JP5667934B2 - Pharmaceuticals comprising novel bicyclic heterocyclic compounds - Google Patents

Description

  The present invention relates to a drug containing a novel compound having a benzimidazole and imidazopyridine skeleton as a bicyclic heterocycle or a pharmaceutically acceptable salt thereof as an active ingredient, particularly SNS (sensory neuron specific sodium channel). The present invention relates to a therapeutic agent or a preventive agent for general pathological conditions. Specifically, the present invention relates to a therapeutic or prophylactic agent for diseases such as neuropathic pain, nociceptive pain, dysuria or multiple sclerosis.

  In 1952, Hodgkins and Huxley showed that the body of neural activity was the Na channel, after which Na channel inhibitors continued to be developed as antiarrhythmic or local anesthetics. In 1961, it was discovered that lidocaine, one of Na channel inhibitors, has an analgesic effect, and its clinical application as an analgesic was started. However, since Na channels are also present in non-neural tissues such as muscles and heart, the side effects caused by systemic administration remained a problem.

On the other hand, with the progress of molecular biology, Na channel subtypes have been revealed one after another, and it is known that there are currently 10 types of α subunits that form Na channel pores. Sensory neuron specific sodium channel (sensory nerve specific Na channel), that is, SNS is one of such Na channel α subunits, and is localized in small diameter cells (C fibers) of dorsal root ganglia involved in nerve perception. Tetrodotoxin (TTX) resistant Na channel, also called SCN10A, PN3 or NaV1.8 (Non-patent Documents 1 and 2). SNS knockout mice are insensitive to mechanical stimuli, and in patients with neuropathic or inflammatory pain, administration of antisense to SNS attenuates hypersensitivity and abnormalities It has been reported.
Therefore, an SNS inhibitor is a therapeutic or preventive agent that has an analgesic effect on diseases such as neuropathic pain and nociceptive pain accompanied by pain, numbness, burning, dull pain, etc. involving C fiber. Thought to get. Furthermore, since SNS is not expressed in non-neural tissues and central nerves, it was considered that a drug that selectively inhibits SNS can be a drug that does not have side effects derived from non-neural tissues or central nerves.

In dysuria, frequent urination, which is the main symptom, is caused by C fiber overactivity, that is, overactive bladder and bladder pain involve dysfunction of the afferent sensory nerve tract from the lower urinary tract It is becoming clear that suppression of C-fiber sensory nerves from the bladder is effective (Non-patent Document 3). Therefore, a drug that inhibits SNS, which is the main body of C fiber nerve activity, is expected to be a therapeutic or preventive drug for dysuria having a novel action point.
On the other hand, it has been recently reported that SNS, which is found only in C fibers, is ectopically expressed in cerebellar Purkinje cells of patients with multiple sclerosis and is involved in the development of abnormal cerebellar firing patterns ( Non-patent document 4). Therefore, an SNS inhibitor is expected to be the first therapeutic or prophylactic agent for the induction of symptoms such as ataxia due to abnormal firing of the cerebellar nerve accompanying SNS expression in multiple sclerosis.

The current state of treatment in the clinical field for the above diseases is shown below.
(1) Neuropathic pain
Neuropathic pain refers to pain in which there is no trauma, or there is no inflammatory involvement of the tissue due to complete cure, and spontaneous pain or chronic pain has occurred due to nerve damage or nerve stimulation. Examples include post-lumbar neuralgia, diabetic neuropathy, postherpetic neuralgia, reflex sympathetic atrophy, phantom limb pain, spinal injury, end-stage cancer pain, and prolonged postoperative pain. NSAIDS (non-steroidal anti-inflammatory drugs) such as aspirin are completely ineffective against neuropathic pain, and opioids such as morphine are problematic in causing drug resistance and causing psychiatric symptoms.
At present, mexiletine, which is indicated for diabetic neuropathy, is the only drug marketed for the treatment of neuropathic pain. Although mexiletine has an analgesic effect, it has been reported that side effects are concerned because it has no selectivity for Na channel, and it cannot be taken at a high dose. In addition, several drugs have been indicated as supplementary in the clinic. For example, antidepressants (sulpiride, trazodone, fluvoxatin, milnacipran), adrenergic agonists (clonidine, dexamedetomidine), NMDA receptor antagonists (ketamine hydrochloride, dextromethorphan), anxiolytics (diazepam, lorazepam, etizolam, Hydroxyzine hydrochloride), anticonvulsants (carbamazepine, phenytoin, sodium valproate, zonisamide), calcium antagonists (nifedipine, verapamil hydrochloride, romeridine hydrochloride) and the like, all of which are used as auxiliary. In view of the above, there is a demand for a therapeutic agent that has no side effects derived from non-neural tissues and central nerves and that has a specific effect on pain.

(2) nociceptive pain
Nociceptive pain refers to pain caused by activation of nociceptors (Aδ, C fibers) due to mechanical, thermal or chemical noxious stimuli due to tissue injury or the like. Nociceptors are sensitized by endogenous chemical stimuli (pain substances) such as serotonin, substance P, bradykinin, prostaglandins, or histamine. Examples of nociceptive pain include low back pain, abdominal pain, rheumatoid arthritis, and pain caused by osteoarthritis. In clinical, NSAIDS (acetylsalicylic acid, acetaminophen, diclofenac sodium, indomethacin, mofezolac, flurbiprofen, loxoprofen sodium, ampiroxicam), corticosteroids (prednisolone, methylprednisolone, dexamethasone, betamethasone), PGE ₁ (prostaglandin Gin E1) (alprostadil, lipoylated alprostadil, limaprostal prostadil) and PGI ₂ (beraprost sodium) are used.

(3) Urinary disturbance
Urination disorder is a disease mainly having frequent urination, urinary leakage, residual urine sensation, and micturition pain. Currently, pharmacotherapy for overactive bladder is centered on muscarinic receptor inhibitors that suppress the bladder parasympathetic nerve pathway, but the limitations are also clear. Capsaicin and resiniferatoxin, which are vanilloid receptor stimulants, have been reported to specifically act on C fibers and suppress their functions, but drugs that act on SNS localized in C fibers were found It has not been.

(4) Multiple sclerosis
Multiple sclerosis is a type of demyelinating disease, and demyelinating foci are scattered in the white matter of the central nervous system, and the foci are also old and new. Lesions frequently occur in white matter around the lateral ventricle, optic nerve, brain stem, and spinal cord. Histologically, the myelin sheath is destroyed and axons and nerve cells are not affected. Clinical symptoms include optic neuritis, diplopia, nystagmus and other eye movement disorders, spastic paralysis, painful tonic seizures, Lermit's syndrome, ataxia, speech disorder, bladder rectal disorder, etc. . The cause is unknown, although the theory of autoimmune disease, infection, etc. has been advocated, and an effective prophylactic and therapeutic agent for multiple sclerosis is now eagerly desired.

  Patent Document 1 described later relates to a selective modulator of the CRF1 receptor, and specifically describes a compound represented by the following formula (A) (k in Example 5). The compounds included in the patent document are characterized by having an amide bond in the methylene on the imidazole ring, and are different in that the compound according to the present invention has an amino group in the methylene on the imidazole ring. Further, Patent Document 1 does not contain any description suggesting the present invention.

  Patent Document 2 described later relates to a Rho kinase inhibitor, and specifically describes a compound represented by the following formula (B) (Example 321). The compound contained in the patent document is different in that the compound does not have a substituent on the nitrogen atom of the imidazole ring, and the compound according to the present invention requires the substituent. Further, Patent Document 2 does not contain any description suggesting the present invention.

International Publication No. 02/28839 Pamphlet International Publication No. 2009/79011 Pamphlet

Nature 379: 257, 1996 Pain 78: 107,1998 Urology 57: 116,2001 Brain Research 959: 235,2003

  The subject of this invention is providing the therapeutic agent or preventive agent with respect to diseases, such as all the pathological states with which SNS is concerned, specifically neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis.

As a result of intensive studies on the above problems, the present inventors have found that a bicyclic compound having an imidazole ring or a pharmaceutically acceptable salt thereof inhibits a TTX-resistant Na channel in human SNS gene-expressing cells. In other words, the present invention has been found by having SNS inhibitory activity and being useful as a therapeutic or prophylactic agent for diseases such as neuropathic pain, nociceptive pain, dysuria or multiple sclerosis.
That is, the present invention is as follows.

[1] The following formula (1):

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkyloxy group having 1 to 6 carbon atoms, or a haloalkyloxy group having 1 to 6 carbon atoms. (Wherein R ¹ can be substituted at any substitutable position on the benzene ring or pyridine ring);
L represents a single bond, —O— or —CH ₂ O— (the L can be substituted at any substitutable position on the benzene ring or pyridine ring);
R ² represents a substituted or unsubstituted 6 to 10 membered aryl group or a substituted or unsubstituted 5 to 10 membered aromatic heterocyclic group,
X represents a carbon atom or a nitrogen atom,
R ³ represents a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted group. 3 to 8 membered cycloalkyl group, substituted or unsubstituted 4 to 8 membered cycloalkenyl group, substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic group, or substituted or unsubstituted 5 to 10 member Represents an unsaturated aliphatic heterocyclic group of
R ⁴ represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3 to 8 membered cycloalkyl group,
R ^5a and R ^5b independently represent a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R ⁴ and R ^5a are bonded to each other, and a nitrogen atom to which R ⁴ is bonded and R ^5a Represents a 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring formed together with the carbon atom to which R is bonded (wherein R ^5b is a hydrogen atom);
R ⁶ and R ⁷ are independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted carbon number 2 to 2; 6 alkynyl groups, substituted or unsubstituted 3 to 8 membered cycloalkyl groups, substituted or unsubstituted 4 to 8 membered cycloalkenyl groups, substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic groups Represents a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group R ⁶ and R ⁷ are combined to form a substituted or unsubstituted 4 to 8 membered saturated nitrogen-containing aliphatic heterocyclic ring or a substituted or unsubstituted 5 to 10 member formed together with the nitrogen atom to which they are attached. Of unsaturated nitrogen-containing aliphatic compounds An aromatic ring (the saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring contains at least one nitrogen atom and further contains 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom). Represent. ] Or a pharmaceutically acceptable salt thereof (hereinafter, sometimes referred to as "compound according to the present invention" or "compound (1)");

[2] The following formula (2):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ , L and X are as defined in [1]. ] The pharmaceutical which consists of the compound (henceforth "compound (2)") as described in [1] represented by this, or its pharmaceutically acceptable salt;

[3] The following formula (3):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ , L and X are as defined in [1]. ] The pharmaceutical which consists of a compound (henceforth a "compound (3)") as described in [1] represented by these, or its pharmaceutically acceptable salt;

[4] A pharmaceutical comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein R ² is a substituted or unsubstituted phenyl group;
[5] R ³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted ^3- to 8-membered cycloalkyl group, a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic ring A pharmaceutical comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is a group or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group;

[6] R ⁶ and R ⁷ are each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3- to 8-membered cycloalkyl group, substituted or unsubstituted 4 A saturated 8-membered aliphatic heterocyclic group or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, or R ⁶ and R ⁷ are bonded to each other, and the nitrogen atom to which they are bonded A substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring or a substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocyclic ring (including the saturated or unsaturated The nitrogen aliphatic heterocycle contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms and 1 to 3 nitrogen atoms.) The compound according to any one of [1] to [5] or A medicament comprising a pharmaceutically acceptable salt thereof;

[7] A pharmaceutical comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. ;
[8] The compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein R ^5a and R ^5b are each independently a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. A medicament comprising an acceptable salt;
[9] A medicament comprising the compound according to any one of [1] to [8], wherein X is a carbon atom, or a pharmaceutically acceptable salt thereof;
[10] A pharmaceutical comprising the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom or a halogen atom;

[11] A medicament comprising the compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, wherein L is a single bond;
[12] A pharmaceutical comprising the compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, wherein L is -O-;
[13] A pharmaceutical comprising the compound according to any one of [1] to [10] or a pharmaceutically acceptable salt thereof, wherein L is —CH ₂ O—;
[14] N ² -{[1- (2-Ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} glycinamide,
N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -2-methylalaninamide,
N ² -{[1-cyclopropyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-cyclobutyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-chlorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-fluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-fluorophenoxy) -1- (3-methoxypropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (2-chloro-4-fluorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-ethyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (2,4-difluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (2-ethoxyethyl) -5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-ethyl-5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (3-methoxypropyl) -6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-methylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide, or
N ² -{[5-chloro-6- (3,4-difluorophenyl) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
Or a pharmaceutical comprising a pharmaceutically acceptable salt thereof;
[15] A sensory nerve-specific Na channel (SNS) inhibitor comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof as an active ingredient;
[16] A sensory nerve-specific Na channel (SNS) inhibitor according to [15], which is a therapeutic or prophylactic agent for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis;

[17] A pharmaceutical composition comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

  According to the present invention, an SNS inhibitor comprising a novel bicyclic compound or a pharmaceutically acceptable salt thereof is provided. The SNS inhibitor of the present invention is useful as a therapeutic or prophylactic agent for all pathological conditions involving SNS, specifically for patients with neuropathic pain, nociceptive pain, dysuria or multiple sclerosis. Applicable.

In this specification, for example, C _1-6 has 1 to 6 carbon atoms, C _1-4 has 1 to 4 carbon atoms, and C ₆ represents 6 carbon atoms. . The same applies to other numbers.

In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  “Alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group (1-propyl group), isopropyl group (2-propyl group). Group), butyl group (1-butyl group), sec-butyl group (2-butyl group), isobutyl group (2-methyl-1-propyl group), tert-butyl group (2-methyl-2-propyl group) , A pentyl group (1-pentyl group), a hexyl group (1-hexyl group), and the like. A preferable alkyl group includes an alkyl group having 1 to 4 carbon atoms.

  The “haloalkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 identical or different halogen atoms, specifically, a trifluoromethyl group, 2, Examples include 2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloroethyl group, pentafluoroethyl group, 3,3,3-trifluoropropyl group. Preferable haloalkyl groups include haloalkyl groups having 1 to 4 carbon atoms.

  The “alkenyl group” means a straight chain or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl group, 1-propenyl group, 2-propenyl group, 1-methylvinyl group, 1-methylvinyl group, Butenyl group, 1-ethylvinyl group, 1-methyl-2-propenyl group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-pentenyl group, 1-hexenyl group etc. are mentioned. Preferable alkenyl groups include alkenyl groups having 2 to 4 carbon atoms.

  The “alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, and specifically includes an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 1-butynyl group, Examples thereof include a methyl-2-propynyl group, a 3-butynyl group, a 1-pentynyl group, and a 1-hexynyl group. Preferable alkynyl groups include alkynyl groups having 2 to 4 carbon atoms.

  The “alkyloxy group” means a linear or branched alkyloxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, a 1-methylethoxy group, a butoxy group, 1 -Methylpropoxy group, 2-methylpropoxy group, 1,1-dimethylethoxy group, pentyloxy group, hexyloxy group and the like. As a preferable alkyloxy group, a C1-C4 alkyloxy group is mentioned.

  The “haloalkyloxy group” means a linear or branched alkyloxy group having 1 to 6 carbon atoms substituted with 1 to 5 identical or different halogen atoms, specifically a trifluoromethoxy group, Examples include 2,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 2-chloroethoxy group, pentafluoroethoxy group, 3,3,3-trifluoropropoxy group, and the like. Preferred haloalkyloxy groups include haloalkyloxy groups having 1 to 4 carbon atoms.

  The “cycloalkyl group” means a 3- to 8-membered monocyclic or bicyclic cycloalkyl group, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclo An octyl group etc. are mentioned. Preferred cycloalkyl groups include 4-6 membered cycloalkyl groups.

  The “cycloalkenyl group” means a 4- to 8-membered monocyclic or bicyclic cycloalkenyl group, and specific examples include a cyclobutenyl group, a cyclopentenyl group, a cyclohexenyl group, a cycloheptenyl group, and a cyclooctenyl group. The position of the double bond on the ring is not particularly limited. Preferred cycloalkenyl groups include 5- or 6-membered cycloalkenyl groups.

  “Saturated aliphatic heterocyclic group” means a 4- to 8-membered monocyclic or bicyclic saturated aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. (However, the number of oxygen atoms and sulfur atoms contained in the saturated aliphatic heterocyclic ring is 2 at the maximum, respectively), and the bonding position of the hetero atom is not particularly limited as long as it is chemically stable. Specifically, azetidinyl group, pyrrolidinyl group, piperidyl group, piperidino group, piperazinyl group, azepanyl group, azocanyl group, tetrahydrofuryl group, tetrahydrothienyl group, tetrahydropyranyl group, morpholinyl group, morpholino group, thiomorpholinyl group, 1, Examples include 4-dioxanyl group, 1,2,5-thiadiazinyl group, 1,4-oxazepanyl group, 1,4-diazepanyl group and the like.

  The “unsaturated aliphatic heterocyclic group” is a 5- to 10-membered single atom containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and containing 1 to 3 double bonds. Means a cyclic or bicyclic unsaturated aliphatic heterocyclic group (provided that the saturated aliphatic heterocyclic ring has a maximum of two oxygen and sulfur atoms, respectively), heteroatoms and double bonds The bonding position is not particularly limited as long as it is chemically stable. Specific examples include a pyrrolinyl group, an imidazolinyl group, and a tetrahydroisoquinolyl group, and a 2-pyrrolinyl group and a 2-imidazolinyl group are preferable.

  The “saturated nitrogen-containing aliphatic heterocycle” includes at least one nitrogen atom and may further contain 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. An 8-membered monocyclic or bicyclic saturated aliphatic heterocyclic ring (provided that the number of oxygen atoms and sulfur atoms contained in the saturated aliphatic heterocyclic ring is 2 at most, respectively) The bonding position is not particularly limited as long as it is chemically stable. Specific examples include azetidine ring, pyrrolidine ring, imidazolidine ring, pyrazolidine ring, piperidine ring, piperazine ring, azepane ring, azocan ring, morpholine ring, thiomorpholine ring, oxazolidine ring, thiazolidine ring and the like.

  The “unsaturated nitrogen-containing aliphatic heterocycle” includes at least one nitrogen atom and may further contain 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Means an 8-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic ring (provided that the number of oxygen atoms and sulfur atoms contained in the unsaturated aliphatic heterocyclic ring is at most 2 each); The bonding position of the hetero atom is not particularly limited as long as it is chemically stable. Specific examples include a pyrroline ring, a piperidine ring, an imidazoline ring, a pyrazoline ring, an oxazoline ring, a thiazoline ring, a tetrahydroquinoline ring, and a tetrahydroisoquinoline ring.

  The “aryl group” means a 6 to 10-membered monocyclic or bicyclic aryl group, and specific examples include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

  The “aromatic heterocyclic group” means a 5- to 10-membered monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. (However, the maximum number of oxygen atoms and sulfur atoms contained in the aromatic heterocyclic group is 2 respectively.) The bonding position of the hetero atom is not particularly limited as long as it is chemically stable. Specifically, furyl group, thienyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, furazanyl group, oxadiazolyl group, triazolyl group, pyridyl group, pyrimidinyl group, pyrazinyl group, Indolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, imidazo [2,1-b] [1,3] thiazolyl group and the like can be mentioned.

  The “alkylthio group” means a linear or branched alkylthio group having 1 to 6 carbon atoms, specifically, methylthio group, ethylthio group, propylthio group, 1-methylethylthio group, butylthio group, 1- Examples thereof include a methylpropylthio group, a 2-methylpropylthio group, a 1,1-dimethylethylthio group, a pentylthio group, and a hexylthio group. Preferable alkylthio group includes an alkylthio group having 1 to 4 carbon atoms.

  Examples of the alkyl in the “alkylcarbonyl group” include the same alkyl groups as those described above. Preferred alkylcarbonyl groups include acetyl, propionyl and butyryl groups.

  The “alkylcarbonyloxy group” represents a group in which an oxygen atom is bonded to the carbonyl carbon of the “alkylcarbonyl group”.

  Examples of the alkyl in the “alkylsulfonyl group” include the same as the above “alkyl group”. Preferred alkylsulfonyl groups include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and the like.

  Examples of the alkyloxy in the “alkyloxycarbonyl group” include the same as the above “alkyloxy group”. Preferred alkyloxycarbonyl groups include methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, butoxycarbonyl group, tert-butoxycarbonyl group and the like.

"Amino group optionally substituted with one or the same or different two alkyl groups", "Carbamoyl group optionally substituted with one or the same or different two alkyl groups" or "One or Examples of the alkyl group in the “sulfamoyl group optionally substituted with two same or different alkyl groups” include the same as the above “alkyl group”.
Preferred examples of the “amino group optionally substituted with one or the same or different two alkyl groups” include a methylamino group, an ethylamino group, a propylamino group, a dimethylamino group, a diethylamino group, and a methylethylamino group. Is mentioned.
Preferred examples of the “carbamoyl group optionally substituted with one or the same or different two alkyl groups” include a methylcarbamoyl group, an ethylcarbamoyl group, a propylcarbamoyl group, an isopropylcarbamoyl group, a dimethylcarbamoyl group, a diethylcarbamoyl group, A methyl ethyl carbamoyl group etc. are mentioned.
Preferred examples of the “sulfamoyl group optionally substituted with one or the same or different two alkyl groups” include a methylsulfamoyl group, an ethylsulfamoyl group, a propylsulfamoyl group, a dimethylsulfamoyl group, Examples thereof include a diethylsulfamoyl group and a methylethylsulfamoyl group.

  Examples of the “alkyloxycarbonyl group” in “amidino group optionally substituted by one, or the same or different two alkyloxycarbonyl groups” include the same as the above “alkyloxycarbonyl group”. Preferable examples of “amidino group optionally substituted by one or two identical or different alkyloxycarbonyl groups” include methoxycarbonylamidino group, ethoxycarbonylamidino group, propoxycarbonylamidino group and the like.

  The aryl group in the “aryloxy group”, “arylcarbonyl group” and “arylsulfonyl group” has the same meaning as the above “aryl group”.

  The aromatic heterocyclic group in the “aromatic heterocyclic oxy group”, “aromatic heterocyclic carbonyl group” and “aromatic heterocyclic sulfonyl group” has the same meaning as the above “aromatic heterocyclic group”.

  When the “alkyl group”, “alkenyl group” or “alkynyl group” is substituted, the substituent is selected from the following groups (i) to (v), and a plurality of the same or different substituents may be substituted. May be:

(I) a halogen atom, a hydroxyl group, a carboxyl group, a cyano group;
(Ii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(Iii) an alkyloxy group, a haloalkyloxy group, an alkylcarbonyl group, an alkylcarbonyloxy group, an alkyloxycarbonyl group, an alkylthio group, an alkylsulfonyl group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, one or the same or From an amino group which may be substituted with two different alkyl groups, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group One or more substituents may be substituted with the selected substituent. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. Groups. ];

(Iv) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one or two identical or different An amino group optionally substituted with an alkyl group, a carbamoyl group optionally substituted with one or two identical or different alkyl groups, an alkyloxy group, a haloalkyloxy group, an optionally substituted alkyloxy A carbonyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkylsulfonyl group, an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted One or more substituents may be substituted with a substituent selected from an aromatic heterocyclic group. Examples of the alkyloxycarbonyl group, the alkylcarbonyl group, the alkylsulfonyl group, and the substituent of the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, a haloalkyloxy group, and a carbamoyl group, and the aryl group Examples of the substituent of the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. It is done. ];

(V) an aryl group, an aromatic heterocyclic group, an aryloxy group, an aromatic heterocyclic oxy group, an arylcarbonyl group, an aromatic heterocyclic carbonyl group, an arylsulfonyl group, an aromatic heterocyclic sulfonyl group [these groups are Halogen atom, hydroxyl group, carboxyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, may be substituted One or more substituents may be substituted with a substituent selected from a good alkyl group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, and a haloalkyloxy group. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. Group, alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, nitro group, cyano group and carbamoyl group. ].

  “Cycloalkyl group”, “cycloalkenyl group”, “saturated aliphatic heterocyclic group”, “unsaturated aliphatic heterocyclic group”, “saturated nitrogen-containing aliphatic heterocyclic ring” or “unsaturated nitrogen-containing” Examples of the substituent when the “aliphatic heterocycle” is substituted include one or two or more substituents selected from the following groups (vi) to (x):

(Vi) a halogeno group, a hydroxyl group, a carboxyl group, a cyano group, an oxo group, a thioxo group, an amidino group optionally substituted by one or two identical or different alkyloxycarbonyl groups;
(Vii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(Viii) alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkyloxycarbonyl group, alkylthio group, alkylsulfonyl group [these groups are halogen atom, hydroxyl group, carboxyl group A carbamoyl group, an alkyloxy group and / or an alkyloxy group optionally substituted with a carbamoyl group, a haloalkyloxy group, an alkylthio group, an alkyloxy A carbonyl group, an optionally substituted aryloxy group, an optionally substituted aromatic heterocyclic oxy group, an optionally substituted aryl group, an optionally substituted aromatic heterocyclic group and a substituted Selected from amino groups It may be 1 or more substituted with a substituent. The aryloxy group, the aromatic heterocyclic oxy group, the aryl group and the substituent of the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkyloxy group, and a haloalkyloxy group. , Alkyloxycarbonyl group, nitro group, cyano group, carbamoyl group, and the substituent of the amino group includes an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, and a substituted group. And an alkylsulfonyl group which may be substituted, and a carbamoyl group which may be substituted with one or two same or different alkyl groups which may be substituted. Examples of the substituent of the alkyl group on the alkyl group, the alkylcarbonyl group, the alkylsulfonyl group, and the carbamoyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, a haloalkyloxy group, and a carbamoyl group. ];

(Ix) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one or two identical or different An amino group optionally substituted with an alkyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted group One or more substituents may be substituted with a substituent selected from an aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, and a haloalkyloxy group. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. Group, alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, nitro group, cyano group and carbamoyl group. ];
(X) aryl group, aromatic heterocyclic group, aryloxy group, aromatic heterocyclic oxy group, arylcarbonyl group, aromatic heterocyclic carbonyl group, arylsulfonyl group, aromatic heterocyclic sulfonyl group [these groups are Halogen atom, hydroxyl group, carboxyl group, cyano group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, substituted One or more substituents may be substituted with a substituent selected from an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, and a haloalkyloxy group. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. Group, alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, nitro group, cyano group and carbamoyl group. ].

  As the substituent when the “phenyl group”, “aryl group” and “aromatic heterocyclic group” are substituted, 1 to 5 identical groups selected from the following groups (xi) to (xv) Or different substituents include:

(Xi) halogen atom, hydroxyl group, carboxyl group, cyano group, nitro group;
(Xii) a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group;
(Xiii) alkyl group, haloalkyl group, alkenyl group, alkynyl group, alkyloxy group, haloalkyloxy group, alkylcarbonyl group, alkylcarbonyloxy group, alkyloxycarbonyl group, alkylthio group, alkylsulfonyl group [these groups are halogen An atom, a hydroxyl group, a carboxyl group, an amino group optionally substituted by one or two identical or different alkyl groups, an optionally substituted alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, substituted One or more substituents may be substituted with a substituent selected from an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyloxy group, the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, and a nitro group. , A cyano group, and a carbamoyl group. ];

(Xiv) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one or two identical or different An amino group optionally substituted with an alkyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group and an optionally substituted group One or more substituents may be substituted with a substituent selected from an aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, and a haloalkyloxy group. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. Group, alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, nitro group, cyano group and carbamoyl group. ];
(Xv) an aryl group, an aromatic heterocyclic group, an aryloxy group, an aromatic heterocyclic oxy group, an arylcarbonyl group, an aromatic heterocyclic carbonyl group, an arylsulfonyl group, an aromatic heterocyclic sulfonyl group [these groups are Halogen atom, hydroxyl group, carboxyl group, substituted or unsubstituted amino group, substituted or unsubstituted carbamoyl group, substituted or unsubstituted sulfamoyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, may be substituted One or more substituents may be substituted with a substituent selected from a good alkyl group, an optionally substituted aryl group, and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, and a haloalkyloxy group. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. Group, alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, nitro group, cyano group and carbamoyl group. ].

  When the “amino group”, “carbamoyl group” or “sulfamoyl group” is substituted, the substituent is one selected from the following groups (xvi) to (xviii) or two or more same or different The substituents include:

(Xvi) an alkyl group, a haloalkyl group, an alkenyl group, an alkynyl group, an alkylcarbonyl group, an alkylsulfonyl group, an alkyloxycarbonyl group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, one or two of the same or different An amino group optionally substituted with an alkyl group, a carbamoyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, a saturated or unsaturated aliphatic heterocyclic group, an optionally substituted aryl group and a substituted group; One or more substituents may be substituted with a substituent selected from aromatic heterocyclic groups that may be present. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group, a haloalkyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, a nitro group, a cyano group, and a carbamoyl group. Groups. ];

(Xvii) a cycloalkyl group, a cycloalkenyl group, a saturated or unsaturated aliphatic heterocyclic group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, one, or the same or different two An amino group optionally substituted with an alkyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted aromatic group One or more substituents may be substituted with a substituent selected from a group heterocyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, and a haloalkyloxy group. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. Group, alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, nitro group, cyano group and carbamoyl group. ];

(Xviii) aryl group, aromatic heterocyclic group, arylcarbonyl group, aromatic heterocyclic carbonyl group, arylsulfonyl group, aromatic heterocyclic sulfonyl group [these groups are a halogen atom, a hydroxyl group, a carboxyl group, one or An amino group optionally substituted with two identical or different alkyl groups, a carbamoyl group optionally substituted with one or two identical or different alkyl groups, one or two identical or different alkyl groups A sulfamoyl group, an alkyloxy group, a haloalkyloxy group, an alkyloxycarbonyl group, an optionally substituted alkyl group, an optionally substituted aryl group, and an optionally substituted aromatic complex One or more substituents may be substituted with a substituent selected from a cyclic group. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, and a haloalkyloxy group. Examples of the substituent for the aryl group and the aromatic heterocyclic group include a halogen atom, a hydroxyl group, and a carboxyl group. Group, alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group, alkyloxycarbonyl group, nitro group, cyano group and carbamoyl group. ].

  Further, two substituents on the “amino group”, “carbamoyl group” or “sulfamoyl group” may be bonded to form a 5- to 10-membered nitrogen-containing aliphatic heterocyclic ring together with the adjacent nitrogen atom.

  Examples of the nitrogen-containing aliphatic heterocyclic ring include pyrrolidine ring, piperidine ring, azepane ring, azocan ring, piperazine ring, morpholine ring, thiomorpholine ring, and tetrahydroisoquinoline ring. In addition, the nitrogen-containing aliphatic heterocycle is substituted with one or more groups selected from halogen, hydroxyl group, carboxyl group, optionally substituted alkyl group, haloalkyl group, alkyloxy group, haloalkyloxy group. Also good. Examples of the substituent for the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkyloxy group, a haloalkyloxy group, and a carbamoyl group.

  In the compound according to the present invention represented by the general formula (1), suitable substituents are as follows.

R ¹ is a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkyloxy group having 1 to 6 carbon atoms, or a haloalkyloxy group having 1 to 6 carbon atoms, A hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms is preferable, a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms is more preferable, and further preferable. Is a hydrogen atom or a halogen atom, particularly preferably a hydrogen atom. The R ¹ can be substituted with a hydrogen atom at any substitutable position on the benzene ring or pyridine ring.

Specific examples of R ¹ include a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, and a trifluoromethyl group, preferably a hydrogen atom, a fluorine atom, and a chlorine atom, and more preferably Is a hydrogen atom.

L is a single bond, —O— or —CH ₂ O—, preferably a single bond or —O—, more preferably —O—. The L can be substituted with a hydrogen atom at any substitutable position on the benzene ring or pyridine ring. When L is —CH ₂ O—, the oxygen atom of —CH ₂ O— is bonded to the benzene ring or the pyridine ring, and the methylene chain is bonded to R ² .

R ² is a substituted or unsubstituted 6 to 10 membered aryl group or a substituted or unsubstituted 5 to 10 membered aromatic heterocyclic group, preferably a substituted or unsubstituted 6 to 10 membered aryl group. More preferably, it is a substituted or unsubstituted phenyl group.
Preferred substituents for the aryl group or aromatic heterocyclic group for R ² include a halogen atom, a substituted or unsubstituted alkyl group (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms), and a haloalkyl group (preferably carbon). A haloalkyl group having 1 to 6 carbon atoms), an alkyloxy group (preferably an alkyloxy group having 1 to 6 carbon atoms), a haloalkyloxy group (preferably a haloalkyloxy group having 1 to 6 carbon atoms), a cyano group, and the like. Specific examples include a fluorine atom, a chlorine atom, a methyl group, an ethyl group, an isopropyl group, a tert-butyl group, a trifluoromethyl group, a trifluoromethoxy group, a methoxy group, an ethoxy group, and a cyano group. Of these, a fluorine atom, a methyl group, and a trifluoromethoxy group are preferable.
Specific examples of the substituted or unsubstituted aryl group for R ² include a phenyl group or a phenyl group substituted with a preferred substituent of the aryl group.
Specific examples of the aromatic heterocyclic group for R ² include a pyridyl group, a furyl group, a thienyl group, a pyrimidinyl group, a pyrazinyl group, and the like, preferably a pyridyl group and a furyl group.

R ³ represents a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted group. 3 to 8 membered cycloalkyl group, substituted or unsubstituted 4 to 8 membered cycloalkenyl group, substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic group, or substituted or unsubstituted 5 to 10 member An unsaturated aliphatic heterocyclic group, preferably a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3 to 8 membered cycloalkyl group, a substituted or unsubstituted 4 to 8 A membered saturated aliphatic heterocyclic group or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, more preferably a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, substituted or unsubstituted Unsubstituted A 3- to 8-membered cycloalkyl group or a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group, more preferably a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted group 3 to 8 membered cycloalkyl group.

Preferable substituents for the alkyl group in R ³ include a hydroxyl group, an alkyloxy group (preferably an alkyloxy group having 1 to 6 carbon atoms), a 4- to 8-membered saturated aliphatic heterocyclic group, and the like. Examples include hydroxyl group, methoxy group, ethoxy group, isopropoxy group, tetrahydrofuryl group, tetrahydropyranyl group and the like.

Preferred substituents for the saturated aliphatic heterocyclic group for R ³ include an alkylcarbonyl group, an alkyloxycarbonyl group, an alkylsulfonyl group, and a monoalkylcarbamoyl group (these alkyl parts preferably have 1 to 6 carbon atoms). Specific examples include an acetyl group, a tert-butoxycarbonyl group, a methylsulfonyl group, and an isopropylcarbamoyl group.

Specific examples of R ³ include ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyethyl, ethoxyethyl, isopropoxyethyl, hydroxyethyl, methoxypropyl, ethoxypropyl, hydroxy Propyl group, tetrahydropyranyl group, tetrahydrofuryl group, 2,2-dimethyl-2-hydroxyethyl group, tetrahydropyranylmethyl group, tetrahydrofurylmethyl group, 4-piperidyl group, 1- (tert-butoxycarbonyl) piperidine- Examples include 4-yl group, 1-isopropylcarbamoylpiperidin-4-yl group, 1-acetylpiperidin-4-yl group, and 1-methylsulfonylpiperidin-4-yl group. R ³ is more preferably a cyclobutyl group, a 2-ethoxyethyl group, or an ethyl group.

R ⁴ is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3 to 8 membered cycloalkyl group, preferably a hydrogen atom or substituted or unsubstituted carbon number 1 -6 alkyl group, more preferably a hydrogen atom.
Preferred substituents for the alkyl group and cycloalkyl group in R ⁴ include a halogen atom, a hydroxyl group, an alkyloxy group (preferably an alkyloxy group having 1 to 6 carbon atoms), and a 4- to 8-membered saturated aliphatic heterocyclic group. Specific examples include a fluorine atom, a chlorine atom, a hydroxyl group, a methoxy group, an ethoxy group, a tetrahydrofuryl group, and a tetrahydropyranyl group.
Specific examples of R ⁴ include a hydrogen atom, a methyl group, and a cyclopropyl group, preferably a hydrogen atom and a methyl group, and more preferably a hydrogen atom.

R ^5a and R ^5b are each independently a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R ⁴ and R ^5a are bonded to each other, and a nitrogen atom to which R ⁴ is bonded and R ^5a is a 4- to 8-membered saturated nitrogen-containing aliphatic heterocycle formed together with the carbon atom to which R ^5a is bonded (wherein R ^5b is a hydrogen atom), preferably independently a hydrogen atom or It is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. Preferred substituents for the alkyl group in R ^5a and R ^5b include a halogen atom, a hydroxyl group, an alkyloxy group (preferably an alkyloxy group having 1 to 6 carbon atoms), a 4- to 8-membered saturated aliphatic heterocyclic group, and the like. Specifically, fluorine atom, chlorine atom, hydroxyl group, methoxy group, ethoxy group, tetrahydrofuryl group, tetrahydropyranyl group and the like can be mentioned.
Specific examples of R ^5a and R ^5b include independently a hydrogen atom, methyl group, ethyl group, isopropyl group (preferably R ^5a is a hydrogen atom, methyl group, ethyl group, or isopropyl group, and R ^5b is methyl group). Preferably a hydrogen atom or a methyl group (preferably R ^5a is a hydrogen atom and R ^5b is a methyl group).
In addition, when R ^5a and R ^5b are different groups, the carbon atom to which they are bonded is an asymmetric carbon atom, but the steric configuration is the S configuration from the viewpoint of easy availability of raw materials. It is preferable.
Specific examples of a 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring formed by combining R ⁴ and R ^5a together with the nitrogen atom to which R ⁴ is bonded and the carbon atom to which R ^5a is bonded include the azetidine ring , A pyrrolidine ring, a piperidine ring, and the like, and a pyrrolidine ring is preferable.

R ⁶ and R ⁷ are independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted carbon number 2 to 2; 6 alkynyl groups, substituted or unsubstituted 3 to 8 membered cycloalkyl groups, substituted or unsubstituted 4 to 8 membered cycloalkenyl groups, substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic groups A substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group Or R ⁶ and R ⁷ are combined to form a substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring or a substituted or unsubstituted 5- to 10-membered formed with the nitrogen atom to which they are attached. Of unsaturated nitrogen-containing aliphatic compounds An aromatic ring (the saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring contains at least one nitrogen atom and further contains 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom); Yes, preferably independently, a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3 to 8 membered cycloalkyl group, a substituted or unsubstituted 4 to 8 membered saturation An aliphatic heterocyclic group or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, more preferably independently a hydrogen atom, a substituted or unsubstituted alkyl having 1 to 6 carbon atoms. A group, more preferably a hydrogen atom.

Preferable substituents for the alkyl group in R ⁶ and R ⁷ include a hydroxyl group, an alkyloxy group (preferably an alkyloxy group having 1 to 6 carbon atoms), a 4- to 8-membered saturated aliphatic heterocyclic group, and the like. Specific examples include a hydroxyl group, a methoxy group, an ethoxy group, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidyl group, a piperidino group, a piperazinyl group, a morpholino group, and the like, and substituted alkyl in R ⁶ and R ⁷ Specific examples of the group include methoxyethyl group, 2,2-dimethyl-2-hydroxyethyl group, morpholinoethyl group and the like.

Preferable specific examples of R ⁶ and R ⁷ independently include a hydrogen atom, a methyl group, an ethyl group, an isopropyl group, preferably a hydrogen atom or a methyl group, and more preferably a hydrogen atom. .

A substituted or unsubstituted 4 to 8 membered saturated nitrogen-containing aliphatic heterocyclic ring formed with the nitrogen atom to which R ⁶ and R ⁷ are bonded, or a substituted or unsubstituted 5 to 10 membered unsubstituted ring Specific examples of the saturated nitrogen-containing aliphatic heterocyclic ring include a morpholine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring, and the like, preferably a morpholine ring and a piperazine ring.
Preferable substituents of the saturated nitrogen-containing aliphatic heterocyclic ring or the unsaturated nitrogen-containing aliphatic heterocyclic ring include an oxo group, a cyano group, a haloalkyl group (preferably a haloalkyl group having 1 to 6 carbon atoms) and the like. Of these, an oxo group, a cyano group, and a trifluoromethyl group are preferable.

When X is a carbon atom, when X is substituted with R ¹ or L, X is C, and when X is not substituted with R ¹ or L, X is CH.

  Among the compounds (1), suitable compounds include the following compounds or pharmaceutically acceptable salts thereof.

As one preferred embodiment,
R ¹ is a hydrogen atom or a halogen atom,
L is a single bond or —O—;
R ² is a substituted or unsubstituted phenyl group,
X is a carbon atom,
R ³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3 to 8 membered cycloalkyl group, a substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic group or a substituted group Or an unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group,
R ⁴ is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms,
R ^5a and R ^5b are each independently a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms,
R ⁶ and R ⁷ are independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3 to 8 membered cycloalkyl group, a substituted or unsubstituted 4 to 8 member A saturated aliphatic heterocyclic group or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group,
A substituted or unsubstituted 4 to 8 membered saturated nitrogen-containing aliphatic heterocyclic ring formed with the nitrogen atom to which R ⁶ and R ⁷ are bonded, or a substituted or unsubstituted 5 to 10 membered unsubstituted ring A saturated nitrogen-containing aliphatic heterocyclic ring (the saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms, and 1 to 3 nitrogen atoms); There are certain compounds.

As another preferred embodiment,
R ¹ is a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,
L is a single bond or —O—;
R ² is a substituted or unsubstituted 6 to 10 membered aryl group (preferable substituents are a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyloxy group having 1 to 6 carbon atoms, more preferably fluorine. An atom, a methyl group or a trifluoromethoxy group),
X is a carbon atom,
R ³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably the substituent is a hydroxyl group, an alkyloxy group having 1 to 6 carbon atoms, or a 4- to 8-membered saturated aliphatic heterocyclic group, more preferably Is a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuryl group or a tetrahydropyranyl group), a substituted or unsubstituted 3- to 8-membered cycloalkyl group (preferably an unsubstituted 3- to 8-membered cyclohexane). Alkyl group), a substituted or unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group (preferably an unsubstituted 4- to 8-membered saturated aliphatic heterocyclic group), or a substituted or unsubstituted 5- to 10-membered An unsaturated aliphatic heterocyclic group (preferably an unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group),
R ⁴ is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms);
R ^5a and R ^5b are each independently a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms);
A compound in which R ⁶ and R ⁷ are each independently a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms);

Preferably R ¹ is a hydrogen atom or a halogen atom,
L is a single bond or —O—;
R ² is a substituted or unsubstituted phenyl group (preferable substituents are a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyloxy group having 1 to 6 carbon atoms, more preferably a fluorine atom, a methyl group or A trifluoromethoxy group),
X is a carbon atom,
R ³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably the substituent is a hydroxyl group, an alkyloxy group having 1 to 6 carbon atoms, or a 4- to 8-membered saturated aliphatic heterocyclic group, more preferably Is a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuryl group or a tetrahydropyranyl group) or a substituted or unsubstituted 3- to 8-membered cycloalkyl group (preferably an unsubstituted 3- to 8-membered cyclohexane). Alkyl group),
R ⁴ is a hydrogen atom or a methyl group,
R ^5a and R ^5b are independently a hydrogen atom, a methyl group, an ethyl group or an isopropyl group (preferably R ^5a is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group, and R ^5b is a methyl group, an ethyl group, Group or isopropyl group),
A compound in which R ⁶ and R ⁷ are hydrogen atoms;

More preferably, R ¹ is a hydrogen atom,
L is -O-
R ² is a substituted or unsubstituted phenyl group (preferable substituents are a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyloxy group having 1 to 6 carbon atoms, more preferably a fluorine atom, a methyl group or A trifluoromethoxy group),
X is a carbon atom,
R ³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (preferably the substituent is a hydroxyl group, an alkyloxy group having 1 to 6 carbon atoms, or a 4- to 8-membered saturated aliphatic heterocyclic group, more preferably Is a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuryl group or a tetrahydropyranyl group) or a substituted or unsubstituted 3- to 8-membered cycloalkyl group (preferably an unsubstituted 3- to 8-membered cyclohexane). Alkyl group),
R ⁴ is a hydrogen atom or a methyl group,
R ^5a and R ^5b are independently a hydrogen atom or a methyl group (preferably R ^5a is a hydrogen atom and R ^5b is a methyl group),
Examples include compounds in which R ⁶ and R ⁷ are hydrogen atoms.

Preferred compounds of the present invention include compound (2) or compound (3) or a pharmaceutically acceptable salt thereof, more preferably compound (2) or a pharmaceutically acceptable salt thereof.
Specific examples of suitable compounds include the compounds shown in the following examples or pharmaceutically acceptable salts thereof.

As a specific example,
R ¹ is
(1) hydrogen atom,
(2) a halogen atom (preferably a fluorine atom or a chlorine atom),
(3) a C _1-6 alkyl group (preferably methyl), or
(4) C _1-6 haloalkyl group (preferably trifluoromethyl)
And
L is
(1) single bond,
(2) -O-, or
(3) —CH ₂ O—
And
R ² is
(1) (a) a halogen atom (preferably a fluorine atom or a chlorine atom),
(b) a C _1-6 alkyl group (preferably methyl, ethyl, isopropyl, tert-butyl),
(c) a C _1-6 haloalkyl group (preferably trifluoromethyl),
(d) a C _1-6 alkyloxy group (preferably methoxy, ethoxy),
(e) a C _1-6 haloalkyloxy group (preferably trifluoromethoxy), and
(f) a C _6-10 aryl group which may be substituted with 1 to 3 substituents selected from a cyano group (the C _6-10 aryl group is condensed with a ring portion of a C _3-6 cycloalkyl group). (Preferably phenyl, indanyl, more preferably phenyl), or
(2) 5- to 10-membered aromatic heterocyclic group (preferably 5- or 6-membered aromatic heterocyclic group, more preferably pyridyl, furyl)
And
X is a carbon atom or a nitrogen atom,
R ³ is
(1) (a) a C _1-6 alkyloxy group (preferably methoxy, ethoxy, isopropoxy),
(b) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl, tetrahydrofuryl), and
(c) a C _1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted with 1 to 3 substituents selected from a hydroxyl group,
(2) a C _3-8 cycloalkyl group (preferably cyclopropyl, cyclobutyl, cyclopentyl), or
(3) (a) a C _1-6 alkyl-carbonyl group (preferably acetyl),
(b) a C _1-6 alkyloxycarbonyl group (preferably tert-butoxycarbonyl),
(c) a C _1-6 alkylsulfonyl group (preferably methylsulfonyl), and
(d) a 4- to 8-membered saturated group optionally substituted with 1 to 3 substituents selected from a carbamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group (preferably isopropyl) Aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl or piperidyl)
And
R ⁴ is
(1) a hydrogen atom, or
(2) C _1-6 alkyl group (preferably methyl)
And
R ^5a and R ^5b are independently
(1) a hydrogen atom, or
(2) C _1-6 alkyl group (preferably methyl, ethyl, isopropyl)
In it or, alternatively by bonding R ⁴ and R ^5a, together with the carbon atom to which the nitrogen atom and R ^5a R ⁴ are attached are bound, a nitrogen-containing aliphatic heterocyclic 4-8 membered saturated (preferably 5 or A 6-membered saturated nitrogen-containing aliphatic heterocyclic ring, more preferably pyrrolidine) (wherein R ^5b is a hydrogen atom),
R ⁶ and R ⁷ are independently
(1) a hydrogen atom, or
(2) (a) a hydroxyl group,
(b) a C _1-6 alkyloxy group (preferably methoxy), and
(c) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably morpholinyl)
C _1-6 alkyl group _optionally substituted with 1 to 3 substituents selected from (preferably ethyl, isobutyl)
Or R ⁶ and R ⁷ are bonded together with the nitrogen atom to which they are bonded,
(a) an oxo group,
(b) a cyano group, and
(c) C _1-6 haloalkyl group (preferably trifluoromethyl)
A 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring (preferably a 5- or 6-membered saturated nitrogen-containing aliphatic heterocyclic ring, which may be substituted with 1 to 3 substituents selected from Preferred are compounds that form morpholine and piperazine).

As one preferred example,
R ¹ is
(1) a hydrogen atom, or
(2) Halogen atom (preferably fluorine atom, chlorine atom)
And
L is
(1) single bond, or
(2) -O-
And
R ² is
(a) a halogen atom (preferably a fluorine atom or a chlorine atom),
(b) a C _1-6 alkyl group (preferably methyl, ethyl, isopropyl, tert-butyl),
(c) a C _1-6 haloalkyl group (preferably trifluoromethyl),
(d) a C _1-6 alkyloxy group (preferably methoxy, ethoxy),
(e) a C _1-6 haloalkyloxy group (preferably trifluoromethoxy), and
(f) a phenyl group which may be substituted with 1 to 3 substituents selected from a cyano group;
X is a carbon atom,
R ³ is
(1) (a) a C _1-6 alkyloxy group (preferably methoxy, ethoxy, isopropoxy),
(b) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl, tetrahydrofuryl), and
(c) a C _1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted with 1 to 3 substituents selected from a hydroxyl group,
(2) a C _3-8 cycloalkyl group (preferably cyclopropyl, cyclobutyl, cyclopentyl), or
(3) (a) a C _1-6 alkylcarbonyl group (preferably acetyl),
(b) a C _1-6 alkyloxycarbonyl group (preferably tert-butoxycarbonyl),
(c) a C _1-6 alkylsulfonyl group (preferably methylsulfonyl), and
(d) a 4- to 8-membered saturated group optionally substituted with 1 to 3 substituents selected from a carbamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group (preferably isopropyl) Aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl or piperidyl)
And
R ⁴ is
(1) a hydrogen atom, or
(2) C _1-6 alkyl group (preferably methyl)
And
R ^5a and R ^5b are independently
(1) a hydrogen atom, or
(2) C _1-6 alkyl group (preferably methyl, ethyl, isopropyl)
And
R ⁶ and R ⁷ are independently
(1) a hydrogen atom, or
(2) (a) a hydroxyl group,
(b) a C _1-6 alkyloxy group (preferably methoxy), and
(c) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably morpholinyl)
C _1-6 alkyl group _optionally substituted with 1 to 3 substituents selected from (preferably ethyl, isobutyl)
Or R ⁶ and R ⁷ are bonded together with the nitrogen atom to which they are bonded,
(a) an oxo group,
(b) a cyano group, and
(c) C _1-6 haloalkyl group (preferably trifluoromethyl)
A 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring (preferably a 5- or 6-membered saturated nitrogen-containing aliphatic heterocyclic ring, which may be substituted with 1 to 3 substituents selected from Preferred are compounds that form morpholine and piperazine).

As another suitable specific example,
R ¹ is
(1) hydrogen atom,
(2) a halogen atom (preferably a fluorine atom or a chlorine atom), or
(3) C _1-6 alkyl group (preferably methyl)
And
L is
(1) single bond, or
(2) -O-
And
R ² is
(a) a halogen atom (preferably a fluorine atom or a chlorine atom),
(b) a C _1-6 alkyl group (preferably methyl, ethyl, isopropyl, tert-butyl),
(c) a C _1-6 haloalkyl group (preferably trifluoromethyl),
(d) a C _1-6 alkyloxy group (preferably methoxy, ethoxy),
(e) a C _1-6 haloalkyloxy group (preferably trifluoromethoxy), and
(f) a C _6-10 aryl group which may be substituted with 1 to 3 substituents selected from a cyano group (the C _6-10 aryl group is condensed with a ring portion of a C _3-6 cycloalkyl group). (Preferably phenyl, indanyl, more preferably phenyl)
And
X is a carbon atom,
R ³ is
(1) (a) a C _1-6 alkyloxy group (preferably methoxy, ethoxy, isopropoxy),
(b) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl, tetrahydrofuryl), and
(c) a C _1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted with 1 to 3 substituents selected from a hydroxyl group,
(2) a C _3-8 cycloalkyl group (preferably cyclopropyl, cyclobutyl, cyclopentyl), or
(3) (a) a C _1-6 alkylcarbonyl group (preferably acetyl),
(b) a C _1-6 alkyloxycarbonyl group (preferably tert-butoxycarbonyl),
(c) a C _1-6 alkylsulfonyl group (preferably methylsulfonyl), and
(d) a 4- to 8-membered saturated group optionally substituted with 1 to 3 substituents selected from a carbamoyl group optionally mono- or di-substituted with a C _1-6 alkyl group (preferably isopropyl) Aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl or piperidyl)
And
R ⁴ is
(1) a hydrogen atom, or
(2) C _1-6 alkyl group (preferably methyl)
And
R ^5a and R ^5b are independently
(1) a hydrogen atom, or
(2) C _1-6 alkyl group (preferably methyl, ethyl, isopropyl)
And
R ⁶ and R ⁷ are independently
(1) a hydrogen atom, or
(2) (a) a hydroxyl group,
(b) a C _1-6 alkyloxy group (preferably methoxy), and
(c) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably morpholinyl)
A compound which is a C _1-6 alkyl group (preferably ethyl, isobutyl) optionally substituted by 1 to 3 substituents selected from:

Preferably R ¹ is
(1) a hydrogen atom, or
(2) Halogen atom (preferably fluorine atom, chlorine atom)
And
L is
(1) single bond, or
(2) -O-
And
R ² is
(a) a halogen atom (preferably a fluorine atom or a chlorine atom),
(b) a C _1-6 alkyl group (preferably methyl, ethyl, isopropyl, tert-butyl),
(c) a C _1-6 haloalkyl group (preferably trifluoromethyl),
(d) a C _1-6 alkyloxy group (preferably methoxy, ethoxy),
(e) a C _1-6 haloalkyloxy group (preferably trifluoromethoxy), and
(f) a phenyl group which may be substituted with 1 to 3 substituents selected from a cyano group;
X is a carbon atom,
R ³ is
(1) (a) a C _1-6 alkyloxy group (preferably methoxy, ethoxy, isopropoxy),
(b) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl, tetrahydrofuryl), and
(c) a C _1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted with 1 to 3 substituents selected from a hydroxyl group, or
(2) C _3-8 cycloalkyl group (preferably cyclopropyl, cyclobutyl, cyclopentyl)
And
R ⁴ is a hydrogen atom or a methyl group,
R ^5a and R ^5b are independently a hydrogen atom, a methyl group, an ethyl group or an isopropyl group (preferably R ^5a is a hydrogen atom, a methyl group, an ethyl group or an isopropyl group, and R ^5b is a methyl group, Ethyl group or isopropyl group),
A compound in which R ⁶ and R ⁷ are hydrogen atoms;

More preferably, R ¹ is a hydrogen atom,
L is -O-
R ² is
(a) a halogen atom (preferably a fluorine atom or a chlorine atom),
(b) a C _1-6 alkyl group (preferably methyl, ethyl, isopropyl, tert-butyl),
(c) a C _1-6 haloalkyl group (preferably trifluoromethyl),
(d) a C _1-6 alkyloxy group (preferably methoxy, ethoxy),
(e) a C _1-6 haloalkyloxy group (preferably trifluoromethoxy), and
(f) a phenyl group which may be substituted with 1 to 3 substituents selected from a cyano group;
X is a carbon atom,
R ³ is
(1) (a) a C _1-6 alkyloxy group (preferably methoxy, ethoxy, isopropoxy),
(b) a 4- to 8-membered saturated aliphatic heterocyclic group (preferably a 5- or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl, tetrahydrofuryl), and
(c) a C _1-6 alkyl group (preferably methyl, ethyl, propyl, isopropyl, isobutyl) optionally substituted with 1 to 3 substituents selected from a hydroxyl group, or
(2) C _3-8 cycloalkyl group (preferably cyclopropyl, cyclobutyl, cyclopentyl)
And
R ⁴ is a hydrogen atom or a methyl group,
R ^5a and R ^5b are independently a hydrogen atom or a methyl group (preferably R ^5a is a hydrogen atom and R ^5b is a methyl group),
Examples include compounds in which R ⁶ and R ⁷ are hydrogen atoms.

As another preferred specific example,
N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} glycinamide,
N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -2-methylalaninamide,
N ² -{[1-cyclopropyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-cyclobutyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-chlorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-fluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-fluorophenoxy) -1- (3-methoxypropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (2-chloro-4-fluorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-ethyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (2,4-difluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (2-ethoxyethyl) -5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-ethyl-5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (3-methoxypropyl) -6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-methylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide, and
N ² -{[5-chloro-6- (3,4-difluorophenyl) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
As well as their pharmaceutically acceptable salts.

  Compound (1) can be produced, for example, by the method shown below.

Reaction Formula-1

(In the formula, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ , L and X are as defined above.)
Compound (1) can be produced by a reductive amination reaction between compound (1-1) and the corresponding amine compound. Solvents include ether solvents such as tetrahydrofuran and 1,4-dioxane, halogen solvents such as dichloromethane, chloroform and 1,2-dichloroethane, alcohol solvents such as methanol and ethanol, ethyl acetate, N, N-dimethylformamide. Acetonitrile can be used. Preferably, tetrahydrofuran, dichloromethane, and methanol are used. As the reducing agent, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride and the like can be used. The reaction temperature is from −20 ° C. to the reflux temperature of the reaction solvent, particularly preferably from 0 ° C. to around room temperature. As a dehydrating agent, molecular sieves or sodium sulfate may be added. Acetic acid or hydrochloric acid may be added as an additive.

In addition, in compound (1), compound (1A) in which R ⁴ and R ^5a are not bonded can also be produced from compound (1-1) by the method shown in the following reaction formula-2.
Reaction formula-2

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ , L and X are as defined above, provided that R ⁴ and R ^5a are not bonded, Y represents a leaving group such as a halogen atom, a mesyloxy group, and a tosyloxy group.
After reductive amination of compound (1-1) and compound (1-2) to obtain compound (1-3), tetrahydrofuran, 1,4-dioxane, etc. in the presence of compound (1-4) and a base Compound by reacting at 0 ° C. to the reflux temperature of the reaction solvent in an ether solvent of the above, a halogen solvent such as dichloromethane, chloroform, 1,2-dichloroethane, a solvent such as ethyl acetate, N, N-dimethylformamide, and acetonitrile. (1A) can be manufactured. As the base, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide, and organic bases such as triethylamine and diisopropylethylamine can be used, but there is no particular limitation. .

Furthermore, compound (1) can also be produced by the method shown in Reaction Scheme-3.
Reaction formula-3

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ , L, Y and X are as defined above.)
In the presence of a base, compound (1-5) and the corresponding amine compound are converted to an ether solvent such as tetrahydrofuran and 1,4-dioxane, a halogen solvent such as dichloromethane, chloroform and 1,2-dichloroethane, ethyl acetate, N, It can be produced by reacting in a solvent such as N-dimethylformamide and acetonitrile from 0 ° C. to the reflux temperature of the reaction solvent. As the base, inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide, and organic bases such as triethylamine and diisopropylethylamine can be used, but there is no particular limitation. .

Compound (1B) in which R ⁴ is a hydrogen atom in compound (1) can be produced, for example, by the method shown in the following reaction scheme-4.
Reaction formula-4

(Wherein R ¹ , R ² , R ³ , R ^5a , R ^5b , R ⁶ , R ⁷ , L, Y and X are as defined above.)
Compound (1B) is compound (1-7) obtained from compound (1-5) and compound (1-6) in the same manner as in Reaction Scheme-3, trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, It can be produced by reacting in an acidic solvent such as sulfuric acid at room temperature to the reflux temperature of the reaction solvent. It is more preferable to carry out the reaction in trifluoroacetic acid at around 50 ° C.

  The above-mentioned compounds (1-1) and (1-5) can be produced by the methods shown below and methods analogous thereto.

In the above compound (1-1), the compound (2-1) can be produced, for example, by the method shown in the following reaction formula-5.
Reaction formula-5

(In the formula, R ² and R ³ are as defined above.)
2,4-Difluoronitrobenzene and compound (2-2) are mixed at room temperature in the presence of a base in an ether solvent such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane, or a solvent such as N, N-dimethylformamide or acetonitrile. The compound (2-3) can be produced by reacting at a reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

  The compound (2-3) and the compound (2-4) are mixed at room temperature in the presence of a base in an ether solvent such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, or a solvent such as N, N-dimethylformamide or acetonitrile. The compound (2-5) can be produced by reacting at a reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and preferably cesium carbonate is used. As the solvent, 1,4-dioxane is preferable.

  Compound (2-6) can be obtained by reducing the nitro group of compound (2-5) to an amino group. The reduction used in this reaction may be a reduction condition that is usually used, and preferred examples include catalytic reduction using palladium-carbon and the like, and reduction using a metal such as iron. The solvent used for the reduction is preferably selected according to the reduction conditions. For example, in catalytic reduction, methanol, ethanol, tetrahydrofuran, ethyl acetate and the like are preferable. In the reduction using a metal such as iron, tetrahydrofuran, acetic acid, methanol, Examples include ethanol and water. In the catalytic reduction, room temperature is preferable, and in the reduction using a metal such as iron, the reflux temperature of the reaction solvent is preferably from 50 ° C.

  The compound (2-6) and glycolic acid are mixed and heated to 100 ° C. to 150 ° C. to obtain a cyclized product. The compound (2-1) can be obtained by oxidizing the hydroxyl group of the cyclized product. The oxidation used for this reaction may be the oxidation conditions that are usually used. Examples include oxidation with manganese dioxide and chromium, and oxidation with an organic oxidizing agent typified by dimethyl sulfoxide. Oxidation with manganese dioxide and swan oxidation are preferred, and oxidation with manganese dioxide is particularly preferred. The solvent used for the oxidation is preferably selected according to the oxidation conditions. For example, in the case of oxidation with a metal, a halogen solvent such as dichloromethane and chloroform, and an ether solvent such as tetrahydrofuran, dimethoxyethane, and 1,4-dioxane are preferable. In the oxidation with an organic oxidizing agent, a halogen-based solvent such as dichloromethane or chloroform is preferred. Room temperature is preferred for metal oxidation, and room temperature is preferred for oxidation with organic oxidants from -78 ° C.

In the above compound (1-1), the compound (3-1) can also be produced, for example, by the method shown in the following Reaction Scheme-6.
Reaction formula-6

(In the formula, R ² and R ³ are as defined above.)
The compound (3-2) and the compound (3-3) are mixed at room temperature in the presence of a base in an ether solvent such as tetrahydrofuran, dimethoxyethane or 1,4-dioxane, or a solvent such as N, N-dimethylformamide or acetonitrile. The compound (3-4) can be produced by reacting at a reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

  Compound (3-5) can be obtained by reducing the nitro group of compound (3-4) to an amino group. The reduction used in this reaction is preferably a reduction using a metal such as iron or tin. Examples of the solvent used for the reduction include tetrahydrofuran, acetic acid, methanol, ethanol, water, and the like. In the reduction using a metal, the reflux temperature of the reaction solvent is preferably from 50 ° C.

  Compound (3-6) can be obtained by mixing compound (3-5) and glycolic acid and heating to 100 ° C. to 150 ° C. Compound (3-7) can be obtained by oxidizing the hydroxyl group of compound (3-6). The oxidation used for this reaction may be the oxidation conditions that are usually used. Examples include oxidation with manganese dioxide and chromium, and oxidation with an organic oxidizing agent typified by dimethyl sulfoxide. Oxidation with manganese dioxide and swan oxidation are preferred, and oxidation with manganese dioxide is particularly preferred. The solvent used for the oxidation is preferably selected according to the oxidation conditions. For example, in the case of oxidation with a metal, a halogen solvent such as dichloromethane and chloroform, and an ether solvent such as tetrahydrofuran, dimethoxyethane, and 1,4-dioxane are preferable. In the oxidation with an organic oxidizing agent, a halogen-based solvent such as dichloromethane or chloroform is preferred. Room temperature is preferred for metal oxidation, and room temperature is preferred for oxidation with organic oxidants from -78 ° C.

  Compound (3-1) is a solvent from room temperature in a solvent such as dimethoxyethane, 1,4-dioxane, toluene, ethanol using a boranoic acid compound corresponding to compound (3-7), a palladium catalyst, a ligand, and a base. It can manufacture by making it react at the reflux temperature of this. Examples of the palladium catalyst include palladium acetate, tetrakistriphenylphosphine palladium, and trisbenzylideneacetone dipalladium, but are not particularly limited. Examples of the ligand include triphenylphosphine, tri-o-tolylphosphine, and tri-tert-butylphosphine, but are not particularly limited. Examples of the base include sodium carbonate, potassium carbonate and cesium carbonate, but are not particularly limited.

In the compound (1-1) described above, the compound (4-1) can be produced, for example, by the method shown in the following Reaction Scheme-7.
Reaction formula-7

(In the formula, R ² and R ³ are as defined above.)
Compound (4-3) was prepared by combining compound (3-6) and compound (4-2) with a copper catalyst, a ligand and a base, using N-methylpyrrolidinone, 1,4-dioxane, dimethyl sulfoxide, N, It can be produced by reacting in a solvent such as N-dimethylformamide at room temperature to the reflux temperature of the solvent. Examples of the copper catalyst include copper iodide, copper bromide, and copper chloride, but are not particularly limited. Examples of the ligand include 2,2,6,6-tetramethylheptane-3,5-dione and N, N-dimethylglycine, but are not particularly limited. Examples of the base include sodium carbonate, potassium carbonate and cesium carbonate, but are not particularly limited.

  The compound (4-1) can be obtained by oxidizing the hydroxyl group of the compound (4-3). The oxidation used for this reaction may be the oxidation conditions that are usually used. Examples include oxidation with manganese dioxide and chromium, and oxidation with an organic oxidizing agent typified by dimethyl sulfoxide. Oxidation with manganese dioxide and swan oxidation are preferred, and oxidation with manganese dioxide is particularly preferred. The solvent used for the oxidation is preferably selected according to the oxidation conditions. For example, in the case of oxidation with a metal, a halogen-based solvent such as dichloromethane and chloroform, and an ether-based solvent such as tetrahydrofuran, dimethoxyethane, and 1,4-dioxane are preferable. In the oxidation with an organic oxidizing agent, a halogen-based solvent such as dichloromethane or chloroform is preferred. Room temperature is preferred for metal oxidation, and room temperature is preferred for oxidation with organic oxidants from -78 ° C.

In the above compound (1-1), the compound (5-1) can be produced, for example, by the method shown in the following Reaction Scheme-8.
Reaction formula-8

(Wherein R ² , R ³ and Y are as defined above.)
Compound (5-4) is compound (5-2) and compound (5-3) in the presence of a base, ether solvents such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane, N, N-dimethylformamide, etc. The reaction can be carried out by reacting at room temperature to the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, N, N-dimethylformamide is preferable.
Compound (5-1) can be obtained from compound (5-4) in the same manner as in Reaction Scheme-5.

In the above compound (1-1), the compound (6-1) can be produced, for example, by the method shown in the following Reaction Scheme-9.
Reaction formula-9

(In the formula, R ² and R ³ are as defined above.)
2,6-dichloro-3-nitropyridine and compound (6-2) in the presence of a base, ether solvents such as tetrahydrofuran, dimethoxyethane, 1,4-dioxane, N, N-dimethylformamide, acetonitrile, etc. Compound (6-3) can be produced by reacting in a solvent at room temperature to the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and potassium carbonate is preferably used. As the solvent, 1,4-dioxane is preferable.

The compound (6-3) and the compound (6-4) are mixed at room temperature in the presence of a base in an ether solvent such as tetrahydrofuran, dimethoxyethane, or 1,4-dioxane, or a solvent such as N, N-dimethylformamide or acetonitrile. The compound (6-5) can be produced by reacting at a reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium hydride, potassium tert-butoxide and the like can be used, and preferably cesium carbonate is used. As the solvent, 1,4-dioxane is preferable.
Compound (6-1) can be obtained from compound (6-5) by the same method as in Reaction Scheme-5.

In the above compound (1-1), the compound (7-1) can be produced, for example, by the method shown in the following Reaction Scheme-10.
Reaction formula-10

(In the formula, R ² and R ³ are as defined above.)
Compound (7-2) can be obtained from compound (6-3) by the same method as in Reaction Scheme-6.
Compound (7-1) is a solvent from room temperature in a solvent such as dimethoxyethane, 1,4-dioxane, toluene, ethanol, etc., using a boranoic acid compound corresponding to compound (7-2), a palladium catalyst, a ligand, and a base. It can manufacture by making it react at the reflux temperature of this. Examples of the palladium catalyst include palladium acetate, tetrakistriphenylphosphine palladium, and trisbenzylideneacetone dipalladium, but are not particularly limited. Examples of the ligand include triphenylphosphine, tri-o-tolylphosphine, and tri-tert-butylphosphine, but are not particularly limited. Examples of the base include sodium carbonate, potassium carbonate and cesium carbonate, but are not particularly limited.

The aforementioned compound (1-5) can be produced from compound (8-1) by the method shown in the following reaction formula-11, for example.
Reaction formula-11

(In the formula, R ¹ , R ² , R ³ , L, X and Y are as defined above.)
In the step of converting to a leaving group, when the leaving group Y is a mesyloxy group or a tosyloxy group, the corresponding chloride (mesyl chloride, tosyl chloride) is reacted in the presence of a base such as triethylamine or pyridine. Mesyl bodies or tosyl bodies can be obtained. In the case where the leaving group Y is a halogen atom, a comprehensive organic transformation [RC Laroc, VCH Publishers Inc. (1989)], 4th edition Experimental Chemistry Course (Maruzen), New Experimental Chemistry Course (Maruzen), etc. may be used. For example, bromide can be obtained by adding phosphorus tribromide in tetrahydrofuran. Can be obtained.

For each of the above reactions, Examples in the present specification and Comprehensive Organic Transformation [RC Rallock, VCH Publishers Inc. (1989)], 4th edition Experimental Chemistry Course (Maruzen), New Experimental Chemistry Course (Maruzen), and the like.
Moreover, the raw material compound used in the above-described production method can be appropriately prepared using a commercially available product or a method known to those skilled in the art.
Further, when producing the compound according to the present invention or a pharmaceutically acceptable salt thereof, a functional group such as a hydroxyl group, a carboxyl group or an amino group can be protected / deprotected as required in any step. . The types of protecting groups and the methods for protecting and deprotecting may be those well known to those skilled in the art. For example, “Protective Groups in Organic Synthesis (written by TW Green et al., Published by John Wiley & Sons, Inc. 1991) ) ”Etc. may be referred to.

When the compound (1) has a group capable of forming a salt in the structure, it can be converted into an acid addition salt or an alkali addition salt with a pharmaceutically acceptable inorganic acid or organic acid, if necessary. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, formate, acetate, fumarate, Maleate, oxalate, citrate, malate, tartrate, aspartate, glutamate and other organic carboxylic acids, methanesulfonate, benzenesulfonate, p-toluenesulfonate And salts with sulfonic acids such as hydroxybenzene sulfonate and dihydroxybenzene sulfonate. In the case of alkali addition salts, ammonium salts, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, etc. Can be mentioned.
The present invention also includes solvates such as hydrate of compound (1) or a pharmaceutically acceptable salt thereof, ethanol solvate and the like. Furthermore, the present invention also includes all tautomers, stereoisomers such as optical isomers of compound (1), and crystal forms of all embodiments. These can be appropriately purified using methods such as silica gel column chromatography, HPLC, ion exchange chromatography, and recrystallization well known to those skilled in the art.

  In order to obtain the optical isomer purely, an optical resolution method known to those skilled in the art may be used. Specifically, when the compound according to the present invention or an intermediate thereof has a basic functional group, an optically active acid (for example, monodelic acid such as mandelic acid, N-benzyloxyalanine, lactic acid, etc.) in an inert solvent. Salts with carboxylic acids, tartaric acid, o-diisopropylidene tartaric acid, dicarboxylic acids such as malic acid, sulfonic acids such as camphor sulfonic acid, bromocamphor sulfonic acid) and the like. Further, when the compound according to the present invention or an intermediate thereof has an acidic substituent, a salt is formed with an optically active amine (for example, organic amines such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine). You can also. Examples of the temperature at which the salt is formed include a range from room temperature to the boiling point of the solvent.

  The compound having a novel bicyclic heterocycle or a pharmaceutically acceptable salt thereof according to the present invention has SNS inhibitory activity and can be used as a therapeutic or prophylactic agent for neuropathic pain and nociceptive pain. Examples of neuropathic pain include lumbar postoperative neuralgia, diabetic neuropathy, postherpetic neuralgia, reflex sympathetic atrophy, phantom limb pain, spinal injury, end-stage cancer pain, prolonged postoperative pain Is mentioned. Examples of nociceptive pain include low back pain, abdominal pain, rheumatoid arthritis, pain due to osteoarthritis, and the like. The compound according to the present invention or a pharmaceutically acceptable salt thereof can also be used as a therapeutic or prophylactic agent for dysuria. Examples of dysuria include frequent urination and bladder pain due to enlarged prostate. Furthermore, it can also be used as a therapeutic or prophylactic agent that suppresses abnormal nerve firing of the cerebellum in multiple sclerosis. As a drug having no side effect derived from non-neural tissue or central nervous system, a compound having SNS selective inhibitory activity is more preferable.

The therapeutic agent or prophylactic agent for neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis of the present invention is a pharmaceutically acceptable conventional carrier, binder, stabilizer, excipient, Various preparation ingredients such as a diluent, a pH buffer, a disintegrant, a solubilizer, a solubilizer, and an isotonic agent can be added. These therapeutic or prophylactic agents can be administered orally or parenterally. That is, orally, it can be orally administered in a commonly used dosage form such as a tablet, pill, powder, granule, capsule, syrup, emulsion, suspension or the like. Parenterally, it can be made into preparations in the form of, for example, intravenous injection (instillation), intramuscular injection, subcutaneous injection, coating agent, eye drop, eye ointment and the like.
Solid preparations such as tablets bind the active ingredient to usual pharmacologically acceptable carriers or excipients such as lactose, sucrose, corn starch, crystalline cellulose, hydroxypropylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc. And a disintegrant such as sodium carboxymethylcellulose and sodium starch glycolate, a lubricant such as stearic acid and magnesium stearate, or a preservative.
For parenteral administration, the active ingredient is dissolved or suspended in a physiologically acceptable carrier such as water, saline, oil, aqueous dextrose, etc., and an emulsifier, stabilizer, osmotic pressure adjusting salt as an adjuvant, or You may contain a buffering agent as needed.

  The preparation of the compound according to the present invention can be produced according to a conventional method. For example, in the case of a tablet, 20 mg of the compound of Example 1, 100 mg of lactose, 25 mg of crystalline cellulose and 1 mg of magnesium stearate are mixed, and the resulting mixture is tableted. Can be manufactured.

The dose and frequency of administration vary depending on the administration method and the age, weight, medical condition, etc. of the patient, but it is preferable to administer once or twice or more per day. When administered twice or more, it is desirable to administer repeatedly every day or at appropriate intervals.
The dose is 10 μg to 2 g, preferably 1 mg to 1 g, more preferably 10 to 100 mg as the amount of active ingredient per adult patient, and can be administered once or several times a day. Parenteral administration includes a dose of 0.1 to 100 mg / day, more preferably 0.3 to 50 mg / day per adult patient, and can be administered once or divided into several times a day. Sustained release preparations can also be used to reduce the number of administrations.
Further, the therapeutic or prophylactic agent for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis of the present invention can be used as an animal drug.

The present invention will be described more specifically with reference examples and examples. However, the technical scope of the present invention is not limited to these examples. The compound was identified by hydrogen nuclear magnetic resonance absorption spectrum ( ¹ H-NMR) or the like.

In the following, in order to simplify the description of the present specification, the following abbreviations may be used.
Me: methyl, Et: ethyl, Pr: propyl, iPr: isopropyl, Ph: phenyl, Ac: acetyl, Boc: tert-butoxycarbonyl, Bn: benzyl, TBDMS: tert-butyldimethylsilyl, PyBOP: benzotriazole-1- Yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate, Ms: methanesulfonyl, J: coupling constant, s: single line, d: double line, dd: two double lines, ddd: four doubles Line, td: three double lines, t: triple line, dt: two triple lines, q: quadruple line, quint: quintet line, br: broad, m: multiple line.

  Unless otherwise specified, commercially available materials were used for the raw material compounds, reaction reagents and solvents.

Reference example 1:

  To a solution of 2,4-difluoronitrobenzene (15 g, 94 mmol) in dioxane (300 mL) were added potassium carbonate (14.4 g, 104 mmol) and 2-ethoxyethylamine (8.4 g, 104 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. Concentration under reduced pressure gave the desired product (21 g, 98%).

¹ H-NMR (CDCl ₃ ) δ 1.25 (t, J = 7.1Hz, 3H), 3.43 (q, J = 5.2Hz, 2H), 3.58 (q, J = 7.1Hz, 2H), 3.72 (t, J = 5.2Hz, 2H), 6.37 (ddd, J = 9.5, 7.3, 2.5Hz, 1H), 6.51 (dd, J = 11.5, 2.5Hz, 1H), 8.22 (dd, J = 9.5, 6.1Hz, 1H) , 8.38 (br, 1H).

Reference example 2:

  To a dioxane solution (60 mL) of the compound (3.0 g, 13.2 mmol) obtained in Reference Example 1, cesium carbonate (6.4 g, 19.7 mmol) and phenol (1.5 g, 15.8 mmol) were added and heated to 80 ° C. After stirring for 7 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. Concentration under reduced pressure gave the desired product (4.1 g, 100%).

¹ H-NMR (CDCl ₃ ) δ 1.23 (t, J = 7.0Hz, 3H), 3.34 (q, J = 5.2Hz, 2H), 3.55 (q, J = 7.0Hz, 2H), 3.67 (t, J = 5.2Hz, 2H), 6.22 (dd, J = 9.4, 2.5Hz, 1H), 6.29 (d, J = 2.5Hz, 1H), 7.07-7.12 (m, 2H), 7.23 (m, 1H), 7.35 -7.45 (m, 2H), 8.16 (d, J = 9.4Hz, 1H), 8.39 (br, 1H).

Reference Example 3-1:

  To an ethanol solution (50 mL) of the compound obtained in Reference Example 2 (1.8 g, 6.0 mmol) was added 10% palladium-carbon (1 g), and the mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated. The product was dried under reduced pressure to obtain the desired product (1.4 g, 86%).

¹ H-NMR (CDCl ₃ ) δ 1.22 (t, J = 7.0Hz, 3H), 3.21 (t, J = 5.2Hz, 2H), 3.23 (br, 2H), 3.53 (q, J = 7.0Hz, 2H ), 3.67 (t, J = 5.2Hz, 2H), 6.34 (dd, J = 8.3, 2.6Hz, 1H), 6.40 (d, J = 2.6Hz, 1H), 6.67 (d, J = 8.3Hz, 1H) ), 6.92-7.04 (m, 3H), 7.24-7.30 (m, 2H).

Reference Example 3-2:
The object can also be produced by the following method.
Compound obtained in Reference Example 2 in a tetrahydrofuran-methanol-water suspension of iron (13.9 g, 0.25 mol) and ammonium chloride (6.6 g, 0.12 mol) (3: 2: 1, 120 mL) with heating under reflux A tetrahydrofuran-methanol-water mixed solution (3: 2: 1, 60 mL) of (9.8 g, 32 mmol) was added dropwise. After stirring for 2 hours, the reaction solution was cooled and filtered through Celite. Water was added to the filtrate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. Concentration under reduced pressure gave the desired product (8.7 g, 100%).

Reference example 4:

  Glycolic acid (8 g) was added to the compound obtained in Reference Example 3 (5.0 g, 18.4 mmol) and stirred at 120 ° C. for 30 minutes. After cooling, water and chloroform were added to the reaction solution, and neutralized with 30% aqueous sodium hydroxide solution under ice cooling. The organic layer was extracted and dried over sodium sulfate. The residue was purified by silica gel column (chloroform: methanol = 50: 1-30: 1) to obtain a crude product (4.1 g).

Reference example 5:

  Manganese dioxide (8 g) was added to a solution of the compound (4.1 g) obtained in Reference Example 4 in dichloromethane (100 mL), and the mixture was stirred at room temperature. After 2 hours, the reaction solution was filtered through Celite, and the filtrate was concentrated. The residue was purified by silica gel column (ethyl acetate: hexane = 1: 2) to obtain the desired product (3.5 g, 61% (2 steps)).

¹ H-NMR (CDCl ₃ ) δ 1.03 (t, J = 7.0Hz, 3H), 3.37 (q, J = 7.0Hz, 2H), 3.73 (t, J = 5.3Hz, 2H), 4.66 (t, J = 5.3Hz, 2H), 7.04-7.20 (m, 5H), 7.34-7.41 (m, 2H), 7.86 (d, J = 8.8Hz, 1H), 10.05 (s, 1H).

Reference Example 6:

  The crude product obtained from 2,4-difluoronitrobenzene (20.0 g, 126 mmol) and 4-fluorophenol in the same manner as in Reference Examples 1 to 4 is recrystallized from chloroform / hexane and further recrystallized from acetonitrile. The desired product (23.3 g, 56% (4 steps)) was obtained.

¹ H-NMR (CDCl ₃ ) δ 1.05 (t, J = 7.0Hz, 3H), 3.37 (q, J = 7.0Hz, 2H), 3.70 (t, J = 5.1Hz, 2H), 4.34 (t, J = 5.1Hz, 2H), 4.89 (s, 2H), 6.89-7.03 (m, 6H), 7.58 (m, 1H).

Reference example 7:

The target product was obtained from the compound obtained in Reference Example 6 by the same method as in Reference Example 5.
¹ H-NMR (CDCl ₃ ) δ 0.99 (t, J = 7.0Hz, 3H), 3.33 (q, J = 7.0Hz, 2H), 3.69 (t, J = 5.1Hz, 2H), 4.62 (t, J = 5.1Hz, 2H), 6.92-7.09 (m, 6H), 7.81 (m, 1H), 10.00 (s, 1H).

Example 1: N ² -{[1- (2-Ethoxyethyl) -6-phenoxy-1H-benzimidazol-2-yl] methyl} -L-alaninamide

  To a solution of the compound obtained in Reference Example 5 (2.0 g, 6.5 mmol) in dichloromethane (50 mL), (L) -alaninamide hydrochloride (0.96 g, 7.7 mmol) was added and stirred at room temperature. After 1 hour, sodium triacetoxyborohydride (1.6 g, 7.7 mmol) was added and stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (chloroform: methanol = 50: 1 to 10: 1) to obtain the desired product (0.59 g, 24%).

¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.1Hz, 3H), 1.41 (d, J = 7.0Hz, 3H), 3.33 (q, J = 7.0Hz, 1H), 3.38 (q, J = 7.1Hz, 2H), 3.68 (t, J = 5.1Hz, 2H), 4.04 (d, J = 14.7Hz, 1H), 4.12 (d, J = 14.7Hz, 1H), 4.17-4.32 (m, 2H ), 5.50 (brs, 1H), 6.98-7.02 (m, 4H), 7.09 (m, 1H), 7.28-7.36 (m, 3H), 7.68 (m, 1H).

The above compound can also be produced by the following method.
To a solution of the compound obtained in Reference Example 5 (0.15 g, 0.48 mmol) in tetrahydrofuran (10 mL), (L) -alaninamide hydrochloride (0.18 g, 1.45 mmol), sodium sulfate (3 g) and triethylamine (0.20 mL) were added. It was added and stirred at room temperature. After 30 minutes, sodium cyanoborohydride (45 mg, 0.72 mmol) was added and stirred for 2 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was extracted, washed with saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (chloroform: methanol = 50: 1 to 10: 1) to obtain the desired product (0.09 g, 49%).

Example 2: N ² -{[1- (2-Ethoxyethyl) -6-phenoxy-1H-benzimidazol-2-yl] methyl} glycinamide

  To a solution of the compound obtained in Reference Example 5 (44 mg, 0.14 mmol) in methanol (3 mL) was added glycinamide hydrochloride (31 mg, 0.28 mmol), and the mixture was stirred at room temperature. After 1 hour, sodium cyanoborohydride (18 mg, 0.28 mmol) was added and stirred overnight. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (chloroform: methanol = 50: 1-10: 1) to obtain the desired product (23 mg, 43%).

¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.0Hz, 3H), 3.38 (q, J = 7.0Hz, 2H), 3.42 (s, 2H), 3.68 (t, J = 5.1Hz, 2H ), 4.10 (s, 2H), 4.26 (t, J = 5.1Hz, 2H), 5.72 (brs, 1H), 6.96-7.02 (m, 4H), 7.08 (m, 1H), 7.21 (brs, 1H) , 7.28-7.36 (m, 2H), 7.68 (m, 1H).

Example 3: N ² -{[1- (2-Ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} glycinamide

The target product was obtained from the compound obtained in Reference Example 7 by the same method as in Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 3.39 (q, J = 7.0Hz, 2H), 3.42 (s, 2H), 3.69 (t, J = 5.0Hz, 2H ), 4.10 (s, 2H), 4.26 (t, J = 5.0Hz, 2H), 5.54 (brs, 1H), 6.93-7.05 (m, 6H), 7.18 (brs, 1H), 7.67 (m, 1H) .

Example 4: N ² -{[1- (2-Ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-valine amide

The target product was obtained from the compound obtained in Reference Example 7 and (L) -valinamide hydrochloride by the same method as in Example 1.
¹ H-NMR (CDCl ₃ ) δ 0.99 (d, J = 7.0Hz, 3H), 1.02 (d, J = 7.0Hz, 3H), 1.08 (t, J = 7.0Hz, 3H), 2.08 (m, 1H ), 2.97 (d, J = 5.5Hz, 1H), 3.38 (q, J = 7.0Hz, 2H), 3.68 (t, J = 5.1Hz, 2H), 3.98 (d, J = 14.5Hz, 1H), 4.15 (d, J = 14.5Hz, 1H), 4.17-4.40 (m, 2H), 5.56 (brs, 1H), 6.93-7.01 (m, 7H), 7.67 (m, 1H).

Example 5: N ² -{[1- (2-Ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -2-methylalaninamide

The target product was obtained in the same manner as in Example 1 from the compound obtained in Reference Example 7 and 2-methylalaninamide, which was a known compound.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.46 (s, 6H), 3.38 (q, J = 7.0Hz, 2H), 3.69 (t, J = 5.1Hz, 2H ), 4.02 (s, 2H), 4.24 (t, J = 5.1Hz, 2H), 5.43 (brs, 1H), 6.93-7.05 (m, 6H), 7.48 (brs, 1H), 7.68 (m, 1H) .

Examples 6-58:
The compounds of Examples 6 to 58 shown in Tables 1 to 9 are produced from 2,4-difluoronitrobenzene by a method similar to Reference Examples 1 to 7 and Example 1 or Example 2 using commercially available or known compounds. did.

Reference Example 8:

  Phosphorus tribromide (0.18 g, 0.66 mmol) was added to a solution of the compound (0.22 g, 0.66 mmol) obtained in Reference Example 6 in tetrahydrofuran (3 mL) under ice cooling. After stirring for 1 hour, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and used as such in the next reaction.

¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.0Hz, 3H), 3.39 (q, J = 7.0Hz, 2H), 3.70 (t, J = 5.1Hz, 2H), 4.37 (t, J = 5.1Hz, 2H), 4.81 (s, 2H), 6.95-7.05 (m, 6H), 7.69 (m, 1H).

Example ^{59: N 2 - {[1-} (2- ethoxyethyl) -6- (4-fluorophenoxy)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

  To a solution of the compound obtained in Reference Example 8 (107 mg, 0.27 mmol) in acetonitrile (3 mL), diisopropylethylamine (0.10 ml, 0.55 mmol) and N- (2,4-dimethoxybenzyl) alaninamide (97.7 mg, 0.41 mmol) Was added. After stirring at 50 ° C. for 5 hours, an aqueous sodium hydrogen carbonate solution was added and the mixture was extracted with chloroform. After drying over magnesium sulfate and concentration under reduced pressure, trifluoroacetic acid (3 mL) was added, and the mixture was further stirred at 50 ° C. for 2 hr. After neutralization with aqueous sodium hydroxide, extraction with ethyl acetate, drying over magnesium sulfate and concentration under reduced pressure, the residue obtained was recrystallized from chloroform / 2-propanol to obtain the desired product (75 mg, 70%) Got.

¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.0Hz, 3H), 1.41 (d, J = 6.8Hz, 3H), 3.33-3.41 (m, 3H), 3.68 (t, J = 5.1Hz , 2H), 4.03 (d, J = 14.6Hz, 1H), 4.12 (d, J = 14.6Hz, 1H), 4.23-4.27 (m, 2H), 5.58 (brs, 1H), 6.94-7.05 (m, 6H), 7.24 (brs, 1H), 7.67 (m, 1H).

Examples 60-65:
The compounds of Examples 60 to 65 shown in Table 10 were produced from 2,4-difluoronitrobenzene by a method similar to Reference Examples 1 to 4, 8 and Example 59 using commercially available or known compounds.

Reference Example 9:

The target product was obtained from 2-fluoro-4-bromonitrobenzene in the same manner as in Reference Examples 1, 3 and 4.
¹ H-NMR (CDCl ₃ ) δ 1.12 (t, J = 7.0Hz, 3H), 3.43 (q, J = 7.0Hz, 2H), 3.75 (t, J = 5.1Hz, 2H), 4.37 (t, J = 5.1Hz, 2H), 4.88 (s, 2H), 7.36 (dd, J = 8.6, 1.8Hz, 1H), 7.49 (d, J = 1.8Hz, 1H), 7.59 (d, J = 8.6Hz, 1H ).

Reference Example 10:

The target product was obtained from the compound obtained in Reference Example 9 by the same method as in Reference Example 5.
¹ H-NMR (CDCl ₃ ) δ 1.02 (t, J = 7.0Hz, 3H), 3.35 (q, J = 7.0Hz, 2H), 3.71 (t, J = 5.1Hz, 2H), 4.64 (t, J = 5.1Hz, 2H), 7.41 (m, 1H), 7.68-7.73 (m, 2H), 10.05 (s, 1H).

Reference Example 11:

  To a mixed solution of the compound obtained in Reference Example 10 (200 mg, 0.67 mmol) in dioxane-water (4: 1, 15 mL), potassium carbonate (280 mg, 2.02 mmol), phenylboronic acid (123 mg, 1.01 mmol) and tetrakis (triphenyl Phosphine) palladium (154 mg, 0.13 mmol) was added and heated to 110 ° C. After refluxing for 2 hours, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane: ethyl acetate = 90: 10-75: 25-50: 50) to obtain the desired product (115 mg, 58%).

¹ H-NMR (CDCl ₃ ) δ 1.07 (t, J = 7.0Hz, 3H), 3.42 (q, J = 7.0Hz, 2H), 3.81 (t, J = 5.1Hz, 2H), 4.81 (t, J = 5.1Hz, 2H), 7.39 (m, 1H), 7.48 (t, J = 7.6Hz, 2H), 7.63-7.67 (m, 3H), 7.76 (m, 1H), 7.96 (d, J = 8.6Hz , 1H), 10.11 (s, 1H).

Example ^{66: N 2 - {[1-} (2- ethoxyethyl) -6-phenyl -1H- benzimidazol-2-yl] methyl} glycinamide

The target product (31 mg, 38%) was obtained from the compound (68 mg, 0.23 mmol) obtained in Reference Example 11 by the same method as in Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.1Hz, 3H), 3.38 (q, J = 7.1Hz, 2H), 3.41 (s, 2H), 3.75 (t, J = 5.1Hz, 2H ), 4.11 (s, 2H), 4.35 (t, J = 5.1Hz, 2H), 5.68 (brs, 1H), 7.22 (brs, 1H), 7.33 (m, 1H), 7.42-7.51 (m, 4H) , 7.61-7.63 (m, 2H), 7.76 (m, 1H).

Examples 67-73:
In the same manner as in Reference Examples 9 to 11 and Example 66, the compounds of Examples 67 to 73 shown in Table 11 and Table 12 were produced.

Reference Example 12:

  Under a nitrogen atmosphere, a solution of the compound obtained in Reference Example 9 (150 mg, 0.5 mmol) in N-methylpyrrolidinone (5 mL) was added to cesium carbonate (489 mg, 1.5 mmol), 4-tert-butylphenol (225 mg, 1.5 mmol), 2, 2,6,6-Tetramethylheptane-3,5-dione (52 μl, 0.25 mmol) and copper (I) chloride (50 mg, 0.5 mmol) were added and heated to 120 ° C. After stirring for 6 hours, the reaction mixture was added to 2 mol / L hydrochloric acid under ice cooling, and extracted with ethyl acetate. The organic layer was washed with 0.5 mol / L hydrochloric acid, 2 mol / L aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was silica gel column (hexane: ethyl acetate = 100: 0 to 0: 100) to obtain the desired product (56 mg, 30%).

¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.32 (s, 9H), 3.41 (q, J = 7.0Hz, 2H), 3.72 (t, J = 5.1Hz, 2H ), 4.35 (t, J = 5.1Hz, 2H), 4.89 (s, 2H), 6.89-7.02 (m, 4H), 7.31-7.36 (m, 2H), 7.64 (d, J = 8.5Hz, 1H) .

Example 74: N ² -{[6- (4-tert-butylphenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide

From the compound obtained in Reference Example 12, the target product was obtained in the same manner as in Reference Example 5 and Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.32 (s, 9H), 1.41 (d, J = 6.9Hz, 3H), 3.34 (q, J = 6.9Hz, 1H ), 3.38 (q, J = 7.0Hz, 2H), 3.68 (t, J = 5.1Hz, 2H), 4.04 (d, J = 14.9Hz, 1H), 4.12 (d, J = 14.9Hz, 1H), 4.18-4.34 (m, 2H), 5.47 (brs, 1H), 6.89-6.95 (m, 2H), 6.97-7.02 (m, 2H), 7.29 (brs, 1H), 7.31-7.36 (m, 2H), 7.67 (d, J = 8.5 Hz, 1H).

Reference Example 13:

  To a solution of the compound obtained in Reference Example 9 (1.20 g, 4 mmol) in N, N-dimethylformamide (15 mL), imidazole (1.36 g, 20 mmol) and tert-butyldimethylsilyl chloride (904 mg, 6 mmol) were added. After stirring at room temperature for 2 hours, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane: ethyl acetate = 100: 0-85: 15) to give the desired product. (1.65 g, 100%) was obtained.

¹ H-NMR (CDCl ₃ ) δ 0.11 (s, 6H), 0.91 (s, 9H), 1.12 (t, J = 7.0Hz, 3H), 3.41 (q, J = 7.0Hz, 2H), 3.74 (t , J = 5.5Hz, 2H), 4.44 (t, J = 5.5Hz, 2H), 4.99 (s, 2H), 7.34 (dd, J = 1.9, 8.5Hz, 1H), 7.56-7.62 (m, 2H) .

Reference Example 14:

  Under a nitrogen atmosphere, a solution of the compound obtained in Reference Example 13 (207 mg, 0.5 mmol) in N-methylpyrrolidinone (5 mL) was added to cesium carbonate (489 mg, 1.5 mmol), 4-methoxyphenol (186 mg, 1.5 mmol), 2,2 , 6,6-tetramethylheptane-3,5-dione (52 μl, 0.25 mmol) and copper (I) chloride (50 mg, 0.5 mmol) were added and heated to 120 ° C. After stirring for 4 hours, the reaction mixture was added to 2 mol / L hydrochloric acid under ice cooling and extracted with ethyl acetate. The organic layer was washed with 0.5 mol / L hydrochloric acid, 2 mol / L aqueous sodium hydroxide solution, water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was silica gel column (hexane: ethyl acetate = 100: 0 to 0: 100) to obtain the desired product (36 mg, 21%).

¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 3.41 (q, J = 7.0Hz, 2H), 3.70 (t, J = 5.0Hz, 2H), 3.81 (s, 3H ), 4.32 (t, J = 5.0Hz, 2H), 4.88 (s, 2H), 6.84-7.01 (m, 6H), 7.63 (d, J = 8.8Hz, 1H).

Example 75: N ² -{[1- (2-ethoxyethyl) -6- (4-methoxyphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide

  The target product was obtained from the compound obtained in Reference Example 14 by the same method as in Reference Example 5 and Example 1.

¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.41 (d, J = 6.8Hz, 3H), 3.33 (q, J = 6.8Hz, 1H), 3.37 (q, J = 7.0Hz, 2H), 3.67 (t, J = 5.1Hz, 2H), 3.81 (s, 3H), 4.03 (d, J = 14.7Hz, 1H), 4.10 (d, J = 14.7Hz, 1H), 4.17-4.30 (m, 2H), 5.32 (brs, 1H), 6.85-7.00 (m, 6H), 7.27 (brs, 1H), 7.64 (d, J = 8.8Hz, 1H).

Reference Example 15:

To a solution of 3-fluoro-4-nitrophenol (2.5 g, 16.0 mmol) in N, N-dimethylformamide (30 mL) was added potassium carbonate (3.3 g, 24.0 mmol), benzyl bromide (2.1 ml, 17.6 mmol), and 70 Heated to ° C. After stirring for 1 hour, water was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and used as it is in the next reaction.
¹ H-NMR (CDCl ₃ ) δ 5.14 (s, 2H), 6.79-6.86 (m, 2H), 7.38-7.43 (m, 5H), 8.10 (m, 1H).

Reference Example 16:

The target product was obtained from the compound obtained in Reference Example 15 in the same manner as in Reference Examples 1 and 3-5.
¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.0Hz, 3H), 3.40 (q, J = 7.0Hz, 2H), 3.77 (t, J = 5.1Hz, 2H), 4.71 (t, J = 5.1Hz, 2H), 5.15 (s, 2H), 7.04 (d, J = 2.4Hz, 1H), 7.11 (dd, J = 9.0, 2.4Hz, 1H), 7.35-7.49 (m, 5H), 7.79 (d, J = 9.0Hz, 1H), 10.01 (s, 1H).

Example ^{76: N 2 - {[6-} ( benzyloxy) -1- (2-ethoxyethyl)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

The target product was obtained from the compound obtained in Reference Example 16 and (L) -alaninamide hydrochloride by the same method as in Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.39 (d, J = 7.0Hz, 3H), 3.32 (q, J = 7.0Hz, 1H), 3.37 (q, J = 7.0Hz, 2H), 3.68 (t, J = 5.1Hz, 2H), 4.00 (d, J = 14.6Hz, 1H), 4.09 (d, J = 14.6Hz, 1H), 4.16-4.32 (m, 2H ), 5.11 (s, 2H), 5.75 (brs, 1H), 6.87 (d, J = 2.2Hz, 1H), 6.98 (dd, J = 8.8, 2.2Hz, 1H), 7.27-7.53 (m, 6H) , 7.61 (d, J = 8.8Hz, 1H).

Example 77: N ² -{[6- (Benzyloxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -2-methylalaninamide

The target product was obtained from the compound obtained in Reference Example 16 and 2-methylalaninamide by the same method as in Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 1.45 (s, 6H), 3.37 (q, J = 7.0Hz, 2H), 3.69 (t, J = 5.1Hz, 2H ), 4.00 (s, 2H), 4.24 (t, J = 5.1Hz, 2H), 5.12 (s, 2H), 5.47 (brs, 1H), 6.86 (d, J = 2.4Hz, 1H), 6.98 (dd , J = 8.8, 2.4Hz, 1H), 7.31-7.48 (m, 5H), 7.51 (brs, 1H), 7.62 (d, J = 8.8Hz, 1H).

Reference Example 17:

  The desired product was obtained from 3-fluoro-4-nitrophenol in the same manner as in Reference Examples 15, 1 and 3-5.

¹ H-NMR (CDCl ₃ ) δ 1.07 (t, J = 7.0Hz, 3H), 3.40 (q, J = 7.0Hz, 2H), 3.78 (t, J = 5.3Hz, 2H), 4.71 (t, J = 5.3Hz, 2H), 5.10 (s, 2H), 7.03 (d, J = 2.2Hz, 1H), 7.07-7.13 (m, 3H), 7.42-7.47 (m, 2H), 7.79 (d, J = 9.0Hz, 1H), 10.01 (s, 1H).

Example 78: N ² -({1- (2-Ethoxyethyl) -6-[(4-fluorobenzyl) oxy] -1H-benzimidazol-2-yl} methyl) -L-alaninamide

The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 17 and (L) -alaninamide hydrochloride.
¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 1.40 (d, J = 7.0Hz, 3H), 3.32 (q, J = 7.0Hz, 1H), 3.38 (q, J = 7.0Hz, 2H), 3.70 (t, J = 5.1Hz, 2H), 4.01 (d, J = 14.6Hz, 1H), 4.09 (d, J = 14.6Hz, 1H), 4.20-4.32 (m, 2H ), 5.08 (s, 2H), 5.39 (brs, 1H), 6.86 (d, J = 2.2Hz, 1H), 6.96 (dd, J = 8.8, 2.2Hz, 1H), 7.06-7.10 (m, 2H) , 7.25 (brs, 1H), 7.42-7.45 (m, 2H), 7.62 (d, J = 8.8Hz, 1H).

Reference Example 18:

  To a solution of 2,6-dichloro-3-nitropyridine (3.0 g, 15.5 mmol) in dioxane (50 mL), potassium carbonate (2.4 g, 17.0 mmol) and 2-ethoxyethylamine (1.4 g, 17.0 mmol) were added, And stirred. After 3 hours, potassium carbonate (1.8 g, 13.0 mmol) and 2-ethoxyethylamine (0.9 g, 10.0 mmol) were added, and the mixture was stirred at 50 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (ethyl acetate: hexane = 1: 5) to obtain the desired product (3.4 g, 89%).

¹ H-NMR (CDCl ₃ ) δ 1.24 (t, J = 7.0Hz, 3H), 3.57 (q, J = 7.0Hz, 2H), 3.67 (t, J = 5.2Hz, 2H), 3.82 (q, J = 5.2Hz, 2H), 6.61 (d, J = 8.5Hz, 1H), 8.35 (d, J = 8.5Hz, 1H), 8.59 (br, 1H).

Reference Example 19:

The target product was obtained from the compound obtained in Reference Example 18 by the same method as in Reference Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.18 (t, J = 7.0Hz, 3H), 3.39-3.50 (m, 6H), 6.20 (d, J = 9.0Hz, 1H), 7.12-7.17 (m, 2H) , 7.25 (m, 1H), 7.37-7.44 (m, 2H), 8.42 (d, J = 9.0Hz, 1H), 8.66 (br, 1H).

Reference Example 20:

The target product was obtained from the compound obtained in Reference Example 19 by the same method as in Reference Examples 3 to 5.
¹ H-NMR (CDCl ₃ ) δ 1.01 (t, J = 7.0Hz, 3H), 3.38 (q, J = 7.0Hz, 2H), 3.72 (t, J = 5.6Hz, 2H), 4.70 (t, J = 5.6Hz, 2H), 6.98 (d, J = 8.8Hz, 1H), 7.17-7.28 (m, 3H), 7.37-7.46 (m, 2H), 8.16 (d, J = 8.8Hz, 1H), 10.00 (s, 1H).

Example 79: N ² -{[3- (2-ethoxyethyl) -5-phenoxy-3H-imidazo [4,5-b] pyridin-2-yl] methyl} -L-alaninamide

The target product was obtained from the compound obtained in Reference Example 20 by the same method as in Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.41 (d, J = 7.0Hz, 3H), 3.35 (q, J = 7.0Hz, 1H), 3.38 (q, J = 7.0Hz, 2H), 3.71 (t, J = 5.1Hz, 2H), 4.06 (d, J = 15.0Hz, 1H), 4.14 (d, J = 15.0Hz, 1H), 4.32 (t, J = 5.1 Hz, 2H), 5.56 (brs, 1H), 6.67 (d, J = 8.6Hz, 1H), 7.11-7.21 (m, 3H), 7.26 (brs, 1H), 7.35-7.42 (m, 2H), 7.95 (d, J = 8.6Hz, 1H).

Example ^{80: N 2 - {[3-} (2- ethoxyethyl) -5- phenoxy -3H- [4,5-b] pyridine-2- yl] -methyl} glycinamide

The target product was obtained from the compound obtained in Reference Example 20 by the same method as in Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.0Hz, 3H), 3.38 (q, J = 7.0Hz, 2H), 3.42 (s, 2H), 3.72 (t, J = 4.9Hz, 2H ), 4.12 (s, 2H), 4.33 (t, J = 4.9Hz, 2H), 5.73 (brs, 1H), 6.76 (d, J = 8.4Hz, 1H), 7.11-7.22 (m, 3H), 7.26 (brs, 1H), 7.35-7.42 (m, 2H), 7.95 (d, J = 8.4Hz, 1H).

Reference Example 21:

The desired product was obtained from 2,4,5-trifluoronitrobenzene in the same manner as in Reference Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.25 (t, J = 7.1Hz, 3H), 3.43 (q, J = 5.1Hz, 2H), 3.57 (q, J = 7.1Hz, 2H), 3.72 (t, J = 5.1Hz, 2H), 6.66 (dd, J = 12.4, 6.6Hz, 1H), 8.05 (dd, J = 10.2, 8.6Hz, 1H), 8.29 (br, 1H).

Reference Example 22:

The target product was obtained from the compound obtained in Reference Example 21 by the same method as in Reference Examples 2 to 5.
¹ H-NMR (CDCl ₃ ) δ 0.99 (t, J = 7.0Hz, 3H), 3.33 (q, J = 7.0Hz, 2H), 3.71 (t, J = 5.1Hz, 2H), 4.64 (t, J = 5.1Hz, 2H), 7.00-7.10 (m, 4H), 7.13 (d, J = 7.1Hz, 1H), 7.66 (d, J = 10.3Hz, 1H), 10.04 (s, 1H).

Example 81: N ² -{[1- (2-ethoxyethyl) -5-fluoro-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide

The target product was obtained from the compound obtained in Reference Example 22 by the same method as in Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.07 (t, J = 7.0Hz, 3H), 1.41 (d, J = 7.0Hz, 3H), 3.32 (q, J = 7.0Hz, 1H), 3.37 (q, J = 7.0Hz, 2H), 3.66 (t, J = 5.1Hz, 2H), 4.02 (d, J = 14.7Hz, 1H), 4.11 (d, J = 14.7Hz, 1H), 4.17-4.32 (m, 2H ), 5.38 (brs, 1H), 6.90-7.05 (m, 5H), 7.16 (brs, 1H), 7.52 (d, J = 12.1Hz, 1H).

Reference Example 23:

The desired product was obtained from 2,4-difluoronitrobenzene, 4-amino- (1-tert-butoxycarbonyl) piperidine and 4-fluorophenol in the same manner as in Reference Examples 1 to 4.
¹ H-NMR (CDCl ₃ ) δ 1.48 (s, 9H), 1.91-1.95 (m, 2H), 2.22-2.37 (m, 2H), 2.76-2.93 (m, 2H), 4.30 (br, 2H), 4.60 (m, 1H), 4.86 (s, 2H), 6.86-7.05 (m, 5H), 7.14 (d, J = 2.0Hz, 1H), 7.58 (d, J = 8.8Hz, 1H).

Reference Example 24:

The target product was obtained from the compound obtained in Reference Example 23 by the same method as in Reference Example 5.
¹ H-NMR (CDCl ₃ ) δ 1.48 (s, 9H), 1.89-1.93 (m, 2H), 2.23-2.38 (m, 2H), 2.85-2.94 (m, 2H), 4.33 (br, 2H), 5.63 (m, 1H), 6.99-7.10 (m, 5H), 7.18 (d, J = 2.0Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 10.04 (s, 1H).

Example 82: tert-butyl 4- [2-({[(2S) -1-amino-1-oxopropan-2-yl] amino} methyl) -6- (4-fluorophenoxy) -1H-benzimidazole -1-yl] piperidine-1-carboxylate

The target product was obtained from the compound obtained in Reference Example 24 by the same method as in Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.38 (d, J = 7.0Hz, 3H), 1.48 (s, 9H), 1.86-1.89 (m, 2H), 2.30-2.34 (m, 2H), 2.81-2.89 ( m, 2H), 3.28 (q, J = 7.0Hz, 1H), 4.02 (d, J = 14.7Hz, 1H), 4.10 (d, J = 14.7Hz, 1H), 4.31-4.42 (m, 3H), 6.02 (brs, 1H), 6.87-7.04 (m, 6H), 7.15 (d, J = 2.0Hz, 1H), 7.64 (d, J = 8.8Hz, 1H).

Example ^{83: N 2 - {[6-} (4- fluorophenoxy) -1- (piperidin-4-yl)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

  To a solution of the compound obtained in Example 82 (68 mg, 0.13 mmol) in dichloromethane (1.3 mL) was added trifluoroacetic acid (260 μL), and the mixture was stirred at room temperature for 1 hour. A sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue was purified by silica gel column (ethyl acetate: methanol = 99: 1-80: 20) to obtain the desired product (38 mg, 71%).

¹ H-NMR (CDCl ₃ ) δ 1.41 (d, J = 7.0 Hz, 3H), 1.86-1.89 (m, 2H), 2.26-2.40 (m, 2H), 2.72-2.81 (m, 2H), 3.26- 3.33 (m, 3H), 4.02 (d, J = 14.7Hz, 1H), 4.10 (d, J = 14.7Hz, 1H), 4.30 (m, 1H), 5.89 (brs, 1H), 6.89-7.07 (m , 6H), 7.33 (d, J = 2.0Hz, 1H), 7.65 (d, J = 8.8Hz, 1H).

Reference Example 25:

  To a solution of the compound obtained in Reference Example 24 (300 mg, 0.68 mmol) in dichloromethane (6.8 mL) was added trifluoroacetic acid (1.4 mL), and the mixture was stirred at room temperature for 1 hour. A sodium hydroxide aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (6.8 mL), triethylamine (142 μL, 1.02 mmol) and isopropyl isocyanate (100 μL, 1.02 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate. The residue was purified by silica gel column (chloroform: methanol = 99: 1 to 85:15) to obtain the desired product (280 mg, 97%).

¹ H-NMR (CDCl ₃ ) δ 1.18 (d, J = 6.6Hz, 6H), 1.92-1.97 (m, 2H), 2.28-2.42 (m, 2H), 2.91-3.01 (m, 2H), 4.01 ( m, 1H), 4.12-4.17 (m, 2H), 4.33 (m, 1H), 5.65 (m, 1H), 6.97-7.10 (m, 5H), 7.20 (d, J = 2.0Hz, 1H), 7.86 (d, J = 8.8Hz, 1H), 10.04 (s, 1H).

Example 84: 4- [2-({[(2S) -1-amino-1-oxopropan-2-yl] amino} methyl) -6- (4-fluorophenoxy) -1H-benzimidazole-1- Yl] -N- (propan-2-yl) piperidine-1-carboxamide

The target product was obtained from the compound obtained in Reference Example 25 by the same method as in Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.17 (d, J = 6.6Hz, 6H), 1.38 (d, J = 7.0Hz, 3H), 1.90-1.92 (m, 2H), 2.30-2.40 (m, 2H) , 2.87-2.94 (m, 2H), 3.27 (q, J = 7.0Hz, 1H), 3.93-4.18 (m, 5H), 4.36-4.45 (m, 2H), 5.73 (brs, 1H), 6.89-7.03 (m, 6H), 7.16 (d, J = 2.0Hz, 1H), 7.65 (d, J = 8.8Hz, 1H).

Example ^{85: N 2 - {[1-} (1- acetyl-piperidin-4-yl) -6- (4-fluorophenoxy)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

The target product was obtained from the compound obtained in Reference Example 24 and acetyl chloride by the same method as in Reference Example 25 and Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.38 (d, J = 7.0 Hz, 3H), 1.89-2.46 (m, 3H), 2.16 (s, 3H), 2.67 (m, 1H), 3.18-3.32 (m, 2H), 3.65 (m, 1H), 3.99-4.13 (m, 3H), 4.52 (m, 1H), 4.89 (m, 1H), 5.85 (brs, 1H), 6.88-7.05 (m, 6H), 7.11 (d, J = 2.0Hz, 1H), 7.65 (d, J = 8.8Hz, 1H).

Example 86: N ² -({6- (4-fluorophenoxy) -1- [1- (methylsulfonyl) piperidin-4-yl] -1H-benzimidazol-2-yl} methyl) -L-alaninamide

From the compound obtained in Reference Example 24 and methanesulfonyl chloride, the desired product was obtained in the same manner as in Reference Example 25 and Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.37 (d, J = 6.8Hz, 3H), 2.00-2.16 (m, 3H), 2.48-2.61 (m, 2H), 2.88 (m, 1H), 2.86 (s, 3H), 3.25 (q, J = 6.8Hz, 1H), 3.99-4.16 (m, 4H), 4.46 (m, 1H), 5.87 (brs, 1H), 6.81 (brs, 1H), 6.89-7.05 (m , 5H), 7.21 (d, J = 2.0Hz, 1H), 7.65 (d, J = 8.8Hz, 1H).

Reference Example 26:

  To a solution of the compound obtained in Reference Example 7 (2.28 g, 6.9 mmol) in tetrahydrofuran (70 mL), (L) -alanine ethyl ester hydrochloride (2.15 g, 14 mmol), triethylamine (1.95 ml, 14 mmol), sodium sulfate (10 g ) Was added and stirred at room temperature. After stirring for 1 hour, sodium cyanoborohydride (503 mg, 8 mmol) was added and stirred for 4 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (chloroform: methanol = 100: 0 to 95: 5) to obtain the desired product (1.78 g, 60%).

¹ H-NMR (CDCl ₃ ) δ 1.08 (t, J = 7.0Hz, 3H), 1.28 (t, J = 7.1Hz, 3H), 1.35 (d, J = 7.0 Hz, 3H), 3.38 (q, J = 7.0Hz, 2H), 3.48 (q, J = 7.1Hz, 1H), 3.70 (t, J = 5.3Hz, 2H), 4.02 (d, J = 13.9Hz, 1H), 4.10-4.23 (m, 3H ), 4.31-4.42 (m, 2H), 6.90-7.05 (m, 6H), 7.66 (d, J = 8.6Hz, 1H).

Reference Example 27:

  Di-t-butyl dicarbonate (1.64 g, 7.5 mmol) was added to a solution of the compound obtained in Reference Example 26 (2.79 g, 6.5 mmol) in acetonitrile (65 mL), and the mixture was added at 60 ° C. for 3 hours and at 100 ° C. for 3 hours. Stir with heating. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified with a silica gel column (hexane: ethyl acetate = 100: 0 to 70:30) to obtain the desired product (2.24 g, 65%).

¹ H-NMR (CDCl ₃ ) δ 1.00-1.18 (m, 6H), 1.40 (d, J = 7.1Hz, 3H), 1.44 (s, 9H), 3.38 (q, J = 7.0Hz, 2H), 3.68 (t, J = 5.9Hz, 2H), 3.86-4.12 (m, 2H), 4.19-4.55 (m, 3H), 4.75 (d, J = 15.4Hz, 1H), 4.98 (d, J = 15.4Hz, 1H), 6.90-7.08 (m, 6H), 7.64 (d, J = 8.8Hz, 1H).

Reference Example 28:

  To a solution of the compound obtained in Reference Example 27 (2.24 g, 4.2 mmol) in ethanol (40 mL) was added 2 mol / L aqueous sodium hydroxide solution (4.2 ml, 8.4 mmol) in an ice bath. After stirring for 30 minutes under the same conditions, water was added to the reaction solution, and the aqueous layer was washed with ether. The aqueous layer was adjusted to pH = 4 with 2 mol / L hydrochloric acid and extracted with chloroform. The organic layer was extracted, washed with saturated brine, and dried over sodium sulfate to obtain the desired product (2.02 g, 96%).

¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 1.49 (s, 9H), 1.55 (d, J = 7.2Hz, 3H), 3.30-3.50 (m, 2H), 3.63 -3.75 (m, 2H), 3.90 (brs, 1H), 4.13-4.29 (m, 2H), 4.54 (brs, 1H), 5.27 (brs, 1H), 6.91-7.08 (m, 6H), 7.63 (d , J = 8.6Hz, 1H).

Example ^{87: N 2 - {[1-} (2- ethoxyethyl) -6- (4-fluorophenoxy)-1H-benzimidazol-2-yl] methyl}-N-(2-hydroxy-2-methylpropyl ) -L-Alaninamide

  To a solution of the compound obtained in Reference Example 28 (53 mg, 0.1 mmol) in dichloromethane (2 mL), 1-amino-2-methylpropan-2-ol (18 mg, 0.2 mmol), PyBOP [registered trademark, benzotriazole-1- Ir-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate (benzotriazol-1-yl-oxy-tris (pyrrolidino) phosphonium hexafluorophosphate)] (52 mg, 0.1 mmol) was added and stirred at room temperature. After 16 hours, a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (chloroform: methanol = 100: 0 to 98: 2) to obtain the desired product (51 mg, 89%). The residue was dissolved in ethyl acetate (1 mL), 4 mol / L hydrogen chloride in ethyl acetate (1 mL, 4 mmol) was added, and the mixture was stirred at room temperature. After 14 hours, a 2 mol / L aqueous sodium hydroxide solution was added to the residue obtained by concentration under reduced pressure, and the mixture was extracted with chloroform. The organic layer was extracted, washed with saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (chloroform: methanol = 100: 0 to 95: 5) to obtain the desired product (32 mg, 76%).

¹ H-NMR (CDCl ₃ ) δ 1.10 (t, J = 7.0Hz, 3H), 1.29 (s, 6H), 1.36 (d, J = 6.8Hz, 3H), 3.21 (dd, J = 5.3, 3.6Hz , 1H), 3.29-3.51 (m, 4H), 3.61-3.73 (m, 2H), 3.97 (d, J = 14.3Hz, 1H), 4.11 (d, J = 14.3Hz, 1H), 4.21 (dt, J = 15.3, 4.2Hz, 1H), 4.33 (m, 1H), 6.90-7.07 (m, 6H), 7.68 (dd, J = 8.3, 0.9Hz, 1H), 7.83 (brt, J = 6.0Hz, 1H ).

Examples 88-90:
The compounds of Examples 88 to 90 shown in Table 13 were produced by the methods described in the above Reference Examples and Examples, or methods analogous thereto.

Reference Example 29:

  To a solution of alcohol (500 mg, 1.58 mmol) obtained in the same manner as in Reference Examples 1 to 4 in dichloromethane (16 mL) was added thionyl chloride (342 μL, 4.74 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, dissolved in chloroform, and an aqueous sodium hydroxide solution was added. The mixture was extracted with chloroform, washed with saturated brine, and dried over magnesium sulfate. Concentration under reduced pressure gave the desired product (508 mg, 96%).

¹ H-NMR (CDCl ₃ ) δ 3.27 (s, 3H), 3.67 (t, J = 5.1Hz, 2H), 4.38 (t, J = 5.1Hz, 2H), 4.92 (s, 2H), 6.96-7.06 (m, 6H), 7.58 (d, J = 8.4Hz, 1H).

Example ^{91: N 2 - {[6-} (4- fluorophenoxy) -1- (2-methoxyethyl)-1H-benzimidazol-2-yl] methyl} -2-methyl alaninamide

  To a solution of the compound obtained in Reference Example 29 (300 mg, 0.90 mmol) in acetonitrile (4.5 mL), 2,2-dimethylglycine (138 mg, 1.35 mmol), diisopropylethylamine (321 μL, 1.80 mmol), sodium iodide (135 mg, 0.90 mmol) was added and heated to 50 ° C. After stirring overnight, water was added, the mixture was extracted with chloroform, washed with saturated brine, and dried over magnesium sulfate. The residue was purified by silica gel column (ethyl acetate: methanol = 99: 1-80: 20) to obtain the desired product (169 mg, 47%).

¹ H-NMR (CDCl ₃ ) δ 1.45 (s, 6H), 3.26 (s, 3H), 3.66 (t, J = 5.0Hz, 2H), 4.00 (s, 2H), 4.25 (t, J = 5.0Hz , 2H), 5.57 (brs, 1H), 6.94-7.05 (m, 6H), 7.46 (brs, 1H), 7.67 (m, 1H).

Reference Example 30:

N-chlorosuccinimide (0.95 g, 7.1 mmol) was added to a solution of the compound obtained in Reference Example 10 (0.84 g, 2.8 mmol) in N, N-dimethylformamide (30 mL) and heated to 40 ° C. After stirring overnight, water was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and used as it is in the next reaction.
¹ H-NMR (CDCl ₃ ) δ 1.07 (t, J = 7.0Hz, 3H), 3.39 (q, J = 7.0Hz, 2H), 3.76 (t, J = 5.1Hz, 2H), 4.72 (t, J = 5.1Hz, 2H), 8.01-8.02 (m, 2H), 10.09 (s, 1H).

Reference Example 31:

The target product was obtained from the compound obtained in Reference Example 30 by the same method as in Reference Example 11.
¹ H-NMR (CDCl ₃ ) δ 1.05 (t, J = 7.0Hz, 3H), 3.38 (q, J = 7.0Hz, 2H), 3.77 (t, J = 5.1Hz, 2H), 4.76 (t, J = 5.1Hz, 2H), 7.12-7.20 (m, 3H), 7.40-7.46 (m, 2H), 8.02 (s, 1H), 10.12 (s, 1H).

Example 92: N ² - {[5- chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

The target product was obtained from the compound obtained in Reference Example 31 by the same method as in Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.41 (t, J = 7.0Hz, 3H), 3.32-3.42 (m, 3H), 3.71 (t, J = 5.1Hz , 2H), 4.05 (d, J = 14.6Hz, 1H), 4.14 (d, J = 14.6Hz, 1H), 4.23-4.38 (m, 2H), 5.39 (brs, 1H), 7.11-7.17 (m, 3H), 7.21 (brs, 1H), 7.41-7.45 (m, 2H), 7.83 (s, 1H).

Examples 93-108:
The compounds of Examples 93 to 108 shown in Tables 14 to 16 were produced by the methods described in the above Reference Examples and Examples or a method analogous thereto.

Reference Example 32:

The desired product was obtained from 4-bromo-2,5-difluoronitrobenzene in the same manner as in Reference Example 1.
¹ H-NMR (CDCl ₃ ) δ 1.23 (t, J = 7.0Hz, 3H), 3.43 (q, J = 5.2Hz, 2H), 3.56 (q, J = 7.0Hz, 2H), 3.70 (t, J = 5.2Hz, 2H), 7.11 (d, J = 5.9Hz, 1H), 7.93 (d, J = 8.6Hz, 1H).

Reference Example 33:

From the compound obtained in Reference Example 32, the desired product was obtained in the same manner as in Reference Example 3-2.
¹ H-NMR (CDCl ₃ ) δ 1.21 (t, J = 7.3Hz, 3H), 3.51-3.58 (m, 4H), 3.65 (t, J = 5.1Hz, 2H), 6.49 (d, J = 9.5Hz , 1H), 6.72 (d, J = 6.6Hz, 1H).

Reference Example 34:

The target product was obtained from the compound obtained in Reference Example 33 in the same manner as in Reference Example 4.
¹ H-NMR (CDCl ₃ ) δ 1.12 (t, J = 7.0Hz, 3H), 3.43 (q, J = 7.0Hz, 2H), 3.75 (t, J = 5.0Hz, 2H), 4.38 (t, J = 5.0Hz, 2H), 4.88 (s, 2H), 7.45 (d, J = 8.8Hz, 1H), 7.53 (d, J = 5.9Hz, 1H).

Reference Example 35:

From the compound obtained in Reference Example 34, the desired product was obtained in the same manner as in Reference Example 5.
¹ H-NMR (CDCl ₃ ) δ 1.07 (t, J = 7.0Hz, 3H), 3.40 (q, J = 7.0Hz, 2H), 3.76 (t, J = 5.0Hz, 2H), 4.73 (t, J = 5.0Hz, 2H), 7.63 (d, J = 8.5Hz, 1H), 7.87 (d, J = 6.1Hz, 1H), 10.09 (s, 1H).

Reference Example 36:

From the compound obtained in Reference Example 35, the desired product was obtained in the same manner as in Reference Example 11.
¹ H-NMR (CDCl ₃ ) δ 1.06 (t, J = 7.0Hz, 3H), 3.40 (q, J = 7.0Hz, 2H), 3.78 (t, J = 5.1Hz, 2H), 4.78 (t, J = 5.1Hz, 2H), 7.15-7.27 (m, 2H), 7.54-7.66 (m, 4H), 10.11 (s, 1H).

Example ^{109: N 2 - {[1-} (2- ethoxyethyl) -5-fluoro-6- (4-fluorophenyl)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 36 and (L) -alaninamide hydrochloride.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.40 (d, J = 7.0Hz, 3H), 3.31-3.41 (m, 3H), 3.72 (t, J = 5.0Hz , 2H), 4.04 (d, J = 14.8Hz, 1H), 4.12 (d, J = 14.8Hz, 1H), 4.26-4.38 (m, 2H), 5.82 (brs, 1H), 7.11-7.15 (m, 2H), 7.22 (brs, 1H), 7.27 (d, J = 6.6Hz, 1H), 7.47 (d, J = 10.7Hz, 1H), 7.49-7.53 (m, 2H).

Reference Example 37:

The desired product was obtained from 4-bromo-2-fluoronitrobenzene, ethylamine and 4-fluorophenylboranoic acid in the same manner as in Reference Examples 9-11.
¹ H-NMR (CDCl ₃ ) δ 1.49 (t, J = 7.2Hz, 3H), 4.71 (q, J = 7.2Hz, 2H), 7.18 (t, J = 8.5Hz, 2H), 7.58-7.64 (m , 4H), 7.98 (d, J = 9.3Hz, 1H), 10.12 (s, 1H).

Example 110: N ² -{[1-ethyl-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide

The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 37 and (L) -alaninamide hydrochloride.
¹ H-NMR (CDCl ₃ ) δ 1.42-1.48 (m, 6H), 3.32 (q, J = 7.0Hz, 1H), 4.03 (d, J = 14.8Hz, 1H), 4.11 (d, J = 14.8Hz , 1H), 4.24 (q, J = 7.0Hz, 2H), 5.60 (brs, 1H), 7.12-7.18 (m, 3H), 7.43-7.46 (m, 2H), 7.57-7.62 (m, 2H), 7.77 (m, 1H).

Reference Example 38:

The target product was obtained from 4-bromo-2,5-difluoronitrobenzene in the same manner as in Reference Example 37.
¹ H-NMR (CDCl ₃ ) δ 1.48 (t, J = 7.2Hz, 3H), 4.68 (q, J = 7.2Hz, 2H), 7.14-7.20 (m, 2H), 7.46 (d, J = 6.6Hz , 1H), 7.53-7.59 (m, 2H), 7.67 (d, J = 10.5Hz, 1H), 10.11 (s, 1H).

Example 111: N ² -{[1-ethyl-5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide

The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 38 and (L) -alaninamide hydrochloride.
¹ H-NMR (CDCl ₃ ) δ 1.42-1.46 (m, 6H), 3.31 (q, J = 7.0Hz, 1H), 4.01 (d, J = 14.6Hz, 1H), 4.08 (d, J = 14.6Hz , 1H), 4.20 (q, J = 7.0Hz, 2H), 5.41 (brs, 1H), 7.04 (brs, 1H), 7.13-7.18 (m, 2H), 7.28 (d, J = 6.6Hz, 1H) , 7.49 (d, J = 11.0Hz, 1H), 7.52-7.55 (m, 2H).

Reference Example 39:

Bromine (2.75 g, 17.2 mmol) was added to a chloroform (40 mL) solution of 2-chloro-6-fluoroaniline (2.5 g, 17.2 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into an aqueous sodium thiosulfate solution and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (hexane: ethyl acetate = 9: 1-3: 1) to obtain the desired product (3.21 g, 83%).
¹ H-NMR (CDCl ₃ ) δ 7.07 (dd, J = 10.0, 2.0Hz, 1H), 7.19 (t, J = 2.0Hz, 1H).

Reference Example 40:

A solution of sodium peroxoborate tetrahydrate (11.0 g, 71.5 mmol) in acetic acid (50 mL) was heated to 55 ° C, and a solution of the compound (3.21 g, 14.3 mmol) obtained in Reference Example 39 in acetic acid (30 mL) was added. It was added dropwise over 1 hour. After stirring for 3 hours, the temperature was returned to room temperature and insoluble matters were filtered. The filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. The residue was purified by silica gel column (hexane: ethyl acetate = 90: 10-5: 1) to obtain the desired product (1.30 g, 36%).
¹ H-NMR (CDCl ₃ ) δ 7.39 (dd, J = 8.3, 2.0 Hz, 1H), 7.50 (t, J = 2.0 Hz, 1H).

Reference Example 41:

The target product was obtained from the compound obtained in Reference Example 40 and 4-fluorophenylboronic acid in the same manner as in Reference Examples 9-11.
¹ H-NMR (CDCl ₃ ) δ 1.04 (t, J = 7.0Hz, 3H), 3.38 (q, J = 7.0Hz, 2H), 3.79 (t, J = 5.1Hz, 2H), 4.79 (t, J = 5.1Hz, 2H), 7.12-7.18 (m, 2H), 7.51-7.62 (m, 4H), 10.12 (s, 1H).

Example 112: N ² - {[4- chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 41 and (L) -alaninamide hydrochloride.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.40 (d, J = 7.0Hz, 3H), 3.30-3.41 (m, 3H), 3.74 (t, J = 5.0Hz , 2H), 4.07 (d, J = 14.8Hz, 1H), 4.15 (d, J = 14.8Hz, 1H), 4.30-4.44 (m, 2H), 5.65 (brs, 1H), 7.11-7.16 (m, 2H), 7.27 (brs, 1H), 7.35 (d, J = 1.4Hz, 1H), 7.46 (d, J = 1.4Hz, 1H), 7.53-7.57 (m, 2H).

Reference Example 42:

The target product was obtained from 4-bromo-2-fluoro-5-methylaniline in the same manner as in Reference Example 40.
¹ H-NMR (CDCl ₃ ) δ 2.43 (s, 3H), 7.48 (d, J = 10.0Hz, 1H), 7.93 (d, J = 7.8Hz, 1H).

Reference Example 43:

From the compound obtained in Reference Example 42, the desired product was obtained in the same manner as in Reference Example 41.
¹ H-NMR (CDCl ₃ ) δ 1.05 (t, J = 7.0Hz, 3H), 2.34 (s, 3H), 3.40 (q, J = 7.0Hz, 2H), 3.77 (t, J = 5.4Hz, 2H ), 4.75 (t, J = 5.4Hz, 2H), 7.11-7.16 (m, 2H), 7.29-7.33 (m, 2H), 7.40 (s, 1H), 7.70 (s, 1H), 10.10 (s, 1H).

Example ^{113: N 2 - {[1-} (2- ethoxyethyl) -6- (4-fluorophenyl) -5-methyl -1H- benzimidazol-2-yl] methyl}-L-alaninamide

The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 43 and (L) -alaninamide hydrochloride.
¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.41 (d, J = 6.8Hz, 3H), 2.33 (s, 3H), 3.30-3.42 (m, 3H), 3.71 (t, J = 5.0Hz, 2H), 4.05 (d, J = 14.8Hz, 1H), 4.13 (d, J = 14.8Hz, 1H), 4.22-4.38 (m, 2H), 5.43 (brs, 1H) , 7.09-7.14 (m, 3H), 7.29-7.34 (m, 3H), 7.61 (s, 1H).

Reference Example 44:

The target product was obtained from 4-bromo-2,6-difluoroaniline in the same manner as in Reference Example 40.
¹ H-NMR (CDCl ₃ ) δ 7.28-7.32 (m, 2H).

Reference example 45:

From the compound obtained in Reference Example 44, the desired product was obtained in the same manner as in Reference Example 41.
¹ H-NMR (CDCl ₃ ) δ 1.06 (t, J = 7.0Hz, 3H), 3.41 (q, J = 7.0Hz, 2H), 3.81 (t, J = 5.3Hz, 2H), 4.81 (t, J = 5.3Hz, 2H), 7.15-7.19 (m, 2H), 7.27 (dd, J = 11.0, 1.6Hz, 1H), 7.51 (d, J = 1.6Hz, 1H), 7.57-7.61 (m, 2H) , 10.16 (s, 1H).

Example ^{114: N 2 - {[1-} (2- ethoxyethyl) -4-fluoro-6- (4-fluorophenyl)-1H-benzimidazol-2-yl] methyl}-L-alaninamide

The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 45 and (L) -alaninamide hydrochloride.
¹ H-NMR (CDCl ₃ ) δ 1.11 (t, J = 7.0Hz, 3H), 1.42 (d, J = 6.8Hz, 3H), 3.32-3.45 (m, 3H), 3.77 (t, J = 5.0Hz , 2H), 4.08 (d, J = 14.6Hz, 1H), 4.18 (d, J = 14.6Hz, 1H), 4.31-4.46 (m, 2H), 6.00 (brs, 1H), 7.12-7.29 (m, 5H), 7.52-7.59 (m, 2H).

Reference Example 46:

  The target product was obtained from 4-bromo-6-fluoro-3-trifluoromethylaniline in the same manner as in Reference Example 40.

Reference Example 47:

From the compound obtained in Reference Example 46, the desired product was obtained in the same manner as in Reference Example 41.
¹ H-NMR (CDCl ₃ ) δ 1.03 (t, J = 7.0Hz, 3H), 3.38 (q, J = 7.0Hz, 2H), 3.77 (t, J = 5.1Hz, 2H), 4.78 (t, J = 5.1Hz, 2H), 7.09-7.13 (m, 2H), 7.31-7.35 (m, 2H), 7.53 (s, 1H), 8.32 (s, 1H), 10.16 (s, 1H).

Example ^{115: N 2 - {[1-} (2- ethoxyethyl) -6- (4-fluorophenyl) -5- (trifluoromethyl)-1H-benzimidazol-2-yl] methyl}-L-alanine Amide

  The target product was obtained in the same manner as in Example 2 from the compound obtained in Reference Example 47 and (L) -alaninamide hydrochloride.

¹ H-NMR (CDCl ₃ ) δ 1.09 (t, J = 7.0Hz, 3H), 1.43 (d, J = 7.0Hz, 3H), 3.31-3.42 (m, 3H), 3.71 (t, J = 5.0Hz , 2H), 4.09 (d, J = 15.0Hz, 1H), 4.18 (d, J = 15.0Hz, 1H), 4.27-4.38 (m, 2H), 5.34 (brs, 1H), 7.10 (t, J = 8.7Hz, 2H), 7.13 (brs, 1H), 7.25 (s, 1H), 7.31-7.36 (m, 2H), 8.13 (s, 1H).

Reference Example 48:

The desired product was obtained from 2,5-difluoro-4-bromonitrobenzene, 4-aminotetrahydropyran hydrochloride and 4-fluorophenylboronic acid in the same manner as in Reference Examples 1, 3, 4 and 11.
¹ H-NMR (CDCl ₃ ) δ 1.94 (m, 2H), 2.58 (m, 2H), 3.62 (m, 2H), 4.20 (m, 2H), 4.69 (m, 1H), 4.92 (s, 2H) , 7.12-7.21 (m, 2H), 7.45 (d, 1H, J = 10.6Hz), 7.48-7.57 (m, 3H).

Reference Example 49:

To a solution of the compound (0.82 g, 2.38 mmol) obtained in Reference Example 48 in dichloromethane (20 mL), diisopropylethylamine (2.12 mL, 11.9 mmol) and thionyl chloride (1 mol / L dichloromethane solution) (11.9 mL, 11.9 mmol) were added. added. After heating to reflux for 1 hour, the mixture was cooled to 0 ° C. and water was added. The mixture was neutralized with 2 mol / L aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over sodium sulfate. Concentrated under reduced pressure and used directly in the next reaction.
¹ H-NMR (CDCl ₃ ) δ 1.96-2.05 (m, 2H), 2.55-2.70 (m, 2H), 3.58-3.66 (m, 2H), 4.19-4.24 (m, 2H), 4.61 (m, 1H ), 4.88 (s, 2H), 7.15-7.22 (m, 2H), 7.50-7.57 (m, 4H).

Example 116: N ² - {[5- fluoro-6- (4-fluorophenyl) -1- (tetrahydro -2H- pyran-4-yl)-1H-benzimidazol-2-yl] methyl}-L- Alaninamide

To a solution of the compound (0.16 g, 0.44 mmol) obtained in Reference Example 49 in tetrahydrofuran (5 mL) was added N- (2,4-dimethoxybenzyl) alaninamide (0.12 g, 0.49 mmol), diisopropylethylamine (0.12 mL, 0.66). mmol) and sodium iodide (0.07 g, 0.44 mmol) were added. After heating to reflux for 2 hours, the temperature was returned to room temperature and water was added. The mixture was extracted with chloroform, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. Trifluoroacetic acid (2 mL) was added to the residue and heated to 50 ° C. After stirring for 1 hour, the mixture was cooled to 0 ° C., added with chloroform, neutralized with a 2 mol / L aqueous sodium hydroxide solution, and extracted with chloroform. The extract was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified with a silica gel column (chloroform: methanol = 99: 1 to 85:15) and recrystallized with ethyl acetate-hexane to obtain the desired product (0.09 mg, 50%).
¹ H-NMR (CDCl ₃ ) δ 1.40 (d, J = 7.0Hz, 3H), 1.86-1.89 (m, 2H), 2.49-2.64 (m, 2H), 3.32 (m, 1H), 3.53-3.61 ( m, 2H), 4.11-4.20 (m, 4H), 4.53 (m, 1H), 5.43 (brs, 1H), 7.08 (brs, 1H), 7.12-7.18 (m, 2H), 7.43-7.52 (m, 4H).

Reference Example 50:

The desired product was obtained from 2,4-difluoronitrobenzene, 2-aminoethanol and 4-fluorophenol in the same manner as in Reference Examples 1 to 3.
¹ H-NMR (CDCl ₃ ) δ 3.23 (t, J = 4.8Hz, 2H), 3.84 (t, J = 4.8Hz, 2H), 6.28 (d, J = 7.8Hz, 1H), 6.37 (d, J = 2.4Hz, 1H), 6.66 (d, J = 7.8Hz, 1H), 6.27-6.98 (m, 4H).

Reference Example 51:

To a solution of the compound obtained in Reference Example 50 (2.7 g, 10.5 mmol) in N, N-dimethylformamide (50 mL) was added t-butyl-diphenylsilyl chloride (3.6 mL, 12.6 mmol) and imidazole (1.1 g, 15.8 mmol). And stirred at room temperature. After stirring for 1 hour, water was added and extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and directly used in the next reaction.
¹ H-NMR (CDCl ₃ ) δ 1.05 (s, 9H), 3.16 (t, J = 5.1Hz, 2H), 3.87 (t, J = 5.1Hz, 2H), 6.24-6.28 (m, 2H), 6.65 (d, J = 8.1Hz, 1H), 6.82-6.94 (m, 4H), 7.31-7.43 (m, 6H), 7.62-7.72 (m, 4H).

Reference Example 52:

From the compound obtained in Reference Example 51 and (L) -alaninamide hydrochloride, the target product was obtained in the same manner as in Reference Examples 4 and 5 and Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.02 (s, 9H), 1.45 (d, J = 6.8Hz, 3H), 3.34 (q, J = 6.8Hz, 1H), 3.95 (t, J = 5.4Hz, 2H ), 4.09 (d, J = 14.9Hz, 1H), 4.14 (d, J = 14.9Hz, 1H), 4.23-4.36 (m, 2H), 6.08 (brs, 1H), 6.87-6.93 (m, 3H) , 7.00-7.05 (m, 3H), 7.18 (brs, 1H), 7.30-7.36 (m, 4H), 7.41-7.47 (m, 6H), 7.79 (d, J = 8.8Hz, 1H).

Example 117: N ² -{[6- (4-fluorophenoxy) -1- (2-hydroxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide

Tetrabutylammonium fluoride (1 mol / L tetrahydrofuran solution, 3.0 mL, 3.0 mmol) was added to a THF solution (4 mL) of the compound (1.2 g, 2.0 mmol) obtained in Reference Example 52 and stirred at room temperature. After stirring for 1 hour, water was added and the mixture was extracted with chloroform. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified with a silica gel column (chloroform: methanol = 99: 1 to 85:15) and recrystallized with chloroform-hexane to obtain the desired product (300 mg, 40%).
¹ H-NMR (CDCl ₃ ) δ 1.32 (d, J = 7.0Hz, 3H), 3.33 (q, J = 7.0Hz, 1H), 3.92-3.98 (m, 2H), 4.03 (d, J = 13.6Hz , 1H), 4.08 (d, J = 13.6Hz, 1H), 4.30 (t, J = 4.6Hz, 2H), 5.50 (brs, 1H), 6.78 (brs, 1H), 6.92-7.03 (m, 6H) , 7.64 (d, J = 8.8Hz, 1H).

Reference Example 53:

N-chlorosuccinimide (0.64 g, 4.8 mmol) was added to a solution of the compound obtained in Reference Example 1 (1.0 g, 4.4 mmol) in N, N-dimethylformamide (44 mL) and heated to 40 ° C. After stirring overnight, the temperature was returned to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane: ethyl acetate = 95: 5 to 90:10 to 75:25 to 50:50) to obtain the desired product (0.82 g, 72%).
¹ H-NMR (CDCl ₃ ) δ 1.22 (t, J = 7.0Hz, 3H), 3.41 (q, J = 5.2Hz, 2H), 3.55 (q, J = 7.0Hz, 2H), 3.69 (t, J = 5.2Hz, 2H), 6.62 (d, J = 11.5Hz, 1H), 8.27 (d, J = 7.8Hz, 1H), 8.31 (brs, 1H).

Reference Example 54:

The target product was obtained from the compound obtained in Reference Example 53 by the same method as in Reference Examples 2 to 5.
¹ H-NMR (CDCl ₃ ) δ 0.95 (t, J = 7.0Hz, 3H), 3.29 (q, J = 7.0Hz, 2H), 3.67 (t, J = 5.0Hz, 2H), 4.59 (t, J = 5.0Hz, 2H), 6.96-7.10 (m, 5H), 7.98 (s, 1H), 10.02 (s, 1H).

Example 118: N ² -{[5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide

The target product was obtained from the compound obtained in Reference Example 54 and (L) -alaninamide hydrochloride by the same method as in Example 2.
¹ H-NMR (CDCl ₃ ) δ 1.05 (t, J = 7.0Hz, 3H), 1.40 (d, J = 6.8Hz, 3H), 3.29-3.38 (m, 3H), 3.63 (t, J = 5.0Hz , 2H), 4.01 (d, J = 14.8Hz, 1H), 4.10 (d, J = 14.8Hz, 1H), 4.15-4.28 (m, 2H), 5.68 (brs, 1H), 6.87-6.91 (m, 2H), 6.97-7.02 (m, 3H), 7.16 (brs, 1H), 7.80 (s, 1H).

Examples 119-190:
The compounds of Examples 119 to 190 shown in Tables 17 to 31 were produced by the methods described in the above Reference Examples and Examples, or methods analogous thereto.

Reference Example 55:

  To a solution of the compound (1.4 g, 5.0 mmol) obtained from 2-fluoro-5-bromo-nitrobenzene in the same manner as in Reference Examples 9 and 10 in tetrahydrofuran (30 mL), anhydrous sodium sulfate (3.8 g, 26.8 mmol), triethylamine (2.1 mL, 15.4 mmol) and (L) -alaninamide hydrochloride (1.9 g, 15.2 mmol) were added and stirred at room temperature for 30 minutes. Sodium cyanoborohydride (0.33 g, 5.2 mmol) was added to the reaction solution and stirred at room temperature overnight. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by a silica gel column (dichloromethane: methanol = 99: 1 to 95: 5) to obtain the desired product (0.89 g, 51%).

Reference Example 56:

  To a solution of the compound obtained in Reference Example 55 (0.48 g, 1.3 mmol) in dichloroethane (10 mL), di-tert-butyl dicarbonate (1.4 g, 6.5 mmol) and diisopropylethylamine (0.33 mL, 1.95 mmol) were added. Stir at 14 ° C. for 14 hours. Dichloromethane 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. The residue was purified by a silica gel column (dichloromethane: methanol = 99: 1 to 97: 3) to obtain the desired product (500 mg, 82%).

Reference Example 57:

  To the acetonitrile solution (3: 1, 4 mL) of the compound (50 mg, 0.11 mmol) obtained in Reference Example 56, 4-chlorophenylboranoic acid (34 mg, 0.22 mmol), 3 mol / L aqueous sodium bicarbonate solution (90 μl) and tetrakis ( Triphenylphosphine) palladium (13 mg, 0.00112 mmol) was added, and the mixture was stirred at 85 ° C. for 5 hours under an argon atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the residue for liquid separation. The organic layer was washed with water, dried and concentrated, and the residue was purified with a silica gel column (ethyl acetate only) to obtain the desired product (48 mg, 90%).

Example 191: N ² -{[5- (4-chlorophenyl) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide hydrochloride

  A hydrochloric acid-dioxane solution (3 mL) of the compound obtained in Reference Example 57 (48 mg, 0.10 mmol) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting powder was washed with diethyl ether to obtain the desired product (25 mg, 76%).

Example 192: N ² -{[1- (2-Ethoxyethyl) -5- (4-methoxyphenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide trifluoroacetate

  Trifluoroacetic acid (0.3 mL) was added to a dichloromethane solution (3 mL) of the compound (62 mg, 0.13 mmol) obtained by the same method as in the above Reference Example under ice cooling. After warming to room temperature and stirring for 1 hour, the reaction mixture was concentrated and crystallized from diethyl ether to obtain the desired product (48 mg, 76%).

Examples 193-208:
The compounds shown in Table 32 were produced by the methods described in the above Reference Examples and Examples, or methods analogous thereto.
Compound identification was performed from the LC / MS spectrum and retention time according to any of the following methods.

Analysis condition 1
Detector: LCMS / MS API2000 (Applied Biosystems)
Column: Phenomenex Gemini C18 4.6X50mm, 5μm
Detection wavelength: 220nm, 260nm
Flow rate: 1.2mL / min
Elution solvent composition: A solution: 0.05% TFA aqueous solution, 0.05% HCOOH aqueous solution or 10 mM ammonium acetate aqueous solution, B solution: acetonitrile gradient: 0-0.01min B 10%, 0.01-1.50min B 10% to 30%, 1.50-3.00 min B 30% to 90%, 3.00-4.00min B 90%, 4.00-5.00min B 90% to 10%

Analysis condition 2
Detector: LCMS / MS API2000 (Applied Biosystems)
Column: Phenomenex Gemini C18 4.6X50mm, 5μm
Detection wavelength: 220nm, 260nm
Flow rate: 1mL / min
Elution solvent composition: Liquid A: 0.05% TFA aqueous solution, 0.05% HCOOH aqueous solution or 10 mM ammonium acetate aqueous solution, Liquid B: acetonitrile gradient: 0-0.01min B 5%, 0.01-1.00min B 5%, 1.00-7.00min B 5 % to 50%, 7.00-10.00min B 50% to 90%, 10.00-11.00min B 90%, 11.00-12.00min B 90% to 5%

Reference Example 58:

  Tetrahydrofuran of the compound (1.7 g, 6.9 mmol) obtained in Reference Example 18 in a tetrahydrofuran-methanol-water mixed solution (3: 2: 1, 25 mL) of iron (3.7 g, 66 mmol) and ammonium chloride (1.04 g, 19 mmol). -Methanol-water mixed solution (3: 2: 1, 25 mL) was added dropwise at 70 ° C. After 1.5 hours, the reaction solution was cooled to room temperature and filtered through Celite. The filtrate was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to obtain the desired product (1.32 g, 89%). Used in the next reaction without purification.

Reference Example 59:

  The target product was obtained in the same manner as in Reference Examples 4, 5, 55 and 56.

Reference Example 60:

  To a solution of the compound obtained in Reference Example 59 (60 mg, 0.14 mmol) and 4-methylphenylboronic acid (38 mg, 0.28 mmol) in n-butanol (2 mL), potassium phosphate (60 mg, 0.28 mmol), palladium acetate (3.2 mg, 0.014 mmol) and S-phos (11.6 mg, 0.0038 mmol) were added, and the mixture was stirred at 100 ° C. for 14 hours under an argon atmosphere. After cooling, the reaction solution was filtered through celite and washed with methanol. The filtrate was concentrated, ethyl acetate was added, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated. The residue was purified by silica gel column (ethyl acetate: hexane = 65: 35) to obtain the desired product (43 mg, 52%).

Example ^{209: N 2 - {[3-} (2- ethoxyethyl) -5- (4-methylphenyl) -3H- imidazo [4,5-b] pyridin-2-yl] methyl}-L-alaninamide Hydrochloride

  To a dioxane (1 mL) solution of the compound (34 mg) obtained in Reference Example 60, 4 mol / L hydrochloric acid-dioxane (2 mL) was added under ice cooling. The mixture was warmed to room temperature and stirred for 10 hours. The reaction mixture was concentrated, and the resulting powder was washed with diethyl ether to obtain the desired product (28 mg, 95%).

Examples 210-226:
The compounds shown in Table 33 were produced by the methods described in the above Reference Examples and Examples, or methods analogous thereto.
Compound identification was performed from the LC / MS spectrum and retention time under the same conditions as described above.

Examples 227-237:
In the same manner as in Reference Examples 18 to 20 and Example 79, the compounds of Examples 227 to 237 shown in Table 34 and Table 35 were produced.
Compound identification was performed from the LC / MS spectrum and retention time under the same conditions as described above.

  The compounds shown in Tables 36 to 38 can be produced by the methods described in the above Reference Examples and Examples, or methods analogous thereto.

Test example 1
Inhibition experiment of human SNS gene-expressing cells against TTX-resistant Na channel Human SNS gene-expressing cells were obtained by incorporating the human SNS gene into a Chinese hamster ovary cell (CHO-K1) and stably expressing it, originally CHO-K1 cells Has no TTX-resistant Na channel component, the TTX-resistant Na channel component in human SNS gene-expressing cells is SNS. Therefore, the compound according to the present invention is considered to be an SNS inhibitor. .

1) Construction of human SNS-expressing cells and confirmation of SNS function expression The full length of the human SNSα subunit gene is incorporated into an expression plasmid (pcDNA3.1Zeo (+)) containing the Zeocin resistance gene, and the full length of the Annexin II light chain gene is Neomycin. It was introduced into a resistance gene-containing expression plasmid (pcDNA3.1 (+)). These two genes were simultaneously introduced into CHO-K1 cells using lipofectamine 2000, cultured in F-12 medium containing Neomycin and Zeocin, and both drug-resistant cells, that is, cells into which both genes had been incorporated were selected. . Both of these drug-resistant strains were subjected to limiting dilution twice and the SNS gene-incorporated cells were cloned. The introduction of SNS was confirmed by RT-PCR, and a TTX resistance component responding to Na channel stimulation was detected using a membrane potential sensing fluorescent indicator to confirm the functional expression of SNS.

2) Pharmacological effect of human SNS gene-expressing cells on TTX-resistant Na channel Using the human SNS-expressing cells obtained in 1 above, the SNS inhibitory action of the compound according to the present invention was evaluated. That is, a test compound is added to human SNS-expressing cells in advance, and approximately 30 minutes later, veratridine (50 μM), a Na channel stimulator, is added in the presence of TTX (1 μM), and TTX-resistant Na channels are added. The membrane potential was increased, and the inhibitory effect on the membrane potential increase of the test compound was evaluated.

3) Pharmacological evaluation method The SNS inhibition rate of the test compound was determined by the following formula.
SNS inhibition rate (%) = 100 × [(peak value of veratridine stimulation only without evaluation compound) − (peak value of veratridine stimulation with evaluation compound)] / [(peak value of veratridine stimulation only without evaluation compound)] -(Reference value without stimulation)]

4) Test results As a result of evaluating the inhibitory action (SNS inhibition rate) of human SNS-expressing cells on the TTX-resistant Na channel of the compounds obtained in the examples, it was observed that the compound according to the present invention showed an SNS inhibitory action. It was done. The SNS inhibition rate (%) when the compound concentration is 12.5 μM is shown in Tables 39 to 47.

Production Example 1: Manufacture of tablets
The compound of Example 1 (250 g), corn starch (54 g), carboxymethylcellulose calcium (40 g), crystalline cellulose (50 g) and magnesium stearate (6 g) were mixed and granulated by a conventional method, and beaten at 400 mg per tablet. Lock and make 1000 tablets.

Production Example 2: Preparation of Powder After mixing the compound of Example 1 (500 g), lactose (470 g), hydroxypropylcellulose (25 g) and light anhydrous silicic acid (5 g), a powder is prepared.

  The novel bicyclic heterocyclic compound according to the present invention is an excellent treatment for pathological conditions involving SNS, specifically, diseases such as neuropathic pain, nociceptive pain, dysuria or multiple sclerosis. Can be used as a medicine or prophylactic.

Claims (22)

Following formula (1):

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkyloxy group having 1 to 6 carbon atoms, or a haloalkyloxy group having 1 to 6 carbon atoms. (Wherein R ¹ can be substituted at any substitutable position on the benzene ring or pyridine ring);
L represents a single bond, —O— or —CH ₂ O— (the L can be substituted at any substitutable position on the benzene ring or pyridine ring);
R ² represents a substituted or unsubstituted 6 to 10 membered aryl group or a substituted or unsubstituted 5 to 10 membered aromatic heterocyclic group,
X represents a carbon atom or a nitrogen atom,
R ³ represents a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted alkynyl group having 2 to 6 carbon atoms, a substituted or unsubstituted group. 3 to 8 membered cycloalkyl group, substituted or unsubstituted 4 to 8 membered cycloalkenyl group, substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic group, or substituted or unsubstituted 5 to 10 member Represents an unsaturated aliphatic heterocyclic group of
R ⁴ represents a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3 to 8 membered cycloalkyl group,
R ^5a and R ^5b independently represent a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R ⁴ and R ^5a are bonded to each other, and a nitrogen atom to which R ⁴ is bonded and R ^5a Represents a 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring formed together with the carbon atom to which R is bonded (wherein R ^5b is a hydrogen atom);
R ⁶ and R ⁷ are independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted alkenyl group having 2 to 6 carbon atoms, a substituted or unsubstituted carbon number 2 to 2; 6 alkynyl groups, substituted or unsubstituted 3 to 8 membered cycloalkyl groups, substituted or unsubstituted 4 to 8 membered cycloalkenyl groups, substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic groups Represents a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, a substituted or unsubstituted 6- to 10-membered aryl group, or a substituted or unsubstituted 5- to 10-membered aromatic heterocyclic group R ⁶ and R ⁷ are combined to form a substituted or unsubstituted 4 to 8 membered saturated nitrogen-containing aliphatic heterocyclic ring or a substituted or unsubstituted 5 to 10 member formed together with the nitrogen atom to which they are attached. Of unsaturated nitrogen-containing aliphatic compounds An aromatic ring (the saturated or unsaturated nitrogen-containing aliphatic heterocyclic ring contains at least one nitrogen atom and further contains 1 to 2 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom). Represent. Or a pharmaceutically acceptable salt thereof. Following formula (2):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ , L and X are as defined in claim 1. ] The pharmaceutical which consists of a compound of Claim 1 represented by these, or its pharmaceutically acceptable salt. Following formula (3):

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ^5a , R ^5b , R ⁶ , R ⁷ , L and X are as defined in claim 1. Or a pharmaceutically acceptable salt thereof. Pharmaceutical R ² consists of compounds or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 is substituted or unsubstituted phenyl group. R ³ is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3 to 8 membered cycloalkyl group, a substituted or unsubstituted 4 to 8 membered saturated aliphatic heterocyclic group or a substituted group Alternatively, it is an unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, and a medicament comprising the compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof. R ⁶ and R ⁷ are independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a substituted or unsubstituted 3 to 8 membered cycloalkyl group, a substituted or unsubstituted 4 to 8 member A saturated aliphatic heterocyclic group or a substituted or unsubstituted 5- to 10-membered unsaturated aliphatic heterocyclic group, or formed by combining R ⁶ and R ⁷ together with the nitrogen atom to which they are bonded. Substituted or unsubstituted 4- to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring or substituted or unsubstituted 5- to 10-membered unsaturated nitrogen-containing aliphatic heterocyclic ring (the saturated or unsaturated nitrogen-containing aliphatic group) The heterocyclic ring contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms, and 1 to 3 nitrogen atoms.) The compound according to any one of claims 1 to 5 or a pharmaceutical thereof A pharmaceutical comprising an acceptable salt. Pharmaceutical comprising a salt wherein R ⁴ is a compound or a pharmaceutically acceptable according to any one of claims 1 to 6 is a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms. R ^5a and R ^5b are each independently a hydrogen atom or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof. A medicine consisting of salt.   X is a carbon atom, The pharmaceutical which consists of the compound as described in any one of Claims 1-8, or its pharmaceutically acceptable salt. Pharmaceutical wherein R ¹ comprises a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9 is a hydrogen atom or a halogen atom.   L is a single bond, The pharmaceutical which consists of a compound as described in any one of Claims 1-10, or its pharmaceutically acceptable salt.   L is -O-, The pharmaceutical which consists of the compound as described in any one of Claims 1-10, or its pharmaceutically acceptable salt. L is a pharmaceutical comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 is -CH 2 _O-. N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} glycinamide,
N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -2-methylalaninamide,
N ² -{[1-cyclopropyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-cyclobutyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-chlorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-fluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-fluorophenoxy) -1- (3-methoxypropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (2-chloro-4-fluorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-ethyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (2,4-difluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (2-ethoxyethyl) -5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1-ethyl-5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[1- (3-methoxypropyl) -6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[6- (4-methylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
N ² -{[5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide, or
N ² -{[5-chloro-6- (3,4-difluorophenyl) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide,
Alternatively, a medicament comprising a pharmaceutically acceptable salt thereof. N ² -{[1- (2-Ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl] methyl} -2-methylalaninamide or a pharmaceutically acceptable salt thereof . N ² -{[6- (2-Chloro-4-fluorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide or a pharmaceutically acceptable salt thereof A medicine consisting of N ² A pharmaceutical comprising {-[1-ethyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide or a pharmaceutically acceptable salt thereof. N ² -A pharmaceutical comprising {[1- (3-methoxypropyl) -6- (4-methylphenoxy) -1H-benzimidazol-2-yl] methyl} -L-alaninamide or a pharmaceutically acceptable salt thereof. N ² -{[6- (4-Methylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-2-yl] methyl} -L-alaninamide or a pharmaceutically acceptable salt thereof A medicine consisting of salt. A sensory nerve-specific Na channel (SNS) inhibitor comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof as an active ingredient. The sensory nerve-specific Na channel (SNS) inhibitor according to claim 20 , which is a therapeutic agent or a preventive agent for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.