JP2014080394A - Imidazoimidazolone derivatives and pharmaceutical compositions containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compounds having Nav1.7 inhibitory action.SOLUTION: Provided are compounds represented by the formula (I), or pharmaceutically acceptable salts thereof. (In the formula, Rrepresents a hydrogen atom, a substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group; Ris a substituted or unsubstituted alkyl; Ris a substituted or unsubstituted alkyl; and Ris a substituted or unsubstituted alkyl.)

Description

  The present invention relates to a compound useful for treating a disease or condition involving voltage-gated sodium channel Nav1.7 (hereinafter referred to as Nav1.7), and a pharmaceutical composition containing the compound.

Voltage-gated sodium channels are present in excitable cells such as the central, peripheral, cardiac, skeletal and neuroendocrine cells. Responds to depolarization of cell membrane potential and is involved in action potential generation and conduction. Voltage-gated sodium channels play an important role in signal generation and signal conduction in nerves and myocardium and are essential for maintaining the function of the nervous system, heart and muscle. Abnormalities of voltage-gated sodium channels are involved in diseases such as epilepsy (Non-patent document 1), chronic pain (Non-patent document 2), myotonia (Non-patent document 3) and arrhythmia (Non-patent document 4). Is known (Non Patent Literature 5).
The voltage-gated sodium channel is composed of an α subunit that forms an ion channel pore and a β subunit that is an auxiliary subunit. The α subunit is a protein having a molecular weight of about 260 kDa consisting of four homologous domains each having six transmembrane regions (S1 to S6 segments) and a pore loop region existing between the S5 and S6 segments. A channel that permeates sodium ions is formed at the center of the four homology domains. The α subunit has nine subtypes, Nav1.1 to Nav1.9, and the sensitivity and the site of expression of ion channel activity inhibition by tetrodotoxin (TTX), a puffer venom, vary depending on each subtype. It has been known. For example, Nav1.1, Nav1.2, Nav1.3, Nav1.4, Nav1.6 and Nav1.7 have ion channel activity inhibited by TTX. Nav1.5, Nav1.8 and Nav1.9 are less sensitive to TTX. Nav1.1, Nav1.2 and Nav1.3 are the nervous system, Nav1.4 is the skeletal muscle, Nav1.5 is the myocardium, Nav1.6 is the nervous system, and Nav1.7, Nav1.8 and Nav1.9 are mainly It is expressed in the peripheral nervous system. It is known to be involved in biological functions related to each expression site (Non-patent Document 5).

  In particular, Nav1.7 is distributed in the peripheral nervous system, such as the sympathetic and sensory nervous systems, and forms TTX-sensitive sodium channels. Recently, it has become clear that it is specifically involved in pain signals. In KO mice deficient in the Nav1.7 gene in sensory nerves, it has been reported that mechanical and thermal pain thresholds are increased, and increase in pain sensation is suppressed in an inflammatory pain model (Non-Patent Document). 6). In addition, the relationship between the mutation of the gene and pain sensation has been found in humans. From the family analysis of extremity erythema showing increased flushing and pain sensation in the periphery of the limb, SCN9A encoding Nav1.7 It has been reported that a gain of function type mutation has occurred (Non-patent Document 7). Furthermore, it has been reported that a loss of function type (disappearance of sodium channel function) mutation has occurred in SCN9A from a family analysis of analgesia in which only pain sensation has disappeared despite other normal sensations (Non-channel function loss) Patent Document 8). As described above, since a specific relationship between the sodium channel subtype and pain sensation has been suggested, it is considered that Nav1.7 inhibitors are useful as therapeutic agents for various pain diseases.

In addition, lidocaine and mexiletine, which are subtype non-specific sodium channel inhibitors, are known to exhibit analgesic action in clinical practice and are used as pain therapeutic agents (Non-patent Document 9). On the other hand, it is known that it also shows an inhibitory action against Nav1.5 expressed in the myocardium (Non-patent Documents 10 and 11), and safety that can affect heart function that is particularly important in life support. Have concerns.
From the above, it is considered that a Nav1.7 selective inhibitor having a weak inhibitory activity against Nav1.5 exhibits a powerful analgesic action and is very useful as a therapeutic agent for various pain pathologies overcoming safety concerns. It is done.

Patent Documents 1 and 2 describe compounds having a Nav1.7 inhibitory action, but differ in structure from the compounds of the present invention.
Patent Document 3 and Non-Patent Document 12 describe compounds similar in structure to the compounds of the present invention, but there is no description or suggestion regarding Nav1.7 inhibitory action.

International Publication No. 2010/077943 International Publication No. 2012/004743 International Publication No. 2008/540648

Yogeeswari et al., Curr. Drug Targets 2004, 5 (7), 589. Wood, JN et al., J. Neurobiol. 2004, 61 (1), 55. Cannon, SC, Kidney Int. 2000, 57 (3), 772. JACOB TH, J Cardiovasc. Electrophysiol 2010, 21, 107. WILLIAM A. CATTERALL, ALAN L. GOLDIN, AND STEPHEN G. WAXMAN Pharmacol Rev 2005, 57, 397. Nassar et al., Proc Natl Acad Sci USA, 2004, 101 (34), 12706. Waxman, SG Neurology. 2007, 7, 69 (6), 505. Cox et al., Nature 2006, 444, 894. Tremont-Lukats IW et al., Anesth Analg. 2005, 101, 1738. Wang DW et al., Front Pharmacol. 2010, 1, 144. Ruan Y et al., Circulation 2007, 116, 1137. Jiang-Ping Wu et al., J. Med. Chem., 2004, 47 (22), 5356.

  An object of the present invention is to provide a novel compound having a Nav1.7 inhibitory action and a pharmaceutical composition having a Nav1.7 inhibitory action.

（式中、
Ｒ^１は、水素原子、置換若しくは非置換のアルケニル、置換若しくは非置換の芳香族炭素環式基、または置換若しくは非置換の芳香族複素環式基であり；
Ｒ^２は、置換若しくは非置換のアルキルであり；
Ｒ^３は、置換若しくは非置換のアルキルであり；
Ｒ^４は、置換若しくは非置換のアルキルである。）
で示される化合物、またはその製薬上許容される塩。 The present invention relates to the following (1) to (8).
(1)
Formula (I):

(Where
R ¹ is a hydrogen atom, a substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group;
R ² is substituted or unsubstituted alkyl;
R ³ is substituted or unsubstituted alkyl;
R ⁴ is substituted or unsubstituted alkyl. )
Or a pharmaceutically acceptable salt thereof.

(2)
The compound according to (1) or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted aromatic carbocyclic group.
(3)
The compound of the above (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted alkyl.
(4)
R ² is an alkyl substituted with a substituted or unsubstituted aromatic carbocyclic group, or an alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group, according to the above (1) to (3) The compound according to any one of the above or a pharmaceutically acceptable salt thereof.

(5)
The pharmaceutical composition containing the compound in any one of said (1)-(4), or its pharmaceutically acceptable salt.
(6)
The pharmaceutical composition according to the above (5), which has a Nav 1.7 inhibitory action.
(7)
The compound according to any one of the above (1) to (4) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving Nav 1.7.
(8)
A method for treating and / or preventing a disease involving Nav 1.7, which comprises administering the compound according to any one of (1) to (4) above or a pharmaceutically acceptable salt thereof.

  The compound according to the present invention has an inhibitory action against Nav1.7 and is useful as a therapeutic and / or prophylactic agent for a disease or condition involving Nav1.7.

  Below, the meaning of each term used in this specification is explained. Unless otherwise specified, each term is used in the same meaning when used alone or in combination with other terms.

  “Halogen” includes a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.

“Alkyl” includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl and the like.
Examples of the “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and n-pentyl. Yet another embodiment includes methyl, ethyl, n-propyl, isopropyl, tert-butyl.

“Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
Examples of “alkenyl” include vinyl, allyl, propenyl, isopropenyl, and butenyl.

“Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. These may further have a double bond at an arbitrary position.
Examples of “alkynyl” include ethynyl, propynyl, butynyl, pentynyl.

The “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
Examples of the “aromatic carbocyclic group” include phenyl.

単環の非芳香族炭素環式基としては、炭素数３〜１６が好ましく、より好ましくは炭素数３〜１２、さらに好ましくは炭素数４〜８である。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
２環以上の非芳香族炭素環式基としては、例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.

The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.

“Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
The aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
Examples of the bicyclic aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
Examples of the aromatic heterocyclic group having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.

単環の非芳香族複素環式基としては、３〜８員が好ましく、より好ましくは５員または６員である。例えば、ジオキサニル、チイラニル、オキシラニル、オキセタニル、オキサチオラニル、アゼチジニル、チアニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロフリル、テトラヒドロピラニル、ジヒドロチアゾリル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル、等が挙げられる。
２環以上の非芳香族複素環式基としては、例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル、ジヒドロベンゾフラン、ジヒドロベンゾジオキシン等が挙げられる。 “Non-aromatic heterocyclic group” means a 5- to 7-membered non-aromatic heterocyclic group having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring,
A non-aromatic heterocyclic group in which two or more of them are independently fused,
A 5- to 7-membered non-aromatic heterocyclic ring having one or more of the same or different heteroatoms arbitrarily selected from O, S and N in the ring is a ring in one or more of the above “aromatic carbocyclic groups”; A non-aromatic heterocyclic group fused with a ring in the “non-aromatic carbocyclic group”, or a ring in the “aromatic heterocyclic group”, or
A non-aromatic heterocyclic group in which the ring in the “aromatic heterocyclic group” is fused with one or more rings in the “non-aromatic carbocyclic group”;
Is included.
Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.

The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. For example, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl Furyl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl Aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thii Le, triazinyl, and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include indolinyl, isoindolinyl, chromanyl, isochromanyl, dihydrobenzofuran, dihydrobenzodioxin and the like.

“Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.

“Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
Examples of the “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.

“Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom.
Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.

“Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.

“Haloalkyl” means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
Examples of the “haloalkyl” include trifluoromethyl and trichloromethyl.

“Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
Examples of the “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.

  “Alkyloxyalkyl” means a group in which the “alkyloxy” is bonded to the “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.

  “Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.

“Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
Examples of the “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.

  “Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.

  “Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.

“Monoalkylamino” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylamino, ethylamino, isopropylamino and the like can be mentioned.
Examples of the “monoalkylamino” include methylamino and ethylamino.

“Dialkylamino” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkyl groups may be the same or different. For example, dimethylamino, diethylamino, N, N-diisopropylamino, N-methyl-N-ethylamino, N-isopropyl-N-ethylamino and the like can be mentioned.
Examples of the “dialkylamino” include dimethylamino and diethylamino.

The “dialkylaminoalkyl” means a group in which the “alkyl” is substituted with the nitrogen atom of the “dialkylamino”. For example, dimethylaminoalkyl, diethylaminoalkyl, N, N-diisopropylaminoalkyl, N-methyl-N-ethylaminoalkyl, N-isopropyl-N-ethylaminoalkyl and the like can be mentioned.
Examples of the “dialkylaminoalkyl” include dimethylaminoalkyl and diethylaminoalkyl.

“Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
Examples of the “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.

  “Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.

  “Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.

“Monoalkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. Examples thereof include methylcarbonylamino, ethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino and the like.
Examples of the “monoalkylcarbonylamino” include methylcarbonylamino and ethylcarbonylamino.

“Dialkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylcarbonyl groups may be the same or different. For example, dimethylcarbonylamino, diethylcarbonylamino, N, N-diisopropylcarbonylamino and the like can be mentioned.
Examples of the “dialkylcarbonylamino” include dimethylcarbonylamino and diethylcarbonylamino.

“Monoalkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the amino group. For example, methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino and the like can be mentioned.
Examples of the “monoalkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.

“Dialkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the amino group. Two alkylsulfonyl groups may be the same or different. For example, dimethylsulfonylamino, diethylsulfonylamino, N, N-diisopropylsulfonylamino and the like can be mentioned.
Examples of the “dialkylcarbonylamino” include dimethylsulfonylamino and diethylsulfonylamino.

  The “alkylimino” means a group in which the “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.

  “Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.

  The “alkynylimino” means a group in which the “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.

  “Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.

  “Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.

  “Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.

  “Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.

  “Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.

  “Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.

“Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. Examples thereof include methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like.
Examples of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.

  “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.

  “Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.

“Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
Examples of the “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, and propyloxycarbonyl.

  “Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.

  “Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.

  “Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like.

  “Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.

  “Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.

  “Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. For example, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like can be mentioned.

  “Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.

  “Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.

  “Monoalkylcarbamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include methylcarbamoyl and ethylcarbamoyl.

  “Dialkylcarbamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.

  “Monohydroxyalkylcarbamoyl” means a group in which the above “hydroxyalkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the carbamoyl group. Examples thereof include hydroxymethylcarbamoyl, 1-hydroxyethylcarbamoyl, 2-hydroxyethylcarbamoyl and the like.

  “Monoalkylsulfamoyl” means a group in which the above “alkyl” is replaced with one hydrogen atom bonded to the nitrogen atom of the sulfamoyl group. For example, methylsulfamoyl, dimethylsulfamoyl, etc. are mentioned.

  “Dialkylsulfamoyl” means a group in which the above “alkyl” is replaced with two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Two alkyl groups may be the same or different. Examples thereof include dimethylcarbamoyl, diethylcarbamoyl and the like.

  “Trialkylsilyl” means a group in which three of the above “alkyl” are bonded to a silicon atom. The three alkyls may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.

“Aromatic carbocyclic alkyl”, “non-aromatic carbocyclic alkyl”, “aromatic heterocyclic alkyl”, and “non-aromatic heterocyclic alkyl”,
“Aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, and “non-aromatic heterocyclic alkyloxy”,
“Aromatic carbocyclic alkyloxycarbonyl”, “non-aromatic carbocyclic alkyloxycarbonyl”, “aromatic heterocyclic alkyloxycarbonyl”, and “non-aromatic heterocyclic alkyloxycarbonyl”,
“Aromatic carbocyclic alkyloxyalkyl”, “non-aromatic carbocyclic alkyloxyalkyl”, “aromatic heterocyclic alkyloxyalkyl”, and “non-aromatic heterocyclic alkyloxyalkyl”, and “aromatic carbocyclic alkyl” The alkyl part of “amino”, “non-aromatic carbocyclic alkylamino”, “aromatic heterocyclic alkylamino”, and “nonaromatic heterocyclic alkylamino” is the same as the above “alkyl”.

等が挙げられる。
「芳香族炭素環アルキル」の態様としては、ベンジル、フェネチル、ベンズヒドリルが挙げられる。 “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropynyl, benzhydryl, trityl, naphthylmethyl, groups shown below

Etc.
Examples of the “aromatic carbocyclic alkyl” include benzyl, phenethyl, and benzhydryl.

等が挙げられる。 “Non-aromatic carbocyclic alkyl” means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. . For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below

Etc.

等が挙げられる。 “Non-aromatic heterocyclic alkyl” means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyl”, the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below

Etc.

等が挙げられる。 “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropynyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below

Etc.

等が挙げられる。 “Non-aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include. For example, pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy , Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, groups shown below

Etc.

等が挙げられる。 “Non-aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below

Etc.

等が挙げられる。 “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropynyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below

Etc.

等が挙げられる。 “Non-aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below

Etc.

等が挙げられる。 “Non-aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxycarbonyl”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. And “non-aromatic heterocyclic alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below

Etc.

等が挙げられる。 “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropynyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below

Etc.

等が挙げられる。 “Non-aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below

Etc.

等が挙げられる。 “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. In addition, the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below

Etc.

等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In addition, “non-aromatic heterocyclic alkyloxy” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic”. Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below

Etc.

  “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropynylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.

  “Non-aromatic carbocyclic alkylamino” means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.

  The “aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.

  The “non-aromatic heterocyclic alkylamino” means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.

The “aromatic carbocyclic oxy”, “aromatic carbocyclic carbonyl”, “aromatic carbocyclic oxycarbonyl”, “aromatic carbocyclic sulfanyl”, and “aromatic carbocyclic sulfonyl” moieties also include The same as the above “aromatic carbocyclic group”.
“Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
“Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
“Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
“Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
“Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.

“Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic carbocyclic sulfonyl” The “aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
“Non-aromatic carbocyclic oxy” means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
“Non-aromatic carbocycle carbonyl” means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
“Non-aromatic carbocyclic sulfanyl” means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
“Non-aromatic carbocycle sulfonyl” means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.

The “aromatic heterocycle” portion of “aromatic heterocycle oxy”, “aromatic heterocycle carbonyl”, “aromatic heterocycle oxycarbonyl”, “aromatic heterocycle sulfanyl”, and “aromatic heterocycle sulfonyl” The same as the above “aromatic heterocyclic group”.
“Aromatic heterocycle oxy” means a group in which “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
“Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
“Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
“Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
“Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.

“Non-aromatic heterocyclic oxy”, “non-aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic sulfanyl”, and “non-aromatic heterocyclic sulfonyl” The “heterocyclic ring” moiety is the same as the above “non-aromatic heterocyclic group”.
“Non-aromatic heterocyclic oxy” means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom. For example, piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
“Non-aromatic heterocyclic carbonyl” means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group. For example, piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
The “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfanyl” means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfonyl” means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.

Examples of the substituent of “substituted or unsubstituted alkyl” and “substituted or unsubstituted alkenyl” include a substituent selected from the substituent group A. The carbon atom at any position may be bonded to one or more groups selected from the following substituent group A.
Substituent group A: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, alkylsulfonyl, alkenylsulfonyl , Alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfo Ruamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic Group carbocyclic , Non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, Aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic Aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyl Oxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkylamino , Non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, Non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.
Rings such as “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle”, “non-aromatic heterocycle” and the like in Substituent Group A are those in which the atom at any position in the ring is the Substituent Group It may be substituted with one or more groups selected from B.
Substituent group B: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro , Nitroso, azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkyl Carbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, dialkylamino Kill, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, Alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenyls Luffy Alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monohydroxyalkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, Non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic hetero Ring carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbon Ring alkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, aromatic carbocyclic alkyl Xy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, Non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic alkylamino, Non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non Aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfo Le, aromatic heterocyclic sulfonyl, and a non-aromatic heterocyclic sulfonyl.

The substituents on the ring of “substituted or unsubstituted aromatic carbocyclic group”, “substituted or unsubstituted aromatic heterocyclic group” and “substituted or unsubstituted phenyl group” include the following substituents: Is mentioned. An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, Alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, dialkylamino, dialkylaminoalkyl , Alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyl Oxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl Alkynylsulfinyl, monoalkylcarbamoyl, dialkylcarbamoyl, monohydroxyalkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic Aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl , Non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl , Aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, aromatic carbocyclic alkyloxy , Non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non Aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic alkylamino, non-aromatic Aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic Aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl Aromatic heterocyclic sulfonyl, and a non-aromatic heterocyclic sulfonyl.

Preferred embodiments of R ¹ , R ² , R ³ , and R ^{4 in} the compound represented by the formula (I) are shown below.
R ¹ is preferably a hydrogen atom, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted aromatic carbocyclic group.
R ¹ is more preferably a hydrogen atom, an aromatic carbocyclic alkenyl, or a substituted or unsubstituted phenyl group.
R ² is preferably alkyl substituted with a substituted or unsubstituted aromatic carbocyclic group, or alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group.
R ² is more preferably alkyl substituted with a biphenyl group.
R ³ is preferably unsubstituted alkyl.
R ⁴ is preferably unsubstituted alkyl, alkoxyalkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic alkyl, or alkyl substituted with a substituted or unsubstituted aromatic carbocyclic group, or aromatic carbocycle Oxyalkyl.
Moreover, as a compound shown by a formula (I), the compound which combined the preferable aspect of said R < ¹ >, R < ² >, R < ³ > and R < ⁴ > is mentioned.

As a preferable combination of substituents of the compound represented by the formula (I), R ¹ is a substituted or unsubstituted aromatic carbocyclic group, and R ² is a substituted or unsubstituted aromatic carbocyclic group. Compounds that are substituted alkyl, or alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group.

  The compound of formula (I) is not limited to a particular isomer, but all possible isomers (eg keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) , Rotamers, etc.), racemates or mixtures thereof.

One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

  As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid etc.) and organic acids (eg formic acid, acetic acid, Propionic acid, trifluoroacetic acid, citric acid, lactic acid, Stone acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, etc.) Of the salt. Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

  The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, a hydrate etc.) and / or a crystalline polymorph. Various solvates and crystalline polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In some cases, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof may be recrystallized to form a crystalline polymorph thereof.

  The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent. For _{example, CH 3 COO-, C 2 H} 5 COO-, tert-BuCOO-, C 15 H 31 COO-, PhCOO -, (m-NaOOCPh) COO-, NaOOCCH 2 CH 2 COO-, CH 3 CH (NH 2 _{) COO-, CH 2 N (CH} 3) 2 COO-, CH 3 SO 3 -, CH 3 CH 2 SO 3 -, CF 3 SO 3 -, CH 2 FSO 3 -, CF 3 CH 2 SO 3 -, p _{-CH 3 O-PhSO 3 -,} PhSO 3 -, p-CH 3 PhSO 3 - and the like.

  The compound represented by the above general formula (I) has an inhibitory action against Nav1.7, and is useful as a therapeutic and / or prophylactic agent for diseases and / or conditions in which Nav1.7 is involved. Nav1.7 is considered to be involved in pain (Non-Patent Documents 6 to 8, etc.), and as diseases and / or conditions involving Nav1.7, for example, acute pain, chronic pain, neuropathic pain, inflammation Pain, visceral pain, nociceptive pain including postoperative pain, visceral, gastrointestinal tract, skull, musculoskeletal system, spine, genitourinary system, cardiovascular and central nervous system cancer pain, and back There are multiple types of pain including pain and orofacial pain.

  A more preferred compound of the present invention is a pharmaceutical composition having a selective Nav1.7 inhibitory action. In particular, it is known that lidocaine and mexiletine, which are subtype non-specific sodium channel inhibitors, also show an inhibitory action against Nav1.5 expressed in the myocardium (Non-patent Documents 10 and 11). Have safety concerns that can affect cardiac function, which is particularly important in For this reason, it is expected to ensure Nav1.7 inhibition selectivity especially for Nav1.5 inhibition.

(Method for producing the compound of the present invention)
The compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method shown below. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The synthesis of the compound of the present invention can be carried out in consideration of techniques known in the art.
Moreover, the abbreviation used in this specification represents the following meaning.
DBU: 1,8-diazabicyclo [5.4.0] -7-undecene DIEA: N, N-diisopropylethylamine DME: 1,2-dimethoxyethane DMF: N, N-dimethylformamide DMA: N, N-dimethylacetamide DMI: 1,3-dimethyl-2-imidazolidinone DMSO: dimethyl sulfoxide KHMDS: potassium hexamethyldisilazide LDA: lithium diisopropylamide LHMDS: lithium hexamethyldisilazide LTMP: lithium tetramethylpiperidide NaHMDS: sodium hexa Methyl disilazide NBS: N-bromosuccinimide NMP: N-methylpyrrolidone

（式中、Ｌｇは脱離基、ならびにＲ^１、Ｒ^２、Ｒ^３、およびＲ^４は上記（１）と同意義）

(Wherein Lg is a leaving group, and R ¹ , R ² , R ³ , and R ⁴ are as defined above (1))

(First step)
Compound (iii) can be produced by reacting compound (i) with compound (ii) in the presence of a base.
Examples of the base include potassium carbonate, sodium carbonate, cesium carbonate, lithium carbonate, DBU, sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, DIEA, and preferably potassium carbonate.
Examples of the leaving group (Lg) include halogen, —SO ₂ CH ₃ , —SO ₂ CF _{3 and the} like. As halogen, chlorine, iodine, and bromine are preferable.
As reaction temperature, -20 degreeC-50 degreeC, Preferably -10 degreeC-30 degreeC is mentioned.
Examples of the reaction solvent include acetonitrile, DMF, DMA, NMP, DMI, DMSO and the like, and they can be used alone or in combination.

(Second step)
Compound (iv) can be produced by reacting compound (iii) with hydrogen in the presence of 5 to 10% palladium carbon, preferably 10% palladium carbon.
Examples of the hydrogen pressure include 1 to 10 atm, preferably 2 atm.
Examples of the reaction solvent include methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate and the like, and these can be used alone or in combination.

(Third step)
Compound (vi) can be produced by reacting compound (iv) with compound (v) in the presence of a base.
Examples of the base include potassium iodide, potassium carbonate, cesium carbonate, sodium carbonate, DBU, triethylamine, diisopropylethylamine, potassium tert-butoxide and the like, preferably DBU.
The reaction temperature is −20 ° C. to 60 ° C., preferably under ice cooling.
Examples of the solvent include diethyl ether, tetrahydrofuran, acetonitrile, DMF, DMA, NMP, DMI and the like, and these can be used alone or in combination.

(4th process)
Compound (vii) can be produced by reacting compound (vi) with NBS, bromine or the like, preferably NBS.
As reaction temperature, -20 degreeC-50 degreeC, Preferably -10 degreeC-30 degreeC is mentioned.
Examples of the reaction solvent include methanol, ethanol, isopropanol, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, acetonitrile and the like, and these can be used alone or in combination.

(5th process)
Compound (ix) can be produced by reacting compound (vii) with compound (viii) in the presence of a base.
Examples of the base include LHMDS, NaHMDS, KHMDS, n-butyllithium, sodium hydride, LDA, LTMP, potassium tert-butoxide, and preferably LHMDS.
Examples of the leaving group (Lg) include halogen, —SO ₂ CH ₃ , —SO ₂ CF _{3 and the} like. As halogen, chlorine, iodine, and bromine are preferable.
The reaction temperature is -78 ° C to 25 ° C, preferably under ice cooling.
Examples of the reaction solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, DME and the like, and these can be used alone or in combination.

(6th process)
Compound (xi) can be obtained by reacting compound (ix) with boronic acid or boronic ester (x) in the presence of a metal catalyst and a base.
Metal catalysts include palladium acetate, bis (dibenzylideneacetone) palladium, tetrakis (triphenylphosphine) palladium, bis (triphenylphosphine) palladium (II) dichloride, bis (tri-tert-butylphosphine) palladium, bis (Di-tert-butylphosphinoferrocene) palladium (II) dichloride and the like can be mentioned, and 0.001-0.5 molar equivalent can be used with respect to compound (ix).
Bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium phosphate, sodium hydrogen phosphate, phosphoric acid Examples thereof include potassium, potassium hydrogen phosphate, DBU, cesium fluoride, and the like, and 1 to 10 molar equivalents can be used with respect to compound (ix).
Boronic acid or boronic ester (x) can be used in an amount of 1 to 10 molar equivalents relative to compound (ix).
Examples of the reaction temperature include 20 ° C. to the reflux temperature of the solvent. In some cases, it is performed at an appropriate temperature under microwave irradiation.
The reaction time is 0.1 to 48 hours, preferably 0.5 to 12 hours.
Examples of the reaction solvent include tetrahydrofuran, toluene, DME, DMF, DMA, NMP, DMI, ethanol, tert-butanol, 1,4-dioxane, water and the like, and these can be used alone or in combination.

The compound of the present invention has not only a Nav1.7 inhibitory action but also a usefulness as a medicine, and has any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.
h) High selectivity for Nav1.7.

  When the pharmaceutical composition of the present invention is administered, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods. For parenteral administration, any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.

  Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.

  The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc. 100 mg / kg / day, preferably in the range of 0.1-10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

EXAMPLES The present invention will be described in more detail below with reference to examples, reference examples, and test examples of the present invention, but the present invention is not limited thereto.

The NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d ₆ and CDCl ₃ .
LC / MS: Analytical liquid chromatography / mass spectrometry of the compounds shown in the table below was measured under the following analytical conditions [1], [2] or [3]. The analysis condition number of each compound is shown in the following table. The LC / MS analysis results are shown in the following table as retention time (minutes) and [M + H].

Analysis conditions [1]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Moving layer: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile gradient: 0 min 20% B, 0.25 min 20% B, 1.5 min 80% B, 2.25 minutes 80% B, 2.3 minutes 20% B, 2.5 minutes 20% B
Temperature: 45 ° C
Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [2]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Mobile layer: [A] is 10 mmol / L ammonium carbonate aqueous solution, [B] is acetonitrile gradient: 0 min 20% B, 0.25 min 20% B, 1.5 min 80% B, 2.25 min 80% B 2.3 minutes 20% B, 2.5 minutes 20% B
Temperature: 45 ° C
Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [3]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Moving layer: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile gradient: 0 min 5% B, 0.25 min 5% B, 1.5 min 60% B, 2.25 minutes 60% B, 2.3 minutes 5% B, 2.5 minutes 5% B
Temperature: 45 ° C
Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

Analysis conditions [4]
Column: Waters Aquaty BEH C18 50 × 2.1 mm id 1.7 μm
Moving layer: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile gradient: 0 min 5% B, 0.25 min 5% B, 1.5 min 95% B, 2.25 minutes 95% B, 2.3 minutes 5% B, 2.5 minutes 5% B
Temperature: 45 ° C
Flow rate: 0.834 mL / min
Detector: DAD210-400nm
Injection volume: 0.5 μL

2−ブロモプロピオン酸メチル（０．９２８ｍｏｌ）を、２−ニトロイミダゾール（０．８８４ｍｏｌ）のＤＭＦ（１Ｌ）溶液に加えた。室温にて３０分攪拌し、炭酸ナトリウム（０．９２８ｍｏｌ）を加えた。反応液を６０℃に昇温し、１２時間攪拌した。反応液を氷水（１０ｋｇ）に加え、酢酸エチルで抽出した。有機層を水および飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、化合物２（１４２ｇ、収率８０％）を黄色の固体として得た。
1H NMR (400 MHz, DMSO-d6)δ7.83 (s, 1 H), 7.27 (s, 1 H), 5.76-5.70 (m, 1 H), 3.67 (s, 3 H), 1.74 (d, J = 7.28 Hz, 3 H); MS (ESI+) for m/z 200 (M+H)+. (1) Synthesis of compound 2

Methyl 2-bromopropionate (0.928 mol) was added to a solution of 2-nitroimidazole (0.884 mol) in DMF (1 L). The mixture was stirred at room temperature for 30 minutes, and sodium carbonate (0.928 mol) was added. The reaction solution was heated to 60 ° C. and stirred for 12 hours. The reaction mixture was added to ice water (10 kg) and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to obtain Compound 2 (142 g, yield 80%) as a yellow solid.
1H NMR (400 MHz, DMSO-d6) δ7.83 (s, 1 H), 7.27 (s, 1 H), 5.76-5.70 (m, 1 H), 3.67 (s, 3 H), 1.74 (d, J = 7.28 Hz, 3 H); MS (ESI +) for m / z 200 (M + H) +.

１０％パラジウム炭素（５ｇ）を、化合物２（５０ｇ、２５１.２５ｍｍｏｌ）のメタノール(１Ｌ)溶液に加え、３０ｐｓｉの圧力下、室温にて水素添加を行った。６時間後、反応液をセライトろ過し、メタノールで洗浄した。粗製の化合物３を含むろ液は、そのまま次の反応へ用いた。
1H NMR (400 MHz, DMSO-d6)δ6.63 (d, J = 2 Hz, 1 H), 6.39 (d, J = 1 Hz, 1 H), 5.34 (br, 2 H), 4.88 (m, 1 H), 3.64 (s, 3 H), 1.51 (d, J = 7 Hz, 3 H); MS (ESI+) for m/z 169.8 (M+H)+. (2) Synthesis of compound 3

10% palladium on carbon (5 g) was added to a solution of compound 2 (50 g, 251.25 mmol) in methanol (1 L) and hydrogenated at room temperature under 30 psi pressure. After 6 hours, the reaction solution was filtered through Celite and washed with methanol. The filtrate containing the crude compound 3 was directly used for the next reaction.
1H NMR (400 MHz, DMSO-d6) δ6.63 (d, J = 2 Hz, 1 H), 6.39 (d, J = 1 Hz, 1 H), 5.34 (br, 2 H), 4.88 (m, 1 H), 3.64 (s, 3 H), 1.51 (d, J = 7 Hz, 3 H); MS (ESI +) for m / z 169.8 (M + H) +.

化合物３（２５１．２５ｍｍｏｌ）のメタノール溶液に、ＤＢＵ（４５．９ｇ、３０１．５ｍｍｏｌ）を加え、還流条件下、１．５時間攪拌した。反応液を減圧濃縮した。得られた粗製の化合物４は、そのまま次の反応へ用いた。 (3) Synthesis of Compound 4

DBU (45.9 g, 301.5 mmol) was added to a methanol solution of compound 3 (251.25 mmol), and the mixture was stirred for 1.5 hours under reflux conditions. The reaction solution was concentrated under reduced pressure. The obtained crude compound 4 was directly used for the next reaction.

化合物４（０．２５１ｍｏｌ）のアセトニトリル(６００ｍＬ)溶液に、ヨウ化メチル（３４．８ｇ、０．２５１ｍｏｌ）を、０℃で加えた。反応液を６０℃に昇温し、１８時間攪拌した後、冷却し、ろ過した。ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィーにより精製し、化合物５ａ(１５ｇ、収率３９％)を黄色の液体として得た。
1H NMR (400 MHz, CDCl3)δ6.84 (d, J = 1 Hz, 1 H), 6.79 (d, J = 1 Hz, 1 H), 4.42 (m, 1 H), 3.28 (s, 3 H), 1.58 (d, J = 7 Hz, 3 H); MS (ESI+) for m/z 152 (M+H)+. (4-1) Synthesis of compound 5a

To a solution of compound 4 (0.251 mol) in acetonitrile (600 mL), methyl iodide (34.8 g, 0.251 mol) was added at 0 ° C. The reaction solution was heated to 60 ° C. and stirred for 18 hours, then cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 5a (15 g, yield 39%) as a yellow liquid.
1H NMR (400 MHz, CDCl3) δ6.84 (d, J = 1 Hz, 1 H), 6.79 (d, J = 1 Hz, 1 H), 4.42 (m, 1 H), 3.28 (s, 3 H ), 1.58 (d, J = 7 Hz, 3 H); MS (ESI +) for m / z 152 (M + H) +.

化合物４（０．２５１ｍｏｌ）のアセトニトリル(６００ｍＬ)溶液に、ブロモエチルメチルエーテル（３４．８ｇ、０．２５１ｍｏｌ）及びヨウ化カリウム（４１．９ｇ、０．２５１ｍｏｌ）を、０℃で加えた。反応液を６０℃に昇温し、１８時間攪拌した後、冷却し、ろ過した。ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィーにより精製し、化合物５ｂ(２０ｇ、収率４０．６５％)を液体として得た。
1H NMR (400 MHz, CDCl3)δ6.84 (d, J = 2 Hz, 1 H), 6.78 (d, J = 2 Hz, 1 H), 4.44 (m, 1 H), 3.91 (m, 2 H), 3.69 (m, 2 H), 3.31 (d, J = 5 Hz, 3 H), 1.58 (d, J = 7 Hz, 3 H); MS (ESI+) for m/z 196 (M+H)+. (4-2) Synthesis of compound 5b

Bromoethyl methyl ether (34.8 g, 0.251 mol) and potassium iodide (41.9 g, 0.251 mol) were added at 0 ° C. to a solution of compound 4 (0.251 mol) in acetonitrile (600 mL). The reaction solution was heated to 60 ° C. and stirred for 18 hours, then cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 5b (20 g, yield 40.65%) as a liquid.
1H NMR (400 MHz, CDCl3) δ6.84 (d, J = 2 Hz, 1 H), 6.78 (d, J = 2 Hz, 1 H), 4.44 (m, 1 H), 3.91 (m, 2 H ), 3.69 (m, 2 H), 3.31 (d, J = 5 Hz, 3 H), 1.58 (d, J = 7 Hz, 3 H); MS (ESI +) for m / z 196 (M + H) +.

（式中、Ｒａは、メチルまたはメトキシエチル；すなわち、Ｒａがメチルの場合は、化合物５が上記化合物５ａであることを意味し、Ｒａがメトキシエチルの場合、化合物５が上記化合物５ｂであることを意味する）
化合物５（１５１．２５ｍｍｏｌ）の酢酸イソプロピル（１．５Ｌ）溶液に、炭酸カリウム（３．６４ｇ、２６．４４ｍｍｏｌ）を、０℃にて加える。１０分間攪拌した後、ＮＢＳ(４４．７１ｇ、２５１．２３ｍｍｏｌ)を、ジブロモ化体の生成を最小限に抑えるため、少量ずつ３時間にわたって加える。試薬の添加後、酢酸エチルを加え、飽和炭酸水素ナトリウム水溶液および飽和食塩水で洗浄する。有機層を硫酸ナトリウムで乾燥し、減圧留去する。残渣をシリカゲルカラムクロマトグラフィーで精製し、化合物６を得る。

上記の方法に従って、化合物６ａ（３０ｇ、収率８７％）を得た。

1H NMR (400 MHz, CDCl3)δ6.75 (s, 1 H), 4.50-4.45 (q, J = 7, 7 Hz, 1 H), 3.25 (s, 3 H), 1.69 (d, J = 7 Hz, 3 H); (5) Synthesis of compound 6

(In the formula, Ra is methyl or methoxyethyl; that is, when Ra is methyl, it means that the compound 5 is the compound 5a, and when Ra is methoxyethyl, the compound 5 is the compound 5b.) Means)
To a solution of compound 5 (151.25 mmol) in isopropyl acetate (1.5 L), potassium carbonate (3.64 g, 26.44 mmol) is added at 0 ° C. After stirring for 10 minutes, NBS (44.71 g, 251.23 mmol) is added in small portions over 3 hours to minimize the formation of the dibrominated product. After the reagent is added, ethyl acetate is added, and the mixture is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer is dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography to obtain compound 6.

According to the above method, compound 6a (30 g, yield 87%) was obtained.

1H NMR (400 MHz, CDCl3) δ6.75 (s, 1 H), 4.50-4.45 (q, J = 7, 7 Hz, 1 H), 3.25 (s, 3 H), 1.69 (d, J = 7 Hz, 3 H);

（式中、Ｒａは、メチルまたはメトキシエチル；Ｒｂは、置換若しくは非置換のアルキル）
化合物６（８．６９ｍｍｏｌ）と対応するベンジルブロミド（１０．４３ｍｍｏｌ）のテトラヒドロフラン（６０ｍＬ）溶液に、ＬＨＭＤＳ（１０．４３ｍｍｏｌ、１ｍｏｌ／Ｌのテトラヒドロフラン溶液）を、０℃にて滴下する。反応液を０℃にて２時間攪拌し、その後ゆっくりと室温へ昇温し、さらに２時間攪拌する。反応液に、飽和塩化アンモニウム水溶液（３ｍＬ）及び水（１０ｍＬ）を加える。反応溶媒を減圧留去し、残渣を酢酸エチル（３０ｍＬ）で３回抽出する。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧濃縮を行った。残渣をシリカゲルクロマトグラフィーで精製し、化合物７を得る。

上記の方法に従って、化合物７ａ（収率５５．５％）を得た。

1H NMR (400 MHz, CDCl3)δ7.74 (d, J = 8 Hz, 2 H), 7.18 (d, J = 18 Hz, 2 H), 6.72 (s, 1 H), 3.53 (d, J = 14 Hz, 1 H), 3.37 (d, J = 14 Hz, 1 H), 2.97 (s, 6 H), 1.81 (s, 3 H); MS (ESI+) for m/z 400.2 (M+H)+.
(6) Synthesis of compound 7

(In the formula, Ra is methyl or methoxyethyl; Rb is substituted or unsubstituted alkyl)
To a solution of compound 6 (8.69 mmol) and the corresponding benzyl bromide (10.43 mmol) in tetrahydrofuran (60 mL), LHMDS (10.43 mmol, 1 mol / L tetrahydrofuran solution) is added dropwise at 0 ° C. The reaction is stirred at 0 ° C. for 2 hours, then slowly warmed to room temperature and stirred for an additional 2 hours. A saturated aqueous ammonium chloride solution (3 mL) and water (10 mL) are added to the reaction solution. The reaction solvent is distilled off under reduced pressure, and the residue is extracted three times with ethyl acetate (30 mL). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give compound 7.

According to the above method, compound 7a (yield 55.5%) was obtained.

1H NMR (400 MHz, CDCl3) δ7.74 (d, J = 8 Hz, 2 H), 7.18 (d, J = 18 Hz, 2 H), 6.72 (s, 1 H), 3.53 (d, J = 14 Hz, 1 H), 3.37 (d, J = 14 Hz, 1 H), 2.97 (s, 6 H), 1.81 (s, 3 H); MS (ESI +) for m / z 400.2 (M + H) +.

（式中、Ｒａは、メチルまたはメトキシエチル）
化合物６（１２．７６ｍｍｏｌ）と３−ブロモメチルピリジン塩酸塩（２０．４２ｍｍｏｌ）のＤＭＦ（４０ｍＬ）溶液に、水素化ナトリウム（３４．４５ｍｍｏｌ）を、０℃にてゆっくりと加える。反応液を０℃にて２時間攪拌し、その後ゆっくりと室温へ昇温し、さらに２時間攪拌する。反応液に、飽和塩化アンモニウム水溶液（３ｍＬ）及び水（１０ｍＬ）を加える。反応溶媒を減圧留去し、残渣を酢酸エチル（３０ｍＬ）で３回抽出する。有機層を飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した後、減圧濃縮する。残渣をシリカゲルクロマトグラフィーで精製し、化合物７を得る。

上記の方法に従って、化合物７ｂ（収率３７．３％）を得た。

1H NMR (400 MHz, CDCl3)δ8.42 (d, J = 5 Hz, 1 H), 8.27 (s, 1 H), 7.26 (m, 1 H), 7.09 (m, 1 H), 6.72 (s, 1 H), 3.64 (t, J = 6 Hz, 2 H), 3.45 (d, J = 14 Hz, 1 H), 3.32 (t, J = 5 Hz, 2 H), 3.29 (d, J = 14 Hz, 1 H), 3.16 (s, 3 H), 1.80 (s, 3 H); MS (ESI+) for m/z 367.0 (M+H)+. When Rb is a 3-pyridinylmethyl group, the compound can also be synthesized using the following method.
(6-2)

(In the formula, Ra is methyl or methoxyethyl)
To a solution of compound 6 (12.76 mmol) and 3-bromomethylpyridine hydrochloride (20.42 mmol) in DMF (40 mL), sodium hydride (34.45 mmol) is slowly added at 0 ° C. The reaction is stirred at 0 ° C. for 2 hours, then slowly warmed to room temperature and stirred for an additional 2 hours. A saturated aqueous ammonium chloride solution (3 mL) and water (10 mL) are added to the reaction solution. The reaction solvent is distilled off under reduced pressure, and the residue is extracted three times with ethyl acetate (30 mL). The organic layer is washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give compound 7.

According to the above method, compound 7b (yield 37.3%) was obtained.

1H NMR (400 MHz, CDCl3) δ8.42 (d, J = 5 Hz, 1 H), 8.27 (s, 1 H), 7.26 (m, 1 H), 7.09 (m, 1 H), 6.72 (s , 1 H), 3.64 (t, J = 6 Hz, 2 H), 3.45 (d, J = 14 Hz, 1 H), 3.32 (t, J = 5 Hz, 2 H), 3.29 (d, J = 14 Hz, 1 H), 3.16 (s, 3 H), 1.80 (s, 3 H); MS (ESI +) for m / z 367.0 (M + H) +.

（式中、Ｒａは、メチルまたはメトキシエチル；Ｒｂは、置換若しくは非置換のアルキル；Ｒｃは、置換若しくは非置換のアルケニル、置換若しくは非置換の芳香族炭素環式基、または置換若しくは非置換の芳香族複素環式基）
対応するボロン酸（０．５ｍｍｏｌ）を、窒素雰囲気下、ジオキサン（０．５ｍＬ）に懸濁する。窒素雰囲気下、化合物７（０．４ｍｍｏｌ）のジオキサン（２ｍＬ）溶液、炭酸セシウム（０．８ｍｍｏｌ）の水（１．５ｍＬ）溶液、テトラキストリフェニルホスフィンパラジウム（３５ｍｇ、０．０３ｍｍｏｌ）を順に加える。窒素雰囲気下、得られた溶液を１００℃にて６時間攪拌する。溶媒を減圧留去し、残渣に酢酸エチル（３ｍＬ）及び水（３ｍＬ）を加え、分液する。水層を酢酸エチルで洗浄し、合わせた有機層を減圧濃縮する。得られた残渣にＤＭＦ（１．５ｍＬ）を加え、ろ過を行った。ろ液を逆層ＨＰＬＣにより精製し、化合物８を得る。

上記の方法に従って、化合物Ｉ−１５６（６１．４ｍｇ）を得た。

1H NMR (400 MHz, DMSO-d6)δ8.09 (d, J = 8.4 Hz, 2 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.31 (s, 1 H), 7.09 (t, J = 7.9 Hz, 1 H), 6.75 (dd, J = 8.3, 2.55 Hz, 1 H), 6.37 (d, J = 7.58 Hz, 1 H), 6.23 (t, J = 1.92 Hz, 1 H), 3.63 (s, 3 H), 3.32 (s, 3 H), 3.25 (s, 2 H), 2.97 (s, 3 H), 1.93 (s, 3 H); MS (ESI+) for m/z 426.3 (M+H)+. (7) Synthesis of Compound 8

Wherein Ra is methyl or methoxyethyl; Rb is substituted or unsubstituted alkyl; Rc is substituted or unsubstituted alkenyl, substituted or unsubstituted aromatic carbocyclic group, or substituted or unsubstituted Aromatic heterocyclic group)
The corresponding boronic acid (0.5 mmol) is suspended in dioxane (0.5 mL) under a nitrogen atmosphere. Under a nitrogen atmosphere, a dioxane (2 mL) solution of compound 7 (0.4 mmol), a solution of cesium carbonate (0.8 mmol) in water (1.5 mL), and tetrakistriphenylphosphine palladium (35 mg, 0.03 mmol) are sequentially added. The resulting solution is stirred at 100 ° C. for 6 hours under a nitrogen atmosphere. The solvent is distilled off under reduced pressure, and ethyl acetate (3 mL) and water (3 mL) are added to the residue, followed by liquid separation. The aqueous layer is washed with ethyl acetate, and the combined organic layers are concentrated under reduced pressure. DMF (1.5 mL) was added to the obtained residue, and filtration was performed. The filtrate is purified by reverse phase HPLC to give compound 8.

Compound I-156 (61.4 mg) was obtained according to the method described above.

1H NMR (400 MHz, DMSO-d6) δ8.09 (d, J = 8.4 Hz, 2 H), 7.94 (d, J = 8.4 Hz, 2 H), 7.31 (s, 1 H), 7.09 (t, J = 7.9 Hz, 1 H), 6.75 (dd, J = 8.3, 2.55 Hz, 1 H), 6.37 (d, J = 7.58 Hz, 1 H), 6.23 (t, J = 1.92 Hz, 1 H), 3.63 (s, 3 H), 3.32 (s, 3 H), 3.25 (s, 2 H), 2.97 (s, 3 H), 1.93 (s, 3 H); MS (ESI +) for m / z 426.3 ( M + H) +.

化合物４（０．２５１ｍｏｌ）のＤＭＦ(４００ｍＬ)溶液に、ＤＢＵ（３４．４ｇ、０．２５１ｍｏｌ）及び２−クロロメトキシエチルトリメチルシラン（４１．９３ｇ、０．２５１ｍｏｌ）を、０℃で加えた。反応液を室温にて、２時間攪拌した後、氷水（３ｋｇ）にあけ、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残渣を冷却し、ろ過した。ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィーにより精製し、化合物５ｃ(２２ｇ、収率３２．７％)を液体として得た。
1H NMR (400 MHz, CDCl3)δ6.84 (d, J = 1 Hz, 1 H), 6.78 (d, J = 1 Hz, 1 H), 5.12 (s, 2 H), 4.46 (q , J = 7 Hz, 1 H), 3.64 (t, J = 8 Hz, 2 H), 1.59 (d, J = 7 Hz, 3 H), 0.091 (m, 2 H), -0.046 (s, 9 H); MS (ESI+) for m/z 268 (M+H)+. (8) Synthesis of compound 5c

To a solution of Compound 4 (0.251 mol) in DMF (400 mL), DBU (34.4 g, 0.251 mol) and 2-chloromethoxyethyltrimethylsilane (41.93 g, 0.251 mol) were added at 0 ° C. The reaction solution was stirred at room temperature for 2 hours, then poured into ice water (3 kg) and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. After distilling off the solvent under reduced pressure, the residue was cooled and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain compound 5c (22 g, yield 32.7%) as a liquid.
1H NMR (400 MHz, CDCl3) δ6.84 (d, J = 1 Hz, 1 H), 6.78 (d, J = 1 Hz, 1 H), 5.12 (s, 2 H), 4.46 (q, J = 7 Hz, 1 H), 3.64 (t, J = 8 Hz, 2 H), 1.59 (d, J = 7 Hz, 3 H), 0.091 (m, 2 H), -0.046 (s, 9 H); MS (ESI +) for m / z 268 (M + H) +.

（式中、Ｒｂは置換若しくは非置換のアルキル）
化合物５ｃ（２２．４ｍｍｏｌ）と、対応するベンジルブロミド（２４ｍｍｏｌ）のテトラヒドロフラン（２４０ｍＬ）溶液に、ＬＨＭＤＳ（２４ｍｍｏｌ、１ｍｏｌ／Ｌのテトラヒドロフラン溶液）を、０℃にて滴下する。反応液を０℃にて１５分間攪拌する。反応溶媒を減圧留去し、残渣を酢酸エチル（２００ｍＬ）に溶解し、飽和食塩水で洗浄する。有機層を硫酸ナトリウムで乾燥した後、減圧濃縮を行う。残渣をシリカゲルクロマトグラフィーで精製し、化合物９を得る。

上記の方法に従って、化合物９ａ（６．６９ｇ、収率８７％）を得た。

1H NMR (400 MHz, CDCl3)δ8.45 (dd, J = 4.81, 1.66 Hz, 1 H), 8.25 (d, J = 2.25 Hz, 1 H), 7.22 (dt, J = 7.87, 1.95 Hz, 1 H), 7.11 (dd, J = 7.85, 4.80 Hz, 1 H), 6.87 (d, J = 1.59 Hz, 1 H), 6.77 (d, J = 1.61 Hz, 1 H), 4.95 (s, 2 H), 3.44-3.34 (m, 2 H), 3.25 (d, J = 14.09 Hz, 1 H), 3.14 (d, J = 14.10 Hz, 1 H), 1.68 (s, 3 H), 0.93-0.78 (m, 2 H), -0.03 (s, 9 H); MS (ESI+) for m/z 359 (M+H)+. (9) Synthesis of compound 9

(Wherein Rb is substituted or unsubstituted alkyl)
To a solution of compound 5c (22.4 mmol) and the corresponding benzyl bromide (24 mmol) in tetrahydrofuran (240 mL), LHMDS (24 mmol, 1 mol / L tetrahydrofuran solution) is added dropwise at 0 ° C. The reaction is stirred at 0 ° C. for 15 minutes. The reaction solvent is distilled off under reduced pressure, and the residue is dissolved in ethyl acetate (200 mL) and washed with saturated brine. The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by silica gel chromatography to give compound 9.

According to the above method, compound 9a (6.69 g, yield 87%) was obtained.

1H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 4.81, 1.66 Hz, 1 H), 8.25 (d, J = 2.25 Hz, 1 H), 7.22 (dt, J = 7.87, 1.95 Hz, 1 H), 7.11 (dd, J = 7.85, 4.80 Hz, 1 H), 6.87 (d, J = 1.59 Hz, 1 H), 6.77 (d, J = 1.61 Hz, 1 H), 4.95 (s, 2 H ), 3.44-3.34 (m, 2 H), 3.25 (d, J = 14.09 Hz, 1 H), 3.14 (d, J = 14.10 Hz, 1 H), 1.68 (s, 3 H), 0.93-0.78 ( m, 2 H), -0.03 (s, 9 H); MS (ESI +) for m / z 359 (M + H) +.

（式中、Ｒｂは置換若しくは非置換のアルキル）
化合物９（３．０６ｍｍｏｌ）のジクロロメタン（８ｍＬ）溶液に、トリフルオロ酢酸（８ｍＬ）を、室温にて加える。反応液を室温下で１時間攪拌する。反応溶媒を減圧留去し、酢酸エチル(１００ｍＬ)及び飽和炭酸水素ナトリウム水溶液（５０ｍＬ）を加え、分液する。有機層を硫酸マグネシウムで乾燥し、減圧濃縮する。得られた黄色の油状物をメタノール（５ｍＬ）に溶解し、アンモニア水（３５％、５ｍＬ）を加える。１．５時間後、反応液を減圧濃縮し、残渣に酢酸エチル（１００ｍＬ）及び水（５０ｍＬ）を加え分液する。有機層を硫酸マグネシウムで乾燥した後、減圧濃縮を行い、粗製の化合物１０を得る。

上記の方法に従って、化合物１０ａ（０．６９ｇ、収率７８％）を得た。

1H NMR (400 MHz, CDCl3)δ7.46 (d, J = 7.83 Hz, 1 H), 7.32 (t, J = 7.67 Hz, 1 H), 7.23-7.16 (m, 2 H), 6.81 (d, J = 1.76 Hz, 1 H), 6.62 (d, J = 1.76 Hz, 1 H), 3.27 (d, J = 13.96 Hz, 1 H), 3.15 (d, J = 13.96 Hz, 1 H), 1.62 (s, 3 H); MS (ESI+) for m/z 296 (M+H)+. (10) Synthesis of Compound 10

(Wherein Rb is substituted or unsubstituted alkyl)
To a solution of compound 9 (3.06 mmol) in dichloromethane (8 mL) is added trifluoroacetic acid (8 mL) at room temperature. The reaction is stirred at room temperature for 1 hour. The reaction solvent is distilled off under reduced pressure, and ethyl acetate (100 mL) and a saturated aqueous sodium hydrogen carbonate solution (50 mL) are added to separate the layers. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The resulting yellow oil is dissolved in methanol (5 mL) and aqueous ammonia (35%, 5 mL) is added. After 1.5 hours, the reaction solution is concentrated under reduced pressure, and ethyl acetate (100 mL) and water (50 mL) are added to the residue for liquid separation. The organic layer is dried over magnesium sulfate and then concentrated under reduced pressure to obtain crude compound 10.

According to the above method, compound 10a (0.69 g, yield 78%) was obtained.

1H NMR (400 MHz, CDCl3) δ7.46 (d, J = 7.83 Hz, 1 H), 7.32 (t, J = 7.67 Hz, 1 H), 7.23-7.16 (m, 2 H), 6.81 (d, J = 1.76 Hz, 1 H), 6.62 (d, J = 1.76 Hz, 1 H), 3.27 (d, J = 13.96 Hz, 1 H), 3.15 (d, J = 13.96 Hz, 1 H), 1.62 ( s, 3 H); MS (ESI +) for m / z 296 (M + H) +.

（式中、Ｒｂは、置換若しくは非置換のアルキル；Ｒｄは、置換若しくは非置換のアルキル）
化合物１０（０．４５ｍｍｏｌ）を、乾燥ＤＭＦ（１．５ｍＬ）に懸濁し、アルキルハライド（０．４５ｍｍｏｌ）の乾燥ＤＭＦ（１．５ｍＬ）溶液及び炭酸セシウム（０．４５ｍｍｏｌ）を順に加える。得られた反応液を、３時間、５０℃にて加熱する。溶媒を減圧留去し、残渣をＤＭＦ（１．６ｍＬ）に溶解し、ろ過を行う。ろ液を逆層ＨＰＬＣにより精製し、化合物１１を得る。

上記の方法に従って、化合物Ｉ−０９０（６４．３ｍｇ）を得た。

1H NMR (400 MHz, DMSO-d6)δ7.38 (d, J = 1.5 Hz, 1 H), 7.27-7.18 (m, 4 H), 7.15 (t, J = 7.5 Hz, 2 H), 6.90 (d, J = 7.5 Hz, 2 H), 6.81 (d, J = 7.5 Hz, 2 H), 6.74 (d, J = 1.5 Hz, 1 H), 4.72 (d, J = 15.8 Hz, 1 H), 4.55 (d, J = 15.8 Hz, 1 H), 3.41 (d, J = 13.8 Hz, 1 H), 3.26 (d, J = 13.8 Hz, 1 H), 1.69 (s, 3 H) ; MS (ESI+) for m/z 318.3 (M+H)+. (11) Synthesis of Compound 11

(Where Rb is substituted or unsubstituted alkyl; Rd is substituted or unsubstituted alkyl)
Compound 10 (0.45 mmol) is suspended in dry DMF (1.5 mL), and a solution of alkyl halide (0.45 mmol) in dry DMF (1.5 mL) and cesium carbonate (0.45 mmol) are added sequentially. The resulting reaction solution is heated at 50 ° C. for 3 hours. The solvent is distilled off under reduced pressure, and the residue is dissolved in DMF (1.6 mL) and filtered. The filtrate is purified by reverse phase HPLC to give compound 11.

According to the above method, compound I-090 (64.3 mg) was obtained.

1H NMR (400 MHz, DMSO-d6) δ7.38 (d, J = 1.5 Hz, 1 H), 7.27-7.18 (m, 4 H), 7.15 (t, J = 7.5 Hz, 2 H), 6.90 ( d, J = 7.5 Hz, 2 H), 6.81 (d, J = 7.5 Hz, 2 H), 6.74 (d, J = 1.5 Hz, 1 H), 4.72 (d, J = 15.8 Hz, 1 H), 4.55 (d, J = 15.8 Hz, 1 H), 3.41 (d, J = 13.8 Hz, 1 H), 3.26 (d, J = 13.8 Hz, 1 H), 1.69 (s, 3 H); MS (ESI + ) for m / z 318.3 (M + H) +.

（式中、Ｒａは、メチルまたはメトキシエチル；すなわち、Ｒａがメチルの場合は、化合物５が上記化合物５ａであることを意味し、Ｒａがメトキシエチルの場合は、化合物５が上記化合物５ｂであることを意味する；Ｒｂは、置換若しくは非置換のアルキル）
化合物５（０．８ｍｍｏｌ）を、乾燥テトラヒドロフラン（３ｍＬ）に懸濁し、アルキルハライド（０．８８ｍｍｏｌ）の乾燥テトラヒドロフラン（３ｍＬ）溶液を加える。続いてＬＨＭＤＳ（０．８８ｍｍｏｌ）を室温にて加える。得られた反応液を室温にて３時間振とうする。溶媒を減圧留去し、残渣に酢酸エチル（３ｍＬ）及び水（３ｍＬ）を加え分液する。水層を酢酸エチルで洗浄し、有機層を合わせ、減圧濃縮する。残渣をＤＭＦ（１．６ｍＬ）に溶解し、ろ過を行う。ろ液を逆層ＨＰＬＣにより精製し、化合物１１を得る。

上記の方法に従って、化合物Ｉ−１６３（９７ｍｇ、収率５０％）を得た。

1H NMR (400 MHz, DMSO-d6)δ8.23 (s, 1 H), 7.16-7.27 (m, 3 H), 6.89-6.93 (m, 2 H), 6.74 (d, J = 1 Hz, 1 H), 3.33 (d, J = 13 Hz, 1 H), 3.20 (d, J = 13 Hz, 1 H), 2.91 (s, 3 H), 1.64 (s, 3 H); MS (ESI+) for m/z 242 (M+H)+.
When Rd has the same meaning as Ra above, the compound can also be synthesized using the following method.
(11-2) Synthesis of Compound 11

(In the formula, Ra is methyl or methoxyethyl; that is, when Ra is methyl, it means that the compound 5 is the compound 5a, and when Ra is methoxyethyl, the compound 5 is the compound 5b.) Rb is substituted or unsubstituted alkyl)
Compound 5 (0.8 mmol) is suspended in dry tetrahydrofuran (3 mL) and a solution of alkyl halide (0.88 mmol) in dry tetrahydrofuran (3 mL) is added. Subsequently, LHMDS (0.88 mmol) is added at room temperature. The obtained reaction solution is shaken at room temperature for 3 hours. The solvent is distilled off under reduced pressure, and ethyl acetate (3 mL) and water (3 mL) are added to the residue for liquid separation. The aqueous layer is washed with ethyl acetate, and the organic layers are combined and concentrated under reduced pressure. Dissolve the residue in DMF (1.6 mL) and filter. The filtrate is purified by reverse phase HPLC to give compound 11.

According to the above method, compound I-163 (97 mg, yield 50%) was obtained.

1H NMR (400 MHz, DMSO-d6) δ8.23 (s, 1 H), 7.16-7.27 (m, 3 H), 6.89-6.93 (m, 2 H), 6.74 (d, J = 1 Hz, 1 H), 3.33 (d, J = 13 Hz, 1 H), 3.20 (d, J = 13 Hz, 1 H), 2.91 (s, 3 H), 1.64 (s, 3 H); MS (ESI +) for m / z 242 (M + H) +.

According to the above Example, the following compounds were synthesized.

  Hereinafter, biological test examples of the compound of the present invention will be described.

Test Example 1: Evaluation of Nav1.7 inhibitory activity The degree to which the compound of the present invention inhibits Nav1.7 function was evaluated by the following method.

HEK293 cells stably expressing human Nav1.7 were seeded at 8000 cells / well in a 384-well microtiter plate, cultured for 24 hours in a 37 ° C., 5% CO ₂ incubator and used as an assay plate. Each well of the assay plate was washed with assay buffer (10 mmol / L HEPES, 10 mmol / L Glucose, 137 mmol / L NaCl, 4 mmol / L KCl, 1 mmol / L MgCl2, 1.8 mmol / L CaCl2, pH 7.4). . Add 10 μL of fluorescent indicator solution (7.5 μmol / L Asante Natrium Green-2 (TEFLABS), 0.08% Pluronic F-127, dissolved in assay buffer) to the well with 20 μL of assay buffer remaining, and then at room temperature for 1 hour It was allowed to stand (final concentration of Asante Natrium Green-2: 2.5 μmol / L). After washing each well with assay buffer, 20 μL of assay buffer was left, and the well was allowed to stand at room temperature for 5 minutes. The assay plate was set in a kinetic fluorescence measurement apparatus FLIPR TETRA (Molecular devices), and the fluorescence intensity derived from the fluorescent indicator in each well was measured at intervals of 1 to 10 seconds at an excitation wavelength of 488 nm and a measurement wavelength of 510 to 570 nm. . Using a pipetter with built-in FLIPR TETRA in each well, add 10 μL of the compound solution of the present invention diluted with assay buffer immediately after the start of measurement, and further open 10 μL of sodium channel diluted with assay buffer approximately 5 minutes after the start of measurement. The agent Veratridine solution was added and mixed (final concentration of Veratridine: 40 μmol / L). The fluorescence intensity measurement by FLIPR TETRA was continued until about 3 minutes after the addition of Veratridine.

The calculation method of Nav1.7 inhibitory activity (IC50 value) of the compound of the present invention is shown below. For each well, the amount of change represented by the difference between the maximum value and the minimum value of the fluorescence intensity value from immediately before the addition of Veratridine solution to 3 minutes later was calculated. The inhibition rate of the compound of the present invention was calculated from the following formula using a well added with DMSO as a solvent of the compound of the present invention as a negative control and a well added with mexiletine (final concentration of mexiletine: 500 μmol / L) as a positive control.
Inhibition rate = (1- (change amount by the compound of the present invention−change amount by positive control) / (change amount by negative control−change amount by positive subject)) × 100
The inhibition rate was determined for the compound concentrations of the present invention of 0.156, 0.312, 0.625, 1.25, 2.50, 5.00, 10.0, 20.0 μmol / L (8 points), and the IC50 value (μmol / L) was calculated by the logistic approximation method.
The test results of the compounds of the present invention are shown in the following table.

Test Example 2: CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes (CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4), respectively. The degree to which the amount of metabolite produced is inhibited by the compound of the present invention is evaluated.

  The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; compound concentration of the present invention 1, 5, 10, 20 μmol / L (4 points) .

  As a reaction solution in a 96-well plate, each of 5 types of substrate, human liver microsome, and the compound of the present invention are added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH as a coenzyme is added to make a metabolic reaction as an index. To start. After reacting at 37 ° C. for 15 minutes, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the centrifugation supernatant was quantified with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite) , Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) are quantified by LC / MS / MS.

The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, the residual activity (%) was calculated, and the IC ₅₀ was calculated by inverse estimation using a logistic model using the concentration and the inhibition rate. calculate.

Test Example 3: CYP3A4 fluorescence MBI test The CYP3A4 fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of the compounds of the present invention by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by the CYP3A4 enzyme (E. coli expression enzyme) to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC). CYP3A4 inhibition is evaluated using 7-HFC production reaction as an index.

  The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); compound concentration of the present invention, 0.625, 1.25, 2.5, 5, 10, 20 μmol / L (6 points) ).

  The enzyme and the compound solution of the present invention are added to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate A part of the solution was transferred so as to be diluted by 1/10, and a reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction). After reaction for a predetermined time, acetonitrile / 0.5 mol / L The reaction is stopped by adding Tris (trishydroxyaminomethane) = 4/1 (V / V). In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding acetonitrile / 0.5 mol / L Tris (trishydroxyaminomethane) = 4/1 (V / V). The fluorescence value of 7-HFC, which is a metabolite, is measured using a fluorescent plate reader on the plate on which each index reaction has been performed. (Ex = 420nm, Em = 535nm)

A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when each concentration of the compound of the present invention was added was calculated. Is used to calculate IC ₅₀ by inverse estimation using a logistic model. A case where the difference in IC ₅₀ values is 5 μmol / L or more is (+), and a case where the difference is 3 μmol / L or less is (−).

Test Example 4: Examination of BA test oral absorbability Experimental materials and methods (1) Animals used: Mice or SD rats are used.
(2) Breeding conditions: Mice or SD rats are allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral administration and intravenous administration at a predetermined dosage. Set the group as follows. (Dose may vary for each compound)
Oral administration 1-30 mg / kg (n = 2-3)
Intravenous administration 0.5-10 mg / kg (n = 2-3)
(4) Preparation of administration solution: Oral administration is administered as a solution or suspension. Intravenous administration is administered after solubilization.
(5) Administration method: Oral administration is forcibly administered into the stomach with an oral sonde. Intravenous administration is performed from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood is collected over time, and the concentration of the compound of the present invention in plasma is measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention is calculated from the dose ratio of the group and the AUC ratio.

Test Example 5: Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
Twenty microliters of Salmonella typhimurium TA98, TA100) cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 7. 70 mL Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: The cells are suspended in 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L), and 110 mL of Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) To the MicroF buffer). TA100 strain is added to 120 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, and non-metabolic activation condition as a positive control. Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (under metabolic activation conditions, 498 μL of the test bacterial solution and S9 mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL aliquots into 48 wells / dose of the microplate and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).

Test Example 6: hERG test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, it is important for the ventricular repolarization process using CHO cells in which human ether-a-go-related gene (hERG) channels are expressed. Consider the action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ) that plays a role.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), the cells were held at a membrane potential of −80 mV by a whole cell patch clamp method, and after giving a leak potential of −50 mV, depolarization stimulation of +20 mV for 2 seconds, further records the _{I Kr} induced repolarization stimulated when given 2 seconds -50 mV. After the generated current is stabilized, an extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ₂ : 2 mmol / L, MgCl ₂ : 1 mmol) in which the compound of the present invention is dissolved at a desired concentration. / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7. 4) is applied to the cells for 10 minutes at room temperature. The absolute value of the maximum tail current is measured from the obtained I _Kr using analysis software (Falster Patch; Sophion Bioscience A / S) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I _Kr is evaluated.

Test Example 7: Solubility test The solubility of the compound of the present invention is determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution of the present invention to pH 6.8 artificial intestinal fluid (0.2 mol / L potassium dihydrogen phosphate test solution 250 mL, add 0.2 mol / L NaOH test solution 118 mL, water) To 594 μL). After allowing to stand at 25 ° C. for 16 hours, the mixed solution is subjected to suction filtration. The filtrate is diluted 2-fold with methanol / water = 1/1 (V / V), and the concentration in the filtrate is measured by HPLC or LC / MS / MS by the absolute calibration method.

Test Example 8: Metabolic stability test A commercially available pooled human liver microsome and the compound of the present invention are reacted for a certain period of time, and the residual ratio is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism of the compound of the present invention in the liver. To do.

  In 0.2 mL buffer (50 mmol / L Tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes in the presence of 1 mmol / L NADPH React at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution is added to 100 μL of a methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The compound of the present invention in the centrifugal supernatant is quantified by LC / MS / MS, and the residual amount of the compound of the present invention after the reaction is calculated with the compound amount at 0 minute reaction as 100%.

Test Example 9: Powder Solubility Test An appropriate amount of the compound of the present invention is put in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, water is added to 7.0 mL of hydrochloric acid to make 1000 mL), JP-2 solution (Add 500 mL of water to 500 mL of phosphate buffer at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to TCA1.08 g to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.

Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
Are mixed well, compression-molded, pulverized, sized and sieved to give granules of appropriate size.

  The compound according to the present invention has an inhibitory action on Nav1.7 and is considered useful as a therapeutic and / or prophylactic agent for diseases or conditions involving Nav1.7.

Claims (6)

Formula (I):

(Where
R ¹ is a hydrogen atom, a substituted or unsubstituted alkenyl, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group;
R ² is substituted or unsubstituted alkyl;
R ³ is substituted or unsubstituted alkyl;
R ⁴ is substituted or unsubstituted alkyl. )
Or a pharmaceutically acceptable salt thereof.
The compound or a pharmaceutically acceptable salt thereof according to claim ¹ , wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted aromatic carbocyclic group.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ³ is unsubstituted alkyl.
R ² is an alkyl substituted with a substituted or unsubstituted aromatic carbocyclic group, or an alkyl substituted with a substituted or unsubstituted aromatic heterocyclic group. The described compound or a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.
  6. The pharmaceutical composition according to claim 5, which has a Nav 1.7 inhibitory action.