HK1163676B

HK1163676B - Bicyclic heterocyclic compound

Info

Publication number: HK1163676B
Application number: HK12104295.0A
Authority: HK
Inventors: 坪井克宪; 山井悠介; 渡边仁; 木下博纪
Original assignee: 大日本住友制药株式会社
Priority date: 2008-12-26
Filing date: 2009-12-25
Publication date: 2015-07-31

Description

Bicyclic heterocyclic compound

Technical Field

The present invention relates to a drug for the treatment or prevention of a pathology in general involving SNS (sensory neuron-specific sodium channel), which comprises a novel compound having a benzimidazole or imidazopyridine skeleton as a bicyclic heterocycle, or a pharmaceutically acceptable salt thereof, as an active ingredient. In particular, the present invention relates to a drug for the treatment or prevention of diseases (such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis, etc.).

Background

In 1952, Hodgkin and Huxley showed that the main body of neural activity was Na channels, after which Na channel blockers have been developed as antiarrhythmics or local anesthetics. In 1961, lidocaine (which is one of Na channel blockers) was found to provide an analgesic effect, and its clinical use as an analgesic was started. However, since Na channels are also present in non-neural tissues such as muscle, heart, etc., side effects caused by systemic administration still become problematic.

With the progress of molecular biology, Na channel subtypes have been successively elucidated, and it is now known that pore-forming Na channel α subunits include 10 kinds. A sensory neuron-specific sodium channel (sensory nerve-specific Na channel), i.e., SNS, is one of such Na channel α subunits, and is a tetrodotoxin (TTX) -resistant Na channel located in small-diameter cells (C fibers) of dorsal root ganglia (involved in nerve perception), also referred to as SCN10A, PN3, or nav1.8 (non-patent documents 1, 2). It has been reported that SNS knockout mice are insensitive to mechanical stimuli and administration of antisense drugs to SNS to neuropathic pain or inflammatory pain models attenuates hypersensitivity and abnormal perception.

Therefore, SNS inhibitors are considered to provide therapeutic or prophylactic agents that exhibit analgesic effects on diseases such as neuropathic pain, nociceptive pain, and the like, each involving C fibers, accompanied by pain, paralysis, burning sensation, dull pain, and the like. In addition, since SNS is not expressed in non-neural tissues and the central nervous system, a drug that selectively inhibits SNS is considered to be a drug that does not have side effects caused by non-neural tissues or the central nervous system.

Furthermore, in dysuria, frequent urination (which is the main symptom) has been shown to be caused by overactivation of C fibers; in other words, dysfunction of afferent sensory nerve pathways from the lower urinary tract is associated with overactive bladder and bladder pain, and inhibition of C-fiber sensory nerves from the bladder is effective for this symptom (non-patent document 3). Therefore, a drug that inhibits SNS mainly causing the neural activity of C fiber is expected to be a therapeutic or prophylactic drug for dysuria, which has a novel point of action.

On the other hand, a recent report has revealed that SNS found only in C fibers is ectopically expressed in cerebellar purkinje cells of multiple sclerosis patients, and is involved in the occurrence of abnormal discharge patterns (figure pattern) in the cerebellum (non-patent document 4). Thus, the SNS inhibitor is expected to be the first therapeutic or prophylactic agent for the induction of symptoms (such as motor ataxia in multiple sclerosis and the like) caused by abnormal discharge (abnormal ringing) associated with SNS expression in cerebellar neurons.

The actual treatment state of the above-mentioned diseases in clinical practice will be described below.

(1) Neuropathic pain

Neuropathic pain refers to pain that includes spontaneous pain resulting from nerve injury or nerve stimulation, as well as chronic pain, even when trauma is absent or tissue inflammation is absent after complete recovery. Examples thereof include neuralgia after lumbar surgery, diabetic neuropathy, neuralgia after herpes zoster, reflex sympathetic dystrophy, phantom limb pain, spinal cord injury, late cancer pain and prolonged postoperative pain. NSAIDS (non-steroidal anti-inflammatory drugs) such as aspirin and the like are completely ineffective against neuropathic pain, while opioids such as morphine and the like have problems in the induction of drug resistance and psychological symptoms.

Currently, the only drug on the market that is considered to be effective for neuropathic pain is the pulse rhythm (mexiletine) that is suitable for diabetic neuropathy. Since pulse-law is not selective for Na channels, although it provides analgesic effects, side effects are feared and administration at high doses has been reported to be infeasible. Some other drugs are used clinically as adjuvants. Examples include antidepressants (sulpiride, cloperazolone, fluvoxatine, milnacipran), adrenergic agonists (clonidine, dexmedetomidine), NMDA receptor antagonists (ketamine hydrochloride, dextromethorphan), anxiolytics (diazepam, chlordiazepam, etizolam, hydroxyzine hydrochloride), anticonvulsants (carbamazepine, diphenylhydantoin, sodium valproate, zonisamide), calcium antagonists (nifedipine, verapamil hydrochloride, lomerizine hydrochloride), and the like, all of which are used as adjuvants. From the above, a therapeutic drug which is free from side effects derived from non-nerve tissues or the central nervous system and is specifically effective for pain is desired.

(2) Nociceptive pain

Nociceptive pain refers to pain caused by activation of nociceptors (a δ, C fibers) due to mechanical, hyperthermic, or chemical toxic stimuli, due to tissue trauma, etc. Nociceptors are sensitized by endogenous chemical stimuli (pain substances) such as 5-hydroxytryptamine, substance P, bradykinin, prostaglandins and histamine. Examples of nociceptive pain include lumbago, abdominal pain, and pain due to rheumatoid arthritis or osteoarthritis. In clinical practice, NSAIDS (acetylsalicylic acid, acetaminophen, diclofenac, indomethacin, moxezolidin, flurbiprofen, loxoprofen sodium, ampiroxicam), steroids (prednisolone, methylprednisolone, dexamethasone, betamethasone), PGE (PGE) are used₁(prostaglandin E1) (alprostadil, lipoalprostadil, limaprost) and PGI2 (beraprost sodium).

(3) Dysuria (dysuria)

Dysuria is a disease mainly manifested as frequent urination, enuresis, feeling of residual urine, and dysuria as main symptoms. Currently, the primary drug treatment for overactive bladder uses inhibitors of the muscarinic receptors that inhibit the parasympathetic nerve channels of the bladder. However, its limitations are also clear. Capsaicin and resinifera toxin (resinifera) which are capsaicin receptor stimulators have been reported to specifically act on C fibers to inhibit their function. However, no drug that acts on SNS localized to C fibers has been found.

(4) Multiple sclerosis

Multiple sclerosis is a demyelinating disease that exhibits discrete foci of demyelination among white matter of the central nervous system, with various old and new lesions. The injury is more common in the lateral ventricular periphery, optic nerve, brainstem, spinal cord, etc. white matter. Histologically, myelin sheaths are destroyed but axons and nerve cells are not damaged. As clinical symptoms, symptoms such as optic neuritis, double vision, eye movement impairment such as nystagmus, spastic paralysis, painful episodes of tonic convulsions, Lhermitte syndrome, motor ataxia, language disorders, bladder rectal abnormalities, and the like, appear in different combinations. The etiology is unknown, although the theory of autoimmune disease, the theory of infection, etc. is proposed. Currently, effective prophylactic or therapeutic drugs for multiple sclerosis are highly desirable.

The latter-mentioned patent document 1 relates to a selective modulator of CRF1 receptor and specifically describes a compound represented by the following general formula (a) (example 5, k). The compounds included in this patent document are characterized by having an amide bond in a methylene group on the imidazole ring, and are different from the compounds of the present invention having an amino group in a methylene group on the imidazole ring. In addition, patent document 1 does not contain a description at all suggesting the present invention.

[ solution 1]

The latter-mentioned patent document 2 relates to Rho kinase inhibitors, and specifically describes a compound represented by the following general formula (B) (example 321). The compounds included in this patent document have no substituent on the nitrogen atom of the imidazole ring, and are different from the compounds of the present invention which must have such a substituent. In addition, patent document 2 does not contain a description at all that suggests the present invention.

[ solution 2]

Patent document 1: WO 02/28839

Patent document 2: WO 2009/79011

Non-patent document 1: nature 379: 257, 1996

Non-patent document 2: pain 78: 107, 1998

Non-patent document 3: urology 57: 116, 2001

Non-patent document 4: brain Research 959: 235, 2003.

Disclosure of Invention

The problem of the present invention is to provide a drug for the prophylaxis or treatment of a pathology relating generally to SNS, specifically, a disease such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis, or the like.

The present inventors have made intensive studies in an attempt to solve the above-mentioned problems and found that a bicyclic compound having an imidazole ring or a pharmaceutically acceptable salt thereof inhibits TTX-resistant Na channel in human SNS gene-expressing cells, i.e., has SNS inhibitory activity and is useful as a therapeutic or prophylactic agent for diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis, etc., thereby completing the present invention.

Accordingly, the present invention provides the following.

A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof (hereinafter sometimes referred to as "the compound of the present invention"):

a compound represented by the formula:

[ solution 3]

Wherein

R¹Is 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 alkoxy group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms (R)¹Can be substituted at any substitutable position on the phenyl or pyridyl ring),

l is a single bond, -O-or-CH₂O- (L can be substituted at any substitutable position on the phenyl or pyridyl ring),

R²is a substituted or unsubstituted 6-to 10-membered aryl group, or a substituted or unsubstituted 5-to 10-membered aromatic heterocyclic group,

x is a carbon atom or a nitrogen atom,

R³is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or 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 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 4-to 8-membered cycloalkenyl group, a substituted or unsubstituted 4-to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5-to 10-membered unsaturated aliphatic heterocyclic group,

R⁴is 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^5aand R^5bEach independently being a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R⁴And R^5aOptionally linked to R⁴The bonded nitrogen atoms together form a 4-to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring (in this case, R^5bIs a hydrogen atom),

R⁶and R⁷Each independently is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl 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 3 to 8-membered cycloalkyl group, a substituted or unsubstituted 4 to 8-membered cycloalkenyl group, a substituted or unsubstituted 4 to 8-membered saturated aliphatic heterocyclic group, 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 R⁶And R⁷Optionally linked to form, together with 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 (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)

(hereinafter sometimes referred to as "compound (1));

[1] a compound of (1), or a pharmaceutically acceptable salt thereof, represented by the following general formula (2):

[ solution 4]

Wherein R is¹，R²，R³，R⁴，R^5a，R^5b，R⁶，R⁷L and X are as in1]The compound (2) as defined in (1);

[1] a compound of (1), or a pharmaceutically acceptable salt thereof, represented by the following general formula (3):

[ solution 5]

Wherein R is¹，R²，R³，R⁴，R^5a，R^5b，R⁶，R⁷L and X are as in [1]]The compound (3) as defined in (1) (hereinafter sometimes referred to as "compound (3)");

[1]-[3]a compound of any one of (1) or a pharmaceutically acceptable salt thereof, wherein R²Is substituted or unsubstituted phenyl;

[1]-[4]a compound of any one of (1) or a pharmaceutically acceptable salt thereof, wherein R³Is 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 or unsubstituted 5 to 10-membered unsaturated aliphatic heterocyclic group;

[1]-[5]a compound of any one of (1) or a pharmaceutically acceptable salt thereof, wherein R⁶And R⁷Each independently is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl 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 or unsubstituted 5-to 10-membered unsaturated aliphatic heterocyclic group, or R⁶And R⁷Optionally linked to form, together with 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 (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))；

[1]-[6]A compound of any one of (1) or a pharmaceutically acceptable salt thereof, wherein R⁴Is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms;

[1]-[7]a compound of any one of (1) or a pharmaceutically acceptable salt thereof, wherein R^5aAnd R^5bEach independently is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms;

[1] - [8] a compound of any one of claims or a pharmaceutically acceptable salt thereof, wherein X is a carbon atom;

[1]-[9]a compound of any one of (1) or a pharmaceutically acceptable salt thereof, wherein R¹Is a hydrogen atom or a halogen atom;

[1] - [10] or a pharmaceutically acceptable salt thereof, wherein L is a single bond;

[1] - [10] a compound of any one of claims or a pharmaceutically acceptable salt thereof, wherein L is-O-;

[1]-[10]a compound of any one of or a pharmaceutically acceptable salt thereof, wherein L is-CH₂O-；

N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]A methyl group of a glycine amide,

N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]Methyl } -2-methyl-alaninamide,

N²- { [ 1-cyclopropyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [ 1-cyclobutyl-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [6- (4-chlorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [6- (4-fluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [6- (4-fluorophenoxy) -1- (3-methoxypropyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [6- (2-chloro-4-fluorophenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [ 1-Ethyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [6- (2, 4-Difluorophenoxy) -1- (2-hydroxy-2-methylpropyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [1- (2-ethoxyethyl) -5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [ 1-Ethyl-5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [1- (3-methoxypropyl) -6- (4-methylphenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [6- (4-Methylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [ 5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide, or

N²- { [ 5-chloro-6- (3, 4-difluorophenyl) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

or a pharmaceutically acceptable salt thereof;

a medicament comprising a compound of any one of [1] to [14] or a pharmaceutically acceptable salt thereof as an active ingredient;

[15] the medicament of (1), which is an agent for the prophylaxis or treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis;

an SNS inhibitor comprising as an active ingredient a compound of any one of [1] to [14], or a pharmaceutically acceptable salt thereof;

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

Effects of the invention

The present invention provides SNS inhibitors comprising novel bicyclic compounds or pharmaceutically acceptable salts thereof. The SNS inhibitor of the present invention is useful as a medicament for the prophylaxis or treatment of a pathology generally involving SNS, and is particularly suitable for patients suffering from neuropathic pain, nociceptive pain, dysuria, multiple sclerosis, and the like.

Detailed Description

In the present specification, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The "alkyl group" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and specific examples thereof include methyl group, ethyl group, propyl group (1-propyl group), isopropyl group (2-propyl 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), pentyl group (1-pentyl group), hexyl group (1-hexyl group), and the like. The alkyl group is preferably an alkyl group having 1 to 4 carbon atoms.

The "haloalkyl group" means a straight-chain or branched alkyl group having 1 to 6 carbon atoms, which is substituted with the same or different 1 to 5 halogen atoms, and specific examples thereof include a trifluoromethyl group, a 2, 2-difluoroethyl group, a 2,2, 2-trifluoroethyl group, a 2-chloroethyl group, a pentafluoroethyl group, a3, 3, 3-trifluoropropyl group and the like. The haloalkyl group is preferably a haloalkyl group having 1 to 4 carbon atoms.

The "alkenyl group" means a straight-chain or branched alkenyl group having 2 to 6 carbon atoms, and specific examples thereof include vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 1-ethylvinyl, 1-methyl-2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 1-hexenyl and the like. The alkenyl group is preferably an alkenyl group having 2 to 4 carbon atoms.

The "alkynyl group" means a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, and specific examples thereof include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 1-methyl-2-propynyl, 3-butynyl, 1-pentynyl, 1-hexynyl and the like. The alkynyl group is preferably an alkynyl group having 2 to 4 carbon atoms.

The "alkoxy group" means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include methoxy group, ethoxy group, propoxy group, 1-methylethoxy group, butoxy group, 1-methylpropoxy group, 2-methylpropoxy group, 1, 1-dimethylethoxy group, pentyloxy group, hexyloxy group and the like. The alkoxy group is preferably an alkoxy group having 1 to 4 carbon atoms.

The "haloalkoxy group" means a straight-chain or branched alkoxy group having 1 to 6 carbon atoms, which is substituted with the same or different 1 to 5 halogen atoms, and specific examples thereof include trifluoromethoxy group, 2, 2-difluoroethoxy group, 2,2, 2-trifluoroethoxy group, 2-chloroethoxy group, pentafluoroethoxy group, 3,3, 3-trifluoropropoxy group and the like. The haloalkoxy group is preferably a haloalkoxy group having 1 to 4 carbon atoms.

The "cycloalkyl group" means a 3-8 membered monocyclic or bicyclic cycloalkyl group, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. The cycloalkyl group is preferably a 4-to 6-membered cycloalkyl group.

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

The "saturated aliphatic heterocyclic group" means a 4-to 8-membered monocyclic or bicyclic saturated aliphatic heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the number of oxygen atoms and sulfur atoms contained in the saturated aliphatic heterocyclic ring is at most 2 each). The position of the heteroatom is not particularly limited as long as the saturated aliphatic heterocyclic group is chemically stable. Specific examples thereof include azetidinyl, pyrrolidinyl, piperidinyl, piperidino (piperidino group), piperazinyl, azepanyl, azocyclooctyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, morpholinyl, morpholino, thiomorpholinyl, 1, 4-dioxanyl, 1,2, 5-thiadiazinyl, 1, 4-oxazeptyl, 1, 4-diazepanyl and the like.

The "unsaturated aliphatic heterocyclic group" means a 5-to 10-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic group containing 1 to 3 double bonds and 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the number of oxygen atoms and sulfur atoms contained in the unsaturated aliphatic heterocyclic group is at most 2 each). The positions of the hetero atom and the double bond are not particularly limited as long as the unsaturated aliphatic heterocyclic group is chemically stable. Specific examples thereof include pyrrolinyl, imidazolinyl, tetrahydroisoquinoline, etc., and 2-pyrrolinyl and 2-imidazolinyl are preferable.

The "saturated nitrogen-containing aliphatic heterocyclic ring" means a 4-to 8-membered monocyclic or bicyclic saturated aliphatic heterocyclic ring containing at least one nitrogen atom and optionally further containing 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (provided that the number of oxygen atoms and sulfur atoms contained in the saturated aliphatic heterocyclic ring is at most 2 each). The position of the heteroatom is not particularly limited as long as the saturated nitrogen-containing aliphatic heterocycle is chemically stable.Specific examples thereof include an azetidine ring, a pyrrolidine ring, an imidazolidine ring, a pyrazolidine ring, a piperidine ring, a piperazine ring, an azepane ring, an azocane ring, a morpholine ring, a thiomorpholine ring,oxazolidine ring, thiazolidine ring, etc.

The "unsaturated nitrogen-containing aliphatic heterocyclic ring" means a 4-to 8-membered monocyclic or bicyclic unsaturated aliphatic heterocyclic ring containing at least one nitrogen atom and optionally further containing 1 to 3 hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom (provided that the number of oxygen atoms and sulfur atoms contained in the unsaturated aliphatic heterocyclic ring is at most 2 each). The position of the heteroatom is not particularly limited as long as the unsaturated nitrogen-containing aliphatic heterocyclic ring is chemically stable. Specific examples thereof include a pyrroline ring, a piperidine ring, an imidazoline ring, a pyrazoline ring,oxazoline rings, thiazoline rings, tetrahydroquinoline rings, tetrahydroisoquinoline rings, and the like.

The "aryl" means 6-10 membered monocyclic or bicyclic aryl, and specific examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like.

The "aromatic heterocyclic group" means a 5-to 10-membered monocyclic or bicyclic aromatic heterocyclic group containing 1 to 4 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (provided that the number of oxygen atoms and sulfur atoms contained in the aromatic heterocyclic group is at most 2 each). The position of the heteroatom is not particularly limited as long as the aromatic heterocyclic group is chemically stable. Specific examples thereof include furyl, thienyl, pyrrolyl,azolyl radical, isoAzolyl, thiazolyl, isothiazolylImidazolyl, pyrazolyl, furazanyl,oxadiazolyl, triazolyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazo [2,1-b ]][1,3]Thiazolyl, and the like.

The "alkylthio group" means a straight-chain or branched alkylthio group having 1 to 6 carbon atoms, and specific examples thereof include methylthio, ethylthio, propylthio, 1-methylethylthio, butylthio, 1-methylpropylthio, 2-methylpropylthio, 1, 1-dimethylethylthio, pentylthio, hexylthio and the like. The alkylthio group is preferably an alkylthio group having 1 to 4 carbon atoms.

Examples of the alkyl group of the "alkylcarbonyl group" include those similar to the above-mentioned alkyl groups. Preferred examples of the alkylcarbonyl group include acetyl, propionyl, butyryl and the like.

The "alkylcarbonyloxy" refers to a group in which an oxygen atom is bonded to the carbonyl carbon of the aforementioned "alkylcarbonyl".

Examples of the alkyl group of the "alkylsulfonyl" include those similar to the above-mentioned "alkyl group". Preferred examples of the alkylsulfonyl group include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group and the like.

Examples of the alkoxy group of the "alkoxycarbonyl group" include those similar to the above-mentioned "alkoxy group". Preferred examples of the alkoxycarbonyl group include a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group and the like.

Examples of the alkyl group of the "amino group optionally substituted with one alkyl group or two alkyl groups which may be the same or different", "carbamoyl group optionally substituted with one alkyl group or two alkyl groups which may be the same or different" and "aminosulfonyl group optionally substituted with one alkyl group or two alkyl groups which may be the same or different" include those similar to the above "alkyl group".

Preferred examples of "amino group optionally substituted with one alkyl group or two alkyl groups which may be the same or different" include methylamino, ethylamino, propylamino, dimethylamino, diethylamino, methylethylamino and the like.

Preferred examples of "carbamoyl group optionally substituted with one alkyl group or two alkyl groups which may be the same or different" include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, methylethylcarbamoyl and the like.

Preferred examples of "aminosulfonyl optionally substituted by one alkyl group or two alkyl groups which may be the same or different" include methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, methylethylaminosulfonyl and the like.

Examples of the "alkoxycarbonyl group" of the "amidino group optionally substituted with one alkoxycarbonyl group or two alkoxycarbonyl groups which may be the same or different" include those similar to the above-mentioned "alkoxycarbonyl group". Preferred examples of "amidino group optionally substituted with one alkoxycarbonyl group or two alkoxycarbonyl groups which may be the same or different" include methoxycarbonylamidino group, ethoxycarbonylamidino group, propoxycarbonylamidino group and the like.

The aryl groups of the "aryloxy", "arylcarbonyl" and "arylsulfonyl" groups are as defined above for "aryl".

The aromatic heterocyclic groups of the "aromatic heterocyclyloxy", "aromatic heterocyclylcarbonyl" and "aromatic heterocyclylsulfonyl" are as defined above for the "aromatic heterocyclic group".

The substituents of the "alkyl", "alkenyl" and "alkynyl" are selected from the following (i) to (v), and a plurality of substituents which may be the same or different may be present:

(i) halogen atom, hydroxyl group, carboxyl group and cyano group;

(ii) substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, and substituted or unsubstituted aminosulfonyl;

(iii) alkoxy, haloalkoxy, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylthio and alkylsulfonyl

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group (optionally substituted with one alkyl group or two alkyl groups which may be the same or different), an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ];

(iv) cycloalkyl, cycloalkenyl, and saturated or unsaturated aliphatic heterocyclic groups

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, an amino group (optionally substituted with one alkyl group or two alkyl groups which may be the same or different), a carbamoyl group (optionally substituted with one alkyl group or two alkyl groups which may be the same or different), an alkoxy group, a haloalkoxy group, an optionally substituted alkoxycarbonyl 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 aromatic heterocyclic group. Examples of the substituent for the alkoxycarbonyl group, the alkylcarbonyl group, the alkylsulfonyl group and the alkyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group and a carbamoyl group. 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ];

(v) aryl, aromatic heterocyclyl, aryloxy, aromatic heterocyclyloxy, arylcarbonyl, aromatic heterocyclylcarbonyl, arylsulfonyl and aromatic heterocyclylsulfonyl

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, 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 alkoxy group and a haloalkoxy group. 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ].

The substituent for the "cycloalkyl group", "cycloalkenyl group", "saturated aliphatic heterocyclic group", "unsaturated aliphatic heterocyclic group", "saturated nitrogen-containing aliphatic heterocyclic ring" and "unsaturated nitrogen-containing aliphatic heterocyclic ring" is one substituent or two or more substituents which are the same or different, and is selected from the following (vi) to (x):

(vi) a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, an oxo group, a thioxo group, and an amidino group optionally substituted by one alkoxycarbonyl group or by two alkoxycarbonyl groups which may be the same or different;

(vii) substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, and substituted or unsubstituted aminosulfonyl;

(viii) alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylthio and alkylsulfonyl

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a carbamoyl group (optionally substituted with one alkyl group or with two alkyl groups which may be the same or different), an alkoxy group (optionally substituted with an alkoxy group and/or a carbamoyl group), a haloalkoxy group, an alkylthio group, an alkoxycarbonyl group, an optionally substituted aryloxy group, an optionally substituted aromatic heterocyclyloxy group, an optionally substituted aryl group, an optionally substituted aromatic heterocyclyl group and an optionally substituted amino group. Examples of the substituent for the aryloxy group, the aromatic heterocyclyloxy 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group. Examples of the substituent for the amino group include an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, an optionally substituted alkylsulfonyl group, and a carbamoyl group optionally substituted with one alkyl group or with two alkyl groups which may be the same or different. Examples of the substituents for the alkyl group, the alkylcarbonyl group, the alkylsulfonyl group and the carbamoyl group include a halogen atom, a hydroxyl group, a carboxyl group, an alkoxy group, a haloalkoxy group and a carbamoyl group ];

(ix) cycloalkyl, cycloalkenyl, and saturated or unsaturated aliphatic heterocyclic groups

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an oxo group, a thioxo group, an amino group (optionally substituted with one alkyl group or with two alkyl groups which may be the same or different), an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, 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 alkoxy group and a haloalkoxy group. 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ];

(x) Aryl, aromatic heterocyclyl, aryloxy, aromatic heterocyclyloxy, arylcarbonyl, aromatic heterocyclylcarbonyl, arylsulfonyl and aromatic heterocyclylsulfonyl

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, a cyano group, a substituted or unsubstituted amino group, a substituted or unsubstituted carbamoyl group, a substituted or unsubstituted sulfamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, 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 alkoxy group and a haloalkoxy group. 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ].

The substituents of said "phenyl", "aryl" and "aromatic heterocyclic group" are 1 to 5 substituents selected from the following (xi) - (xv):

(xi) Halogen atom, hydroxy group, carboxy group, cyano group, nitro group, methylenedioxy group, ethylenedioxy group and- (CH)₂) n- (n is an integer of 3 to 5);

(xii) Substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, and substituted or unsubstituted aminosulfonyl;

(xiii) Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, alkylthio and alkylsulfonyl

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group (optionally substituted with one alkyl group or two alkyl groups which may be the same or different), an optionally substituted alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. Examples of the substituent for the alkoxy 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ];

(xiv) Cycloalkyl, cycloalkenyl, and saturated or unsaturated aliphatic heterocyclic groups

(xv) Aryl, aromatic heterocyclyl, aryloxy, aromatic heterocyclyloxy, arylcarbonyl, aromatic heterocyclylcarbonyl, arylsulfonyl and aromatic heterocyclylsulfonyl

The substituents of said "amino", "carbamoyl" and "aminosulfonyl" are one substituent or two substituents which may be the same or different, and are selected from the following (xvi) to (xviii):

(xvi) Alkyl, haloalkyl, alkenyl, alkynyl, alkylcarbonyl, alkylsulfonyl and alkoxycarbonyl

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group (optionally substituted with one alkyl group or two alkyl groups which may be the same or different), a carbamoyl group, an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a saturated or unsaturated aliphatic heterocyclic group, an optionally substituted aryl group and an optionally substituted aromatic heterocyclic group. 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ];

(xvii) Cycloalkyl, cycloalkenyl, and saturated or unsaturated aliphatic heterocyclic groups

(xviii) Aryl, aromatic heterocyclyl, arylcarbonyl, aromatic heterocyclylcarbonyl, arylsulfonyl and aromatic heterocyclylsulfonyl

[ these groups are optionally substituted with one or more substituents selected from the group consisting of a halogen atom, a hydroxyl group, a carboxyl group, an amino group (optionally substituted with one alkyl group or with two alkyl groups which may be the same or different), a carbamoyl group (optionally substituted with one alkyl group or with two alkyl groups which may be the same or different), a sulfamoyl group (optionally substituted with one alkyl group or with two alkyl groups which may be the same or different), an alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, 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 alkoxy group and a haloalkoxy group. 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 alkoxy group, a haloalkoxy group, an alkoxycarbonyl group, a nitro group, a cyano group and a carbamoyl group ].

In addition, the two substituents of the "amino", "carbamoyl" or "aminosulfonyl" group are optionally linked together with the adjacent nitrogen atom to form a 5-to 10-membered nitrogen-containing aliphatic heterocyclic ring.

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

In the compound of the present invention represented by the general formula (1), each of these groups is preferably as follows.

R¹Is 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 alkoxy group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms, preferably 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, more preferably a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom or a halogen atom, particularly preferably a hydrogen atom. R¹Can be present in any substitutable position of the benzene or pyridine ring.

R¹Specific examples of (b) include a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a propyl group, a trifluoromethyl group and the like. Among them, a hydrogen atom, a fluorine atom and a chlorine atom are preferable, and a hydrogen atom is more preferable.

L is a single bond, -O-or-CH₂O-, preferably a single bond or-O-, more preferably-O-. L can be present in a benzene ring or pyridineAt any substitutable position of the ring. When L is-CH₂O-is, -CH₂O-having an oxygen atom bonded to the benzene or pyridine ring and a methylene chain bonded to R²。

R²Is 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 a substituted or unsubstituted phenyl group.

R²Preferred examples of the substituent of the aryl group or the aromatic heterocyclic group of (1) include a halogen atom, a substituted or unsubstituted alkyl group (preferably an unsubstituted alkyl group having 1 to 6 carbon atoms), a haloalkyl group (preferably a haloalkyl group having 1 to 6 carbon atoms), an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a haloalkoxy group (preferably a haloalkoxy group having 1 to 6 carbon atoms), a cyano group and the like, specifically, 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, a cyano group and the like. Among them, a fluorine atom, a methyl group and a trifluoromethoxy group are preferable.

R²Specific examples of the substituted or unsubstituted aryl group of (a) include phenyl groups and phenyl groups substituted with the preferred substituents of the above aryl groups, and the like.

R²Specific examples of the aromatic heterocyclic group of (a) include pyridyl, furyl, thienyl, pyrimidinyl, pyrazinyl and the like. Among them, pyridyl and furyl groups are preferable.

R³Is 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 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 4-to 8-membered cycloalkenyl group, a substituted or unsubstituted 4-to 8-membered saturated aliphatic heterocyclic group, or a substituted or unsubstituted 5-to 10-membered 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-membered saturated aliphatic heterocyclic groupA 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, a substituted or unsubstituted 3-to 8-membered cycloalkyl group, or a substituted or unsubstituted 4-to 8-membered saturated aliphatic heterocyclic group, still more preferably a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or a substituted or unsubstituted 3-to 8-membered cycloalkyl group.

R³Preferable examples of the substituent of the alkyl group of (b) include a hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a 4-to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.

R³Preferable examples of the substituent of the saturated aliphatic heterocyclic group of (1) include alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylcarbamoyl (the alkyl moiety preferably has 1 to 6 carbon atoms) and the like, specifically, acetyl, tert-butoxycarbonyl, methylsulfonyl, isopropylcarbamoyl and the like.

R³Specific examples of (B) include ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, methoxyethyl, ethoxyethyl, isopropoxyethyl, hydroxyethyl, methoxypropyl, ethoxypropyl, hydroxypropyl, tetrahydropyranyl, tetrahydrofuranyl, 2, 2-dimethyl-2-hydroxyethyl, tetrahydropyranylmethyl, tetrahydrofuranylmethyl, 4-piperidinyl, 1- (tert-butoxycarbonyl) piperidin-4-yl, 1-isopropylcarbamoylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl and the like. R³More preferred is cyclobutyl, 2-ethoxyethyl or ethyl.

R⁴Is 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 a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom.

R⁴Preferred examples of the substituent of the alkyl group and the cycloalkyl group include halogen atomsA hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a 4-to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a fluorine atom, a chlorine atom, a hydroxyl group, a methoxy group, an ethoxy group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.

R⁴Specific examples of (b) include a hydrogen atom, a methyl group, a cyclopropyl group and the like. Among them, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is more preferable.

R^5aAnd R^5bEach independently is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, or R⁴And R^5aOptionally linked to R⁴The bonded nitrogen atoms together form a 4-to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring (in this case, R^5bIs a hydrogen atom), preferably, each independently is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, R^5aOr R^5bPreferable examples of the substituent of the alkyl group of (b) include a halogen atom, a hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a 4-to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a fluorine atom, a chlorine atom, a hydroxyl group, a methoxy group, an ethoxy group, a tetrahydrofuranyl group, a tetrahydropyranyl group and the like.

R^5aAnd R^5bSpecific examples of (2) each independently include a hydrogen atom, a methyl group, an ethyl group and an isopropyl group (preferably R)^5aIs a hydrogen atom, a methyl, ethyl or isopropyl group, and R^5bIs methyl, ethyl or isopropyl). Among them, a hydrogen atom and a methyl group are preferable (preferably R)^5aIs a hydrogen atom, and R^5bIs methyl).

When R is^5aAnd R^5bWhen different from each other, the carbon atoms to which they are attached are asymmetric carbon atoms, and the steric configuration is preferably an S-configuration from the viewpoint of easy availability of the starting materials.

By R being bound to each other⁴And R^5aAnd R⁴Specific examples of the 4-to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring formed with the bonded nitrogen atoms include nitrogen heterocyclesButane ring, pyrrolidine ring, piperidine ring and the like. Among them, a pyrrolidine ring is preferable.

R⁶And R⁷Each independently is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl 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 3-to 8-membered cycloalkyl group, a substituted or unsubstituted 4-to 8-membered cycloalkenyl group, a substituted or unsubstituted 4-to 8-membered saturated aliphatic heterocyclic group, 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 R⁶And R⁷Optionally joined together with the nitrogen atom to which they are bonded 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 unsaturated 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), preferably each independently a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl 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 or unsubstituted 5-to 10-membered unsaturated aliphatic heterocyclic group, more preferably each independently a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, more preferably a hydrogen atom.

R⁶Or R⁷Preferable examples of the substituent of the alkyl group of (b) include a hydroxyl group, an alkoxy group (preferably an alkoxy group having 1 to 6 carbon atoms), a 4-to 8-membered saturated aliphatic heterocyclic group and the like, specifically, a hydroxyl group, a methoxy group, an ethoxy group, a tetrahydrofuryl group, a tetrahydropyranyl group, a pyrrolidinyl group, a piperidinyl group, a piperidino group, a piperazinyl group, a morpholino group and the like. R⁶Or R⁷Specific examples of the substituted alkyl group of (1) include methoxyethyl, 2, 2-dimethyl-2-hydroxyethyl, morpholinoethyl and the like.

R⁶Or R⁷Is superior toSpecific examples of the substituents include a hydrogen atom, methyl group, ethyl group, isopropyl group and the like. Among them, a hydrogen atom and a methyl group are preferable, and a hydrogen atom is more preferable.

By R being bound to each other⁶And R⁷The substituted or unsubstituted 4-to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring and the substituted or unsubstituted 5-to 10-membered unsaturated nitrogen-containing aliphatic heterocyclic ring which are formed together with the nitrogen atom to which they are bonded include a morpholine ring, a pyrrolidine ring, a piperidine ring, a piperazine ring and the like. Among them, morpholine ring and piperazine ring are preferable.

Preferred examples of the substituent of the above-mentioned saturated nitrogen-containing aliphatic heterocyclic ring and 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. Among them, oxo, cyano and trifluoromethyl are preferable.

Preferred examples of the compound (1) include the following compounds and pharmaceutically acceptable salts thereof.

Preferred embodiments thereof include the following compounds:

R¹is a hydrogen atom or a halogen atom,

l is a single bond or-O-,

R²is a substituted or unsubstituted phenyl group, which is,

x is a carbon atom and is a hydrogen atom,

R³is 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 or unsubstituted 5-to 10-membered unsaturated aliphatic heterocyclic group,

R⁴is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms,

R^5aand R^5bEach independently is a hydrogen atom, or a substituted or unsubstituted alkyl group having 1 to 6 carbon atomsAnd are and

R⁶and R⁷Each independently is a hydrogen atom, a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms, a haloalkyl 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 or unsubstituted 5-to 10-membered unsaturated aliphatic heterocyclic group, or

R⁶And R⁷Optionally together with the nitrogen atom to which they are bonded, form 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 (which contains 0 to 2 oxygen atoms, 0 to 2 sulfur atoms, and 1 to 3 nitrogen atoms).

Other preferred embodiments thereof include the following compounds:

R¹is a hydrogen atom, a halogen atom or an alkyl group having 1 to 6 carbon atoms,

l is a single bond or-O-,

R²is a substituted or unsubstituted 6-to 10-membered aryl group (the substituent is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms, more preferably a fluorine atom, a methyl group or a trifluoromethoxy group),

x is a carbon atom and is a hydrogen atom,

R³is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (the substituent is preferably a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a 4 to 8-membered saturated aliphatic heterocyclic group, more preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuranyl group or a tetrahydropyranyl group), a substituted or unsubstituted 3 to 8-membered cycloalkyl group (preferably an unsubstituted 3 to 8-membered cycloalkyl 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 unsaturated aliphatic heterocyclic group (preferably an unsubstituted 5 to 10-membered unsaturated aliphatic heterocyclic group),

R⁴is 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^5aand R^5bEach 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), and

R⁶and R⁷Each 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).

Among them, preferred are the compounds wherein

R¹Is a hydrogen atom or a halogen atom,

l is a single bond or-O-,

R²is a substituted or unsubstituted phenyl group (the substituent is preferably a halogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkoxy group having 1 to 6 carbon atoms, more preferably a fluorine atom, a methyl group or a trifluoromethoxy group),

x is a carbon atom and is a hydrogen atom,

R³is a substituted or unsubstituted alkyl group having 1 to 6 carbon atoms (the substituent is preferably a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a 4-to 8-membered saturated aliphatic heterocyclic group, more preferably a hydroxyl group, a methoxy group, an ethoxy group, an isopropoxy group, a tetrahydrofuranyl group or a tetrahydropyranyl group), or a substituted or unsubstituted 3-to 8-membered cycloalkyl group (preferably an unsubstituted 3-to 8-membered cycloalkyl group),

R⁴is a hydrogen atom or a methyl group,

R^5aand R^5bEach independently is a hydrogen atom, methyl, ethyl or isopropyl (preferably R)^5aIs a hydrogen atom, a methyl, ethyl or isopropyl group, and R^5bIs methyl, ethyl or isopropyl), and

R⁶and R⁷Is a hydrogen atom, and is a hydrogen atom,

and

more preferred are the compounds wherein

R¹Is a hydrogen atom, and is a hydrogen atom,

l is-O-,

x is a carbon atom and is a hydrogen atom,

R⁴is a hydrogen atom or a methyl group,

R^5aand R^5bEach independently is a hydrogen atom or a methyl group (preferably R)^5aIs a hydrogen atom, and R^5bIs methyl), and

R⁶and R⁷Is a hydrogen atom.

The compound of the present invention is preferably compound (2) or compound (3) or a pharmaceutically acceptable salt thereof, more preferably compound (2) or a pharmaceutically acceptable salt thereof.

Preferred specific examples of the compound include the following compounds and pharmaceutically acceptable salts thereof.

Specific examples of the compound include compounds wherein R is¹Is that

(1) A hydrogen atom, and a nitrogen atom,

(2) a halogen atom (preferably a fluorine atom, a chlorine atom),

(3) C_1-6alkyl (preferably methyl) or

(4) C_1-6A haloalkyl group (preferably a trifluoromethyl group),

l is

(1) A single bond, a double bond,

(2) -O-or

(3)-CH₂O-，

R²Is that

(1) C_6-10Aryl radical (the radical C)_6-10Aryl optionally with C_3-6Cycloalkane fused) (preferably phenyl, indanyl, more preferably phenyl) optionally substituted with 1-3 substituents selected from:

(a) a halogen atom (preferably a fluorine atom, a chlorine atom),

(b) C_1-6alkyl (preferably methyl, ethyl, isopropyl, tert-butyl),

(c) C_1-6a haloalkyl group (preferably a trifluoromethyl group),

(d) C_1-6alkoxy groups (preferably methoxy, ethoxy),

(e) C_1-6haloalkoxy (preferably trifluoromethoxy) and

(f) cyano radicals, or

(2) A 5-to 10-membered aromatic heterocyclic group (preferably a 5-or 6-membered aromatic heterocyclic group, more preferably pyridyl, furyl),

x is a carbon atom or a nitrogen atom,

R³is that

(1) C_1-6Alkyl groups (preferably methyl, ethyl, propyl,isopropyl, isobutyl), optionally substituted with 1-3 substituents selected from:

(a) C_1-6alkoxy (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 group, tetrahydrofuranyl group), and

(c) a hydroxyl group(s),

(2) C_3-8cycloalkyl (preferably cyclopropyl, cyclobutyl, cyclopentyl), or

(3) A 4-8 membered saturated aliphatic heterocyclic group (preferably a 5-or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl, piperidinyl) which is optionally substituted with 1-3 substituents selected from:

(a) C_1-6alkyl-carbonyl (preferably acetyl),

(b) C_1-6alkoxy-carbonyl (preferably tert-butoxycarbonyl),

(c) C_1-6alkylsulfonyl (preferably methylsulfonyl), and

(d) optionally is covered with C_1-6Alkyl (preferably isopropyl) mono-or disubstituted carbamoyl,

R⁴is that

(1) A hydrogen atom, or

(2) C_1-6An alkyl group (preferably a methyl group),

R^5aand R^5bEach independently is

(1) A hydrogen atom, or

(2) C_1-6Alkyl (preferably methyl, ethyl, isopropyl), or

R⁴And R^5aOptionally with R⁴The nitrogen atoms bonded togetherLinked to form a 4-to 8-membered saturated nitrogen-containing aliphatic heterocyclic ring (preferably a 5-or 6-membered saturated nitrogen-containing aliphatic heterocyclic ring, more preferably pyrrolidine) (in this case, R^5bIs a hydrogen atom), and

R⁶and R⁷Each independently is

(1) A hydrogen atom, or

(2) C_1-6Alkyl (preferably ethyl, isobutyl), optionally substituted with 1-3 substituents selected from:

(a) a hydroxyl group(s),

(b) C_1-6alkoxy (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), or

R⁶And R⁷Optionally joined together with the nitrogen atom to which they are bound to form a 4-8 membered saturated nitrogen-containing aliphatic heterocyclic ring (preferably a 5-or 6-membered saturated nitrogen-containing aliphatic heterocyclic ring, more preferably morpholine, piperazine) optionally substituted with 1-3 substituents selected from:

(a) an oxo group, and a pharmaceutically acceptable salt thereof,

(b) cyano radicals, and

(c) C_1-6haloalkyl (preferably trifluoromethyl).

Preferred specific examples of the compound include the following compounds, among them

R¹Is that

(1) A hydrogen atom, or

(2) A halogen atom (preferably a fluorine atom, a chlorine atom),

l is

(1) A single bond, or

(2)-O-，

R²Is phenyl optionally substituted with 1 to 3 substituents selected from the group consisting of:

(a) a halogen atom (preferably a fluorine atom, a chlorine atom),

(b) C_1-6alkyl (preferably methyl, ethyl, isopropyl, tert-butyl),

(c) C_1-6a haloalkyl group (preferably a trifluoromethyl group),

(d) C_1-6alkoxy groups (preferably methoxy, ethoxy),

(e) C_1-6haloalkoxy (preferably trifluoromethoxy), and

(f) the cyano group(s),

x is a carbon atom and is a hydrogen atom,

R³is that

(1) C_1-6Alkyl (preferably methyl, ethyl, propyl, isopropyl, isobutyl), optionally substituted with 1-3 substituents selected from:

(a) C_1-6alkoxy (preferably methoxy, ethoxy, isopropoxy),

(c) a hydroxyl group(s),

(2) C_3-8cycloalkyl (preferably cyclopropyl, cyclobutyl, cyclopentyl), or

(3) A 4-8 membered saturated aliphatic heterocyclic group (preferably a 5-or 6-membered saturated aliphatic heterocyclic group, more preferably tetrahydropyranyl, piperidinyl), optionally substituted with 1-3 substituents selected from:

(a) C_1-6alkyl-carbonyl (preferably acetyl),

(b) C_1-6alkoxy-carbonyl (preferably tert-butoxycarbonyl),

(c) C_1-6alkylsulfonyl (preferably methylsulfonyl), and

R⁴is that

(1) A hydrogen atom, or

(2) C_1-6An alkyl group (preferably a methyl group),

R^5aand R^5bEach independently is

(1) A hydrogen atom, or

(2) C_1-6Alkyl (preferably methyl, ethyl, isopropyl), and

R⁶and R⁷Each independently is

(1) A hydrogen atom, or

(2)C_1-6Alkyl (preferably ethyl, isobutyl), optionally substituted with 1-3 substituents selected from:

(a) a hydroxyl group(s),

(b) C_1-6alkoxy (preferably methoxy), and

(a) an oxo group, and a pharmaceutically acceptable salt thereof,

(b) cyano radicals, and

(c) C_1-6haloalkyl (preferably trifluoromethyl).

Other preferred specific examples of the compound include the following compounds, wherein

R¹Is that

(1) A hydrogen atom, and a nitrogen atom,

(2) a halogen atom (preferably a fluorine atom, a chlorine atom), or

(3) C_1-6An alkyl group (preferably a methyl group),

l is

(1) A single bond, or

(2)-O-，

R²Is C_6-10Aryl radical (the radical C)_6-10Aryl optionally with C_3-6Cycloalkane fused) (preferably phenyl, indanyl, more preferably phenyl) optionally substituted with 1 to 3 substituents selected from:

(a) a halogen atom (preferably a fluorine atom, a chlorine atom),

(b) C_1-6alkyl (preferably methyl, ethyl, isopropyl, tert-butyl),

(c) C_1-6a haloalkyl group (preferably a trifluoromethyl group),

(d) C_1-6alkoxy groups (preferably methoxy, ethoxy),

(e) C_1-6haloalkoxy (preferably trifluoromethoxy), and

(f) the cyano group(s),

x is a carbon atom and is a hydrogen atom,

R³is that

(1) C_1-6Alkyl (preferably methyl, ethyl, propyl, isopropyl, iso-propyl)Butyl), optionally substituted with 1-3 substituents selected from:

(a) C_1-6alkoxy (preferably methoxy, ethoxy, isopropoxy),

(c) a hydroxyl group(s),

(2) C_3-8cycloalkyl (preferably cyclopropyl, cyclobutyl, cyclopentyl), or

(a) C_1-6alkyl-carbonyl (preferably acetyl),

(b) C_1-6alkoxy-carbonyl (preferably tert-butoxycarbonyl),

(c) C_1-6alkylsulfonyl (preferably methylsulfonyl), and

R⁴is that

(1) A hydrogen atom, or

(2) C_1-6An alkyl group (preferably a methyl group),

R^5aand R^5bEach independently is

(1) A hydrogen atom, or

(2) C_1-6Alkyl (preferably methyl, ethyl, isopropyl), and

R⁶and R⁷Each independently is

(1) A hydrogen atom, or

(a) a hydroxyl group(s),

(b) C_1-6alkoxy (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 a morpholinyl group).

Among them, preferred are compounds wherein

R¹Is that

(1) A hydrogen atom, or

(2) A halogen atom (preferably a fluorine atom, a chlorine atom),

l is

(1) A single bond, or

(2)-O-，

(a) a halogen atom (preferably a fluorine atom, a chlorine atom),

(b) C_1-6alkyl (preferably methyl, ethyl, isopropyl, tert-butyl),

(c) C_1-6a haloalkyl group (preferably a trifluoromethyl group),

(d) C_1-6alkoxy groups (preferably methoxy, ethoxy),

(e) C_1-6haloalkoxy (preferably trifluoromethoxy), and

(f) the cyano group(s),

x is a carbon atom and is a hydrogen atom,

R³is that

(a) C_1-6alkoxy (preferably methoxy, ethoxy, isopropoxy),

(c) hydroxy, or

(2) C_3-8Cycloalkyl (preferably cyclopropyl, cyclobutyl, cyclopentyl),

R⁴is a hydrogen atom or a methyl group,

R⁶and R⁷Is a hydrogen atom, and is a hydrogen atom,

and

more preferred are the compounds wherein

R¹Is a hydrogen atom, and is a hydrogen atom,

l is-O-,

(a) a halogen atom (preferably a fluorine atom, a chlorine atom),

(b) C_1-6alkyl (preferably methyl, ethyl, isopropyl, tert-butyl),

(c) C_1-6a haloalkyl group (preferably a trifluoromethyl group),

(d) C_1-6alkoxy groups (preferably methoxy, ethoxy),

(e) C_1-6haloalkoxy (preferably trifluoromethoxy), and

(f) the cyano group(s),

x is a carbon atom and is a hydrogen atom,

R³is that

(a) C_1-6alkoxy (preferably methoxy, ethoxy, isopropoxy),

(c) hydroxy, or

(2) C_3-8Cycloalkyl (preferably cyclopropyl, cyclobutyl, cyclopentyl),

R⁴is a hydrogen atom or a methyl group, and

R⁶and R⁷Is a hydrogen atom.

Other preferred specific examples of the compound include:

N²- { [ 1-cyclopropyl-6- (4-fluorophenoxy) -1H-benzeneand-Imidazol-2-yl]methyl-L-alaninamide, or a salt thereof,

N²- { [ 5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide, and

N²- { [ 5-chloro-6- (3, 4-difluorophenyl) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide, and

pharmaceutically acceptable salts of these compounds.

The compound (1) can be produced, for example, according to the method shown below.

Reaction scheme-1

[ solution 6]

Wherein R is¹，R²，R³，R⁴，R^5a，R^5b，R⁶，R⁷L and X are as defined above.

The compound (1) can be produced by subjecting the compound (1-1) to reductive amination with a corresponding amine compound. As the solvent, ether solvents such as tetrahydrofuran, 1, 4-bisAlkanes and the like, halogenated solvents such as dichloromethane, chloroform, 1, 2-dichloroethane and the like, alcohol solvents such as methanol, ethanol and the like, ethyl acetate, N-dimethylformamide, acetonitrile and the like can be used. Among them, tetrahydrofuran, dichloromethane and methanol are preferable. As the reducing agent, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, or the like can be used. The reaction temperature is-20 ℃ to the reflux temperature of the reaction solvent, and particularly preferably 0 ℃ to near room temperature. Molecular sieves or sodium sulfate may be added as dehydrating agents. Acetic acid or hydrochloric acid may be added as an additive.

A compound (1A) which is wherein R⁴And R^5aCompound (1), which is not linked, can also be prepared from compound (1-1) according to the method shown in the following reaction scheme-2.

Reaction scheme-2

[ solution 7]

Wherein R is¹，R²，R³，R⁴，R^5a，R^5b，R⁶，R⁷L and X are as defined above, except that R⁴And R^5aNot linked, and Y is a leaving group such as a halogen atom, methanesulfonyloxy group, toluenesulfonyloxy group, etc.

Compound (1-1) is reductively aminated with compound (1-2) to give compound (1-3), and then compound (1-3) is subjected to reductive amination with compound (1-2) in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, 1, 4-bisAn alkane, etc.), a halogenated solvent (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, etc.), ethyl acetate, N-dimethylformamide, acetonitrile, etc., at a temperature between 0 ℃ and the reflux temperature of the reaction solvent to give compound (1A). The base is not particularly limited, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butoxide and the like, and organic bases such as triethylamine, diisopropylethylamine and the like can be used.

In addition, the compound (1) can also be prepared according to the method shown in the following reaction scheme-3.

Reaction scheme-3

[ solution 8]

Wherein R is¹，R²，R³，R⁴，R^5a，R^5b，R⁶，R⁷L, Y and X are as defined above.

Compound (1) can be produced by reacting compound (1-5) with the corresponding amine compound in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, 1, 4-bisAn alkane, etc.), a halogenated solvent (e.g., dichloromethane, chloroform, 1, 2-dichloroethane, etc.), ethyl acetate, N-dimethylformamide, acetonitrile, etc., at a temperature between 0 ℃ and the reflux temperature of the reaction solvent. The base is not particularly limited, and inorganic bases such as potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butoxide and the like, and organic bases such as triethylamine, diisopropylethylamine and the like can be used.

A compound (1B) which is wherein R⁴The compound (1) which is a hydrogen atom can be produced, for example, by the method shown in the following reaction scheme-4.

Reaction scheme-4

[ solution 9]

Wherein R is¹，R²，R³，R^5a，R^5b，R⁶，R⁷L, Y and X are as defined above.

Compound (1B) can be produced by reacting compound (1-7), which is obtained from compound (1-5) and compound (1-6) in the same manner as in reaction scheme-3, in an acidic solvent such as trifluoroacetic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid and the like at a temperature between room temperature and the reflux temperature of the reaction solvent. More preferably, the reaction is carried out in trifluoroacetic acid at about 50 ℃.

The above-mentioned compounds (1-1) and (1-5) can be prepared by the methods shown below and in analogy thereto.

Among the above-mentioned compounds (1-1), the compound (2-1) can be prepared, for example, by the method shown in the following reaction scheme-5.

Reaction scheme-5

[ solution 10]

Wherein R is²And R³As defined above.

Compound (2-3) can be prepared by reacting 2, 4-difluoronitrobenzene with compound (2-2) in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkane, etc.), N-dimethylformamide, acetonitrile, etc., at a temperature between room temperature and the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium t-butoxide and the like are preferably used, and potassium carbonate is preferably used. As a solvent, 1, 4-bisAlkanes are preferred.

Compound (2-5) can be prepared by reacting compound (2-3) with compound (2-4) in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkane, etc.), N-dimethylformamide, acetonitrile, etc., at a temperature between room temperature and the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butoxide, etc. can be used, and cesium carbonate is preferably used. As a solvent, 1, 4-bisAlkanes are preferred.

The compound (2-6) can be produced by reducing the nitro group of the compound (2-5) to an amino group. The reduction reaction used in the reaction may be carried out under ordinary reduction conditions. It is preferable to use catalytic reduction using palladium-carbon or the like, reduction using a metal such as iron or the like, and other similar reductions. The solvent used for the reduction is preferably selected according to the reduction conditions. For example, for the catalytic reduction, methanol, ethanol, tetrahydrofuran, ethyl acetate, etc. are preferably selected, and for the reduction with a metal such as iron, etc., tetrahydrofuran, acetic acid, methanol, ethanol, water, etc. are selected. The catalytic reduction is preferably carried out at room temperature, and the reduction reaction using a metal such as iron or the like is preferably carried out at a temperature of between 50 ℃ and the reflux temperature of the reaction solvent.

The compound (2-1) can be produced by mixing the compound (2-6) with glycolic acid and then heating it from 100 ℃ to 150 ℃ and by oxidizing the hydroxyl group of the corresponding cyclic compound obtained. The oxidation for this reaction can be carried out under ordinary oxidation conditions. Examples of the oxidizing conditions include oxidation with manganese dioxide, chromium oxide, etc., and oxidation with an organic oxidizing agent represented by dimethyl sulfoxide. Oxidation with manganese dioxide and Swern oxidation are preferred. Among these, oxidation with manganese dioxide is particularly preferable. The solvent used for the oxidation is preferably selected according to the oxidation conditions. For example, for oxidation with a metal, it is preferable to select a halogenated solvent such as dichloromethane, chloroform, etc., and an ether solvent such as tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkanes, and the like. For oxidation with an organic oxidant, halogenated solvents such as dichloromethane, chloroform, and the like are preferred. The oxidation with the metal is preferably carried out at room temperature, and the oxidation reaction with the organic oxidizing agent is preferably carried out at-78 ℃ to room temperature.

Among the above-mentioned compounds (1-1), the compound (3-1) can also be prepared, for example, by the method shown in the following reaction scheme-6.

Reaction scheme-6

[ solution 11]

Wherein R is²And R³As defined above.

Compound (3-4) can be prepared by reacting compound (3-2) with compound (3-3) in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkane, etc.), N-dimethylformamide, acetonitrile, etc., at a temperature between room temperature and the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium t-butoxide and the like are preferably used, and potassium carbonate is preferably used. As a solvent, 1, 4-bisAlkanes are preferred.

The compound (3-5) can be produced by reducing the nitro group of the compound (3-4) to an amino group. The reduction used in the reaction is preferably a reduction reaction using a metal such as iron, tin, or the like. The solvent used for the reduction is preferably tetrahydrofuran, acetic acid, methanol, ethanol, water or the like. The reduction reaction using the metal is preferably carried out at a temperature of between 50 ℃ and the reflux temperature of the reaction solvent.

The compound (3-6) can be produced by mixing the compound (3-5) with glycolic acid and then heating it from 100 ℃ to 150 ℃. The compound (3-7) can be produced by oxidizing the hydroxyl group of the compound (3-6). The oxidation for this reaction can be carried out under ordinary oxidation conditions. Examples of the oxidizing conditions include oxidation with manganese dioxide, chromium oxide, etc., and oxidation with an organic oxidizing agent represented by dimethyl sulfoxide. Oxidation with manganese dioxide and Swern oxidation are preferred. Among these, oxidation with manganese dioxide is particularly preferable. The solvent used for the oxidation is preferably selected according to the oxidation conditions. For example, for oxidation reactions using metals, halogenated solvents such as dichloromethane, chloroform, etc., ether solvents such as tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkanes and the like are preferred, and for the oxidation reaction with an organic oxidizing agent, halogenated solvents such as methylene chloride, chloroform and the like are preferred. The oxidation reaction with the metal is preferably carried out at room temperature, and the oxidation reaction with the organic oxidizing agent is preferably carried out at-78 ℃ to room temperature.

Compound (3-1) can be prepared by reacting compound (3-7) with the corresponding boronic acid compound in a solvent such as dimethoxyethane, 1, 4-bis (meth) acrylic acid using a palladium catalyst, a ligand and a baseAlkane, toluene, ethanol, etc., at a temperature between room temperature and the reflux temperature of the solvent. Examples of the catalyst include, but are not particularly limited to, palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone dipalladium and the like. The ligand is not particularly limited, and examples thereof include triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine and the like. The base is not particularly limited, and examples thereof include sodium carbonate, potassium carbonate, cesium carbonate and the like.

Among the above-mentioned compounds (1-1), the compound (4-1) can also be prepared, for example, according to the method shown in the following reaction scheme-7.

Reaction scheme-7

[ solution 12]

Wherein R is²And R³As defined above.

Compound (4-3) can be obtained by reacting compound (3-6) with compound (4-2) in a solvent such as N-methylpyrrolidone, 1, 4-bisAlkane, dimethylsulfoxide, N-dimethylformamide and the like, at a temperature between room temperature and the reflux temperature of the solvent. The copper catalyst is not particularly limited, and examples thereof include cuprous iodide, cupric bromide, cupric chloride and the like. The ligand is not particularly limited, and examples thereof include 2,2,6, 6-tetramethylheptane-3, 5-dione, N, N-dimethylglycine and the like. Although the base is not particularly limited, examples thereof include sodium carbonate, potassium carbonate, cesium carbonate and the like.

The compound (4-1) can be produced by oxidizing the hydroxyl group of the compound (4-3). The oxidation for this reaction can be carried out under ordinary oxidation conditions. Examples of the oxidizing conditions include oxidation with manganese dioxide, chromium oxide, etc., and oxidation with an organic oxidizing agent represented by dimethyl sulfoxide. Oxidation with manganese dioxide and Swern oxidation are preferred. Among these, oxidation with manganese dioxide is particularly preferable. The solvent used for the oxidation is preferably selected according to the oxidation conditions. For example, for the oxidation reaction using a metal, it is preferable to select a halogenated solvent such as methylene chloride, chloroform and the like, and an ether solvent such as tetrahydrofuran, dimethoxymethane and the likeEthane, 1, 4-diAlkanes, and the like. For the oxidation reaction using an organic oxidizing agent, halogenated solvents such as dichloromethane, chloroform and the like are preferable. The oxidation reaction with the metal is preferably carried out at room temperature, and the oxidation reaction with the organic oxidizing agent is preferably carried out at-78 deg.C to room temperature.

Among the above-mentioned compounds (1-1), the compound (5-1) can also be prepared, for example, by the method shown in the following reaction scheme-8.

Reaction scheme-8

[ solution 13]

Wherein R is²，R³And Y is as defined above.

Compound (5-4) can be prepared by reacting compound (5-2) with compound (5-3) in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkane, etc.), N-dimethylformamide, etc., at a temperature between room temperature and the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium t-butoxide and the like are preferably used, and potassium carbonate is preferably used. As the solvent, N-dimethylformamide is preferable.

Compound (5-1) can be obtained from compound (5-4) in the same manner as in scheme-5.

Among the above-mentioned compounds (1-1), the compound (6-1) can be produced, for example, according to the following reaction scheme-9.

Reaction scheme-9

[ solution 14]

Wherein R is²And R³As defined above.

Compound (6-3) can be prepared by reacting 2, 6-dichloro-3-nitropyridine with compound (6-2) in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkane, etc.), N-dimethylformamide, acetonitrile, etc., at a temperature between room temperature and the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butoxide, etc. are preferably used, and potassium carbonate is preferably used. As a solvent, 1, 4-bisAlkanes are preferred.

Compound (6-5) can be prepared by reacting compound (6-3) with compound (6-4) in the presence of a base in a solvent such as an ether solvent (e.g., tetrahydrofuran, dimethoxyethane, 1, 4-bisAlkane, etc.), N-dimethylformamide, acetonitrile, etc., at a temperature between room temperature and the reflux temperature of the reaction solvent. As the base, potassium carbonate, cesium carbonate, sodium hydroxide, sodium hydride, potassium tert-butoxide, etc. can be used, and cesium carbonate is preferably used. As a solvent, 1, 4-bisAlkanes are preferred.

Compound (6-1) can be obtained from compound (6-5) in the same manner as in scheme-5.

Among the above-mentioned compounds (1-1), the compound (7-1) can be prepared, for example, by the method shown in the following reaction scheme-10.

Reaction scheme-10

[ solution 15]

Wherein R is²And R³As defined above.

Compound (7-2) can be obtained from compound (6-3) in the same manner as in scheme-6.

Compound (7-1) can be obtained by reacting compound (7-2) with the corresponding boric acid compound in a solvent such as dimethoxyethane, 1, 4-bis (meth) oxyethane, using a palladium catalyst, a ligand and a baseAlkane, toluene, ethanol, etc., at a temperature between room temperature and the reflux temperature of the solvent. Examples of the palladium catalyst include, but are not particularly limited to, palladium acetate, tetrakis (triphenylphosphine) palladium, dibenzylideneacetone dipalladium and the like. The ligand is not particularly limited, and examples thereof include triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine and the like. The base is not particularly limited, and examples thereof include sodium carbonate, potassium carbonate, cesium carbonate and the like.

The above-mentioned compound (1-5) can be prepared from the compound (8-1), for example, by the method shown in the following reaction scheme-11.

Reaction scheme-11

[ solution 16]

Wherein R is¹，R²，R³L, X and Y are as defined above.

As a step of converting the leaving group, when the leaving group Y is a methanesulfonyloxy group or a toluenesulfonyloxy group, the corresponding chloride (methanesulfonyl chloride, toluenesulfonyl chloride) is reacted in the presence of a base such as triethylamine, pyridine or the like to give the corresponding methanesulfonyl or toluenesulfonyl form. When the leaving group Y is a halogen atom, the methods described in Comprehensive Organic Transformation [ R.C. Larock, VCH Publishers Inc. (1989) ], 4th Edition Jikken Kagaku Kouza (Maruzen), Shinjikken Kagaku Koza (Courses in Experimental Chemistry) (Maruzen), etc. can be used. For example, the corresponding bromide can be obtained by adding phosphorus tribromide, which has been dissolved in tetrahydrofuran.

Each of the above reactions can be carried out according to the method described in the examples of the present specification, Comprehensive Organic Transformation [ R.C. Larock, VCH Publishers Inc. (1989) ], 4th Edition Jikken Kagaku Kouza (Maruzen), Shinjikken Kagaku Koza (Courses in Experimental Chemistry) (Maruzen).

In addition, the starting material compounds used in the above production methods can be suitably prepared by using commercially available products or according to methods well known to those of ordinary skill in the art.

In addition, when preparing the compound of the present invention or a pharmaceutically acceptable salt thereof, functional groups such as hydroxyl group, carboxyl group, amino group, etc. can be protected or deprotected in any step if necessary. The types of protecting groups and the methods of protection and deprotection are those well known to those of ordinary skill in the art. See, for example, "Protective Groups in Organic Synthesis (T.W. Greene et al, John Wiley & Sons, Inc. published in 1991)" and the like.

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 a base addition salt with an inorganic acid or an organic acid as required, which are acceptable as a medicament. Examples of the pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate and the like, salts formed with organic carboxylic acids such as formate, acetate, fumarate, maleate, oxalate, citrate, malate, tartrate, aspartate, glutamate and the like, salts formed with sulfonic acids such as methanesulfonate, benzenesulfonate, p-toluenesulfonate, hydroxybenzenesulfonate, dihydroxybenzenesulfonate and the like, and examples of the pharmaceutically acceptable alkali metal addition salts include ammonium salts, lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts and the like.

In addition, the present invention also includes hydrates and solvates of the compound (1) or a pharmaceutically acceptable salt thereof such as ethanolate and the like. Further, the present invention includes any tautomers and stereoisomers such as optical isomers and the like and any crystal forms of the compound (1). These can be suitably purified by methods known to those of ordinary skill in the art such as silica gel column chromatography, HPLC, ion exchange chromatography, recrystallization, and the like.

In order to obtain the above optical isomers in pure form, optical resolution methods well known to those of ordinary skill in the art may be used. Specifically, when the compound of the present invention or an intermediate thereof has a basic functional group, it can form a salt with an optically active acid (for example, a monocarboxylic acid such as mandelic acid, N-benzyloxyalanine, lactic acid and the like, a dicarboxylic acid such as tartaric acid, o-diisopropylidenetartaric acid, malic acid and the like, a sulfonic acid such as camphorsulfonic acid, bromocamphorsulfonic acid and the like) in an inert solvent. In addition, when the compound of the present invention or an intermediate thereof has an acidic functional group, it can also form a salt with an optically active amine (for example, an organic amine such as α -phenylethylamine, quinine (kinin), quinidine (quinidine), cinchonidine (cincinnidine), cinchonine (cincinnine), strychnene (strychnene), or the like). The temperature at which the salt is formed is from room temperature to the boiling point of the solvent.

The novel compound having a bicyclic heterocycle of the present invention or a pharmaceutically acceptable salt thereof has SNS inhibitory activity and can be used as a therapeutic or prophylactic agent for neuropathic pain and nociceptive pain. Examples of neuropathic pain here include neuralgia after lumbar surgery, diabetic neuropathy, neuralgia after herpes zoster, reflex sympathetic dystrophy, phantom limb pain, spinal cord injury, late stage cancer pain and prolonged postoperative pain. Examples of nociceptive pain include lumbago, abdominal pain, rheumatoid arthritis, pain due to osteoarthritis, and the like. In addition, the compound of the present invention or a pharmaceutically acceptable salt thereof can also be used as a therapeutic or prophylactic agent for dysuria. Examples of dysuria here include frequent urination, bladder pain due to benign prostatic hypertrophy, and the like. In addition, it can also be used as a therapeutic or prophylactic agent for inhibiting abnormal neurofever (firing) in the cerebellum of multiple sclerosis. As a drug having no side effect by non-nerve tissue or central nervous system, a compound having SNS selective inhibitory activity is more preferable.

The therapeutic or prophylactic agent of the present invention for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis can contain various additional components used in the formulation, such as a common carrier, a binder, a stabilizer, an excipient, a diluent, a pH buffer, a disintegrant, a solubilizing agent, a dissolution aid, an isotonic agent and the like, which are pharmaceutically acceptable. In addition, these therapeutic or prophylactic agents can be administered orally or parenterally. That is, for oral administration, the drug can be orally administered in a form generally employed, for example, in a form such as a tablet, a pill, a powder, a pellet, a capsule, a syrup, an emulsion, a suspension, and the like. For parenteral administration, the medicament can be formulated, for example, as preparations for intravenous injection (drip infusion), intramuscular injection, subcutaneous injection, liniment, eye drops, ophthalmic ointment, and the like.

Solid preparations such as tablets are prepared by mixing the active ingredient with a generally pharmacologically acceptable carrier or excipient such as lactose, sucrose, corn starch and the like, a binder such as crystalline cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and the like, a disintegrant such as sodium carboxymethylcellulose, sodium starch glycolate and the like, a lubricant such as stearic acid, magnesium stearate and the like, a preservative and the like.

For parenteral administration, the active ingredient may be dissolved or suspended in a physiologically acceptable carrier such as water, saline, oil, aqueous glucose solution or the like, and may be added with an emulsifier, a stabilizer, a salt for adjusting osmotic pressure or a buffer as an auxiliary, when necessary.

Formulations of the compounds of the present invention can be prepared according to conventional methods. For example, a tablet can be prepared by mixing the compound of example 1 (20 mg), lactose (100 mg), crystalline cellulose (25 mg) and magnesium stearate (1 mg), and then tabletting the obtained mixture.

Although the dose and frequency of administration may vary depending on the administration method, and the age, body weight, disease state and the like of the patient, the method of local administration to the lesion part of the disease is preferable. It is also preferred that the administration is once or twice or more daily. When administered twice or more times, continuous administration or repeated administration at appropriate intervals is desirable.

The dose is from 10. mu.g to 2 g, preferably from 1 mg to 1g, more preferably from 10 to 100 mg, which can be administered once a day or in portions, based on the amount of active ingredient per single administration to an adult patient. For parenteral administration, the dose can be 0.1 to 100 mg/day, more preferably 0.3 to 50 mg/day for adult patients, and the dose can be administered once or in portions a day. In order to reduce the frequency of administration, sustained release formulations can also be used.

In addition, the therapeutic or prophylactic agent of the present invention for neuropathic pain, nociceptive pain, dysuria or multiple sclerosis can also be used as an animal agent.

Examples

The present invention is explained in more detail below by referring to reference examples and examples; however, the technical scope of the present invention is not limited to such embodiments and the like. (ii) absorption spectroscopy of the compound by hydrogen nuclear magnetic resonance (¹H-NMR).

Hereinafter, abbreviations shown below are sometimes used to simplify the description of the present specification.

Me: methyl group, Et: ethyl, Pr: propyl, iPr: isopropyl group, Ph: phenyl, Ac: acetyl, Boc: tert-butoxycarbonyl, Bn: benzyl, TBDMS: tert-butyldimethylsilyl, PyBOP: benzotriazol-1-yl-oxy-tris (pyrrolidino) phosphoniumHexafluorophosphate, J: binding constant, s: singlet, d: double line state, dd: double line state, ddd: 4 double line, td: 3 double line, t: triplet state, dt: double triplet, q: quadruple line state, quick: quintuple, br: width, m: multiple line states.

The starting material compounds, reaction reagents and solvents used are commercially available products unless otherwise specified.

Reference example 1:

to a solution of 2, 4-difluoronitrobenzene (15 g, 94 mmol) in bisTo a solution in an alkane (300 mL) was added potassium carbonate (14.4 g, 1)04 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, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the objective product (21 g, 98%).

¹H-NMR (CDCl₃) 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 the compound (3.0 g, 13.2 mmol) obtained in reference example 1 in bisTo the resulting solution in alkane (60 mL) was added cesium carbonate (6.4 g, 19.7 mmol) and phenol (1.5 g, 15.8 mmol), and the mixture was heated to 80 ℃. 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, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the objective product (4.1 g, 100%).

¹H-NMR (CDCl₃) 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 a solution (50 mL) of the compound obtained in reference example 2 (1.8 g, 6.0mmol) in ethanol was added 10% palladium on carbon (1g), and the mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere. The reaction mixture was filtered through celite, and the filtrate was concentrated and dried under reduced pressure to give the desired product (1.4 g, 86%).

¹H-NMR (CDCl₃) 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 above-mentioned object product can also be prepared by the following method.

While refluxing under heating, a solution (60 mL) of the compound (9.8 g, 32 mmol) obtained in reference example 2 in a mixed solvent of tetrahydrofuran-methanol-water (3:2:1) was added dropwise to a suspension (3:2:1, 120 mL) of iron (13.9 g, 0.25 mol) and ammonium chloride (6.6 g, 0.12 mol) in tetrahydrofuran-methanol-water. After stirring for 2 hours, the reaction mixture was cooled and then filtered through celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure to obtain the objective product (8.7 g, 100%).

Reference example 4:

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

Reference example 5:

to a solution of the compound obtained in reference example 4 (4.1 g) in dichloromethane (100 mL) was added manganese dioxide (8 g), and the mixture was stirred at room temperature. After stirring for 2 hours, the reaction mixture 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 objective product (3.5 g, 61%, 2 steps).

¹H-NMR (CDCl₃) 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 objective 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 was recrystallized from chloroform/hexane, and then further recrystallized from acetonitrile to obtain the objective product (23.3 g, 56%, 4 steps).

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 6 in the same manner as in reference example 5.

¹H-NMR (CDCl₃) 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: N²- { [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) was added (L) -alaninamide hydrochloride (0.96 g, 7.7 mmol), and the resulting mixture was stirred at room temperature. After stirring for 1 hour, sodium triacetoxyborohydride (1.6 g, 7.7 mmol) was added thereto, and the mixture was stirred for 2 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform: methanol = 50:1-10:1) to obtain the objective product (0.59 g, 24%).

¹H-NMR (CDCl₃) 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 compounds can also be prepared by the following methods.

To a solution of the compound obtained in reference example 5 (0.15g, 0.48 mmol) in tetrahydrofuran (10 mL) were added (L) -alaninamide hydrochloride (0.18g, 1.45 mmol), sodium sulfate (3g) and triethylamine (0.20 mL), and the resulting mixture was stirred at room temperature. After stirring for 30 minutes, sodium cyanoborohydride (45 mg, 0.72 mmol) was added thereto, and the mixture was stirred for 2 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer was extracted, washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform: methanol = 50:1-10:1) to obtain the objective product (0.09 g, 49%).

Example 2: N²- { [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 glycylamine hydrochloride (31 mg, 0.28 mmol), and the resulting mixture was stirred at room temperature. After stirring for 1 hour, sodium cyanoborohydride (18 mg, 0.28 mmol) was added thereto, and the mixture was stirred overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform: methanol = 50:1-10:1) to obtain the objective product (23 mg, 43%).

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]Methyl glycinamide

The objective product was obtained from the compound obtained in reference example 7 in the same manner as in example 2.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy group) -1H-benzimidazol-2-yl]methyl-L-valinamide

The desired product was obtained from the compound obtained in reference example 7 and (L) -valinamide hydrochloride in the same manner as in example 1.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]Methyl } -2-methyl-alaninamide

The objective product was obtained from the compound obtained in reference example 7 and 2-methylalaninamide (which is a known compound) in the same manner as in example 1.

¹H-NMR (CDCl₃) 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 to 58:

the compounds of examples 6 to 58 shown in tables 1 to 9 were prepared from 2, 4-difluoronitrobenzenes using commercially available or known compounds in the same manner as in reference examples 1 to 7, example 1 or example 2.

[ tables 1-1]

[ tables 1-2]

[ Table 2-1]

[ tables 2-2]

[ Table 3-1]

[ tables 3-2]

[ Table 4-1]

[ tables 4-2]

[ Table 5-1]

[ tables 5-2]

[ Table 6-1]

[ tables 6-2]

[ Table 7-1]

[ tables 7-2]

[ Table 8-1]

[ tables 8-2]

[ Table 9-1]

[ tables 9-2]

Reference example 8:

to a solution of the compound obtained in reference example 6 (0.22 g, 0.66mmol) in tetrahydrofuran (3 mL) was added phosphorus tribromide (0.18g, 0.66mmol) under ice-cooling. After stirring for 1 hour, an aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate, dried over magnesium sulfate, and then concentrated under reduced pressure. The concentrate was used directly in the subsequent reaction.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide

To a solution of the compound (107 mg, 0.27 mmol) obtained in reference example 8 in acetonitrile (3 mL) were added diisopropylethylamine (0.10 mL, 0.55 mmol) and N- (2, 4-dimethoxybenzyl) alaninamide (97.7 mg, 0.41 mmol). After stirring at 50 ℃ for 5 hours, an aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. Trifluoroacetic acid (3 mL) was added thereto, and the mixture was further stirred at 50 ℃ for 2 hours, neutralized with an aqueous sodium hydroxide solution, and then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The obtained residue was recrystallized from chloroform/2-propanol to obtain the objective product (75 mg, 70%).

¹H-NMR (CDCl₃) δ1.08(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 to 65:

the compounds of examples 60 to 65 shown in Table 10 were prepared from 2, 4-difluoronitrobenzenes using commercially available or known compounds in the same manner as in reference examples 1 to 4, 8 and example 59.

[ Table 10-1]

[ Table 10-2]

Reference example 9:

the objective product was obtained from 2-fluoro-4-bromonitrobenzene in the same manner as in reference examples 1, 3 and 4.

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 9 in the same manner as in reference example 5.

¹H-NMR (CDCl₃) 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 solution of the compound (200 mg, 0.67 mmol) obtained in reference example 10 in IITo a solution (4:1, 15 mL) formed in a mixed solvent of an alkane and water were added potassium carbonate (280 mg, 2.02 mmol), phenylboronic acid (123 mg, 1.01 mmol) and tetrakis (triphenylphosphine) palladium (154 mg, 0.13 mmol), and the mixture was heated to 110 ℃. After refluxing for 2 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (hexane: ethyl acetate = 90:10-75:25-50:50) to obtain an aimed product (115 mg, 58%).

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6-phenyl-1H-benzimidazol-2-yl]Methyl glycinamide

The objective product (31 mg, 38%) was obtained from the compound (68 mg, 0.23 mmol) obtained in reference example 11 in the same manner as in example 2.

¹H-NMR (CDCl₃) δ1.08(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 to 73:

the compounds of examples 67 to 73 shown in tables 11 and 12 were prepared in the same manner as in reference examples 9 to 11 and example 66.

[ Table 11]

[ Table 12]

Reference example 12:

to a solution of the compound (150 mg, 0.5 mmol) obtained in reference example 9 in N-methylpyrrolidone (5 mL) was added cesium carbonate (489 mg, 1.5 mmol), 4-tert-butylphenol (225 mg, 1.5 mmol), 2,2,6, 6-tetramethylheptane-3, 5-dione (52. mu.L, 0.25 mmol) and copper (I) chloride (50 mg, 0.5 mmol) under a nitrogen atmosphere, and the resulting mixture was heated to 120 ℃. After stirring for 6 hours, the reaction mixture was added to 2 mol/L hydrochloric acid under ice-cooling, and the mixture was 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 then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (hexane: ethyl acetate = 100:0-0:100) to obtain an aimed product (56 mg, 30%).

¹H-NMR (CDCl₃) 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: N²- { [6- (4-tert-butylphenoxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 12 in the same manner as in reference example 5 and example 1.

¹H-NMR (CDCl₃) 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) were added imidazole (1.36 g, 20 mmol) and tert-butyldimethylsilyl chloride (904 mg, 6 mmol). After stirring at room temperature for 2 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (hexane: ethyl acetate = 100:0-85:15) to obtain the objective product (1.65 g, 100%).

¹H-NMR (CDCl₃) δ0.11(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:

to a solution of the compound (207 mg, 0.5 mmol) obtained in reference example 13 in N-methylpyrrolidone (5 mL) was added cesium carbonate (489 mg, 1.5 mmol), 4-methoxyphenol (186 mg, 1.5 mmol), 2,2,6, 6-tetramethylheptane-3, 5-dione (52. mu.L, 0.25 mmol) and copper (I) chloride (50 mg, 0.5 mmol) under a nitrogen atmosphere, and the resulting mixture was heated to 120 ℃. After stirring for 4 hours, the reaction mixture was added to 2 mol/L hydrochloric acid under ice-cooling, and the mixture was 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 then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (hexane: ethyl acetate = 100:0-0:100) to obtain an aimed product (36 mg, 21%).

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-methoxyphenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 14 in the same manner as in reference example 5 and example 1.

¹H-NMR (CDCl₃) 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, 16.0mmol) in N, N-dimethylformamide (30 mL) were added potassium carbonate (3.3 g, 24.0 mmol) and benzyl bromide (2.1 mL, 17.6 mmol), and the mixture was heated at 70 ℃. After stirring for 1 hour, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure, and the obtained residue was directly used for the subsequent reaction.

¹H-NMR (CDCl₃) δ5.14(s, 2H), 6.79-6.86(m, 2H), 7.38-7.43(m, 5H), 8.10(m, 1H)。

Reference example 16:

the objective product was obtained from the compound obtained in reference example 15 in the same manner as in reference examples 1 and 3 to 5.

¹H-NMR (CDCl₃) 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: N²- { [6- (benzyloxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 16 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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: N²- { [6- (benzyloxy) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]Methyl } -2-methyl-alaninamide

The objective product was obtained from the compound obtained in reference example 16 and 2-methylalaninamide in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from 3-fluoro-4-nitrophenol in the same manner as in reference examples 15, 1 and 3-5.

¹H-NMR (CDCl₃) 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: N²- ({1- (2-ethoxyethyl) -6- [ (4-fluorobenzyl) oxy)]-1H-benzimidazol-2-yl } methyl) -L-alaninamide

The objective product was obtained from the compound obtained in reference example 17 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 bisTo a solution in an alkane (50 mL) were added potassium carbonate (2.4 g, 17.0 mmol) and 2-ethoxyethylamine (1.4 g, 17.0 mmol), and the mixture was stirred at 50 ℃. After stirring for 3 hours, potassium carbonate (1.8 g, 13.0 mmol) and 2-ethoxyethylamine (0.9 g, 10.0 mmol) were added thereto, and the resulting mixture was stirred at 50 ℃ for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer is saturated with waterAnd brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column (ethyl acetate: hexane = 1:5) to obtain the objective product (3.4 g, 89%).

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 18 in the same manner as in reference example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 19 in the same manner as in reference examples 3 to 5.

¹H-NMR (CDCl₃) 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: N²- { [3- (2-ethoxyethyl) -5-phenoxy-3H-imidazo [4, 5-b)]Pyridin-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 20 in the same manner as in example 1.

¹H-NMR (CDCl₃) 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 = 5.1Hz, 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: N²- { [3- (2-ethoxyethyl) -5-phenoxy-3H-imidazo [4, 5-b)]Pyridin-2-yl]Methyl glycinamide

The objective product was obtained from the compound obtained in reference example 20 in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from 2,4, 5-trifluoronitrobenzene in the same manner as in reference example 1.

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 21 in the same manner as in reference examples 2 to 5.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -5-fluoro-6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 22 in the same manner as in example 1.

¹H-NMR (CDCl₃) 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 objective product was obtained from 2, 4-difluoronitrobenzene, 4-amino- (1-tert-butoxycarbonyl) piperidine and 4-fluorophenol in the same manner as in reference examples 1-4.

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 23 in the same manner as in reference example 5.

¹H-NMR (CDCl₃) 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 82:4- [2- ({ [ (2S) -1-amino-1-oxopropan-2-yl)]Amino } methyl) -6- (4-fluorophenoxy) -1H-benzimidazol-1-yl]Piperidine-1-carboxylic acid tert-butyl ester

The objective product was obtained from the compound obtained in reference example 24 in the same manner as in example 1.

¹H-NMR (CDCl₃) 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: N²- { [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 μ L), and the resulting mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (ethyl acetate: methanol = 99:1-80:20) to obtain an aimed product (38 mg, 71%).

¹H-NMR (CDCl₃) δ 1.41(d, J = 7.0Hz, 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, 0.68mmol) in dichloromethane (6.8 mL) was added trifluoroacetic acid (1.4 mL), and the resulting mixture was stirred at room temperature for 1 hour. An aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane (6.8 mL), and triethylamine (142. mu.L, 1.02 mmol) and isopropyl isocyanate (100. mu.L, 1.02 mmol) were then added thereto, 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, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform: methanol = 99:1-85:15) to obtain the objective product (280 mg, 97%).

¹H-NMR (CDCl₃) 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-benzimidazol-1-yl]-N- (propan-2-yl) piperidine-1-carboxamide

The objective product was obtained from the compound obtained in reference example 25 in the same manner as in example 1.

¹H-NMR (CDCl₃) 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: N²- { [1- (1-acetylpiperidin-4-yl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 24 and acetyl chloride according to the same method as in reference example 25 and example 1.

¹H-NMR (CDCl₃) δ 1.38(d, J = 7.0Hz, 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: N²- ({6- (4-fluorophenoxy) -1- [1- (methylsulfonyl) piperidin-4-yl)]-1H-benzimidazol-2-yl } methyl) -L-alaninamide

The objective product was obtained from the compound obtained in reference example 24 and methanesulfonyl chloride in the same manner as in reference example 25 and example 1.

¹H-NMR (CDCl₃) 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 (2.28g, 6.9 mmol) in tetrahydrofuran (70 mL) were added (L) -alanine ethyl ester hydrochloride (2.15 g, 14 mmol), triethylamine (1.95 mL, 14 mmol) and sodium sulfate (10g), and the resulting mixture was stirred at room temperature. After stirring for 1 hour, sodium cyanoborohydride (503 mg, 8mmol) was added thereto, and the mixture was stirred for 4 hours. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was extracted, washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column (chloroform: methanol = 100:0-95:5) to obtain the objective product (1.78 g, 60%).

¹H-NMR (CDCl₃) 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:

to a solution of the compound (2.79 g, 6.5 mmol) obtained in reference example 26 in acetonitrile (65 mL) was added di-tert-butyl dicarbonate (1.64 g, 7.5 mmol), and the resulting mixture was stirred with heating at 60 ℃ for 3 hours and then at 100 ℃ for 3 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure, and the residue was purified by a silica gel column (hexane: ethyl acetate = 100:0-70:30) to obtain the objective product (2.24 g, 65%).

¹H-NMR (CDCl₃) 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) under ice-cooling. After stirring for 30 minutes under the same conditions, water was added to the reaction mixture, and then the aqueous layer was washed with diethyl ether. The aqueous layer was adjusted to pH = 4 with 2 mol/L hydrochloric acid, and the mixture was extracted with chloroform. The organic layer was extracted, washed with saturated brine, and then dried over sodium sulfate to obtain the objective product (2.02 g, 96%).

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]Methyl } -N- (2-hydroxy-2-methylpropyl) -L-alaninamide

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

¹H-NMR (CDCl₃) 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 to 90:

the compounds of examples 88 to 90 shown in Table 13 were prepared according to the methods described in the above-mentioned reference examples and examples or methods similar to these methods.

[ Table 13]

Reference example 29:

to a solution of the compound (500 mg, 1.58 mmol) obtained in the same manner as in reference example 1-4 in dichloromethane (16 mL) was added thionyl chloride (342. mu.L, 4.74 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the obtained residue was dissolved in chloroform, to which an aqueous sodium hydroxide solution was added. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure to give the objective product (508 mg, 96%).

¹H-NMR (CDCl₃) 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: N²- { [6- (4-fluorophenoxy) -1- (2-methoxyethyl) -1H-benzimidazol-2-yl]Methyl } -2-methyl-alaninamide

To a solution of the compound (300 mg, 0.90 mmol) obtained in reference example 29 in acetonitrile (4.5 mL) were added 2, 2-dimethylglycine (138 mg, 1.35 mmol), diisopropylethylamine (321 μ L, 1.80 mmol) and sodium iodide (135 mg, 0.90 mmol), and the resulting mixture was heated to 50 ℃ and stirred overnight. Water was added thereto, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column (ethyl acetate: methanol = 99:1-80:20) to obtain the objective product (169 mg, 47%).

¹H-NMR (CDCl₃) 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:

to a solution of the compound (0.84 g, 2.8 mmol) obtained in reference example 10 in N, N-dimethylformamide (30 mL) was added N-chlorosuccinimide (0.95 g, 7.1 mmol), and the resulting mixture was heated to 40 ℃. After stirring overnight, water was added thereto, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated under reduced pressure and used directly for the subsequent reaction.

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 30 in the same manner as in reference example 11.

¹H-NMR (CDCl₃) 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: N²- { [ 5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 31 in the same manner as in example 1.

¹H-NMR (CDCl₃) 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 to 108:

the compounds of examples 93 to 108 shown in tables 14 to 16 were prepared according to the methods described in the above-mentioned reference examples and examples or methods similar thereto.

[ Table 14-1]

[ tables 14-2]

[ Table 15]

[ Table 16-1]

[ Table 16-2]

Reference example 32:

the objective product was obtained from 4-bromo-2, 5-difluoronitrobenzene in the same manner as in reference example 1.

¹H-NMR (CDCl₃) 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:

the objective product was obtained from the compound obtained in reference example 32 in the same manner as in reference example 3-2.

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 33 in the same manner as in reference example 4.

¹H-NMR (CDCl₃) 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:

the objective product was obtained from the compound obtained in reference example 34 in the same manner as in reference example 5.

¹H-NMR (CDCl₃) 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:

the objective product was obtained from the compound obtained in reference example 35 in the same manner as in reference example 11.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The desired product was obtained from the compound obtained in reference example 36 and (L) -alaninamide hydrochloride according to the same method as in example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from 4-bromo-2-fluoronitrobenzene, ethylamine and 4-fluorophenylboronic acid in the same manner as in reference examples 9 to 11.

¹H-NMR (CDCl₃) 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: N²- { [ 1-Ethyl-6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 37 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from 4-bromo-2, 5-difluoronitrobenzene in the same manner as in reference example 37.

¹H-NMR (CDCl₃) 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: N²- { [ 1-Ethyl-5-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 38 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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:

to a solution of 2-chloro-6-fluoroaniline (2.5 g, 17.2 mmol) in chloroform (40 mL) was added bromine (2.75 g, 17.2 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous sodium thiosulfate solution, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (hexane: ethyl acetate = 9:1-3:1) to obtain the objective product (3.21 g, 83%).

¹H-NMR (CDCl₃) δ 7.07(dd, J = 10.0, 2.0Hz, 1H), 7.19(t, J = 2.0Hz, 1H)。

Reference example 40:

a solution of sodium perborate tetrahydrate (11.0 g, 71.5 mmol) in acetic acid (50 mL) was heated to 55 ℃ and then a solution of the compound obtained in reference example 39 (3.21 g, 14.3 mmol) in acetic acid (30 mL) was added dropwise over 1 hour. After stirring for 3 hours, the mixture was cooled to room temperature and insoluble material was filtered off. The filtrate was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (hexane: ethyl acetate = 90:10-5:1) to obtain the objective product (1.30 g, 36%).

¹H-NMR (CDCl₃) δ 7.39(dd, J = 8.3, 2.0Hz, 1H), 7.50(t, J = 2.0Hz, 1H)。

Reference example 41:

the objective product was obtained from the compound obtained in reference example 40 and 4-fluorophenylboronic acid in the same manner as in reference examples 9 to 11.

¹H-NMR (CDCl₃) 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: N²- { [ 4-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 41 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from 4-bromo-2-fluoro-5-methylaniline in the same manner as in reference example 40.

¹H-NMR (CDCl₃) δ 2.43(s, 3H), 7.48(d, J = 10.0Hz, 1H), 7.93(d, J = 7.8Hz, 1H)。

Reference example 43:

the objective product was obtained from the compound obtained in reference example 42 in the same manner as in reference example 41.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenyl) -5-methyl-1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 43 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from 4-bromo-2, 6-difluoroaniline in the same manner as in reference example 40.

¹H-NMR (CDCl₃) δ 7.28-7.32(m, 2H)。

Reference example 45:

the objective product was obtained from the compound obtained in reference example 44 in the same manner as in reference example 41.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -4-fluoro-6- (4-fluorophenyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 45 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 objective product was obtained from 4-bromo-6-fluoro-3-trifluoromethylaniline in the same manner as in reference example 40.

Reference example 47:

the objective product was obtained from the compound obtained in reference example 46 in the same manner as in reference example 41.

¹H-NMR (CDCl₃) 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: N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenyl) -5- (trifluoromethyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 47 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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 objective 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.

¹H-NMR (CDCl₃) 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 obtained in reference example 48 (0.82 g, 2.38 mmol) in dichloromethane (20 mL) were added diisopropylethylamine (2.12 mL, 11.9 mmol) and thionyl chloride (1 mol/L dichloromethane solution, 11.9 mL, 11.9 mmol). Heated under reflux for 1 hour, the mixture was cooled to 0 ℃ and then water was added thereto. The mixture was neutralized with a 2 mol/L aqueous solution of sodium hydroxide, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure, and the obtained residue was used directly for the subsequent reaction.

¹H-NMR (CDCl₃) 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: N²- { [ 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) were added N- (2, 4-dimethoxybenzyl) alaninamide (0.12 g, 0.49 mmol), diisopropylethylamine (0.12 mL, 0.66mmol) and sodium iodide (0.07 g, 0.44 mmol). Heated under reflux for 2 hours, the mixture was cooled to room temperature, and then water was added thereto. The mixture was extracted with chloroform, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. Trifluoroacetic acid (2 mL) was added to the residue, and the mixture was heated to 50 ℃. After stirring for 1 hour, the mixture was cooled to 0 ℃ and chloroform was added thereto, and then the mixture was neutralized with a 2 mol/L aqueous sodium hydroxide solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (chloroform: methanol = 99:1-85:15) and recrystallized from ethyl acetate-hexane to obtain the objective product (0.09 mg, 50%).

¹H-NMR (CDCl₃) 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 objective product was obtained from 2, 4-difluoronitrobenzene, 2-aminoethanol and 4-fluorophenol in the same manner as in reference examples 1 to 3.

¹H-NMR (CDCl₃) 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 examples51:

To a solution of the compound obtained in reference example 50 (2.7 g, 10.5 mmol) in N, N-dimethylformamide (50 mL) were added tert-butyl-diphenylsilyl chloride (3.6 mL, 12.6 mmol) and imidazole (1.1 g, 15.8 mmol), and the mixture was stirred at room temperature. After stirring for 1 hour, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure, and the obtained residue was directly used for the subsequent reaction.

¹H-NMR (CDCl₃) 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:

the objective product was obtained from the compound obtained in reference example 51 and (L) -alaninamide hydrochloride in the same manner as in reference examples 4 and 5 and example 2.

¹H-NMR (CDCl₃) 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: N²- { [6- (4-fluorophenoxy) -1- (2-hydroxyethyl) -1H-benzimidazol-2-yl]methyl-L-alaninamide

To a solution (4 mL) of the compound obtained in reference example 52 (1.2 g, 2.0 mmol) in THF was added tetrabutylammonium fluoride (1 mol/L tetrahydrofuran solution, 3.0 mL, 3.0 mmol), and the mixture was stirred at room temperature. After stirring for 1 hour, water was added thereto, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by a silica gel column (chloroform: methanol = 99:1-85:15) and recrystallized from chloroform-hexane to obtain an objective product (300 mg, 40%).

¹H-NMR (CDCl₃) 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:

to a solution of the compound (1.0 g, 4.4 mmol) obtained in reference example 1 in N, N-dimethylformamide (44 mL) was added N-chlorosuccinimide (0.64 g, 4.8 mmol), and the resulting mixture was heated to 40 ℃. After stirring overnight, the mixture was cooled to room temperature. Water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column (hexane: ethyl acetate = 95:5-90:10-75:25-50:50) to obtain the objective product (0.82 g, 72%).

¹H-NMR (CDCl₃) 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 objective product was obtained from the compound obtained in reference example 53 in the same manner as in reference examples 2 to 5.

¹H-NMR (CDCl₃) 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: N²- { [ 5-chloro-1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]methyl-L-alaninamide

The objective product was obtained from the compound obtained in reference example 54 and (L) -alaninamide hydrochloride in the same manner as in example 2.

¹H-NMR (CDCl₃) 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)。

Example 119-190:

the compounds of example 119-190 shown in tables 17-31 were prepared according to the methods described in the above-mentioned reference examples and examples or methods similar thereto.

[ Table 17-1]

[ tables 17-2]

[ Table 18-1]

[ Table 18-2]

[ Table 19-1]

[ tables 19-2]

[ Table 20]

[ Table 21]

[ Table 22-1]

[ Table 22-2]

[ Table 23-1]

[ Table 23-2]

[ Table 24]

[ Table 25-1]

[ Table 25-2]

[ Table 26-1]

[ Table 26-2]

[ Table 27-1]

[ tables 27-2]

[ Table 28]

[ Table 29]

[ Table 30-1]

[ Table 30-2]

[ Table 31]

Reference example 55:

to a solution of the compound (1.4 g, 5.0 mmol) obtained from 2-fluoro-5-bromo-nitrobenzene in tetrahydrofuran (30 mL) in the same manner as in reference examples 9 and 10 were added 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), and the resulting mixture was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (0.33 g, 5.2 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated. The residue was purified by a silica gel column (dichloromethane: methanol = 99:1-95:5) to obtain the objective 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 methylene chloride (10 mL) were added di-tert-butyl dicarbonate (1.4 g, 6.5 mmol) and diisopropylethylamine (0.33 mL, 1.95 mmol), and the resulting mixture was stirred at 80 ℃ 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 = 99:1-97:3) to obtain the objective product (500 mg, 82%).

Reference example 57:

to a solution (3:1, 4 mL) of the compound obtained in reference example 56 (50 mg, 0.11 mmol) in an aqueous acetonitrile solution was added 4-chlorophenylboronic acid (34 mg, 0.22 mmol), a3 mol/L aqueous sodium hydrogencarbonate solution (90. mu.L) and tetrakis (triphenylphosphine) palladium (13 mg, 0.00112 mmol), and the mixture was stirred at 85 ℃ for 5 hours under an argon atmosphere. The reaction mixture was filtered through celite and the filtrate was concentrated. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue for partitioning. The organic layer was washed with water, dried and concentrated. The residue was purified by column on silica gel (ethyl acetate alone) to give the objective product (48 mg, 90%).

Example 191: N²- { [5- (4-chlorophenyl) -1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide hydrochloride

From the compound (48 mg, 0.10 mmol) obtained in reference example 57 in hydrochloric acid-bisThe resulting solution in alkane (3 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the resulting powder was washed with diethyl ether to give the desired product (25 mg, 76%).

Example 192: N²- { [1- (2-ethoxyethyl) -5- (4-methoxyphenyl) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide trifluoroacetate salt

To a solution (3 mL) of the compound (62 mg, 0.13 mmol) obtained in the above-mentioned reference example in methylene chloride was added trifluoroacetic acid (0.3 mL) under ice-cooling. The mixture was warmed to room temperature and then stirred for 1 hour. The reaction mixture was concentrated and recrystallized from ether to give the objective product (48 mg, 76%).

Example 193-208:

the compounds shown in table 32 were prepared according to the methods described in the above-mentioned reference examples and examples or methods similar to these methods.

The compounds were identified by LC/MS spectra and retention times according to any of the following methods.

Analysis Condition 1

A detection instrument: LCMS/MS API2000 (manufactured by Applied Biosystems)

Column: phenomenex Gemini C184.6X50 mm, 5 μm

Detection wavelength: 220 nm and 260 nm

Flow rate: 1.2 mL/min

Elution solvent composition: solution A: 0.05% aqueous TFA, 0.05% aqueous HCOOH or 10 mM aqueous ammonium acetate, solution B: acetonitrile

Gradient: 0-0.01 min B10%, 0.01-1.50 min B10% -30%, 1.50-3.00 min B30% -90%, 3.00-4.00 min B90%, 4.00-5.00 min B90% -10%

Analysis Condition 2

A detection instrument: LCMS/MS API2000 (manufactured by Applied Biosystems)

Column: phenomenex Gemini C184.6X50 mm, 5 μm

Detection wavelength: 220 nm and 260 nm

Flow rate: 1 mL/min

Gradient: 0-0.01 min B5%, 0.01-1.00 min B5%, 1.00-7.00 min B5% -50%, 7.00-10.00 min B50% -90%, 10.00-11.00 min B90%, 11.00-12.00 min B90% -5%.

[ Table 32-1]

[ Table 32-2]

Reference example 58:

to a solution (25 mL) of iron (3.7 g, 66mmol) and ammonium chloride (1.04 g, 19 mmol) in a mixed solvent of tetrahydrofuran-methanol-water (3:2:1) was added dropwise a solution (25 mL) of the compound (1.7 g, 6.9 mmol) obtained in reference example 18 in a mixed solvent of tetrahydrofuran-methanol-water (3:2:1) at 70 ℃. After 1.5 hours, the mixture was cooled to room temperature and the reaction mixture was filtered through celite. The filtrate was concentrated, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give the desired product (1.32 g, 89%). The product was used in the subsequent reaction without purification.

Reference example 59:

the objective product was obtained in the same manner as in reference examples 4,5, 55 and 56.

Reference implementationExample 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) were added potassium phosphate (60 mg, 0.28 mmol), palladium acetate (3.2 mg, 0.014 mmol) and 2-dicyclohexylphosphorus-2 ',6' -dimethoxybiphenyl (S-phos) (11.6 mg, 0.0038 mmol), and the mixture was stirred at 100 ℃ for 14 hours under an argon atmosphere. After cooling, the reaction mixture was filtered through celite and then washed with methanol. The filtrate was concentrated, ethyl acetate was added thereto, and the mixture was washed with a saturated aqueous sodium bicarbonate solution and saturated brine, dried and concentrated. The residue was purified by a silica gel column (ethyl acetate: hexane = 65:35) to obtain the objective product (43 mg, 52%).

Example 209: N²- { [3- (2-ethoxyethyl) -5- (4-methylphenyl) -3H-imidazo [4,5-b]Pyridin-2-yl]Methyl } -L-alaninamide hydrochloride

To the compound (34 mg) obtained in reference example 60 in II under ice-coolingTo the resulting solution in alkane (1 mL) was added 4 mol/L hydrochloric acid-bisAlkane (2 mL). The mixture was warmed to room temperature and then stirred for 10 hours. The reaction mixture was concentrated, and the resulting powder was washed with diethyl ether to give the objective product (28 mg, 95%).

Example 210-226:

the compounds shown in table 33 were prepared according to the methods described in the above-mentioned reference examples and examples or methods similar to these methods.

The compounds were identified by LC/MS spectra and retention times under conditions similar to those described above.

[ Table 33-1]

[ Table 33-2]

[ tables 33-3]

Example 227-:

the compounds of example 227-237 shown in Table 34 and Table 35 were prepared in the same manner as in reference examples 18-20 and example 79.

[ Table 34]

[ Table 35]

The compounds shown in tables 36 to 38 were prepared according to the methods described in the above-mentioned reference examples and examples or methods similar thereto.

[ Table 36]

[ Table 37]

[ Table 38]

Experimental example 1

Inhibition experiment of TTX-resistant Na channel on human SNS gene expression cells

Human SNS gene-expressing cells were obtained by introducing a human SNS gene into Chinese hamster ovary cells (CHO-K1) and allowing stable expression thereof. Since CHO-K1 cells do not inherently have a TTX-resistant Na channel component, the TTX-resistant Na channel component of human SNS gene-expressing cells is SNS and the compounds of the invention are considered SNS inhibitors.

1) Confirmation of construction of human SNS-expressing cell and expression of SNS function

The full-length human SNS α subunit gene was introduced into an expression plasmid (pcDNA3.1Zeo (+)) having a Zeocin resistance gene, and the full-length Annexin II light chain gene was introduced into an expression plasmid (pcDNA3.1(+)) containing a Neomycin (Neomycin) resistance gene. Both genes were introduced into CHO-K1 cells simultaneously by using cationic liposome (lipofectamine) 2000, cultured in F-12 medium containing Neomycin (Neomycin) and Zeocin, and cells resistant to both drugs, i.e., cells containing both genes were selected. The strains resistant to both drugs were subjected to limiting dilution twice, and SNS gene-introduced cells were cloned. The SNS of the transgene was confirmed by RT-PCR, TTX-resistant components responsive to Na channel stimulation were detected by using membrane potential sensitive fluorescent indicators, and functional expression of SNS was confirmed.

2) Pharmacological Effect on TTX-resistant Na channels in human SNS Gene expressing cells

The SNS inhibitory effect of the compound of the present invention was evaluated by using the human SNS expressing cell obtained in the above 1. Specifically, a test compound was added to human SNS-expressing cells in advance, veratridine (50 μ M), a Na channel stimulator, was added in the presence of TTX (1 μ M) after about 30 minutes, the membrane potential (potential) was increased via a TTX-resistant Na channel, and then the inhibitory effect of the test compound on the increase of the membrane potential (potential) was evaluated.

3) Pharmacological evaluation method

The SNS inhibition rate of the test compound was determined by the following calculation formula.

SNS inhibition (%) = 100 × [ (peak veratridine stimulated without test compound) - (peak veratridine stimulated with test compound) ]/[ (peak veratridine stimulated without test compound) - (standard value without stimulation) ]

4) Test results

The compounds obtained in these examples were evaluated by the inhibitory effect on TTX-resistant Na channels of human SNS-expressing cells (SNS inhibition rate). As a result, the compound of the present invention was observed to show SNS inhibitory effect. SNS inhibition ratios (%) when the compound concentration was 12.5. mu.M are shown in tables 39 to 47.

[ Table 39]

[ Table 40]

[ Table 41]

[ Table 42]

[ Table 43]

[ Table 44]

[ Table 45]

[ Table 46]

[ Table 47]

Industrial applicability

The novel bicyclic heterocyclic compound of the present invention can be used as an excellent drug for the prophylaxis or treatment of pathologies generally involving SNS, in particular, diseases such as neuropathic pain, nociceptive pain, dysuria, multiple sclerosis and the like.

Claims

1. A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof:

wherein R is¹Is a hydrogen atom, and is a hydrogen atom,

l is-O-,

(a) a halogen atom,

(b) C_1-6an alkyl group, a carboxyl group,

(c) C_1-6a halogenated alkyl group,

(d) C_1-6an alkoxy group,

(e) C_1-6haloalkoxy, and

(f) the cyano group(s),

x is a carbon atom and is a hydrogen atom,

R³is that

(1) C_1-6Alkyl, optionally substituted with 1-3 substituents selected from:

(a) C_1-6an alkoxy group,

(b) a 4-8 membered saturated aliphatic heterocyclic group, and

(c) hydroxy, or

(2) C_3-8A cycloalkyl group,

R⁴is a hydrogen atom or a methyl group, and

R^5aand R^5bEach independently is a hydrogen atom or a methyl group, and

R⁶and R⁷Is a hydrogen atom;

provided that N is not included²- { [ 1-cyclopentyl-6-phenoxy-1H-benzimidazol-2-yl]Methyl glycinamide and N²- { [1- (2-ethoxyethyl) -6- (4-methoxyphenoxy) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide.

2.N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]A methyl group of a glycine amide,

or a pharmaceutically acceptable salt thereof.

3.N²- { [1- (2-ethoxyethyl) -6- (4-fluorophenoxy) -1H-benzimidazol-2-yl]Methyl } -2-methyl alaninamide or a pharmaceutically acceptable salt thereof.

4.N²- { [6- (2-chloro-4-fluorophenoxy)1- (2-ethoxyethyl) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide or a pharmaceutically acceptable salt thereof.

5.N²- { [ 1-Ethyl-6- (4-methylphenoxy) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide or a pharmaceutically acceptable salt thereof.

6.N²- { [1- (3-methoxypropyl) -6- (4-methylphenoxy) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide or a pharmaceutically acceptable salt thereof.

7.N²- { [6- (4-Methylphenoxy) -1- (tetrahydro-2H-pyran-4-yl) -1H-benzimidazol-2-yl]Methyl } -L-alaninamide or a pharmaceutically acceptable salt thereof.

8. A medicament for the prophylaxis or treatment of neuropathic pain, nociceptive pain, dysuria, or multiple sclerosis, comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

9. An SNS inhibitor comprising the compound of any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof as an active ingredient.

10. A pharmaceutical composition comprising a compound of any one of claims 1-7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.