preferably e and f are independently 1 or 2.
[0800] Preferably, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen.
[0081] And, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IV) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document]
[0082] In the above formula (IV), preferably <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is 0, and preferably <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 1 or 2. Preferably, j is 1, 2 or 3.
[0083] Preferably, <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen. Preferably, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen.
[0084] Preferably, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl which may be substituted with the same or different and 1 to 3 halogens, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, and more preferably hydrogen.
[0085] Preferred examples of R4 include hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, and more preferably hydrogen, isopropyl, and cyclopentyl, and even more preferably hydrogen.
[0086] And, R<com:Sup>3< / com:Sup> and -OR<com:Sup>4< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (III) with <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>. [Image disponible dans le document PDF, Image available in the PDF document] (III)
[0087] In the above formula (III), preferably h is 1, 2 or 3, and more preferably 2 or 3.
[8800] Preferably, <com:Math><semantics>R6a<annotation encoding="application / x-tex">R^{6a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6b<annotation encoding="application / x-tex">R^{6b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R6c<annotation encoding="application / x-tex">R^{6c}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, and more preferably hydrogen.
[0089] Preferred examples of <com:Math><semantics>R6a<annotation encoding="application / x-tex">R^{6a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6b<annotation encoding="application / x-tex">R^{6b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R6c<annotation encoding="application / x-tex">R^{6c}< / annotation>< / semantics>< / com:Math> include hydrogen, fluorine, hydroxyl, methyl, trifluoromethyl, methoxy, ethoxy, and trifluoromethoxy, and more preferably hydrogen, fluorine, and methyl, and even more preferably hydrogen.
[0090] Preferably, m is 1 or 2, and more preferably 1.
[0091] L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> provided that when m is 2 or 3, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different.
[0092] Preferably, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> include hydrogen and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 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 more preferably hydrogen.
[0093] Preferred examples of <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> include hydrogen, methyl, and ethyl, and more preferably hydrogen.
[0094] Preferably, Substituent-group A includes fluorine, chlorine, hydroxyl, <com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkoxy, and <com:Math><semantics>C5−6<annotation encoding="application / x-tex">C_{5-6}< / annotation>< / semantics>< / com:Math> cycloalkoxy, and more preferably fluorine, hydroxyl, and <com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkoxy.
[0095] Preferably, Substituent-group B includes fluorine, chlorine, hydroxyl, <com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkoxy, and <com:Math><semantics>C5−6<annotation encoding="application / x-tex">C_{5-6}< / annotation>< / semantics>< / com:Math> 77 cycloalkoxy, and more preferably fluorine, hydroxyl, <com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkyl, and <com:Math><semantics>C1−2<annotation encoding="application / x-tex">C_{1-2}< / annotation>< / semantics>< / com:Math> alkoxy.
[0096] An embodiment of the compound of formula (I) includes the following compound or a pharmaceutically acceptable salt thereof: <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are independently, hydrogen, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, provided that at least one of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> is the above <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> 10 aryloxy, 5- to 12-membered heteroaryl or 5- to 12-membered heteroaryloxy, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, provided that both of <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are not hydrogen, or <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIa) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (IIa) in formula (IIa), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 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 C<com:Sub>3-7< / com:Sub> cycloalkyl which may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, V is single bond or oxygen atom, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> in L, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IVa) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] in formula (IVa), <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 1 or 2, j is 1, 2 or 3, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 halogens, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 halogens, <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is hydrogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy (wherein each alkyl moiety of the alkyl and the alkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, C<com:Sub>3-7< / com:Sub> 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), <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy, (wherein each cycloalkyl moiety of the cycloalkyl and the cycloalkoxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B), L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math>, provided that when m is 2, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different, <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, or R<com:Sup>3< / com:Sup> and -OR<com:Sup>4< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIIa) with <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] (IIIa) in formula (IIIa), h is 1, 2 or 3, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, and C<com:Sub>3-7< / com:Sub> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, or C<com:Sub>3-10< / com:Sub> cycloalkyl, <com:Math><semantics>R6a<annotation encoding="application / x-tex">R^{6a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R6b<annotation encoding="application / x-tex">R^{6b}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R6c<annotation encoding="application / x-tex">R^{6c}< / annotation>< / semantics>< / com:Math> are independently hydrogen, halogen, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, m is 1 or 2, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math>, provided that when m is 2, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl which may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Β, and 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B.
[0097] Another embodiment of the compound of formula (I) includes the following compound or a pharmaceutically acceptable salt thereof: <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are hydrogen, at least one of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are independently <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with the same or different and 1 to 5 halogens, or R<com:Sup>2< / com:Sup> and R<com:Sup>3< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIb) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] in formula (IIb), e and f are independently 1 or 2, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−6<annotation encoding="application / x-tex">C_{1-6}< / annotation>< / semantics>< / com:Math> alkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> 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 C<com:Sub>3-7< / com:Sub> cycloalkyl which may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted 85 with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, V is single bond or oxygen atom, <com:Math><semantics>R5a<annotation encoding="application / x-tex">R^{5a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5b<annotation encoding="application / x-tex">R^{5b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R5c<annotation encoding="application / x-tex">R^{5c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R5d<annotation encoding="application / x-tex">R^{5d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen, or in <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> in L, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IVa) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] in formula (IVa), <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 1 or 2, j is 1 or 2, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, R4 is hydrogen, <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math>, provided that when m is 2, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different, <com:Math><semantics>R9a<annotation encoding="application / x-tex">R^{9a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9b<annotation encoding="application / x-tex">R^{9b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R9c<annotation encoding="application / x-tex">R^{9c}< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R9d<annotation encoding="application / x-tex">R^{9d}< / annotation>< / semantics>< / com:Math> are independently hydrogen or halogen, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, or <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with the same or different and 1 to 3 halogens, or <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIIa) with R<com:Sup>2< / com:Sup> [Image disponible dans le document PDF, Image available in the PDF document] (IIIa) in formula (IIIa), h is 1, 2 or 3, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> is hydrogen or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, R<com:Sup>6a< / com:Sup>, R<com:Sup>6b< / com:Sup>, and R<com:Sup>6c< / com:Sup> are independently hydrogen, halogen, or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens, m is 1 or 2, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math>, provided that when m is 2, each <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math> are independently the same or different, <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are independently hydrogen or <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with the same or different and 1 to 3 halogens.
[0098] Another embodiment of the compound of formula (I) includes the following compound or a pharmaceutically acceptable salt thereof: <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math> are hydrogen, one of <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> 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-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, or 2,4- dichlorophenoxy, and the other is hydrogen, both of <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math> are methyl, or R<com:Sup>2< / com:Sup> and R<com:Sup>3< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIc) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (IIC) in formula (IIc), e and f are independently 1 or 2, R4 is hydrogen, V is single bond or oxygen atom, or <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> may be combined together with the carbon atom to which they are attached to form the following group of formula (IVc) with <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>−OR4<annotation encoding="application / x-tex">-OR^4< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> [Image disponible dans le document PDF, Image available in the PDF document] in formula (IVc), <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are hydrogen, <com:Math><semantics>m1<annotation encoding="application / x-tex">m^1< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>0<annotation encoding="application / x-tex">0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m2<annotation encoding="application / x-tex">m^2< / annotation>< / semantics>< / com:Math> is 1 or 2, j is 1 or 2, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math>, and both of <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are hydrogen, R4 is hydrogen, isopropyl or cyclopentyl, or R<com:Sup>3< / com:Sup> and -OR<com:Sup>4< / com:Sup> may be combined together with the carbon atom to which they are attached to form the following group of formula (IIIb) with R<com:Sup>2< / com:Sup> [Image disponible dans le document PDF, Image available in the PDF document] (IIIb) in formula (IIIa), R<com:Sup>2< / com:Sup> is hydrogen, and h is 2, m is 1, L is <com:Math><semantics>CR7R8<annotation encoding="application / x-tex">CR^7R^8< / annotation>< / semantics>< / com:Math>, and both of <com:Math><semantics>R7<annotation encoding="application / x-tex">R^7< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R8<annotation encoding="application / x-tex">R^8< / annotation>< / semantics>< / com:Math> are independently hydrogen or methyl.
[0099] Processes to prepare the compounds of the present invention are mentioned below. The compound (I) of the present invention can be prepared, for example, according to Processes 1 to 5 shown below.
[0100] Process 1: Compound (I) wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ORa<annotation encoding="application / x-tex">OR^a< / annotation>< / semantics>< / com:Math>, i.e., Compound (S-5) or a pharmaceutically acceptable salt thereof can be prepared, for example, according to the following process. [Image disponible dans le document PDF, Image available in the PDF document] In the above scheme, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, L, and m are as defined in Term 1; RaO- means Rlb which is selected from <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, or 5- to 12-membered heteroaryloxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B; and <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are independently a leaving group such as halogen, trifluoromethanesulfonyloxy, and methanesulfonyloxy.
[0101] Step <com:Math><semantics>(1−1)<annotation encoding="application / x-tex">(1-1)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Nitroaniline compound (s-2) by reacting Nitrobenzene compound (s-1) and an amine compound. 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, diisopropylethylamine, and DABCO<Formule mathématique disponible dans le document PDF, Math available in the PDF document>$^{\text{\tiny TM}}$ (1,4- diazabicyclo[2,2,2]octane). When the amine compound is used in large excess, it is not necessary to use such base. The solvent used herein includes ethers such as THF, dimethoxyethane, and 1,4-dioxane; DMF; NMP; acetonitrile; and the like. The reaction time is generally about 10 minutes to about 10 hours, and the reaction temperature is 0°C to boiling point of a solvent used herein.
[0102] Step <com:Math><semantics>(1−2)<annotation encoding="application / x-tex">(1-2)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound <com:Math><semantics>(s−3)<annotation encoding="application / x-tex">(s-3)< / annotation>< / semantics>< / com:Math> by reacting Nitroaniline compound (s-2) and a compound having hydroxyl. 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; acetonitrile; and the like. The reaction time is generally about 10 minutes to about 10 hours, and 92 the reaction temperature is 0°C to boiling point of a solvent used herein.
[0103] Step <com:Math><semantics>(1−3)<annotation encoding="application / x-tex">(1-3)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Amino compound (s-4) by reducing Nitro compound <com:Math><semantics>(s−3)<annotation encoding="application / x-tex">(s-3)< / annotation>< / semantics>< / com:Math>. The reaction condition of the present step includes a general condition to reduce nitro group, for example, catalytic reduction under hydrogenation with palladium-carbon or the like, metallic reduction with zinc, iron or the like, and hydride reduction with lithium aluminium hydride or the like. The solvent used herein may be chosen from generally-used solvents depending on each reduction condition, and includes methanol, ethanol, THF, ethyl acetate, or the like for catalytic reduction; THF, acetic acid, methanol, ethanol, or the like for metallic reduction; and diethyl ether, THF, or the like for hydride reduction. The reaction time is generally about 10 minutes to about 24 hours, and the reaction temperature is 0°C to boiling point of a solvent used herein.
[0104] Step <com:Math><semantics>(1−4)<annotation encoding="application / x-tex">(1-4)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (S-5) by reacting Phenylenediamine compound (s-4) and formic acid or a formic acid equivalent to be cyclized. The formic acid equivalent includes orthoformates such as methyl orthoformate and ethyl orthoformate. In the present step, a catalyst may be used, which includes an organic acid such as formic acid and acetic acid, and Lewis acid such as ytterbium triflate. The solvent used herein includes alcohols such as methanol and ethanol. It is also possible to use formic acid, orthoformate and the like as a solvent, which are mentioned above as a reactant. The reaction time is generally about 10 minutes to about 24 hours, and the reaction temperature is room temperature to boiling point of a solvent used herein.
[0105] Compound (I) wherein any one or more of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and R<com:Sup>1d< / com:Sup> is OR<com:Sup>a< / com:Sup> or a pharmaceutically acceptable salt thereof can be also prepared in a similar manner as the above process.
[0106] Process 2: Compound (I) wherein <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>< / com:Math> (alkyl or cycloalkyl), i.e., Compound (S-7) or a pharmaceutically acceptable salt thereof can be prepared, for example, according to the following process. [Image disponible dans le document PDF, Image available in the PDF document] In the above scheme, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, L, and m are as defined in Term 1; <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math> is the same definition as the above <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>; and <com:Math><semantics>R4a<annotation encoding="application / x-tex">R^{4a}< / annotation>< / semantics>< / com:Math> is the same as <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, provided that hydrogen is excluded.
[0107] Step <com:Math><semantics>(2−1)<annotation encoding="application / x-tex">(2-1)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Ether compound (S-7) by reacting Alcohol compound <com:Math><semantics>(s−6)<annotation encoding="application / x-tex">(s-6)< / annotation>< / semantics>< / com:Math> which is Compound <com:Math><semantics>(s−5)<annotation encoding="application / x-tex">(s-5)< / annotation>< / semantics>< / com:Math> wherein <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math> is hydrogen, and, for example, a compound of <com:Math><semantics>R4aX3<annotation encoding="application / x-tex">R^{4a}X^3< / annotation>< / semantics>< / com:Math> in the presence of a base. The base used herein includes sodium hydride, potassium hydride, lithium hydride, butyllithium, potassium butoxide, and the like. The solvent used herein includes ethers such as diethyl ether and THF; DMF; NMP; dimethyl sulfoxide; and the like. The reaction time is generally about 10 minutes to about 24 hours, and the reaction temperature is 0°C to boiling point of a solvent used herein.
[0108] Process 3: Compound (I) wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>Rb<annotation encoding="application / x-tex">R^{b}< / annotation>< / semantics>< / com:Math> (aryl or heteroaryl), i.e., Compound (S-10) or a pharmaceutically acceptable salt thereof can be prepared, for example, according to the following process. [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] In the above scheme, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, L, and m are as defined in Term 1; <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> is as defined above; and <com:Math><semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl or 5- to 12-membered heteroaryl, wherein the aryl and the heteroaryl may be independently substituted with 1 to 5 substituents selected independently from the group consisting of halogen, cyano, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, C<com:Sub>3-7< / com:Sub> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, 3- to 7-membered non-aromatic heterocyclyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylthio optionally-substituted with 1 to 3 substituents selected independently from Substituent-group <com:Math><semantics>Ar<annotation encoding="application / x-tex">A_{r}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkylsulfonyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group Α.
[0109] Step <com:Math><semantics>(3−1)<annotation encoding="application / x-tex">(3-1)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Amino compound <com:Math><semantics>(s−8)<annotation encoding="application / x-tex">(s-8)< / annotation>< / semantics>< / com:Math> by selectively reducing the nitro group in Nitrobenzene compound <com:Math><semantics>(s−2)<annotation encoding="application / x-tex">(s-2)< / annotation>< / semantics>< / com:Math>. The reaction condition of the present step includes catalytic reduction under hydrogenation with sulfur-poisoning platinum-carbon or the like; metallic reduction with zinc, iron, tin or the like; and hydride reduction with lithium aluminium hydride or the like. The solvent used herein may be chosen from generally-used solvents depending on each reduction condition, and includes methanol, ethanol, THF, ethyl acetate, or the like for catalytic reduction; THF, acetic acid, methanol, ethanol, or the like for metallic reduction; and diethyl ether, THF, or the like for hydride reduction. The reaction time is generally about 10 minutes to about 24 hours, and the reaction temperature is 0°C to boiling point of a solvent used herein.
[0110] Step <com:Math><semantics>(3−2)<annotation encoding="application / x-tex">(3-2)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound <com:Math><semantics>(s−9)<annotation encoding="application / x-tex">(s-9)< / annotation>< / semantics>< / com:Math> by treating Amino compound (s-8) in a similar manner of Step <com:Math><semantics>(1−4)<annotation encoding="application / x-tex">(1-4)< / annotation>< / semantics>< / com:Math>.
[0111] Step <com:Math><semantics>(3−3)<annotation encoding="application / x-tex">(3-3)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (S-10) by reacting Compound (s-9) and a boronic acid compound having Rb group or its ester compound in the presence of a base and a catalyst. Specifically, this step is a process by means of Suzuki coupling reaction. The base used herein includes sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. The catalyst used herein includes palladium acetate, tetrakis (triphenylphosphine) palladium, tris(dibenzylideneacetone)dipalladium, and the like. The solvent used herein includes 1,4-dioxane, toluene, 1,2- dimethoxyethane, and the like. The reaction time is generally about 30 minutes to about 24 hours, and the reaction temperature is room temperature to boiling point of a solvent used herein.
[0112] Compound (I) wherein any one or more of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and R<com:Sup>1d< / com:Sup> is R<com:Sup>b< / com:Sup> or a pharmaceutically acceptable salt thereof can be also prepared in a similar manner as the above process.
[0113] Process 4: Compound (I) wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>Rb<annotation encoding="application / x-tex">R^{b}< / annotation>< / semantics>< / com:Math>, i.e., Compound (S-10) or a pharmaceutically acceptable salt thereof can be also prepared, for example, according to the following process. [Image disponible dans le document PDF, Image available in the PDF document] In the above scheme, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, L, and m are as defined in Term 1; <com:Math><semantics>Rb<annotation encoding="application / x-tex">R^b< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X2<annotation encoding="application / x-tex">X^2< / annotation>< / semantics>< / com:Math> are as defined above; and <com:Math><semantics>R10<annotation encoding="application / x-tex">R^{10}< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>R11<annotation encoding="application / x-tex">R^{11}< / annotation>< / semantics>< / com:Math> are independently optionally-substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl, optionally-substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkoxy, optionally-substituted <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> dialkylamino, optionally-substituted <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl, optionally-substituted <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryloxy, optionally-substituted 5- to 12-membered heteroaryl, optionally-substituted 5- to 12-membered heteroaryloxy, or hydroxyl. Preferably, <com:Math><semantics>R10R11B<annotation encoding="application / x-tex">R^{10}R^{11}B< / annotation>< / semantics>< / com:Math>- includes the following structures, but not limited thereto. [Image disponible dans le document PDF, Image available in the PDF document]
[0114] Step <com:Math><semantics>(4−1)<annotation encoding="application / x-tex">(4-1)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Boronate ester compound (s-11) by reacting Compound (s-9) and a diboron compound such as bis(pinacolato)diboron in the presence of a catalyst and a base. The catalyst used herein includes dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium, tetrakis (triphenylphosphine) palladium, tris (dibenzylideneacetone) dipalladium, bis (triphenylphosphine) palladium dichloride, and the like. The base used herein includes potassium acetate, tripotassium phosphate, potassium carbonate, and the like. The solvent used herein includes 1,4-dioxane, toluene, 1,2- dimethoxyethane, and the like. The reaction time is generally about 1 hour to about 48 hours, and the reaction temperature is room temperature to boiling point of a solvent used herein. 100
[0115] Step <com:Math><semantics>(4−2)<annotation encoding="application / x-tex">(4-2)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (S-10) by reacting Boronate ester compound (s-11) and a halide compound having Rb group or a triflate compound having Rb group (such as <com:Math><semantics>Rb−X<annotation encoding="application / x-tex">R^b-X< / annotation>< / semantics>< / com:Math> (X: halogen atom) or <com:Math><semantics>CF3SO2O−Rb<annotation encoding="application / x-tex">CF_3SO_2O-R^b< / annotation>< / semantics>< / com:Math>) in the presence of a catalyst and a base. Specifically, this step is a process by means of Suzuki coupling reaction. The base used herein includes sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and the like. The catalyst used herein includes palladium acetate, tetrakis (triphenylphosphine) palladium, tris(dibenzylideneacetone)dipalladium, and the like. The solvent used herein includes 1,4-dioxane, toluene, 1,2- dimethoxyethane, and the like. The reaction time is generally about 30 minutes to about 48 hours, and the reaction temperature is room temperature to boiling point of a solvent used herein.
[0116] Compound (I) wherein any one or more of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and R<com:Sup>1d< / com:Sup> is R<com:Sup>b< / com:Sup> or a pharmaceutically acceptable salt thereof can be also prepared in a similar manner as the above process.
[0117] Process 5: Compound (I) wherein <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>ORa<annotation encoding="application / x-tex">OR^a< / annotation>< / semantics>< / com:Math>, i.e., Compound (S-5) or a pharmaceutically acceptable salt thereof can be also prepared, for example, according to the following process. [Image disponible dans le document PDF, Image available in the PDF document] - In the above scheme, <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1d<annotation encoding="application / x-tex">R^{1d}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R2<annotation encoding="application / x-tex">R^2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R3<annotation encoding="application / x-tex">R^3< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R4<annotation encoding="application / x-tex">R^4< / annotation>< / semantics>< / com:Math>, L, and m are as defined in Term 1; and <com:Math><semantics>Ra<annotation encoding="application / x-tex">R^a< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math> are as defined above. Bn means benzyl group. Instead of benzyl group, similar protective group to benzyl group may be also used, for example, substituted benzyl group which is disclosed in Greene, T.W. and Wuts, P.G.M. (2006). Protective Groups in Organic Synthesis. 4th Edition, John Wiley & Sons, Inc., New York.
[0118] Step <com:Math><semantics>(5−1)<annotation encoding="application / x-tex">(5-1)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (s-13), for example, by reacting Compound (s-12) with <com:Math><semantics>Bn−X3<annotation encoding="application / x-tex">Bn-X^3< / annotation>< / semantics>< / com:Math> in the presence of a base. The base used herein includes sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, and the like. Bn-<com:Math><semantics>X3<annotation encoding="application / x-tex">X^3< / annotation>< / semantics>< / com:Math> may include benzyl chloride, benzyl bromide and the like. As appropriate, sodium iodide, potassium iodide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, or the like may be added thereto. The solvent used herein includes acetone, acetonitrile, THF, diethyl ether, 1,4-dioxane, 1,2- dimethoxyethane, DMF, NMP, and the like. The reaction time is generally about 30 minutes to about 24 hours, and the reaction temperature is 0°C to boiling point of a solvent used herein. In addition, Compound (s-13) can be also prepared from Compound (s-12) according to the method (condition) disclosed in Protective Groups in Organic Synthesis (Ibid) and such.
[0119] Step <com:Math><semantics>(5−2)<annotation encoding="application / x-tex">(5-2)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (s-14) from Compound <com:Math><semantics>(s−13)<annotation encoding="application / x-tex">(s-13)< / annotation>< / semantics>< / com:Math> in a similar manner of Step <com:Math><semantics>(1−1)<annotation encoding="application / x-tex">(1-1)< / annotation>< / semantics>< / com:Math>.
[0120] Step <com:Math><semantics>(5−3)<annotation encoding="application / x-tex">(5-3)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (s-15) from Compound <com:Math><semantics>(s−14)<annotation encoding="application / x-tex">(s-14)< / annotation>< / semantics>< / com:Math> in a similar manner of Step <com:Math><semantics>(3−1)<annotation encoding="application / x-tex">(3-1)< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(i.e.,a)<annotation encoding="application / x-tex">(i.e., a)< / annotation>< / semantics>< / com:Math> manner to selectively reduce a nitro group).
[0121] Step <com:Math><semantics>(5−4)<annotation encoding="application / x-tex">(5-4)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (s-16) from Compound <com:Math><semantics>(s−15)<annotation encoding="application / x-tex">(s-15)< / annotation>< / semantics>< / com:Math> in a similar manner of Step <com:Math><semantics>(1−4)<annotation encoding="application / x-tex">(1-4)< / annotation>< / semantics>< / com:Math>.
[0122] Step <com:Math><semantics>(5−5)<annotation encoding="application / x-tex">(5-5)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound <com:Math><semantics>(s−17)<annotation encoding="application / x-tex">(s-17)< / annotation>< / semantics>< / com:Math>, for example, by hydrogenating Compound (s-16) to deprotect it to the hydroxyl group. The catalyst used herein is a heterogenous catalyst such as palladium-carbon. The condition of hydrogenation means "under hydrogen atmosphere" or "in the presence of formic acid, ammonium formate, or the like". The solvent used herein includes methanol, ethanol, THF, ethyl acetate, and the like. The reaction time is generally about 30 minutes to about 24 hours, and the reaction temperature is 0°C to boiling point of a solvent used herein. In addition, Compound (s-17) can be also prepared from Compound (s-16) according to the method (condition) disclosed in Protective Groups in Organic Synthesis (Ibid) and such.
[0123] Step <com:Math><semantics>(5−6)<annotation encoding="application / x-tex">(5-6)< / annotation>< / semantics>< / com:Math>: This step is a process to prepare Compound (S-5) from Compound <com:Math><semantics>(s−17)<annotation encoding="application / x-tex">(s-17)< / annotation>< / semantics>< / com:Math>, which includes the following two reaction conditions, but not limited thereto. 1) As a reaction condition using a base, it includes a process to prepare Compound <com:Math><semantics>(S−5)<annotation encoding="application / x-tex">(S-5)< / annotation>< / semantics>< / com:Math> from Compound <com:Math><semantics>(s−17)<annotation encoding="application / x-tex">(s-17)< / annotation>< / semantics>< / com:Math> and <com:Math><semantics>Ra−X4<annotation encoding="application / x-tex">R^{a}-X^{4}< / annotation>< / semantics>< / com:Math> wherein <com:Math><semantics>Ra<annotation encoding="application / x-tex">R^{a}< / annotation>< / semantics>< / com:Math> in <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math> is <com:Math><semantics>C1−4<annotation encoding="application / x-tex">C_{1-4}< / annotation>< / semantics>< / com:Math> alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, <com:Math><semantics>C3−7<annotation encoding="application / x-tex">C_{3-7}< / annotation>< / semantics>< / com:Math> cycloalkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group B, <com:Math><semantics>C6−10<annotation encoding="application / x-tex">C_{6-10}< / annotation>< / semantics>< / com:Math> aryl optionally-substituted with 1 to 3 substituents selected independently from Substituent- group B, or 5- to 12-membered heteroaryl optionally- substituted with 1 to 3 substituents selected independently from Substituent-group B, and <com:Math><semantics>X4<annotation encoding="application / x-tex">X^4< / annotation>< / semantics>< / com:Math> is the same as the above <com:Math><semantics>X1<annotation encoding="application / x-tex">X^1< / annotation>< / semantics>< / com:Math>, according to a similar reaction to Step <com:Math><semantics>(1−2)<annotation encoding="application / x-tex">(1-2)< / annotation>< / semantics>< / com:Math>. 2) As a reaction condition using a catalyst and a base, it includes a process of using a boronic acid compound having Ra or a halogen compound having Ra. The catalyst used herein includes copper (II) acetate, copper (I) iodide, copper (II) oxide, and the like. The base used herein includes potassium carbonate, cesium carbonate, potassium hydroxide, triethylamine, and the like. The solvent used herein includes chloroform, 1,4-dioxane, DMF, dimethyl sulfoxide, NMP (N-methyl-2-pyrrolidinone), and the like. The reaction time is generally about 30 minutes to about 24 hours, and the reaction temperature is room temperature to boiling point of a solvent used herein.
[0124] Compound (I) wherein any one or more of <com:Math><semantics>R1a<annotation encoding="application / x-tex">R^{1a}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1b<annotation encoding="application / x-tex">R^{1b}< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>R1c<annotation encoding="application / x-tex">R^{1c}< / annotation>< / semantics>< / com:Math> and R<com:Sup>1d< / com:Sup> is OR<com:Sup>a< / com:Sup> or a pharmaceutically acceptable salt thereof can be also prepared in a similar manner as the above process.
[0125] The above reduction of nitro group [Step (1-3), Step <com:Math><semantics>(3−1)<annotation encoding="application / x-tex">(3-1)< / annotation>< / semantics>< / com:Math>, Step <com:Math><semantics>(5−3)<annotation encoding="application / x-tex">(5-3)< / annotation>< / semantics>< / com:Math>] and the subsequent cyclization [Step <com:Math><semantics>(1−<annotation encoding="application / x-tex">(1-< / annotation>< / semantics>< / com:Math> 4), Step <com:Math><semantics>(3−2)<annotation encoding="application / x-tex">(3-2)< / annotation>< / semantics>< / com:Math>, Step <com:Math><semantics>(5−4)<annotation encoding="application / x-tex">(5-4)< / annotation>< / semantics>< / com:Math>] can be sequentially done, for example, by adding formic acid or a formic acid equivalent such as orthoformate in the reduction step <com:Math><semantics>(s−3)<annotation encoding="application / x-tex">(s-3)< / annotation>< / semantics>< / com:Math> or <com:Math><semantics>(s−14)<annotation encoding="application / x-tex">(s-14)< / annotation>< / semantics>< / com:Math>, thus the cyclized compounds <com:Math><semantics>(S−5)<annotation encoding="application / x-tex">(S-5)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>(s−9)<annotation encoding="application / x-tex">(s-9)< / annotation>< / semantics>< / com:Math>, or <com:Math><semantics>(s−16)<annotation encoding="application / x-tex">(s-16)< / annotation>< / semantics>< / com:Math> can be prepared in one step. The reaction time is 10 minutes to 12 hours, and the reaction temperature is room temperature to boiling point of a solvent used herein.
[0126] The room temperature in the above processes means specifically 10°C to 30°C.
[0127] The starting materials and intermediates in the above processes are known compounds or can be prepared with known compounds according to a known method. In case that any functional group other than a target reaction site can be reacted or can be unsuitable in the above processes, the functional group other than the target reaction site can be protected for the reaction, and the protective group can be cleaved to give a desired compound after the reaction is completed. The protective group used herein includes, for example, a conventional protective group disclosed in the aforementioned Protective Groups in Organic Synthesis (Ibid) and such. Specifically, the protective group for amino group includes, for example, ethoxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and the like; and the protective group for hydroxyl includes, for example, tri-lower alkylsilyl, acetyl, benzyl, and the like.
[0128] The introduction and cleavage of protective groups can be done by a conventional method in organic chemistry (for example, see, the aforementioned Protective Groups in Organic Synthesis (Ibid)), or a similar method.
[0129] By appropriately changing functional group(s) in an intermediate or final product in the above processes, it is also possible to prepare a different compound defined in the present invention. The conversion of functional group(s) can be done according to a conventional method (e.g. Comprehensive Organic Transformations, R. C. Larock (1989)).
[0130] The intermediates and desired compounds in the above processes can be isolated / purified by a purification generally-used in synthetic organic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Some intermediates can be used in next step without any purification. The optical isomers of the present invention can be isolated by using a known division method at an appropriate step, for example, separation with an optically-active column, and fractionated crystallization. And, it is workable to use an optically-active starting material. The compounds of the present invention may be sometimes an optical isomer, a stereoisomer, a tautomer such as a keto- enol compound, and / or a geometric isomer, hence which include all possible isomers including the above isomers, and a mixture thereof.
[0131] The compounds of the present invention may also include the compound of formula (I), a prodrug thereof, and a 108 pharmaceutically acceptable salt thereof, besides the above isomers. And, the compounds of the present invention or a pharmaceutically acceptable salt thereof may be in a form of an adduct with water or each solvent, hence which also include such adducts. In addition, the compounds of the present invention may also include various embodiments of the crystals and the compounds in which a part or all of atoms composing the compounds are replaced with another isotope (for example, replacing hydrogen with deuterium, and replacing <com:Math><semantics>12<annotation encoding="application / x-tex">^{12}< / annotation>< / semantics>< / com:Math>C with <com:Math><semantics>14<annotation encoding="application / x-tex">^{14}< / annotation>< / semantics>< / com:Math>C).
[0132] The term "prodrug of the compound of formula (I)" used herein means a compound which can be converted to the compound of formula (I) by reacting with an enzyme, gastric acid, etc. under intravitally physiological condition, i.e., a compound which can be enzymatically oxidized, reduced, hydrolyzed, or taken somehow to be converted to the compound of formula (I), and a compound which can be hydrolyzed with gastric acid or the like to be converted to the compound of formula (I).
[0133] The "pharmaceutically acceptable salt" 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 sodium salt and potassium salt; an alkaline earth metal salt such as calcium salt and magnesium salt; a water-soluble amine addition salt such as ammonium salt and N-methylglucamine (meglumine); and a lower alkanol ammonium 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, benzene sulfonate, p-toluenesulfonate, and pamoate[1,1'-methylene-bis-(2-hydroxy-3-naphthoate)].
[0134] Salts of the present compound can be prepared, for example, in the following manners. For example, when the present compound is obtained in a salt form, the salt thereof can be prepared by directly purifying it. When the present compound is obtained in a free form, the salt thereof can be prepared by dissolving or suspending it in an appropriate organic solvent, adding a possible acid or base thereto, and then treating the obtained mixture in a general manner.
[0135] The compound of formula (I) prepared by the above processes may be isolated / purified in a conventional manner 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. The purification by column chromatography can be done with an acid-, basic-, or variously-chemical-treating silica gel, alumina, or the like. The elute solvent used herein includes, for example, hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, acetonitrile / water, methanol / water, and the like.
[0136] The novel compounds of the present invention or a pharmaceutically acceptable salt thereof having a benzimidazole ring have a property inhibiting Nav 1.7 and thereby can be used as a medicament for treating or preventing a pain involving peripheral nerve such as C-fibres and <com:Math><semantics>Aδ<annotation encoding="application / x-tex">A\delta< / annotation>< / semantics>< / com:Math>-fibres, spontaneous pain such as numbress, burning pain, dull pain, pricking 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. The neuropathic pain includes, for example, diabetic neuropathy, postherpetic neuralgia, chemotherapy-induced neuropathy, cancer pain, sensory nerve damage caused by viral infection in human immune deficiency syndrome, trigeminal neuralgia, complex regional pain syndrome, reflex sympathetic dystrophy, neuralgia after low back surgery, phantom limb pain, pain 111 after spinal cord injury, persistent postoperative pain, inflammatory demyelinating polyradiculopathy, alcoholic neuropathy, entrapment peripheral neuropathy, iatrogenic neuropathy, sudden sensorineural disorder, malnutrition- induced neuropathy, radiation-induced neuropathy, radiculopathy, toxic peripheral neuropathy, traumatic peripheral neuropathy, brachial plexus avulsion injury, glossopharyngeal neuralgia, autoimmune neuropathy, and chronic cauda equina syndrome. The nociceptive pain or inflammatory pain includes low back pain, abdominal pain, chronic rheumatoid arthritis, a pain caused by osteoarthritis, myalgia, acute postoperative pain, fracture pain, pain after burn injury, and the like. In addition, the present compounds or a pharmaceutically acceptable salt thereof can be also used as a medicament for treating or preventing dysuria. The dysuria includes frequent urination, bladder pain caused by prostatic hyperplasia, and the like. Furthermore, the present compounds or a pharmaceutically acceptable salt thereof can be also used as a medicament for treating or preventing ataxia developed by suppressing abnormal nervous firing in the cerebellum in multiple sclerosis. In addition, the present compounds or a pharmaceutically acceptable salt thereof can be a drug having no side effect in heart or central nerve which is a problem in existing medication, since they have a selective inhibitory activity to Nav 1.7.
[0137] The present compounds may be administered orally, parenterally or rectally, and the daily dose can vary depending on the compound, the mode of administration, patient's condition / age, etc. For oral administration, for example, the present compounds may be administered generally in a dosage of about 0.01 to 1000 mg, preferably about 0.1 to 500 mg a day per kilogram of body weight of human or mammal and once to several times. For parenteral administration such as intravenous injection, for example, the present compounds may be administered generally in a dosage of about 0.01 to 300 mg, preferably about 1 to 100 mg per kilogram of body weight of human or mammal.
[0138] The present compounds can be orally or parenterally administered directly or as a suitable formulation comprising it. The formulation thereof may be, for example, tablet, capsule, powder, granule, liquid, suspension, injection, patch, gel patch, and the like, but not limited thereto. The formulation can be prepared with pharmaceutically acceptable additive agents in known means. The additive agents can be chosen for any purpose, including an excipient, a disintegrant, a binder, a fluidizer, a 113 lubricant, a coating agent, a solubilizer, a solubilizing agent, a thickener, dispersant, a stabilizing agent, a sweetening agent, a flavor, and the like. Specifically, they include, for example, lactose, mannitol, microcrystalline cellulose, low-substituted hydroxypropylcellulose, cornstarch, partially- pregelatinized starch, carmellose calcium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropyl methylcellulose, polyvinyl alcohol, magnesium stearate, sodium stearyl fumarate, polyethylene glycol, propylene glycol, titanium oxide, talc, and the like.
[0139] The present compounds and a pharmaceutically acceptable salt thereof may be used in combination with, for example, a non-steroidal anti-inflammatory agent such as celecoxib, Voltaren, ibuprofen, loxoprofen, acetaminophen, diclofenac and dexamethasone, and an opioid analgesic such as tramadol, morphine and oxycodone, in order to strengthen the action thereof. In addition, the present compounds and a pharmaceutically acceptable salt thereof may be also 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 antidepressive agent (such as amitriptyline and duloxetine), an anticonvulsant agent, an 114 anxiolytic agent, a dopamine receptor agonist, an antiparkinsonian agent, a hormone preparation, a migraine medication, an adrenergic <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math> receptor antagonist, a drug for treating dementia, a drug for treating mood disorder, or the like. Preferred drugs used in combination with the present compound and a pharmaceutically acceptable salt thereof include an antiepileptic agent such as pregabalin and carbamazepine, an antidepressive agent such as amitriptyline and duloxetine, a narcotic analgesic such as morphine, oxycodone and tramadol, an anti-inflammatory agent such as acetaminophen, diclofenac and dexamethasone, an aldose reductase inhibitor such as epalrestat, and a prostaglandin derivative such as limaprost alfadex. In order to reduce the side effects thereof, the present compounds and a pharmaceutically acceptable salt thereof may be used in combination with an antiemetic drug and a sleep-inducing drug. The administration interval of the present compound and its concomitant drug is not limited, i.e., the concomitant drug may be administered at the same time as the present compound or at a suitable interval. Or, the present compound and its concomitant drug can be formulated into a combination drug. The dose of the combination drug can be suitably determined based on the standard of the clinically- used dose thereof. The combination ratio of the present compound and its concomitant drug can be suitably determined based on its subject patient, administration route, disease, pathology, concomitant drug, etc. For example, when the subject patient is a human being, the concomitant drug may be used in 0.01 to 1000 part by weight per part of the present compound. Examples
[0140] The present invention is explained in more detail in the following by referring to Examples and Pharmacological tests; however, the technical scope of the present invention is not limited to such Examples and the like. The silica gel chromatography or amino silica gel column chromatography used in the working examples was a product made by YAMAZEN CORPORATION. Each compound was identified with a proton nuclear magnetic resonance spectrum (1H-NMR), high- performance liquid chromatograph-mass spectrometer (LCMS), etc. <com:Math><semantics>1H-NMR<annotation encoding="application / x-tex">{}^{1}\text{H-NMR}< / annotation>< / semantics>< / com:Math> was measured with JNM-LA300 (JEOL<com:Sup>TM< / com:Sup>) or JNM-AL400 <com:Math><semantics>(JEOLTM)<annotation encoding="application / x-tex">(JEOL^{TM})< / annotation>< / semantics>< / com:Math>.
[0141] The condition of powder X-ray diffractometry was as follows. Measuring set: X'pert-MPD (Spectris Co., Ltd.) X-ray: Cu <com:Math><semantics>Kα1 / 45<annotation encoding="application / x-tex">K\alpha_1 / 45< / annotation>< / semantics>< / com:Math> kV / 40 mA 116 Entrance slit: 15 mm (Auto) / Divergence-preventing slit: 15 mm (Auto) Sample plate: non-reflecting Si plate Step size: 0.017° 5 Scanning range: <com:Math><semantics>4−40∘<annotation encoding="application / x-tex">4-40^{\circ}< / annotation>< / semantics>< / com:Math> (20) Integration time: 100 seconds / step
[0142] High-performance liquid chromatography-mass spectrometer: 10 The measuring condition of LCMS is shown below, and the detected value of mass spectrography [MS <com:Math><semantics>(m / z)<annotation encoding="application / x-tex">(m / z)< / annotation>< / semantics>< / com:Math>] is shown as <com:Math><semantics>M+H<annotation encoding="application / x-tex">M+H< / annotation>< / semantics>< / com:Math>. MS detector: ACQUITY<com:Sup>TM< / com:Sup> SQD HPLC: ACQUITY UPLC 15 Column: ACQUITY BEH C18 1.7 µm, 2.1 x 50 mm Flow rate: 0.75 mL / min Wave length: 254 nm Mobile phase: A: 0.05% aqueous formic acid B: acetonitrile 20 Time program: Step time (min) 1 <com:Math><semantics>0.0−1.3<annotation encoding="application / x-tex">0.0-1.3< / annotation>< / semantics>< / com:Math> A: B = 90 : 10 => 1 : 99 2 <com:Math><semantics>1.3−1.5<annotation encoding="application / x-tex">1.3-1.5< / annotation>< / semantics>< / com:Math> A: B = 1: 99 3 <com:Math><semantics>1.5−2.0<annotation encoding="application / x-tex">1.5-2.0< / annotation>< / semantics>< / com:Math> A: B = 90: 10
[0143] Unless otherwise specified, the starting material compounds, reaction reagents and solvents used herein were commercially available products or were prepared according to known methods.
[0144] In the following Examples and Pharmacological tests, abbreviations shown below may be sometimes used to simplify the description of the present specification. Me: methyl, Ac: acetyl, Ph: phenyl, THF: tetrahydrofuran, DMF: N, N- dimethylformaldehyde, NMP: N-methyl-2-pyrrolidinone, DMAP: N, N-dimethyl-4-aminopyridine, HEPES: 2-[4-(2-hydroxyethyl)- 1-piperazinyl]ethanesulfonic acid, EGTA: 0,0'-bis(2- aminoethyl) ethylene glycol-N, N, N', N'-tetraacetate, AD-mix- <com:Math><semantics>β<annotation encoding="application / x-tex">\beta< / annotation>< / semantics>< / com:Math>: a mixture reagent of hydroquinidine-1,4-phthalazinediyl diether / potassium carbonate / potassium ferricyanide / potassium osmate dihydrate = <com:Math><semantics>2 / 624 / 624 / 1<annotation encoding="application / x-tex">2 / 624 / 624 / 1< / annotation>< / semantics>< / com:Math> (molar ratio), Pd / C: palladium / carbon, Pt-S / C: sulfur-poisoned platinum / carbon, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, td: 3 doublets, tt: 3 triplet, m: multiplet, br: broad.
[0145] Example 1: Preparation of <com:Math><semantics>1−[6−(4−fluorophenoxy)−1H−<annotation encoding="application / x-tex">1-[6-(4-fluorophenoxy)-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 1) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]
[0146] Step (i): Preparation of 1-[(5-fluoro-2-nitrophenyl)amino]- 2-methylpropan-2-ol (Compound 62) A mixture of Compound 61 <com:Math><semantics>(1.59 g)<annotation encoding="application / x-tex">(1.59 \text{ g})< / annotation>< / semantics>< / com:Math>, 1-amino-2- methylpropan-2-ol (0.98 g), diisopropylethylamine (5.22 mL), and DMF (50 mL) was stirred at 60°C for 2 hours. To the reaction mixture were added water and a mixture of ethyl acetate / hexane <com:Math><semantics>(=1 / 1)<annotation encoding="application / x-tex">(= 1 / 1)< / annotation>< / semantics>< / com:Math>, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to give Compound 62 as a crude product.
[0147] Step (ii): Preparation of <com:Math><semantics>1−[(5−(4−fluorophenoxy)−2−<annotation encoding="application / x-tex">1-[(5-(4-fluorophenoxy)-2-< / annotation>< / semantics>< / com:Math> nitrophenyl]amino) -2-methylpropan-2-ol (Compound 63) A mixture of the crude product of Compound 62 prepared in Step (i), 4-fluorophenol (1.68 g), cesium carbonate (6.52 g), and NMP (25 mL) was stirred at 100°C for 2 hours. To the reaction mixture was added water and a mixture of ethyl acetate / hexane <com:Math><semantics>(=1 / 1)<annotation encoding="application / x-tex">(= 1 / 1)< / annotation>< / semantics>< / com:Math> , and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: hexane / ethyl acetate = <com:Math><semantics>3 / 1<annotation encoding="application / x-tex">3 / 1< / annotation>< / semantics>< / com:Math>) to give Compound 63 (3.10 g).
[0148] Step (iii): Preparation of <com:Math><semantics>1−{[2−amino−5−(4−amino−5)]<annotation encoding="application / x-tex">1-\{[2-amino-5-(4-amino-5)]< / annotation>< / semantics>< / com:Math> fluorophenoxy)phenyl]amino)-2-methylpropan-2-ol (Compound 64) A mixture of Compound 63 (3.10 g), ammonium formate <com:Math><semantics>(2.95 g)<annotation encoding="application / x-tex">(2.95 \text{ g})< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>10% Pd / C<annotation encoding="application / x-tex">10\% \text{ Pd / C}< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(0.30 g)<annotation encoding="application / x-tex">(0.30 \text{ g})< / annotation>< / semantics>< / com:Math>, and methanol <com:Math><semantics>(47 mL)<annotation encoding="application / x-tex">(47 \text{ mL})< / annotation>< / semantics>< / com:Math> was stirred at 50°C for 2 hours. The reaction mixture was filtered through Celite™, and the filtrate was concentrated under reduced pressure. To the residue were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: chloroform / methanol = <com:Math><semantics>99 / 1<annotation encoding="application / x-tex">99 / 1< / annotation>< / semantics>< / com:Math>) to give Compound 64 (2.70 g).
[0149] Step (iv): Preparation of <com:Math><semantics>1−[6−(4−fluorophenoxy)−1H−<annotation encoding="application / x-tex">1-[6-(4-fluorophenoxy)-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 1) Α mixture of Compound <com:Math><semantics>64<annotation encoding="application / x-tex">64< / annotation>< / semantics>< / com:Math> (0.60 g), trimethyl orthoformate (1.73 mL), and p-toluenesulfonic acid monohydrate (0.079 g) was stirred at 60°C for 1 hour. To the reaction mixture were added saturated aqueous sodium hydrogen carbonate and ethyl acetate, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: chloroform / methanol = <com:Math><semantics>95 / 5<annotation encoding="application / x-tex">95 / 5< / annotation>< / semantics>< / com:Math>) to give Compound 1 (0.41 g). <com:Sup>1< / com:Sup>H-NMR (DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>: 1.06 (6H, s), 4.08 (2H, s), 4.72 (1H, s), <com:Math><semantics>6.87(1H,m),6.96−6.99(2H,m),7.17(2H,m),7.39(1H,m),<annotation encoding="application / x-tex">6.87 (1H, m), 6.96-6.99 (2H, m), 7.17 (2H, m), 7.39 (1H, m),< / annotation>< / semantics>< / com:Math> 7.62 (1H, m), 8.09 (1H, s). <com:Math><semantics>XRD<annotation encoding="application / x-tex">XRD< / annotation>< / semantics>< / com:Math>; <com:Math><semantics>2θ=12.1<annotation encoding="application / x-tex">2\theta = 12.1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>13.6<annotation encoding="application / x-tex">13.6< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>15.0<annotation encoding="application / x-tex">15.0< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>15.2<annotation encoding="application / x-tex">15.2< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>16.8<annotation encoding="application / x-tex">16.8< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>18.5<annotation encoding="application / x-tex">18.5< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>19.1<annotation encoding="application / x-tex">19.1< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>19.6<annotation encoding="application / x-tex">19.6< / annotation>< / semantics>< / com:Math>, 19.9, 20.1, 20.7, 21.8, 23.5, 24.0, 24.5, 25.2, 26.0, 26.7, 30.4, 34.8
[0150] Example 2: Preparation of 6-(4-fluorophenoxy)-1- (tetrahydrofuran-2-ylmethyl)-1H-benzimidazole (Compound 2) [Image disponible dans le document PDF, Image available in the PDF document] Compound 2 (0.26 g) was prepared according to the process of Example 1 by using the starting material, (tetrahydrofuran-2-yl)methanol (0.607 g) instead of 1-amino- 2-methylpropan-2-ol. <com:Sup>1< / com:Sup>H-NMR (DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>: 1.49 (1H, m), 1.75 (2H, m), 1.94 (1H, m), <com:Math><semantics>3.63(2H,m),4.07−4.34(3H,m),6.87−6.90(1H,m),6.97−<annotation encoding="application / x-tex">3.63 (2H, m), 4.07-4.34 (3H, m), 6.87-6.90 (1H, m), 6.97-< / annotation>< / semantics>< / com:Math> 7.02 (2H, m), 7.19 (2H, m), 7.35 (1H, m), 7.62 (1H, m), 8.14 (1H, s).
[0151] Example 3: Preparation of 6-(4-fluorophenoxy)-1-[2-(propan- 2-yloxy)ethyl]-1H-benzimidazole (Compound 3) [Image disponible dans le document PDF, Image available in the PDF document] A mixture of Compound 65 (0.050 g) prepared according to Example 1 with an appropriate starting material, sodium hydride (0.011 g), and DMF (1.0 mL) was stirred at 0°C for 30 minutes. To the reaction solution was added 2- bromopropane (0.045 g), and the mixture was stirred at room temperature further for 2 hours. To the reaction mixture were added saturated aqueous ammonium chloride, and ethyl acetate, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: chloroform / methanol = 99 / 1) to give Compound 3 (9 mg). <com:Sup>1< / com:Sup>H-NMR (DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>: 0.94 (6H, d, J = 6.1 Hz), 3.44 (1H, m), <com:Math><semantics>3.64<annotation encoding="application / x-tex">3.64< / annotation>< / semantics>< / com:Math> (2H, t, <com:Math><semantics>J=5.0<annotation encoding="application / x-tex">J = 5.0< / annotation>< / semantics>< / com:Math> Hz), <com:Math><semantics>4.30<annotation encoding="application / x-tex">4.30< / annotation>< / semantics>< / com:Math> (2H, t, <com:Math><semantics>J=5.0<annotation encoding="application / x-tex">J = 5.0< / annotation>< / semantics>< / com:Math> Hz), <com:Math><semantics>6.87<annotation encoding="application / x-tex">6.87< / annotation>< / semantics>< / com:Math>- <com:Math><semantics>7.02(3H,m),7.18(2H,m),7.32(1H,m),7.62(1H,m),8.13<annotation encoding="application / x-tex">7.02 (3H, m), 7.18 (2H, m), 7.32 (1H, m), 7.62 (1H, m), 8.13< / annotation>< / semantics>< / com:Math> (1H, s).
[0152] Example 4: Preparation of <com:Math><semantics>1−[2−(cyclopentyloxy)ethyl]−6−(4−<annotation encoding="application / x-tex">1-[2-(cyclopentyloxy)ethyl]-6-(4-< / annotation>< / semantics>< / com:Math> fluorophenoxy) -1H-benzimidazole (Compound 4) [Image disponible dans le document PDF, Image available in the PDF document] 123 Compound 4 (0.007 g) was prepared according to the process of Example 3 by using bromocyclopentane (0.049 g) instead of 2-bromopropane. <com:Math><semantics>LCMS:T=0.828,m / z=341<annotation encoding="application / x-tex">LCMS:T = 0.828, m / z = 341< / annotation>< / semantics>< / com:Math>
[0153] Example 5: Preparation of <com:Math><semantics>1−[6−(4−fluorophenyl)−1H−<annotation encoding="application / x-tex">1-[6-(4-fluorophenyl)-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 5) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]
[0154] Step (i): Preparation of 1-[(5-bromo-2-nitrophenyl)amino]- 2-methylpropan-2-ol (Compound 67) Compound 67 (1.20 g) was prepared according to the process of Step (i) in Example 1 by using Compound 66 (1.1 g) instead of Compound 61.
[0155] Step (ii): Preparation of 1-[(2-amino-5-bromophenyl)amino]- 2-methylpropan-2-ol (Compound 68) Compound 68 (0.811 g) was prepared according to the process of Step (iii) in Example 1 by using Compound 67 (1.20 g) instead of Compound 63, and 3% Pt-S / C (0.24 g) instead of 10% Pd / C as a catalyst.
[0156] Step (iii): Preparation of 1-(6-bromo-1H-benzimidazol-1-yl)- 2-methylpropan-2-ol (Compound 69) Compound 69 (0.210 g) was prepared according to the process of Step (iv) in Example 1 by using Compound 68 (0.259) g) instead of Compound 64, and acetic acid (0.060 g) instead of p-toluenesulfonic acid monohydrate.
[0157] Step (iv): Preparation of <com:Math><semantics>1−[6−(4−fluorophenyl)−1H−<annotation encoding="application / x-tex">1-[6-(4-fluorophenyl)-1H-< / annotation>< / semantics>< / com:Math> benzimidazol-1-yl]-2-methylpropan-2-ol (Compound 5) Α mixture of Compound 69 <com:Math><semantics>(0.050g)<annotation encoding="application / x-tex">(0.050 \, \text{g})< / annotation>< / semantics>< / com:Math>, 4- fluorophenylboronic acid (0.052 g), tetrakis (triphenylphosphine) palladium (0.043 g), and 1,4- dioxane (1.0 mL) was stirred at 80°C for 1 hour. To the reaction mixture were added water and ethyl acetate, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: chloroform / methanol = <com:Math><semantics>99 / 1<annotation encoding="application / x-tex">99 / 1< / annotation>< / semantics>< / com:Math>) to give Compound 5 (30 mg). <com:Sup>1< / com:Sup>H-NMR (DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>: 1.11 (6H, s), 4.20 (2H, s), 4.79 (1H, s), <com:Math><semantics>7.29(2H,m)<annotation encoding="application / x-tex">7.29 (2H, m)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.45(1H,m)<annotation encoding="application / x-tex">7.45 (1H, m)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.66−7.76(3H,m)<annotation encoding="application / x-tex">7.66-7.76 (3H, m)< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>7.94(1H,s)<annotation encoding="application / x-tex">7.94 (1H, s)< / annotation>< / semantics>< / com:Math>, 8.13 (1H, s).
[0158] Examples 6 - 10: Examples 6 to 10 shown in the following table were prepared according to the process of Example 5 by using each appropriate starting material. [Table 1] [Image disponible dans le document PDF, Image available in the PDF document] 1 1 T.
[0159] Example 11: Preparation οf [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan- 2-ol (Compound 11) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]
[0160] Step (i): Preparation of 2-methyl-1-<com:Math><semantics>[6−(4,4,5,5−tetramethyl−<annotation encoding="application / x-tex">[6-(4,4,5,5-tetramethyl-< / annotation>< / semantics>< / com:Math> 1,3,2-dioxaboran-2-yl)-1H-benzimidazol-1-yl]propan-2-ol (Compound 70) Α mixture of Compound 69 (0.10 g), bis (pinacolato) diboron (0.142 g), dichloro[1,1'- bis (diphenylphosphino) ferrocene]palladium (0.054 g), potassium acetate (0.146 g), and 1,4-dioxane (2.0 mL) was stirred at 90°C for 2 hours. To the reaction mixture were added water and ethyl acetate, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: hexane / ethyl acetate = 8 / 1) to give Compound 70 (90 mg).
[0161] Step (ii): Preparation of 2-methyl-1-{6-[5- (trifluoromethyl)pyridin-2-yl]-1H-benzimidazol-1-yl}propan- 2-ol (Compound 11) A mixture of Compound 70 (90 mg), <com:Math><semantics>2−bromo−5−<annotation encoding="application / x-tex">2-bromo-5-< / annotation>< / semantics>< / com:Math> trifluoromethylpyridine (0.126 g), 3 mol / L aqueous sodium carbonate (0.372 mL), tetrakis(triphenylphosphine)palladium (86 mg), and 1,4-dioxane (2 mL) was stirred at 80°C for 1 hour. To the reaction mixture were added water and ethyl acetate, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: a mixed solvent of chloroform and methanol) to give Compound 11 (40 mg). <com:Sup>1< / com:Sup>H-NMR (DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>: 1.13 (6H, s), 4.25 (2H, s), 4.83 (1H, s), 7.74 (1H, m), 8.04 (1H, m), 8.24 (3H, m), 8.49 (1H, s), 9.02 (1H, s).
[0162] Example 12: Preparation of 1-[2-(cyclopentyloxy)ethyl]-6-[5- (trifluoromethyl)pyridin-2-yl]-1H-benzimidazole (Compound 12) [Image disponible dans le document PDF, Image available in the PDF document] _____________________________________ nitrophenyl)amino]ethan-1-ol (Compound 71) Compound 71 (0.698 g) was prepared according to the process of Step (i) in Example 5 by using 2-aminoethanol (0.458 g) instead of 1-amino-2-methylpropan-2-ol.
[0164] Step (ii): Preparation of 2-[(2-amino-5- bromophenyl)amino]ethan-1-ol (Compound 72) Compound 72 (0.561 g) was prepared according to the process of Step (ii) in Example 5 by using Compound 71 (0.698) g) instead of Compound 67.
[0165] Step (iii): Preparation of 2-(6-bromo-1H-benzimidazol-1- yl)ethan-1-ol (Compound 73) Compound 73 (0.19 g) was prepared according to the process of Step (iii) in Example 5 by using Compound 72 (0.231 g) instead of Compound 68.
[0166] Step (iv): Preparation of 6-bromo-1-[2- (cyclopentyloxy)ethyl]-1H-benzimidazole (Compound 74) Compound 74 (0.025 g) was prepared according to the process of Example 3 by using Compound 73 (0.19 g) instead of Compound 65.
[0167] Step (v): Preparation of <com:Math><semantics>1−[2−(cyclopentyloxy)ethyl]−6−<annotation encoding="application / x-tex">1-[2-(cyclopentyloxy)ethyl]-6-< / annotation>< / semantics>< / com:Math> <com:Math><semantics>(4,4,5,5−tetramethyl−1,3,2−dioxaboran−2−yl)−1H−<annotation encoding="application / x-tex">(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-< / annotation>< / semantics>< / com:Math> benzimidazole (Compound 75) Compound 75 was prepared according to the process of Step (i) in Example 11 by using Compound 74 (0.015 g) instead of Compound 69. The crude product was used in the next step without purification.
[0168] Step (vi): Preparation of 1-[2-(cyclopentyloxy)ethyl]-6-[5- (trifluoromethyl)pyridin-2-yl]-1H-benzimidazole (Compound 12) Compound 12 (0.018 g) was prepared according to the process of Step (ii) in Example 11 by using Compound 75 instead of Compound 70. <com:Math><semantics>LCMS:T=0.974<annotation encoding="application / x-tex">LCMS:T = 0.974< / annotation>< / semantics>< / com:Math>, <com:Math><semantics>m / z=376<annotation encoding="application / x-tex">m / z = 376< / annotation>< / semantics>< / com:Math>
[0169] Example 13: Preparation of 2-methyl-1-(6-phenoxy-1H- benzimidazol-1-yl)propan-2-ol (Compound 13) [Image disponible dans le document PDF, Image available in the PDF document]
[0170] Step (i): Preparation of 4-(benzyloxy)-2-fluoro-1- nirobenzene (Compound 77) Under a nitrogen atmosphere, potassium carbonate (27.1 g) was added to a solution of Compound 76 (20.5 g) in DMF (326 mL) at room temperature, and then the mixture was stirred. The reaction mixture was heated to 97°C, and benzyl bromide (27.9 g) was added dropwise thereto over 20 minutes. The reaction mixture was stirred further for 1 hour. To the reaction mixture were added ethyl acetate and water, and the objective product was extracted in the organic layer. The organic layer was washed twice with water, and then concentrated under reduced pressure. To the obtained residue was added toluene (162 mL), and the mixture was concentrated under reduced pressure. (The above extraction procedure was repeated twice.) The obtained residue was slurry-washed with a mixture of ethyl acetate / hexane (= 1 / 4) to give Compound 77 <com:Math><semantics>(28.0g)<annotation encoding="application / x-tex">(28.0 g)< / annotation>< / semantics>< / com:Math>.
[0171] Step (ii): Preparation of <com:Math><semantics>1−{[5−(benzyloxy)−2−(ii)}}<annotation encoding="application / x-tex">1-\{[5-(benzyloxy)-2-(ii)\}\}< / annotation>< / semantics>< / com:Math> nitrophenyl]amino}-2-methylpropan-2-ol (Compound 78) Under a nitrogen atmosphere, diisopropylethylamine (32) g) was added to a solution of Compound 77 (24.5 g) in NMP (248 mL) at room temperature. The reaction mixture was heated to 88°C, and 1-amino-2-methylpropan-2-ol (11.48 g) 132 was added dropwise thereto over 12 minutes. The reaction mixture was stirred further for 1 hour. To the reaction mixture were added ethyl acetate and water, and the objective product was extracted in the organic layer. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with water. The organic layer was concentrated under reduced pressure. To the obtained residue was added toluene (248 mL), and the mixture was concentrated under reduced pressure. (The above extraction procedure was repeated twice.) To the obtained residue was added water (248 mL) dropwise. The precipitated crystal was collected on a filter, and dried to give Compound 78 (32.8 g).
[0172] Step (iii): Preparation of 1-[6-(benzyloxy)-1H-benzimidazol- 1-yl]-2-methylpropan-2-ol (Compound 79) To a solution of Compound 78 <com:Math><semantics>(0.5 g)<annotation encoding="application / x-tex">(0.5 \text{ g})< / annotation>< / semantics>< / com:Math> in methanol <com:Math><semantics>(7.9)<annotation encoding="application / x-tex">(7.9)< / annotation>< / semantics>< / com:Math> mL) were added trimethyl orthoformate (4.37 mL), formic acid <com:Math><semantics>(0.6 mL)<annotation encoding="application / x-tex">(0.6 \text{ mL})< / annotation>< / semantics>< / com:Math>, and zinc <com:Math><semantics>(0.52 g)<annotation encoding="application / x-tex">(0.52 \text{ g})< / annotation>< / semantics>< / com:Math>, and the mixture was stirred heating at 70°C for 1 hour. The reaction mixture was filtered through Celite™, and the filtrate was concentrated under reduced pressure. To the residue were added a water solution of Rochelle salt (30 mL) and ethyl acetate (30 mL), and the objective product was extracted in the organic layer. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give Compound 79 <com:Math><semantics>(0.45g)<annotation encoding="application / x-tex">(0.45 g)< / annotation>< / semantics>< / com:Math>.
[0173] Step (iv): Preparation of 1-(2-hydroxy-2-methylpropyl)-1H- benzimidazol-6-ol (Compound 80) To a solution of Compound 79 <com:Math><semantics>(0.5 g)<annotation encoding="application / x-tex">(0.5 \text{ g})< / annotation>< / semantics>< / com:Math> in methanol <com:Math><semantics>(5.6 g)<annotation encoding="application / x-tex">(5.6 \text{ g})< / annotation>< / semantics>< / com:Math> mL) at room temperature was added 10% palladium-carbon (50% water-content, 0.1 g), and the mixture was stirred under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite™, and the filtrate was concentrated under reduced pressure. To the obtained residue was added ethyl acetate / hexane, and the mixture was slurry-washed at room temperature. The obtained crystal was collected on a filter, and dried to give Compound 80 (0.32 g).
[0174] Step (v): Preparation of 2-methyl-1-(6-phenoxy-1H- benzimidazol-1-yl)propan-2-ol (Compound 13) Α reaction mixture of Compound 80 (0.10 g), phenylboronic acid (0.118 g), copper acetate (0.132 g), triethylamine (0.198 mL), and chloroform (2.5 mL) was stirred at 35°C for 2 hours. To the reaction mixture were added saturated aqueous ammonium chloride, and ethyl acetate, and the objective product was extracted in the organic layer. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (eluate: chloroform / methanol = <com:Math><semantics>98 / 2<annotation encoding="application / x-tex">98 / 2< / annotation>< / semantics>< / com:Math>) to give Compound 13 (0.013 g). <com:Sup>1< / com:Sup>H-NMR (DMSO-d6) <com:Math><semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>< / com:Math>: 1.06 (6H, s), 4.08 (2H, s), 4.73 (1H, s), <com:Math><semantics>6.87−6.94<annotation encoding="application / x-tex">6.87-6.94< / annotation>< / semantics>< / com:Math> (3H, m), <com:Math><semantics>7.05<annotation encoding="application / x-tex">7.05< / annotation>< / se...
Claims
1. A compound of formula (I): [Image disponible dans le document PDF, Image available in the PDF document] (I) or a pharmaceutically acceptable salt thereof, wherein one of R 1 b R^{1b} or R 1 c R^{1c} is C 6 − 10 C_{6-10} aryl, C 6 − 10 C_{6-10} aryloxy, 5- to 12- membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein the heteroaryl or the heteroaryl moiety of the heteroaryloxy has the same or different 1 to 4 heteroatoms selected from nitrogen, sulfur atom, or oxygen, and each aryl moiety of the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen, and C 1 − 4 C_{1-4} alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and the other of R1b or R1c is hydrogen, R 2 R^2 and R 3 R^3 are each independently hydrogen or C 1 − 6 C_{1-6} alkyl which may be independently substituted with 1 to 5 substituents selected independently from the group consisting of cyano, halogen, hydroxyl, and C 1 − 4 C_{1-4} alkoxy optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, R 4 R^4 is hydrogen, C 1 − 4 C_{1-4} alkyl optionally-substituted with the same or different 1 to 3 halogens, or C 3 − 7 C_{3-7} cycloalkyl which may be substituted with 1 to 3 substituents selected independently from the group consisting of halogen, hydroxyl, and C 1 − 4 C_{1-4} alkoxy optionally substituted with 1 to 3 substituents selected independently from Substituent-group Α, m is 1, 2 or 3, L is C R 7 R 8 CR^7R^8 , wherein when m is 2 or 3, each C R 7 R 8 CR^7R^8 are independently the same or different, R 7 R^7 and R 8 R^8 are independently hydrogen or methyl, or in R 2 R^2 , R 3 R^3 and − O R 4 -OR^4 , R 2 R^2 and R 3 R^3 may be combined together with the carbon atom to which they are attached to form the following group of formula (II) with -OR4 [Image disponible dans le document PDF, Image available in the PDF document] (II) in formula (II), e and f are independently 1 or 2, R 4 R^4 is hydrogen, V is single bond or oxygen atom, R 5 a R^{5a} , R 5 b R^{5b} , R 5 c R^{5c} , and R 5 d R^{5d} are hydrogen or halogen, or in R 2 R^2 , R 3 R^3 , − O R 4 -OR^4 and C R 7 R 8 CR^7R^8 in L, R 2 R^2 and R 7 R^7 may be combined together with the carbon atoms to which they are each attached to form the following group of formula (IV) with R 3 R^3 , − O R 4 -OR^4 and R 8 R^8 [Image disponible dans le document PDF, Image available in the PDF document] in formula (IV), m 1 m^1 is 0 0 , the sum of m 2 m^2 and j is 2 or 4, 10 R 3 R^3 is hydrogen or methyl, R 4 R^4 is hydrogen, R 8 R^8 is hydrogen, and L is as defined above, R 9 a R^{9a} , R 9 b R^{9b} , R 9 c R^{9c} , and R 9 d R^{9d} are hydrogen, or 15 in R 2 R^2 , R 3 R^3 and − O R 4 -OR^4 , R 3 R^3 and − O R 4 -OR^4 may be combined together with the carbon atom to which they are attached to form the following group of formula (III) with R 2 [Image disponible dans le document PDF, Image available in the PDF document] (III) in formula (III), h is 2, R 2 is hydrogen, R 6 a R^{6a} , R 6 b R^{6b} , and R 6 c R^{6c} are each hydrogen, and wherein not all of R 2 R^2 , R 3 R^3 and − O R 4 -OR^4 are combined together to form a ring, Substituent-group A is independently halogen, hydroxyl, C 1 − 4 C_{1-4} alkoxy, C 3 − 7 C_{3-7} cycloalkyl, or C 3 − 7 C_{3-7} cycloalkoxy, and provided that the following compounds are excluded: 6 − [ 6 − c h l o r o − 2 − ( m o r p h o l i n − 4 − y l ) p y r i m i d i n − 4 − y l ] − 1 − ( 2 − y l ) 6-[6-chloro-2-(morpholin-4-yl)pyrimidin-4-yl]-1-(2-yl) methoxyethyl) -1H-benzimidazole, 2 − [ 5 − ( 3 , 5 − d i m e t h y l − 1 , 2 − o x a z o l − 4 − y l ) − 1 H − b e n z i m i d a z o l − 1 − 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 − m e t h o x y e t h y l ) − 1 − ( 2 , 2 , 2 − t r i f l u o r o e t h y l ) − 1 H − 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 − m e t h y l − 1 − ( 1 − m e t h y l p i p e r i d i n − 4 − y l ) − 1 H − 1 , 2 , 4 − 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 − h y d r o x y e t h y l ) − 1 H − b e n z i m i d a z o l − 6 − y l ] − 2 − ( 3 − 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 − h y d r o x y e t h y l ) − 1 H − b e n z i m i d a z o l − 5 − y l ] − 1 H − 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 − [ ( 1 S , 3 S ) − 3 − methoxycyclohexyl ] − 1 } 2-\text{chloro}-6-\{7-\text{fluoro}-1-[(1S,3S)-3-\text{methoxycyclohexyl}]-1\} 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.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein both of R 2 R^2 and R 3 R^3 are not hydrogen.
3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 2 R^2 and R 3 R^3 are independently C 1 − 6 C_{1-6} alkyl optionally- substituted with the same or different 1 to 5 halogens.
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 R^2 and R 3 R^3 are independently hydrogen or C 1 − 6 C_{1-6} alkyl optionally-substituted with the same or different 1 to 5 halogens.
5. The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 3 and -OR 4 are not combined together with the carbon atom to which they are attached to form the ring of formula (III).
6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein m is 1 or 2.
7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R 7 R^7 and R 8 R^8 are hydrogen, and m is 1.
8. The compound of any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R 1 c R^{1c} is C 6 − 10 C_{6-10} aryl, C 6 − 10 C_{6-10} aryloxy, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroaryloxy, wherein the heteroaryl or the heteroaryl moiety of the heteroaryloxy has the same or different 1 to 4 heteroatoms selected from nitrogen, sulfur atom, or oxygen, and each aryl moiety of 196 the aryl and the aryloxy and each heteroaryl moiety of the heteroaryl and the heteroaryloxy may be independently substituted with 1 to 3 substituents selected independently from the group consisting of halogen and C 1 − 4 C_{1-4} alkyl optionally-substituted with 1 to 3 substituents selected independently from Substituent-group A, and R 1b is hydrogen.
9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: 1-[6-(4-fluorophenoxy)-1H-benzimidazol-1-yl]-2- methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazole, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)phenyl]-1H-benzimidazole, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)phenyl]-1H-benzimidazole, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] (trifluoromethyl)pyridin-2-yl]-1H-benzimidazole, [Image disponible dans le document PDF, Image available in the PDF document] yl]propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, 2-methyl-1-(6-{[6-(trifluoromethyl)pyridin-3-yl]oxy}- 1H-benzimidazol-1-yl)propan-2-ol, 2-methyl-1-(6-{[5-(trifluoromethyl)pyridin-2-yl]oxy}- 1H-benzimidazol-1-yl)propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzimidazol-1-yl)propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol, 1-(5-{[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]oxy}- 1H-benzimidazol-1-yl)-2-methylpropan-2-ol, 1-{5-[(5-chloro-3-fluoropyridin-2-yl)oxy]-1H- benzimidazol-1-yl}-2-methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl)methyl]oxetan-3-ol, 198 [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl) methyl]cyclobutanol, [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzimidazol-1-yl)butan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol, 3-({6-[4-(trifluoromethyl)phenoxy]-1H-benzimidazol-1- yl}methyl)oxetan-3-ol, [Image disponible dans le document PDF, Image available in the PDF document] yl}methyl)oxetan-3-ol, [Image disponible dans le document PDF, Image available in the PDF document] methylbutan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] yl]methyl}oxetan-3-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl) cyclohexanol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}-2-methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] 2-methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}methyl)oxetan-3-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}-2-methylbutan-2-ol, 199 [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}-2-methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}-2-methylpropan-2-ol, 3-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-1H- benzimidazol-1-yl}methyl)oxetan-3-ol, or ( 3 S ) − 2 − m e t h y l − 3 − ( 6 − [ 5 − ( t r i f l u o r o m e t h y l ) p y r i d i n − 2 − (3S)-2-methyl-3-(6-{[5-(trifluoromethyl)pyridin-2-} yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds: [Image disponible dans le document PDF, Image available in the PDF document] methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, 200 [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzimidazol-1-yl)propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzimidazol-1-yl)propan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzimidazol-1-yl)-2-methylpropan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] 1H-benzimidazol-1-yl)butan-2-ol, 2 − m e t h y l − 1 − ( 6 − { [ 5 − ( 2 , 2 , 2 − t r i f l u o r o e t h y l ) p y r i d i n − 2 − 2-methyl-1-(6-\{[5-(2,2,2-trifluoroethyl)pyridin-2- yl]oxy}-1H-benzimidazol-1-yl)propan-2-ol, 3-({6-[4-(trifluoromethoxy)phenoxy]-1H-benzimidazol-1- yl}methyl)oxetan-3-ol, [Image disponible dans le document PDF, Image available in the PDF document] methylbutan-2-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl) cyclohexanol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}-2-methylpropan-2-ol, 3-({6-[2-methoxy-4-(trifluoromethyl)phenyl]-1H- benzimidazol-1-yl}methyl)oxetan-3-ol, [Image disponible dans le document PDF, Image available in the PDF document] benzimidazol-1-yl}methyl)oxetan-3-ol, or ( 3 S ) − 2 − m e t h y l − 3 − ( 6 − { [ 5 − ( t r i f l u o r o m e t h y l ) p y r i d i n − 2 − (3S)-2-methyl-3-(6-\{[5-(trifluoromethyl)pyridin-2- yl]oxy}-1H-benzimidazol-1-yl)butan-2-ol.
11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or additive agent.
12. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in treatment of a disease involving Nav 1.7 in SCN9A.
13. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in treatment of neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, or multiple sclerosis.
14. A pharmaceutical combination comprising the compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, and at least one drug selected from an antiepileptic agent, an antidepressive agent, a narcotic analgesic, an anti-inflammatory agent, a reductase inhibitor, or a prostaglandin derivative drug.
15. Use of the compound as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, or multiple sclerosis.
16. Use of the compound as defined in any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for treatment of neuropathic pain, nociceptive pain, inflammatory pain, small-fiber neuropathy, erythromelalgia, paroxysmal extreme pain disorder, dysuria, or multiple sclerosis.
17. Use of the compound as defined in any one of claims 1 to 10, to treat a disease involving Nav 1.7 in SCN9A.
18. Use of the compound as defined in any one of claims 1 to 10, in the manufacture of a medicament for treating a disease involving Nav 1.7 in SCN9A.