JP2014080395A - Aminolactam derivatives and pharmaceutical compositions containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide: compounds having voltage-dependent sodium channel Nav1.7 inhibitory action involved in acute pain, chronic pain, neuropathic pain, nociceptive pain including inflammatory pain, visceral pain and postoperative pain, cancer pain associated with viscera, gastrointestinal tract, skull, musculoskeletal system, spine, urogenital system, cardiovascular system and central nervous system, and complex pain types including back pain and orofacial pain; and compositions containing the compounds.SOLUTION: Provided are, as represented by the specified general formula (I), 6-membered ring lactam compounds having a substituted amino group at position 3, or 7-membered ring aminolactam compounds having a substituted amino group at position 4, or pharmaceutically acceptable salts thereof. (In the formula, Ris a hydrogen atom, a substituted or unsubstituted alkyl, or the like.)

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 describes a compound having a structure similar to that of the compound 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. 2010/086251

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.

  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、
−Ａ−は、

であり、
−Ｘ−は、−Ｃ（＝Ｏ）−、または−ＳＯ_２−であり；
Ｒ^１は、水素原子、置換若しくは非置換のアルキル、または置換若しくは非置換の非芳香族炭素環式基であり；
Ｒ^２は、置換若しくは非置換のアルキル、または置換若しくは非置換の芳香族炭素環式基であり；
Ｒ^３は、置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基であり；
Ｒ^４は、置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族複素環式基、または置換若しくは非置換の芳香族炭素環式基であり；
Ｒ^５は、水素原子、または置換若しくは非置換のアルキルであり；
Ｒ^６は、置換若しくは非置換のアルキル、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基である。）
で示される化合物（ただし、

で示される化合物を除く）、またはその製薬上許容される塩。
上記の「−Ａ−」において、結合手「ａ」は、式（Ｉ）の環上のカルボニル基に隣接するメチレン基と結合し、結合手「ｂ」は、式（Ｉ）の環上の「ＮＲ^１」基に隣接するメチレン基と結合する。 The present invention relates to the following (1) to (13).
(1)
Formula (I):

(Where
-A- is

And
-X- is, -C (= O) -, or -SO ₂ - and is;
R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted non-aromatic carbocyclic group;
R ² is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aromatic carbocyclic group;
R ³ represents substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted Or an unsubstituted non-aromatic heterocyclic group;
R ⁴ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic group;
R ⁵ is a hydrogen atom or substituted or unsubstituted alkyl;
R ⁶ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted Or it is an unsubstituted non-aromatic heterocyclic group. )
A compound represented by (however,

Or a pharmaceutically acceptable salt thereof.
In the above "-A-", the bond "a" is bonded to a methylene group adjacent to the carbonyl group on the ring of formula (I), and the bond "b" is on the ring of formula (I). Bonded to the methylene group adjacent to the “NR ¹ ” group.

（式中、−Ｘ−、Ｒ^２、およびＲ^３は、上記（１）と同意義）
である、上記（１）記載の化合物またはその製薬上許容される塩。
（３）
Ｒ^３が、置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族炭素環式基、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る、上記（１）または（２）記載の化合物またはその製薬上許容される塩。 (2)
-A-

(Wherein, -X-, R ² , and R ³ have the same meaning as in the above (1)).
Or a pharmaceutically acceptable salt thereof.
(3)
R ³ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group The compound according to (1) or (2) above or a pharmaceutically acceptable salt thereof.

（式中、−Ｘ−、Ｒ^４、Ｒ^５、およびＲ^６は、上記（１）と同意義）
である、上記（１）記載の化合物またはその製薬上許容される塩。
（５）
Ｒ^４が、置換若しくは非置換の芳香族炭素環式基である、上記（１）または（４）記載の化合物またはその製薬上許容される塩。
（６）
Ｒ^５が、水素原子である、上記（１）、（４）、および（５）のいずれかに記載の化合物またはその製薬上許容される塩。
（７）
Ｒ^６が、置換若しくは非置換の芳香族炭素環式基である、上記（１）、および（４）〜（６）のいずれかに記載の化合物またはその製薬上許容される塩。 (4)
-A-

(In the formula, -X-, R ⁴ , R ⁵ , and R ⁶ have the same meanings as the above (1)).
Or a pharmaceutically acceptable salt thereof.
(5)
The compound of the above (1) or (4) or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a substituted or unsubstituted aromatic carbocyclic group.
(6)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1), (4), and (5), wherein R ⁵ is a hydrogen atom.
(7)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) and (4) to (6) above, wherein R ⁶ is a substituted or unsubstituted aromatic carbocyclic group.

(8)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (7), wherein R ¹ is substituted or unsubstituted alkyl.
(9)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (7), wherein R ¹ is alkyl substituted with a substituted or unsubstituted aromatic carbocyclic group.

(10)
The pharmaceutical composition containing the compound in any one of said (1)-(9), or its pharmaceutically acceptable salt.
(11)
The pharmaceutical composition according to the above (10), which has a Nav 1.7 inhibitory action.
(12)
The compound or a pharmaceutically acceptable salt thereof according to any one of (1) to (9) above, for use in the treatment and / or prevention of diseases involving Nav 1.7.
(13)
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 (9) 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.

  “Alkylene” is a straight or branched divalent hydrocarbon 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. Includes groups. Examples include methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene and the like.

  The “alkenylene” 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 an arbitrary position. And a linear or branched divalent hydrocarbon group. For example, vinylene, propenylene, butenylene, pentenylene and the like can be mentioned.

  “Alkynylene” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. A linear or branched divalent hydrocarbon group is included. These may further have a double bond at an arbitrary position. For example, ethynylene, propynylene, butynylene, pentynylene, hexynylene and the like can be mentioned.

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.

“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.

  “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” 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 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, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl Monoalkylamino, dialkylamino, dialkylaminoalkyl, alkylsulfonyl, alkenylsulfur Nyl, alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxy Imino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkyl Rubamoyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocycle 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, 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 hetero Ring 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 sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.

“Substituted or unsubstituted aromatic carbocyclic group”, “substituted or unsubstituted non-aromatic carbocyclic group”, “substituted or unsubstituted aromatic heterocyclic group”, “substituted or unsubstituted non-substituted aromatic carbocyclic group” Examples of the substituent on the ring of “aromatic heterocyclic group” and “substituted or unsubstituted phenyl group” include the following substituents. 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, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, mono Alkylamino, dialkylamino, dialkylaminoalkyl, alkylsulfonyl, alkenylsulfoni , Alkynylsulfonyl, monoalkylcarbonylamino, dialkylcarbonylamino, monoalkylsulfonylamino, dialkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino , Alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbon Moyl, dialkylcarbamoyl, monoalkylsulfamoyl, dialkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocycle 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, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic al Killoxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl, aromatic hetero Ring 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 sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.

Further, the “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.

であるとは、式（Ｉ）で示される化合物が

であることを意味する。 In formula (I), -A- is

Is a compound represented by the formula (I)

It means that.

であるとは、式（Ｉ）で示される化合物が

であることを意味する。 In formula (I), -A- is

Is a compound represented by the formula (I)

It means that.

Preferred embodiments of -X-, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ^{6 in} the compound represented by the formula (I) are shown below.
—X— is preferably —SO ₂ —.
R ¹ is preferably substituted or unsubstituted alkyl.
R ¹ is more preferably substituted with an alkoxyalkyl, a non-aromatic carbocyclic alkyl, an alkyl substituted with a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group. Is alkyl.
R ¹ is more preferably alkyl substituted with a substituted or unsubstituted aromatic carbocyclic group.
R ² is preferably an unsubstituted alkyl, an alkyl substituted with a substituted or unsubstituted phenyl group, or a substituted or unsubstituted phenyl group.
R ³ is preferably substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, or substituted or unsubstituted aromatic heterocyclic group It is a group.
R ⁴ is preferably a substituted or unsubstituted aromatic carbocyclic group.
R ⁴ is more preferably a substituted or unsubstituted phenyl group.
R ⁵ is preferably a hydrogen atom.
R ⁶ is preferably a substituted or unsubstituted aromatic carbocyclic group.
R ⁶ is more preferably a substituted or unsubstituted phenyl group.
Examples of the compound of formula (I), the ^{-X-, R 1, R 2,} R 3, R 4, compounds that combine the preferred embodiments of ^{R 5} and ^{R 6} can be mentioned.

  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.
DCC: dicyclohexylcarbodiimide DIEA: N, N-diisopropylethylamine DMA: N, N-dimethylacetamide DMAP: 4-dimethylaminopyridine DME: 1,2-dimethoxyethane DMF: N, N-dimethylformamide DMI: 1,3-dimethyl 2-Imidazolidinone DMSO: Dimethyl sulfoxide EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HATU: 2- (1H-7-azabenzotriazol-1-yl) 1,1,3 , 3-tetramethyluronium hexafluorophosphate methane aminium LDA: lithium diisopropylamide LHMDS: lithium hexamethyldisilazide NaHMDS: sodium hexamethyldisilazide NMP: N-methylpyrrolidone _Pd 2 (d _{a) 3:} tris (dibenzylideneacetone) bis palladium PyBop: hexafluorophosphate (
Benzotriazol-1-yloxy) tripyrrolidinophosphonium

（式中、Ｅｔはエチル基、Ｌｇは脱離基、ならびにＲ^１、Ｒ^２、Ｒ^３、および−Ｘ−は上記（１）と同意義）

(In the formula, Et is an ethyl group, Lg is a leaving group, and R ¹ , R ² , R ³ , and -X- 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 sodium hydroxide, potassium hydroxide, potassium tert-butoxide, LHMDS, NaHMDS, LDA, sodium hydride and the like, preferably sodium hydride.
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, -60 degreeC-50 degreeC, Preferably -10 degreeC-30 degreeC is mentioned.
Examples of the reaction solvent include tetrahydrofuran, DME, DMF, DMA, NMP, DMI, toluene and the like, and they can be used alone or in combination.

(Second step)
Compound (iv) can be produced by reacting compound (iii) with an acid and water.
Examples of the acid include 5-20% hydrochloric acid aqueous solution, 5-20% sulfuric acid aqueous solution, and preferably 10% hydrochloric acid aqueous solution.
As reaction temperature, 20 to 70 degreeC, Preferably 55 degreeC is mentioned.
Examples of the reaction solvent include methanol, ethanol, isopropanol, tetrahydrofuran and the like, and these can be used alone or in combination.

(Third step)
Compound (vi) can be obtained by condensing compound (iv) with amine (v) or a salt thereof in the presence or absence of a condensing agent and reducing with a reducing agent.
Examples of the condensing agent include 4-toluenesulfonic acid, methanesulfonic acid, acetic acid, anhydrous magnesium sulfate, tetraisopropyl orthotitanate, titanium tetrachloride, molecular sieves, etc., and 1 to 10 moles relative to compound (iv). An equivalent amount can be used.
Amine (v) or a salt thereof can be used in an amount of 1 to 10 molar equivalents relative to compound (iv).
Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, picoline borane, borane and its complex, lithium borohydride, potassium borohydride, diisobutylaluminum hydride, and the like. It can be used in an amount of 1 to 10 molar equivalents relative to compound (iv).
As reaction temperature, -78 degreeC-the reflux temperature of a solvent, Preferably 0-25 degreeC is mentioned.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include tetrahydrofuran, toluene, dichloromethane, chloroform, methanol, ethanol, acetic acid, water and the like, and these can be used alone or in combination.

(4th process)
Compound (x) can be produced by reacting compound (vi) with acid chloride (vii) or sulfonyl chloride (viii) in the presence of a base.
Examples of the base include pyridine, DMAP, triethylamine, DIEA, N-methylimidazole and the like, preferably triethylamine.
As reaction temperature, -10 degreeC-120 degreeC, Preferably 25 degreeC is mentioned.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, DME, dichloromethane, DMF, DMA, NMP and the like, and these can be used alone or in combination.

As an alternative method of the fourth step, compound (x) can be produced by reacting compound (vi) with carboxylic acid (ix) in the presence of a condensing agent and a base.
Examples of the base include pyridine, DMAP, triethylamine, DIEA, N-methylimidazole and the like, preferably triethylamine.
Examples of the condensing agent include EDC, DCC, HATU, PyBop, and preferably EDC.
As reaction temperature, -10 degreeC-120 degreeC, Preferably 25 degreeC is mentioned.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, DME, dichloromethane, DMF, DMA, NMP and the like, and these can be used alone or in combination.

（式中、Ｌｇは脱離基、ならびにＲ^１、Ｒ^４、Ｒ^５、Ｒ^６、および−Ｘ−は上記（１）と同意義）

(Wherein Lg is a leaving group, and R ¹ , R ⁴ , R ⁵ , R ⁶ , and -X- are as defined above (1)).

(First step)
Compound (ii) can be produced by reacting nitro compound (i) with methyl acrylate in the presence of a base.
Examples of the base include sodium hydroxide, potassium hydroxide, potassium tert-butoxide, benzyltrimethylammonium hydroxide and the like. Preferably, potassium hydroxide is used. The base can be used in an amount of 0.5 to 10 equivalents relative to the nitro compound (i).
As reaction temperature, 0 degreeC-50 degreeC, Preferably 25 degreeC is mentioned.
Examples of the reaction solvent include methanol, ethanol, tert-butanol, 1,4-dioxane, tetrahydrofuran, DME, diethyl ether, water, DMF, DMA, NMP and the like, and these can be used alone or in combination.

(Second step)
Compound (iv) can be produced by reacting compound (ii) with compound (iii) and paraformaldehyde.
As reaction temperature, 20 degreeC-recirculation | reflux temperature, Preferably 80 degreeC is mentioned.
Examples of the reaction solvent include ethanol, isopropanol, tert-butanol, 1,4-dioxane, tetrahydrofuran, DME, DMF, DMA, NMP and the like, and these can be used alone or in combination.

(Third step)
Compound (v) can be produced by reacting compound (iv) with hydrogen in the presence of a metal catalyst.
Raney nickel is mentioned as a metal catalyst.
Examples of the hydrogen pressure include 1 to 10 atm, preferably 1 atm.
As reaction temperature, 0 degreeC-50 degreeC, Preferably 25 degreeC is mentioned.
Examples of the reaction solvent include ethanol, methanol, isopropanol and the like, and these can be used alone or in combination.

(4th process)
Compound (ix) can be produced by reacting compound (v) with acid chloride (vi) or sulfonyl chloride (vii) in the presence of a base.
Examples of the base include pyridine, DMAP, triethylamine, DIEA, N-methylimidazole and the like, preferably triethylamine.
As reaction temperature, -10 degreeC-120 degreeC, Preferably 25 degreeC is mentioned.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, DME, dichloromethane, DMF, DMA, NMP and the like, and these can be used alone or in combination.

As another method of the fourth step, compound (ix) can also be produced by reacting compound (v) with carboxylic acid (viii) in the presence of a condensing agent and a base.
Examples of the base include pyridine, DMAP, triethylamine, DIEA, N-methylimidazole and the like, preferably triethylamine.
Examples of the condensing agent include EDC, DCC, HATU, PyBop, and preferably EDC.
As reaction temperature, -10 degreeC-120 degreeC, Preferably 25 degreeC is mentioned.
The reaction time is 0.5 to 48 hours, preferably 1 to 6 hours.
Examples of the reaction solvent include 1,4-dioxane, tetrahydrofuran, diethyl ether, DME, dichloromethane, DMF, DMA, NMP and the like, and these can be used alone or in combination.

(5th process)
Compound (xi) can be produced by reacting compound (ix) with compound (x) in the presence of a base.
Examples of the base include sodium hydride, potassium tert-butoxide, LHMDS, NaHMDS, LDA and the like. Preferably sodium hydride is mentioned. The base can be used in the amount of 0.5 to 10 equivalents based on compound (ix).
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, -10 degreeC-50 degreeC, Preferably 25 degreeC is mentioned.
Examples of the reaction solvent include 1,4-dioxane, toluene, tetrahydrofuran, DME, DMF, DMA, NMP, DMI 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 5% B, 0.25 min 5% B, 1.5 min 60% B, 2.25 min 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 [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

シクロヘキサン−１，３−ジオン（４４５ｇ、３．９６ｍｏｌ）のエタノール（４００５ｍＬ）溶液に、ヒドロキシルアミン塩酸塩（２７５．７ｇ、３．９６ｍｏｌ）を加え、反応液を１００℃にて１．５時間加熱した。反応液を室温に冷却し、減圧濃縮した。残渣をジクロロメタン（５．０Ｌ）に溶解し、１０％炭酸カリウム水溶液で、ｐＨが中性になるまで洗浄した。有機層を水および飽和食塩水で洗浄し、硫酸ナトリムで乾燥した。有機層を減圧濃縮した。２０％酢酸エチル−ヘキサン（４５０．０ｍＬ）を加え、５分間攪拌した。ろ過後、得られた固体をジエチルエーテルで洗浄、減圧乾燥し、化合物１（１１７．０ｇ、収率１９％）を白色固体として得た。
1H NMR δ (ppm)(CDCl3)： 8.2 (br s, 1 H), 5.93 (s, 1 H), 3.91 (q, J = 7 Hz, 2 H), 2.30 (m, 4 H), 1.83 (m, 2 H), 1.32 (t, J = 7 Hz, 3 H). (1) Synthesis of Compound 1

Hydroxylamine hydrochloride (275.7 g, 3.96 mol) was added to a solution of cyclohexane-1,3-dione (445 g, 3.96 mol) in ethanol (4005 mL), and the reaction solution was heated at 100 ° C. for 1.5 hours. did. The reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5.0 L) and washed with 10% aqueous potassium carbonate solution until the pH was neutral. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure. 20% ethyl acetate-hexane (450.0 mL) was added and stirred for 5 minutes. After filtration, the obtained solid was washed with diethyl ether and dried under reduced pressure to obtain Compound 1 (117.0 g, yield 19%) as a white solid.
1H NMR δ (ppm) (CDCl3): 8.2 (br s, 1 H), 5.93 (s, 1 H), 3.91 (q, J = 7 Hz, 2 H), 2.30 (m, 4 H), 1.83 ( m, 2 H), 1.32 (t, J = 7 Hz, 3 H).

化合物１（５０．０ｇ、０．３２ｍｏｌ）を乾燥テトラヒドロフラン（１Ｌ）に溶解し、０〜５℃へ冷却し、トリエチルアミン（９０．０ｍＬ）を加えた。４−トルエンスルホン酸クロリド（７３．７ｇ、０．３８ｍｏｌ）を、０〜５℃にてゆっくり加えた。反応液を０〜５℃にて１．５時間攪拌した。反応液に１０％炭酸カリウム水溶液（１．０Ｌ）を加え、室温にゆっくりと昇温し、室温にて１８時間攪拌した。反応液を減圧濃縮し、１ｍｏｌ／Ｌ塩酸水溶液を用いて中和した。得られた水層をジクロロメタン（７５０ｍＬ）で抽出した。有機層をまとめ、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、ジエチルエーテルで洗浄し、乾燥を行い、化合物２（３５．０ｇ、収率７０％）を白色固体として得た。
1H NMR δ (ppm)(CDCl3): 6.03 (br s, 1 H), 5.08 (s, 1 H), 3.80 (q, J = 7 Hz, 2 H), 3.23 (m, 2 H), 2.49 (t, J = 7 Hz, 2 H), 1.96 (m, 2 H), 1.32 (t, J = 7 Hz, 3 H). (2) Synthesis of compound 2

Compound 1 (50.0 g, 0.32 mol) was dissolved in dry tetrahydrofuran (1 L), cooled to 0-5 ° C., and triethylamine (90.0 mL) was added. 4-Toluenesulfonic acid chloride (73.7 g, 0.38 mol) was slowly added at 0-5 ° C. The reaction was stirred at 0-5 ° C for 1.5 hours. A 10% aqueous potassium carbonate solution (1.0 L) was added to the reaction solution, the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and neutralized with 1 mol / L hydrochloric acid aqueous solution. The resulting aqueous layer was extracted with dichloromethane (750 mL). The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, washed with diethyl ether and dried to obtain compound 2 (35.0 g, yield 70%) as a white solid.
1H NMR δ (ppm) (CDCl3): 6.03 (br s, 1 H), 5.08 (s, 1 H), 3.80 (q, J = 7 Hz, 2 H), 3.23 (m, 2 H), 2.49 ( t, J = 7 Hz, 2 H), 1.96 (m, 2 H), 1.32 (t, J = 7 Hz, 3 H).

化合物２（５．０ｇ、３２．２１ｍｍｏｌ）をＤＭＦ（５０．０ｍＬ）に溶解し、６０％水素化ナトリウム（１．４１ｇ、３５．４３ｍｍｏｌ）を０℃にて加え、０℃にて３０分間攪拌した。ベンジルブロミド（６．０６ｇ、３５．４３ｍｍｏｌ）を滴下し、０℃にて１時間攪拌した。反応液をゆっくりと室温へ昇温し、さらに３時間攪拌した。０℃へ冷却し、飽和塩酸アンモニウム水溶液を加えた。反応液を酢酸エチル（５０ｍＬ）で抽出した。有機層をまとめ、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。減圧濃縮し、粗製の化合物３（５．０ｇ）を得た。
1H NMR δ (ppm)(CDCl3): 7.28 (m, 5 H), 5.14 (s, 1H), 4.65 (s, 2 H), 3.80 (q, J = 7 Hz, 2 H), 3.30 (t, J = 6 Hz, 2 H), 2.34 (t, J = 7 Hz, 2 H), 1.78 (m, 2 H), 1.31 (t, J = 7 Hz, 3 H), MS (ESI+) m/z 246.6 (M+H)+. (3) Synthesis of compound 3

Compound 2 (5.0 g, 32.21 mmol) was dissolved in DMF (50.0 mL), 60% sodium hydride (1.41 g, 35.43 mmol) was added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. did. Benzyl bromide (6.06 g, 35.43 mmol) was added dropwise and stirred at 0 ° C. for 1 hour. The reaction was slowly warmed to room temperature and stirred for an additional 3 hours. Cool to 0 ° C. and add saturated aqueous ammonium hydrochloride. The reaction solution was extracted with ethyl acetate (50 mL). The organic layers were combined, washed with water and saturated brine, and dried over sodium sulfate. Concentration under reduced pressure gave crude compound 3 (5.0 g).
1H NMR δ (ppm) (CDCl3): 7.28 (m, 5 H), 5.14 (s, 1H), 4.65 (s, 2 H), 3.80 (q, J = 7 Hz, 2 H), 3.30 (t, J = 6 Hz, 2 H), 2.34 (t, J = 7 Hz, 2 H), 1.78 (m, 2 H), 1.31 (t, J = 7 Hz, 3 H), MS (ESI +) m / z 246.6 (M + H) +.

化合物３（５．０ｇ、０．０２ｍｏｌ）のエタノール(５０ｍＬ)溶液に、１０％塩酸水溶液（２２．５ｍＬ）を加え、６０℃にて５時間加熱した。反応液を室温へ冷却し、減圧濃縮した。残渣にジクロロメタンを加え、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した。有機層を硫酸ナトリウムで乾燥し、減圧濃縮し、化合物４（４．５ｇ）を茶色の液体として得た。
1H NMR δ (ppm)(CDCl3): 7.35 (m, 5 H), 4.63 (s, 2 H), 3.61 (s, 2 H), 3.53 (t, J = 6 Hz, 2 H), 2.53 (t, J = 7 Hz, 2 H), 1.78 (m, 2 H). (4) Synthesis of compound 4

To a solution of compound 3 (5.0 g, 0.02 mol) in ethanol (50 mL) was added 10% aqueous hydrochloric acid (22.5 mL), and the mixture was heated at 60 ° C. for 5 hours. The reaction was cooled to room temperature and concentrated under reduced pressure. Dichloromethane was added to the residue, and the mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give compound 4 (4.5 g) as a brown liquid.
1H NMR δ (ppm) (CDCl3): 7.35 (m, 5 H), 4.63 (s, 2 H), 3.61 (s, 2 H), 3.53 (t, J = 6 Hz, 2 H), 2.53 (t , J = 7 Hz, 2 H), 1.78 (m, 2 H).

化合物４（３．０ｇ、１３．８ｍｍｏｌ）のジクロロメタン(５０ｍＬ)溶液に、３−メトキシアニリン（２．０４ｇ、１６．５７ｍｍｏｌ）を加え、室温にて３０分間攪拌した。水素化トリアセトキシホウ素ナトリウム（５．８５ｇ、２６．７ｍｍｏｌ）、および酢酸（０．９ｍＬ，１６．５７ｍｍｏｌ）を加え、室温にて１８時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加えた。有機層を分離し、水層をジクロロメタン（５０ｍＬ）で抽出した。有機層をまとめ、飽和食塩水で洗浄した後、硫酸ナトリウムで乾燥した。溶液を減圧濃縮し、得られた粗製の化合物５．３ｇをシリカゲルクロマトグラフィーにより精製し、化合物５ａ（２．１ｇ、４７．０％）を茶色の液体として得た。
1H NMR δ (ppm)(DMSO-d6): 7.35 (m, 2 H), 7.26 (m, 3 H), 6.98 (t, J = 8 Hz, 1 H), 6.17 (m, 3 H), 5.60 (d, J = 8 Hz, 1 H), 4.64 (d, J = 15 Hz, 1 H), 4.43 (d, J = 15 Hz, 1 H), 3.68 (s, 3 H), 3.51 (m, 1 H), 3.25 (m, 2 H), 3.73 (m, 1 H), 2.58 (d, J = 13 Hz, 1 H), 1.99 (m, 1 H), 1.74 (m, 1 H), 1.65 (m, 1 H), 1.43 (m, 1 H). MS (ESI+) m/z 325 (M+H)+. (5) Synthesis of compound 5a

To a solution of compound 4 (3.0 g, 13.8 mmol) in dichloromethane (50 mL) was added 3-methoxyaniline (2.04 g, 16.57 mmol), and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (5.85 g, 26.7 mmol) and acetic acid (0.9 mL, 16.57 mmol) were added, and the mixture was stirred at room temperature for 18 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution. The organic layer was separated and the aqueous layer was extracted with dichloromethane (50 mL). The organic layers were combined, washed with saturated brine, and dried over sodium sulfate. The solution was concentrated under reduced pressure, and 5.3 g of the obtained crude compound was purified by silica gel chromatography to obtain compound 5a (2.1 g, 47.0%) as a brown liquid.
1H NMR δ (ppm) (DMSO-d6): 7.35 (m, 2 H), 7.26 (m, 3 H), 6.98 (t, J = 8 Hz, 1 H), 6.17 (m, 3 H), 5.60 (d, J = 8 Hz, 1 H), 4.64 (d, J = 15 Hz, 1 H), 4.43 (d, J = 15 Hz, 1 H), 3.68 (s, 3 H), 3.51 (m, 1 H), 3.25 (m, 2 H), 3.73 (m, 1 H), 2.58 (d, J = 13 Hz, 1 H), 1.99 (m, 1 H), 1.74 (m, 1 H), 1.65 (m, 1 H), 1.43 (m, 1 H). MS (ESI +) m / z 325 (M + H) +.

（式中、−Ｘ−は、−Ｃ（＝Ｏ）−、または−ＳＯ_２−；
Ｒａは、水素原子、置換若しくは非置換のアルキル、または置換若しくは非置換の非芳香族炭素環式基；
Ｒｂは、置換若しくは非置換のアルキル、または置換若しくは非置換の芳香族炭素環式基；
Ｒｃは、置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基；
すなわち、Ｒａがベンジルであり、Ｒｂが２−メトキシフェニルの場合は、化合物５が上記化合物５ａであることを意味する）
化合物５（０．４５ｍｍｏｌ）をジクロロメタン（４ｍＬ）に溶解し、トリエチルアミン（７５．０μＬ、０．５４ｍｍｏｌ）、および対応する酸クロリドまたはスルホニルクロリド（０．５４ｍｍｏｌ）を順に加える。対応する酸クロリドまたはスルホニルクロリドが塩酸塩である場合、トリエチルアミン（７５．０μＬ、０．５４ｍｍｏｌ）をさらに加える。窒素雰囲気下、室温にて１６時間振とうする。反応液を減圧濃縮し、残渣をＤＭＦ（２ｍＬ）に溶解し、必要であればろ過を行う。得られた溶液を逆層ＨＰＬＣにより分取精製する。
上記反応（５）と類似の反応および上記反応（６）に従って、化合物Ｉ‐１５４を得た。

1H NMR δ (ppm)(DMSO-d6): 9.06 (dd, J = 2.41, 0.82 Hz, 1 H), 8.92 (dd, J = 4.82, 1.56 Hz, 1 H), 8.31 (ddd, J = 8.09, 2.44, 1.57 Hz, 1 H), 7.72 (ddd, J = 8.08, 4.83, 0.85 Hz, 1 H), 7.47-7.20 (m, 10 H), 4.67 (d, J = 14.73 Hz, 1 H), 4.59 (d, J = 16.55 Hz, 1 H), 4.40 (d, J = 16.55 Hz, 1 H), 4.30 (d, J = 14.74 Hz, 1 H), 4.04-3.94 (m, 1 H), 3.43-3.31 (m, 1 H), 3.14 (dd, J = 15.27, 5.64 Hz, 1 H), 3.05 (dd, J = 13.16, 10.89 Hz, 1 H), 2.07 (d, J = 13.16 Hz, 1 H), 1.73-1.59 (m, 3 H), 1.37-1.25 (m, 1 H); MS (ESI+) for m/z 450.3 (M+H)+. (6) Synthesis of compound 6

(In the formula, -X- represents -C (= O)-, or -SO _2- ;
Ra represents a hydrogen atom, substituted or unsubstituted alkyl, or substituted or unsubstituted non-aromatic carbocyclic group;
Rb represents substituted or unsubstituted alkyl, or substituted or unsubstituted aromatic carbocyclic group;
Rc is substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted Unsubstituted non-aromatic heterocyclic group;
That is, when Ra is benzyl and Rb is 2-methoxyphenyl, it means that compound 5 is compound 5a)
Compound 5 (0.45 mmol) is dissolved in dichloromethane (4 mL) and triethylamine (75.0 μL, 0.54 mmol) and the corresponding acid chloride or sulfonyl chloride (0.54 mmol) are added sequentially. If the corresponding acid chloride or sulfonyl chloride is the hydrochloride salt, additional triethylamine (75.0 μL, 0.54 mmol) is added. Shake for 16 hours at room temperature under a nitrogen atmosphere. The reaction solution is concentrated under reduced pressure, and the residue is dissolved in DMF (2 mL), and if necessary, filtered. The resulting solution is purified by reverse phase HPLC.
According to a reaction similar to the above reaction (5) and the above reaction (6), compound I-154 was obtained.

1H NMR δ (ppm) (DMSO-d6): 9.06 (dd, J = 2.41, 0.82 Hz, 1 H), 8.92 (dd, J = 4.82, 1.56 Hz, 1 H), 8.31 (ddd, J = 8.09, 2.44, 1.57 Hz, 1 H), 7.72 (ddd, J = 8.08, 4.83, 0.85 Hz, 1 H), 7.47-7.20 (m, 10 H), 4.67 (d, J = 14.73 Hz, 1 H), 4.59 (d, J = 16.55 Hz, 1 H), 4.40 (d, J = 16.55 Hz, 1 H), 4.30 (d, J = 14.74 Hz, 1 H), 4.04-3.94 (m, 1 H), 3.43- 3.31 (m, 1 H), 3.14 (dd, J = 15.27, 5.64 Hz, 1 H), 3.05 (dd, J = 13.16, 10.89 Hz, 1 H), 2.07 (d, J = 13.16 Hz, 1 H) , 1.73-1.59 (m, 3 H), 1.37-1.25 (m, 1 H); MS (ESI +) for m / z 450.3 (M + H) +.

（式中、ＲａおよびＲｃは、反応（６）と同意義）
化合物５（０．４５ｍｍｏｌ）をＤＭＦ（２ｍＬ）に溶解する。得られた溶液にＤＩＥＡ（４００．０μＬ，２．２５ｍｍｏｌ）、対応する酸クロリド（０．５４ｍｍｏｌ）、およびＤＭＡＰ（５．５ｍｇ、０．０４５ｍｍｏｌ）を加える。反応液をマイクロウェーブ条件下、１２０℃にて、１５０Ｗで２０分間攪拌する。反応液を必要であればろ過し、逆層ＨＰＬＣにより分取精製する。
上記の方法に従って、化合物Ｉ‐３０３を得た。

1H NMR δ (ppm)(DMSO-d6): 8.48 (s, 1 H), 7.43-7.35 (m, 3 H), 7.33-7.28 (m, 3 H), 7.07 (dd, J = 8.36, 2.48 Hz, 1 H), 7.01 (s, 1 H), 6.95 (d, J = 7.85 Hz, 1 H), 5.94 (s, 1 H), 4.76-4.64 (m, 2 H), 4.45 (d, J = 14.80 Hz, 1 H), 3.81 (s, 3 H), 3.44 (dd, J = 15.21, 10.73 Hz, 1 H), 3.19 (dd, J = 15.18, 6.01 Hz, 1 H), 3.04 (dd, J = 13.16, 11.33 Hz, 1 H), 2.83 (d, J = 13.21 Hz, 1 H), 2.13-2.04 (m, 1 H), 1.83-1.74 (m, 1 H), 1.62 (qd, J = 12.54, 3.76 Hz, 1 H), 1.48-1.36 (m, 1 H). When Rb is 2-methoxyphenyl, the compound can also be synthesized using the following method.
(6-2)

(In the formula, Ra and Rc are the same as in reaction (6)).
Compound 5 (0.45 mmol) is dissolved in DMF (2 mL). To the resulting solution is added DIEA (400.0 μL, 2.25 mmol), the corresponding acid chloride (0.54 mmol), and DMAP (5.5 mg, 0.045 mmol). The reaction solution is stirred at 150 ° C. for 20 minutes at 120 ° C. under microwave conditions. If necessary, the reaction solution is filtered and purified by reverse phase HPLC.
Compound I-303 was obtained according to the method described above.

1H NMR δ (ppm) (DMSO-d6): 8.48 (s, 1 H), 7.43-7.35 (m, 3 H), 7.33-7.28 (m, 3 H), 7.07 (dd, J = 8.36, 2.48 Hz , 1 H), 7.01 (s, 1 H), 6.95 (d, J = 7.85 Hz, 1 H), 5.94 (s, 1 H), 4.76-4.64 (m, 2 H), 4.45 (d, J = 14.80 Hz, 1 H), 3.81 (s, 3 H), 3.44 (dd, J = 15.21, 10.73 Hz, 1 H), 3.19 (dd, J = 15.18, 6.01 Hz, 1 H), 3.04 (dd, J = 13.16, 11.33 Hz, 1 H), 2.83 (d, J = 13.21 Hz, 1 H), 2.13-2.04 (m, 1 H), 1.83-1.74 (m, 1 H), 1.62 (qd, J = 12.54 , 3.76 Hz, 1 H), 1.48-1.36 (m, 1 H).

亜硝酸ナトリウム（２７６ｇ、４．０ｍｏｌ）および尿素（１８０ｇ、３．０ｍｏｌ）をＤＭＦ（２Ｌ）に溶解し、１−ブロモ−２−メチルプロパン（２７４ｇ、２．０ｍｏｌ）を加えた。反応液を４０℃にて６時間攪拌した。反応液を酢酸エチル（２Ｌ）で希釈し、飽和食塩水で洗浄、硫酸ナトリウムで乾燥した。溶液を減圧濃縮し、粗製の化合物７（４２３ｇ、収率３８％）を得た。
1H NMR δ (ppm) (CDCl3): 4.19 (d, J = 7.2 Hz, 2 H), 2.48-2.41 (m, 1 H), 1.02 (d, J = 6.8 Hz, 6 H). (7) Synthesis of compound 7

Sodium nitrite (276 g, 4.0 mol) and urea (180 g, 3.0 mol) were dissolved in DMF (2 L) and 1-bromo-2-methylpropane (274 g, 2.0 mol) was added. The reaction was stirred at 40 ° C. for 6 hours. The reaction mixture was diluted with ethyl acetate (2 L), washed with saturated brine, and dried over sodium sulfate. The solution was concentrated under reduced pressure to obtain crude compound 7 (423 g, 38% yield).
1H NMR δ (ppm) (CDCl3): 4.19 (d, J = 7.2 Hz, 2 H), 2.48-2.41 (m, 1 H), 1.02 (d, J = 6.8 Hz, 6 H).

化合物７（４２３．０ｇ、０．５８ｍｏｌ）およびアクリル酸メチル（６５．０ｇ、０．７５ｍｏｌ）を１，４−ジオキサンと水の混合液（１Ｌ）に溶解し、飽和水酸化カリウム水溶液（２１．０ｇ、０．３８ｍｏｌ）を滴下した。反応液を室温にて１２時間攪拌した後、酢酸エチルを加え、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥、減圧濃縮し、粗製の化合物８（９０．０ｇ、収率６３％）を得た。
1H NMR δ (ppm) (CDCl3): 4.32-4.27 (m, 1 H), 3.68 (s, 3 H), 2.41-2.13 (m, 5 H), 1.01 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H). (8) Synthesis of Compound 8

Compound 7 (423.0 g, 0.58 mol) and methyl acrylate (65.0 g, 0.75 mol) were dissolved in a mixture (1 L) of 1,4-dioxane and water, and a saturated aqueous potassium hydroxide solution (21. 0 g, 0.38 mol) was added dropwise. The reaction solution was stirred at room temperature for 12 hours, ethyl acetate was added, and the mixture was washed with saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude compound 8 (90.0 g, yield 63%).
1H NMR δ (ppm) (CDCl3): 4.32-4.27 (m, 1 H), 3.68 (s, 3 H), 2.41-2.13 (m, 5 H), 1.01 (d, J = 6.8 Hz, 3 H) , 0.98 (d, J = 6.8 Hz, 3 H).

化合物８（１０．０ｇ、５０．０ｍｍｏｌ）と１，３，５−トリメチル−１，３，５−トリアジナン（１２．３ｇ、９０．０ｍｍｏｌ）を混合し、１００℃にて１２時間攪拌した。反応液に酢酸エチルを加え、水および飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥、減圧濃縮し、化合物９（７．５ｇ、収率７５％）を得た。
1H NMR δ (ppm) (CDCl3): 4.05 (dd, J = 14.0, 2.8 Hz, 1 H), 3.52 (d, J = 14.0 Hz, 1 H), 2.96 (s, 3 H), 2.66-2.61 (m, 1 H), 2.51-2.44 (m, 1 H), 2.38-2.26 (m, 2 H), 2.12-2.04 (m, 1 H), 1.01 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H). LCMS m/z 201 (M+H)+. (9) Synthesis of compound 9a

Compound 8 (10.0 g, 50.0 mmol) and 1,3,5-trimethyl-1,3,5-triazinan (12.3 g, 90.0 mmol) were mixed and stirred at 100 ° C. for 12 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain Compound 9 (7.5 g, yield 75%).
1H NMR δ (ppm) (CDCl3): 4.05 (dd, J = 14.0, 2.8 Hz, 1 H), 3.52 (d, J = 14.0 Hz, 1 H), 2.96 (s, 3 H), 2.66-2.61 ( m, 1 H), 2.51-2.44 (m, 1 H), 2.38-2.26 (m, 2 H), 2.12-2.04 (m, 1 H), 1.01 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H). LCMS m / z 201 (M + H) +.

アクリル酸メチル（０．５８ｍｏｌ）およびニトロメタン（１．７４ｍｏｌ）を１，４−ジオキサン（１．０Ｌ）に溶解し、水酸化カリウム（０．２９ｍｏｌ）を水（１００ｍＬ）に溶解した水溶液を、０℃にて加えた。反応混合液を室温にて２４時間攪拌し、減圧濃縮した。残渣を酢酸エチルに溶解し、飽和食塩水で洗浄、硫酸ナトリウムで乾燥した。有機層を減圧濃縮し、得られた粗製の化合物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１０（３２．７ｇ、収率３８％）を得た。
1H NMR δ (ppm) (CDCl3): 4.48 (t, J = 6.8 Hz, 2 H), 3.70 (s, 3 H), 2.48 (t, J = 7.2 Hz, 2 H), 2.32 (p, J = 6.8 Hz, 2 H). (10) Synthesis of Compound 10

An aqueous solution prepared by dissolving methyl acrylate (0.58 mol) and nitromethane (1.74 mol) in 1,4-dioxane (1.0 L) and potassium hydroxide (0.29 mol) in water (100 mL) Added at ° C. The reaction mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting crude compound was purified by silica gel column chromatography to obtain compound 10 (32.7 g, yield 38%).
1H NMR δ (ppm) (CDCl3): 4.48 (t, J = 6.8 Hz, 2 H), 3.70 (s, 3 H), 2.48 (t, J = 7.2 Hz, 2 H), 2.32 (p, J = (6.8 Hz, 2 H).

化合物１０（９．５ｇ、０．０６ｍｏｌ）、ブロモベンゼン（５．０ｇ、０．０３ｍｏｌ）、炭酸セシウム（１２．３ｇ、０．０４ｍｏｌ）、ＤＭＥ（５０ｍＬ）の混合物に、Ｐｄ_２（ｄｂａ）_３（０．８７ｇ、０．９５ｍｏｌ）および化合物１２（０．５９ｇ、１．９０ｍｍｏｌ）を加えた。反応混合物を、窒素雰囲気下、５０℃にて終夜攪拌した。反応混合物を濃縮し、水で希釈し、酢酸エチル（２５ｍＬ）で抽出した。有機層をまとめ、水、飽和食塩水で洗浄し、硫酸ナトリウムで乾燥、減圧濃縮した。粗製の化合物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１１（５．９０ｇ、収率８９％）を無色の油状物として得た。
1H NMR δ (ppm) (CDCl3): 7.46-7.40 (m, 5 H), 5.57 (q, J = 6.4 Hz, 1 H), 3.67 (s, 3 H), 2.81-2.74 (m, 1 H), 2.48-2.39 (m, 1 H), 2.36 (t, J = 6.8 Hz, 2 H). LCMS m/z 177 (M-NO2). (11) Synthesis of Compound 11

To a mixture of compound 10 (9.5 g, 0.06 mol), bromobenzene (5.0 g, 0.03 mol), cesium carbonate (12.3 g, 0.04 mol), DME (50 mL), Pd ₂ (dba) ₃ (0.87 g, 0.95 mol) and compound 12 (0.59 g, 1.90 mmol) were added. The reaction mixture was stirred at 50 ° C. overnight under a nitrogen atmosphere. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate (25 mL). The organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to give compound 11 (5.90 g, 89% yield) as a colorless oil.
1H NMR δ (ppm) (CDCl3): 7.46-7.40 (m, 5 H), 5.57 (q, J = 6.4 Hz, 1 H), 3.67 (s, 3 H), 2.81-2.74 (m, 1 H) , 2.48-2.39 (m, 1 H), 2.36 (t, J = 6.8 Hz, 2 H). LCMS m / z 177 (M-NO2).

メチルアミン（４５ｍｍｏｌ）をエタノール（４０ｍＬ）に溶解し、パラホルムアルデヒド（２２．５ｍｍｏｌ）を加えた。反応混合液を５分間攪拌し、化合物１１（２２．５ｍｍｏｌ）を加えた。反応混合液を加熱還流させ、１２時間攪拌した。反応液からエタノールを減圧留去し、水で希釈、酢酸エチル（３０ｍＬ）で抽出した。有機層をまとめ、水、飽和食塩水で洗浄した。硫酸ナトリウムで乾燥、減圧濃縮し、化合物９ｂ（４．７ｇ、収率８９％）を得た。
1H NMR δ (ppm) (CDCl3): 7.44 (m, 5 H), 4.46 (dd, J = 13.6, 2.4 Hz, 1 H), 3.83 (d, J = 14.0 Hz, 1 H), 3.16-3.10 (m, 1 H), 3.04 (s, 3 H), 2.65-2.47 (m, 3 H). LCMS m/z 235 (M+H)+. (12) Synthesis of compound 9b

Methylamine (45 mmol) was dissolved in ethanol (40 mL) and paraformaldehyde (22.5 mmol) was added. The reaction mixture was stirred for 5 minutes and compound 11 (22.5 mmol) was added. The reaction mixture was heated to reflux and stirred for 12 hours. Ethanol was distilled off from the reaction solution under reduced pressure, diluted with water, and extracted with ethyl acetate (30 mL). The organic layers were combined and washed with water and saturated brine. The extract was dried over sodium sulfate and concentrated under reduced pressure to obtain Compound 9b (4.7 g, yield 89%).
1H NMR δ (ppm) (CDCl3): 7.44 (m, 5 H), 4.46 (dd, J = 13.6, 2.4 Hz, 1 H), 3.83 (d, J = 14.0 Hz, 1 H), 3.16-3.10 ( m, 1 H), 3.04 (s, 3 H), 2.65-2.47 (m, 3 H). LCMS m / z 235 (M + H) +.

（式中、Ｒｄは水素原子、置換若しくは非置換のアルキル、または置換若しくは非置換の非芳香族炭素環式基；Ｒｅは置換若しくは非置換のアルキル、置換若しくは非置換の非芳香族複素環式基、または置換若しくは非置換の芳香族炭素環式基；
化合物９において、Ｒｄがメチルであり、Ｒｅがイソプロピルである化合物は、上記化合物９ａを意味し、Ｒｄがメチルであり、Ｒｅがフェニルである化合物は、上記化合物９ｂを意味する）
化合物９（１９．０ｍｍｏｌ）をエタノール（１５０ｍＬ）に溶解し、ラネーニッケル（５．０ｇ）を加える。反応混合物を常圧の水素雰囲気下、室温にて６時間攪拌する。反応後、触媒をろ過し、ろ液を減圧濃縮する。得られた粗製の化合物を逆層ＨＰＬＣにより精製し、化合物１３を得る。
上記の方法に従って、化合物１３ａを得た。

1H NMR δ (ppm) (CDCl3): 7.49-7.47 (m, 2 H), 7.40-7.36 (m, 2 H), 7.31-7.26 (m, 1 H), 3.67 (d, J = 12.4 Hz, 1 H), 3.31 (dd, J = 12.4, 1.6 Hz, 1 H), 3.00 (s, 3 H), 2.64-2.56 (m, 1 H), 2.37-2.27 (m, 2 H), 2.05-1.98 (m, 1 H). LCMS m/z 205 (M+H)+.
上記の方法に従って、化合物１３ｂを得た。

1H NMR δ (ppm) (CD3OD): 7.56-7.54 (m, 2 H), 7.42-7.38 (m, 2 H), 7.32-7.29 (m, 1 H), 4.94-4.92 (m, 1 H), 3.83 (d, J = 0.8 Hz, 1 H), 3.46 (d, J = 0.8 Hz, 1 H), 2.59-2.51 (m, 1 H), 2.39-2.32 (m, 3 H), 2.31-2.12 (m, 3 H), 2.05-2.00 (m, 1 H), 1.78-1.77 (m, 2 H). LCMS m/z 245 (M+H)+.
上記の方法に従って、化合物１３ｃを得た。

1H NMR δ (ppm) (CDCl3): 8.51 (d, J = 4.8 Hz, 1 H), 7.67-7.62 (m, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.17 (dd, J = 7.2, 5.2 Hz, 1 H), 4.83 (d, J = 15.2 Hz, 1 H), 4.55 (d, J = 15.2 Hz, 1 H), 3.35 (d, J = 12.4 Hz, 1 H), 3.05 (dd, J = 12.0, 2.0 Hz, 1 H), 2.68-2.60 (m, 1 H), 2.49-2.42 (m, 1 H), 1.78-1.72 (m, 2 H), 1.66-1.60 (m, 1 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 3 H). LCMS m/z 248 (M+H)+. (13) Synthesis of Compound 13

Wherein Rd is a hydrogen atom, substituted or unsubstituted alkyl, or a substituted or unsubstituted non-aromatic carbocyclic group; Re is substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic heterocyclic A group or a substituted or unsubstituted aromatic carbocyclic group;
In the compound 9, a compound in which Rd is methyl and Re is isopropyl means the above compound 9a, and a compound in which Rd is methyl and Re is phenyl means the above compound 9b)
Compound 9 (19.0 mmol) is dissolved in ethanol (150 mL) and Raney nickel (5.0 g) is added. The reaction mixture is stirred at room temperature for 6 hours under atmospheric hydrogen atmosphere. After the reaction, the catalyst is filtered and the filtrate is concentrated under reduced pressure. The resulting crude compound is purified by reverse phase HPLC to give compound 13.
Compound 13a was obtained according to the method described above.

1H NMR δ (ppm) (CDCl3): 7.49-7.47 (m, 2 H), 7.40-7.36 (m, 2 H), 7.31-7.26 (m, 1 H), 3.67 (d, J = 12.4 Hz, 1 H), 3.31 (dd, J = 12.4, 1.6 Hz, 1 H), 3.00 (s, 3 H), 2.64-2.56 (m, 1 H), 2.37-2.27 (m, 2 H), 2.05-1.98 ( m, 1 H). LCMS m / z 205 (M + H) +.
Compound 13b was obtained according to the method described above.

1H NMR δ (ppm) (CD3OD): 7.56-7.54 (m, 2 H), 7.42-7.38 (m, 2 H), 7.32-7.29 (m, 1 H), 4.94-4.92 (m, 1 H), 3.83 (d, J = 0.8 Hz, 1 H), 3.46 (d, J = 0.8 Hz, 1 H), 2.59-2.51 (m, 1 H), 2.39-2.32 (m, 3 H), 2.31-2.12 ( m, 3 H), 2.05-2.00 (m, 1 H), 1.78-1.77 (m, 2 H). LCMS m / z 245 (M + H) +.
Compound 13c was obtained according to the method described above.

1H NMR δ (ppm) (CDCl3): 8.51 (d, J = 4.8 Hz, 1 H), 7.67-7.62 (m, 1 H), 7.33 (d, J = 8.0 Hz, 1 H), 7.17 (dd, J = 7.2, 5.2 Hz, 1 H), 4.83 (d, J = 15.2 Hz, 1 H), 4.55 (d, J = 15.2 Hz, 1 H), 3.35 (d, J = 12.4 Hz, 1 H), 3.05 (dd, J = 12.0, 2.0 Hz, 1 H), 2.68-2.60 (m, 1 H), 2.49-2.42 (m, 1 H), 1.78-1.72 (m, 2 H), 1.66-1.60 (m , 1 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.82 (d, J = 6.8 Hz, 3 H). LCMS m / z 248 (M + H) +.

（式中、Ｒｄは反応（１０）と同意義）
化合物９（３７．０ｍｍｏｌ）を１，４−ジオキサン（５０ｍＬ）に溶解し、塩酸水溶液（３ｍｏｌ／Ｌ、１５０ｍＬ）および亜鉛粉末（０．３７ｍｏｌ）を加える。反応混合液を室温にて１６時間攪拌する。反応後、ろ過し、ろ液を水酸化ナトリウム水溶液（５ｍｏｌ／Ｌ）を加えて塩基性にし、酢酸エチル（２００ｍＬ）を加えると固体が析出する。混合物をろ過し、有機層を分離する。水層を酢酸エチル（１００ｍＬ）で抽出する。有機層を硫酸ナトリウムで乾燥し、減圧濃縮する。得られた残渣を逆層ＨＰＬＣにより精製し、化合物１３を得る。
上記の方法に従って、化合物１３ｄを得た。

1H NMR δ (ppm) (CDCl3): 7.42-7.40 (m, 1 H), 7.30-7.23 (m, 3 H), 3.73-3.62 (m, 2 H), 3.02 (s, 3 H), 2.78-2.72 (m, 1 H), 2.61-2.55 (m, 1 H), 2.18-2.01 (m, 4 H). LCMS m/z 239 (M+H)+. When Re is 2-chlorophenyl, the compound can also be synthesized using the following method.
(13-2) Synthesis of Compound 13

(Wherein Rd has the same meaning as in reaction (10))
Compound 9 (37.0 mmol) is dissolved in 1,4-dioxane (50 mL) and aqueous hydrochloric acid (3 mol / L, 150 mL) and zinc powder (0.37 mol) are added. The reaction mixture is stirred at room temperature for 16 hours. After the reaction, the mixture is filtered, and the filtrate is made basic by adding an aqueous sodium hydroxide solution (5 mol / L). When ethyl acetate (200 mL) is added, a solid is precipitated. The mixture is filtered and the organic layer is separated. Extract the aqueous layer with ethyl acetate (100 mL). The organic layer is dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by reverse phase HPLC to give compound 13.
Compound 13d was obtained according to the method described above.

1H NMR δ (ppm) (CDCl3): 7.42-7.40 (m, 1 H), 7.30-7.23 (m, 3 H), 3.73-3.62 (m, 2 H), 3.02 (s, 3 H), 2.78- 2.72 (m, 1 H), 2.61-2.55 (m, 1 H), 2.18-2.01 (m, 4 H). LCMS m / z 239 (M + H) +.

（式中、ＲｄおよびＲｅは反応（１０）と同意義；Ｒｆは置換若しくは非置換のアルキル、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、または置換若しくは非置換の非芳香族複素環式基）
化合物１３（０．５ｍｍｏｌ）にジクロロメタン（４ｍＬ）を加え、対応する酸クロリド（０．５ｍｍｏｌ）とトリエチルアミン（１．５ｍｍｏｌ）を加える。反応液を窒素雰囲気下、３０℃にて１６時間攪拌する。反応液を減圧濃縮し、残渣にメタノール（２ｍＬ）を加える。必要な場合はろ過を行う。残渣を逆層ＨＰＬＣにより精製し、化合物１４を得る。
上記の方法に従って、化合物Ｉ‐３０４を得た。

1H NMR δ (ppm) (CDCl3) 7.26-7.19 (m, 5 H), 7.16-7.12 (m, 2 H), 6.96 (t, J = 8.4 Hz, 2 H), 6.67 (s, 1 H), 3.95-3.90 (m, 1 H), 3.80-3.74 (m, 1 H), 3.49 (d, J = 13.2 Hz, 1 H), 3.43-3.38 (m, 4 H), 3.35 (s, 3 H), 2.99-2.92 (m, 2 H), 2.47-2.21 (m, 3 H). LCMS m/z 385 (M+H)+.
上記の方法に従って、化合物Ｉ−１３４を得た。

1H NMR δ (ppm) (CDCl3) 7.27 (d, J =8.8 Hz, 2 H), 6.90 (d, J =8.8 Hz, 2 H), 6.34 (br, 1 H), 3.81-3.71 (m, 5 H), 3.06 (q, J = 10.8 Hz, 2 H), 2.99 (s, 3 H), 2.77-2.74 (m, 1 H), 2.46-2.24 (m, 3 H). LCMS m/z 345 (M+H)+. (14) Synthesis of Compound 14

Wherein Rd and Re are as defined in reaction (10); Rf is a substituted or unsubstituted alkyl, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted nonaromatic carbocyclic group, Substituted or unsubstituted aromatic heterocyclic group, or substituted or unsubstituted non-aromatic heterocyclic group)
Dichloromethane (4 mL) is added to compound 13 (0.5 mmol) and the corresponding acid chloride (0.5 mmol) and triethylamine (1.5 mmol) are added. The reaction is stirred at 30 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure, and methanol (2 mL) is added to the residue. Filter if necessary. The residue is purified by reverse layer HPLC to give compound 14.
Following the above method, compound I-304 was obtained.

1H NMR δ (ppm) (CDCl3) 7.26-7.19 (m, 5 H), 7.16-7.12 (m, 2 H), 6.96 (t, J = 8.4 Hz, 2 H), 6.67 (s, 1 H), 3.95-3.90 (m, 1 H), 3.80-3.74 (m, 1 H), 3.49 (d, J = 13.2 Hz, 1 H), 3.43-3.38 (m, 4 H), 3.35 (s, 3 H) , 2.99-2.92 (m, 2 H), 2.47-2.21 (m, 3 H). LCMS m / z 385 (M + H) +.
Compound I-134 was obtained according to the method described above.

1H NMR δ (ppm) (CDCl3) 7.27 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 6.34 (br, 1 H), 3.81-3.71 (m, 5 H), 3.06 (q, J = 10.8 Hz, 2 H), 2.99 (s, 3 H), 2.77-2.74 (m, 1 H), 2.46-2.24 (m, 3 H). LCMS m / z 345 ( M + H) +.

である場合には、以下の方法を用いて化合物を合成することもできる。
（１４−２）化合物１４の合成

化合物１３（０．５ｍｍｏｌ）にジクロロメタン（２ｍＬ）を加え、対応するカルボン酸（０．５ｍｍｏｌ）とＨＡＴＵ（０．５ｍｍｏｌ）のＤＭＦ（２ｍＬ）混合物、およびトリエチルアミン（１．５ｍｍｏｌ）を加える。反応液を窒素雰囲気下、３０℃にて１６時間攪拌する。反応液を減圧濃縮し、残渣にメタノール（２ｍＬ）を加える。必要な場合はろ過を行う。残渣を逆層ＨＰＬＣにより精製し、化合物１４を得る。
上記の方法に従って、化合物Ｉ−０１２を得た。

LCMS m/z 360.3 (M+H)+. Rf is

In this case, the compound can also be synthesized using the following method.
(14-2) Synthesis of Compound 14

To compound 13 (0.5 mmol) is added dichloromethane (2 mL) and the corresponding carboxylic acid (0.5 mmol) and HATU (0.5 mmol) in DMF (2 mL) and triethylamine (1.5 mmol) are added. The reaction is stirred at 30 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure, and methanol (2 mL) is added to the residue. Filter if necessary. The residue is purified by reverse layer HPLC to give compound 14.
Compound I-012 was obtained according to the method described above.

LCMS m / z 360.3 (M + H) +.

（式中、Ｒｄ、ＲｅおよびＲｆは反応（１０）と同意義）
化合物１３（０．５ｍｍｏｌ）にジクロロメタン（４ｍＬ）を加え、対応するスルホニルクロリド（０．５ｍｍｏｌ）を０℃にて加える。ピリジン（１．５ｍｍｏｌ）とＤＭＡＰ（０．０５ｍｍｏｌ）をさらに加える。反応液を窒素雰囲気下、３０℃にて１６時間攪拌する。反応液を減圧濃縮し、残渣にメタノール（２ｍＬ）を加える。必要な場合はろ過を行う。残渣を逆層ＨＰＬＣにより精製し、化合物１５を得る。
上記の方法に従って、化合物Ｉ−１４２を得た。

1H NMR δ (ppm) (CDCl3) 7.40-7.34 (m, 3 H), 7.24-7.20 (m, 2 H), 6.95 (d, J = 8.8 Hz, 2 H), 6.53 (d, J = 8.8 Hz, 2 H), 5.383 (s, 1 H), 3.91 (d, J = 13.6 Hz, 1 H), 3.77-3.72 (m, 4 H), 2.96 (s, 3 H), 2.59-2.54 (m, 2 H), 2.18-2.12 (m, 2 H). LCMS m/z 375 (M+H)+.
上記の方法に従って、化合物Ｉ−０６４を得た。

1H NMR δ (ppm) (CDCl3) 7.39-7.26 (m, 10 H), 4.87 (s, 1 H), 4.77 (d, J = 14.0 Hz, 1 H), 4.51 (d, J = 14.4 Hz, 1 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.64 (d, J = 13.2 Hz, 1 H), 2.71-2.62 (m, 2 H), 2.37-2.32 (m, 2 H), 2.27 (s, 3 H). LCMS m/z 359 (M+H)+. (15) Synthesis of Compound 15

(In the formula, Rd, Re, and Rf are as defined in the reaction (10)).
To compound 13 (0.5 mmol) is added dichloromethane (4 mL) and the corresponding sulfonyl chloride (0.5 mmol) is added at 0 ° C. Additional pyridine (1.5 mmol) and DMAP (0.05 mmol) are added. The reaction is stirred at 30 ° C. for 16 hours under a nitrogen atmosphere. The reaction mixture is concentrated under reduced pressure, and methanol (2 mL) is added to the residue. Filter if necessary. The residue is purified by reverse layer HPLC to give compound 15.
Compound I-142 was obtained according to the method described above.

1H NMR δ (ppm) (CDCl3) 7.40-7.34 (m, 3 H), 7.24-7.20 (m, 2 H), 6.95 (d, J = 8.8 Hz, 2 H), 6.53 (d, J = 8.8 Hz , 2 H), 5.383 (s, 1 H), 3.91 (d, J = 13.6 Hz, 1 H), 3.77-3.72 (m, 4 H), 2.96 (s, 3 H), 2.59-2.54 (m, 2 H), 2.18-2.12 (m, 2 H). LCMS m / z 375 (M + H) +.
Compound I-064 was obtained according to the method described above.

1H NMR δ (ppm) (CDCl3) 7.39-7.26 (m, 10 H), 4.87 (s, 1 H), 4.77 (d, J = 14.0 Hz, 1 H), 4.51 (d, J = 14.4 Hz, 1 H), 3.93 (d, J = 13.2 Hz, 1 H), 3.64 (d, J = 13.2 Hz, 1 H), 2.71-2.62 (m, 2 H), 2.37-2.32 (m, 2 H), 2.27 (s, 3 H). LCMS m / z 359 (M + H) +.

２−ピリジンカルボキシアルデヒド（１００．０ｇ、０．９３ｍｏｌ）とニトロメタン（８３ｍＬ，１．１ｍｏｌ）にメタノール（８５０ｍＬ）を加え、アルゴン雰囲気下―１５℃へ冷却した。水酸化ナトリウム（３９．０ｇ、０．９８ｍｏｌ）を水（１００ｍＬ）に溶かした溶液を２０分間かけて滴下した。淡黄色の固体が析出し、０℃にて１０分攪拌した。氷水（６００ｍＬ）を加え、さらに１５分攪拌後、飽和塩化アンモニウム水溶液（７００ｍＬ）を加えた。有機層をジクロロメタンで抽出し、硫酸ナトリウムで乾燥、減圧濃縮し、化合物１６（１２０．０ｇ、収率７６％）を得た。 (16) Synthesis of Compound 16

Methanol (850 mL) was added to 2-pyridinecarboxaldehyde (100.0 g, 0.93 mol) and nitromethane (83 mL, 1.1 mol), and the mixture was cooled to −15 ° C. under an argon atmosphere. A solution of sodium hydroxide (39.0 g, 0.98 mol) in water (100 mL) was added dropwise over 20 minutes. A pale yellow solid was precipitated and stirred at 0 ° C. for 10 minutes. Ice water (600 mL) was added, and after stirring for another 15 minutes, saturated aqueous ammonium chloride solution (700 mL) was added. The organic layer was extracted with dichloromethane, dried over sodium sulfate, and concentrated under reduced pressure to obtain Compound 16 (120.0 g, yield 76%).

化合物１６（１００．０ｇ、０．６０ｍｏｌ）を無水酢酸（１００ｍＬ）に溶解し、アルゴン雰囲気下、０℃へ冷却した。ＤＭＡＰ（８．０ｇ、６０．０ｍｍｏｌ）を加え、反応液を室温にて１６時間攪拌した。反応液をジクロロメタンで抽出し、飽和食塩水で洗浄、減圧濃縮した。得られた残渣を再びジクロロメタンに溶解し、２ｍｏｌ／Ｌの水酸化ナトリウム水溶液、飽和食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥、減圧濃縮し、化合物１７（１００．０ｇ）を得た。
LCMS m/z 151 (M+H)+. (17) Synthesis of Compound 17

Compound 16 (100.0 g, 0.60 mol) was dissolved in acetic anhydride (100 mL) and cooled to 0 ° C. under an argon atmosphere. DMAP (8.0 g, 60.0 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was extracted with dichloromethane, washed with saturated brine, and concentrated under reduced pressure. The obtained residue was again dissolved in dichloromethane and washed with 2 mol / L aqueous sodium hydroxide solution and saturated brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain Compound 17 (100.0 g).
LCMS m / z 151 (M + H) +.

化合物１７（４０５．０ｇ、２．７ｍｏｌ）を無水テトラヒドロフラン（２Ｌ）に溶解し、０℃へ冷却した。氷酢酸（３４０ｍＬ）、およびＮａＢＨ_４（１１３．０ｇ、３．０ｍｏｌ）を加えた。得られた懸濁液を室温にて１２時間攪拌し、水を加えた。反応混合物を、シリカゲルパッドろ過処理を行い、減圧濃縮し、化合物１８（１４０．０ｇ、収率３４％）を茶色の固体として得た。
1H NMR δ (ppm) (CDCl3): 8.81 (d, J = 5.6 Hz, 1 H), 7.92 (td, J = 8.0, 1.2 Hz, 1 H), 7.49-7.49 (m, 2 H), 4.93 (t, J = 6.0 Hz, 2 H), 3.87 (t, J = 6.0 Hz, 2 H).
上記化合物１８を用い、上記反応（８）および（９）の類似の反応、ならびに上記反応（１３）〜（１５）の反応を経て、実施例化合物を得ることができる。 (18) Synthesis of Compound 18

Compound 17 (405.0 g, 2.7 mol) was dissolved in anhydrous tetrahydrofuran (2 L) and cooled to 0 ° C. Glacial acetic acid (340 mL) and NaBH ₄ (113.0 g, 3.0 mol) were added. The resulting suspension was stirred at room temperature for 12 hours and water was added. The reaction mixture was subjected to silica gel pad filtration and concentrated under reduced pressure to give compound 18 (140.0 g, yield 34%) as a brown solid.
1H NMR δ (ppm) (CDCl3): 8.81 (d, J = 5.6 Hz, 1 H), 7.92 (td, J = 8.0, 1.2 Hz, 1 H), 7.49-7.49 (m, 2 H), 4.93 ( t, J = 6.0 Hz, 2 H), 3.87 (t, J = 6.0 Hz, 2 H).
The Example compound can be obtained through the similar reaction of the above reactions (8) and (9) and the reactions of the above reactions (13) to (15) using the above compound 18.

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

以下に、本発明化合物の生物試験例を記載する。

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 (11)

Formula (I):

(Where
-A- is

And
-X- is, -C (= O) -, or -SO ₂ - and is;
R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl, or a substituted or unsubstituted non-aromatic carbocyclic group;
R ² is a substituted or unsubstituted alkyl, or a substituted or unsubstituted aromatic carbocyclic group;
R ³ represents substituted or unsubstituted alkyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted Or an unsubstituted non-aromatic heterocyclic group;
R ⁴ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic heterocyclic group, or a substituted or unsubstituted aromatic carbocyclic group;
R ⁵ is a hydrogen atom or substituted or unsubstituted alkyl;
R ⁶ is substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, or substituted Or it is an unsubstituted non-aromatic heterocyclic group. )
A compound represented by (however,

Or a pharmaceutically acceptable salt thereof.
-A-

(Wherein, -X-, R ² , and R ³ are as defined in claim 1).
The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
R ³ is a substituted or unsubstituted alkyl, a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.
-A-

(Wherein, -X-, R ⁴ , R ⁵ , and R ⁶ are as defined in claim 1).
The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
The compound according to claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a substituted or unsubstituted aromatic carbocyclic group.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1, 4, and 5, wherein R ⁵ is a hydrogen atom.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 and 4 to 6, wherein R ⁶ is a substituted or unsubstituted aromatic carbocyclic group.
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted or unsubstituted alkyl.
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R ¹ is substituted or unsubstituted aromatic carbocyclic alkyl.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.
  The pharmaceutical composition according to claim 10, which has a Nav 1.7 inhibitory action.