WO2021187605A1 - Composé hétérocyclique carbonylé à fonction cyano en alpha contenant de l'azote - Google Patents

Composé hétérocyclique carbonylé à fonction cyano en alpha contenant de l'azote Download PDF

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WO2021187605A1
WO2021187605A1 PCT/JP2021/011242 JP2021011242W WO2021187605A1 WO 2021187605 A1 WO2021187605 A1 WO 2021187605A1 JP 2021011242 W JP2021011242 W JP 2021011242W WO 2021187605 A1 WO2021187605 A1 WO 2021187605A1
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group
substituted
halogen atom
cyano
piperidine
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PCT/JP2021/011242
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English (en)
Japanese (ja)
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拓也 肥後
渉 佐々木
秀憲 轟木
巧 池野
南実 長岡
葵 太田
賢治 諸熊
隆俊 金山
博幸 森友
佑介 加治原
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田辺三菱製薬株式会社
アステラス製薬株式会社
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Publication of WO2021187605A1 publication Critical patent/WO2021187605A1/fr

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
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    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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    • C07D—HETEROCYCLIC COMPOUNDS
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    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Definitions

  • histamine H 3 receptor agonist is particularly useful as a low central transition histamine H 3 receptor agonist
  • pharmaceutical compositions may be used for example as the active ingredient of the pharmaceutical composition for preventing or treating premature ejaculation, It relates to a nitrogen-containing heterocyclic ⁇ -cyanocarbonyl compound.
  • Ejaculatory dysfunction which is one of the male sexual dysfunctions, includes premature or rapid ejaculation, delayed ejaculation, complete inability to ejaculate, and retrograde ejaculation. And ejaculation pain (painful ejaculation) and the like.
  • Premature ejaculation is the most common ejaculatory disorder and has been reported to occur in about 4% of men.
  • premature ejaculation always or almost always ejaculates before or within about 1 minute after vaginal insertion, and it is not possible to delay ejaculation every time or almost every time during vaginal insertion. It is characterized by having self-negative results such as distress, anxiety, frustration or avoiding sexual intercourse (see, for example, Non-Patent Document 1).
  • premature ejaculation causes pain to the person or partner by reaching ejaculation earlier than the person desires before or shortly after insertion into the vagina.
  • Psychotherapy behavioral therapy and drug therapy are used to treat premature ejaculation with the aim of prolonging the latency from vaginal insertion to ejaculation during sexual intercourse and increasing patient and partner satisfaction.
  • Local anesthetics applied to the glans penis or selective serotonin reuptake inhibitors (SSRIs) are recommended by the guidelines of the American Urological Society as drugs that have been confirmed to have some efficacy in patients with premature ejaculation (for example,). See Non-Patent Document 2).
  • a local anesthetic such as a preparation containing a combination of benzocaine or lidocaine-prilocaine to the penis raises the threshold of the penile sensory nerve for sexual stimulation, and prolongation of ejaculatory latency has been confirmed.
  • local anesthetics can cause a local allergic reaction to one or both of the premature ejaculation patient and the partner, and the spread of the drug can result in reduced sexual satisfaction of the partner.
  • SSRI which is the other recommended therapeutic agent, is known to frequently cause dizziness and nausea as side effects, and has problems in terms of safety and convenience as a therapeutic agent for premature ejaculation. Is the current situation.
  • SSRI which is the other recommended therapeutic agent
  • Histamine is a physiologically active amine produced in mast cells, basophils, enterochromaffin-like cells or central neurons.
  • Histamine receptors H 1 , H 2 , H 3 , and H 4 , have been reported, all of which are G protein-coupled receptors.
  • Histamine H 3 receptors controls the adenylate cyclase activity through G i proteins by adjusting the cyclic adenosine monophosphate (cAMP) amount, are involved in vivo signaling.
  • cAMP cyclic adenosine monophosphate
  • Histamine H 3 receptors expressed in presynaptic central nervous system acts in the direction of suppressing the neuronal activity by reducing the production and release of histamine and other neurotransmitters, H 3 receptor antagonists awake It is known to have an action and a cognitive function improving action (see, for example, Non-Patent Document 3). Therefore, H 3 receptor agonists such as histamine to act on the H 3 receptors in the central nervous system, it is feared to cause deterioration of somnolence and cognitive function. Histamine H 3 receptors in peripheral sensory nerves are expressed in rodents, activation of histamine H 3 receptors have been reported to inhibit pain behaviors by mechanical stimuli (e.g., Non-Patent Documents See 4 and 5).
  • Non-Patent Documents 6 and 7 In male sexual function, histamine via the histamine H 1, H 2, and H 3 each receptor, to relax corpus cavernosum smooth muscle, likely to elicit an erection has been suggested (e.g., Non-Patent Documents 6 and 7). Further, erectile function by taking histamine H 2 receptor antagonists have been reported to decrease (e.g., see Non-Patent Document 7). However, there is no report on the role of histamine H 3 receptors in ejaculation.
  • Patent Documents 1 and 2 disclose nitrogen-containing heterocyclic carbonyl compounds. However, the compounds only discloses the antagonist of histamine H 3 receptor, agonist is not disclosed. Further, a compound having a cyano group at the ⁇ -position of the carbonyl group, such as that contained in the compound of the present invention, is not disclosed.
  • Patent Document 3 a compound having histamine H 3 receptor agonist activity are disclosed. However, the compound has a different structure from that of the present invention.
  • histamine H 3 receptor agonist is particularly useful as a low histamine H 3 receptor agonist of central migration, particularly a compound which can be used as an active ingredient of pharmaceutical composition for preventing or treating premature ejaculation ..
  • the histamine H 3 receptor agonist particularly expected as a preventive or therapeutic agent for premature ejaculation, particularly nitrogen-containing heterocyclic ⁇ -cyano carbonyl compounds are less centrally migratory, compounds for the prevention or treatment of premature ejaculation excellent histamine H 3 receptor agonist as, i.e. to complete the discovery to the present invention that the low histamine H 3 receptor agonist of central migration.
  • M and L are independent of each other and are single-bonded or indicate a linear alkylene group, and -X'-indicates -CR b R c- , -NR b- , or -O-.
  • R b and R c form an oxo group together, or independently of each other, a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic heterocyclic group, or -COR d and-.
  • R d is (i) an alkyl group which may be substituted; (ii) a cycloalkyl group which may be substituted; (iii) an alkoxy group which may be substituted; (iv) an amino which may be substituted.
  • R e is an optionally substituted aliphatic heterocyclic group, an aromatic substituted Selected from heterocyclic groups and optionally substituted aromatic hydrocarbon groups, d) optionally substituted aromatic heterocyclic groups, e) optionally substituted aliphatic heterocyclic groups, f). It is an alkoxy group which may be substituted, g) an aminocarbonyl group which may be substituted, and h) a carbonylamino group which may be substituted.
  • the pharmaceutical composition is a prophylactic or therapeutic agent for a disease selected from premature leakage, migraine, pain (eg, neuropathic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • Premature leakage migraine, pain (eg, neuropathic pain), asthma, rhinitis, which comprises administering to a subject an effective amount of the compound according to [1] or a pharmaceutically acceptable salt thereof.
  • [12] Described in [1] for the prevention or treatment of diseases selected from premature leakage, migraine, pain (eg, neuropathic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • diseases selected from premature leakage, migraine, pain (eg, neuropathic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • Compound or pharmaceutically acceptable salt thereof thereof.
  • the compound according to [12] or a pharmaceutically acceptable salt thereof, wherein the disease selected is premature ejaculation.
  • the present invention is selected from premature leakage, migraine, pain (eg, neurogenic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease, including the compounds of the invention or pharmaceutically acceptable salts thereof.
  • Prevention or treatment of diseases that are selected from pharmaceutical compositions, premature leaks, migraine, pain (eg, neurogenic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • it is selected from the use of the pharmaceutical composition of the present invention for the manufacture of a therapeutic drug, premature leakage, migraine, pain (eg, neurogenic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • Diseases selected from the use of the pharmaceutical compositions of the invention for the prevention or treatment of the disease premature leakage, migraine, pain (eg, neurogenic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • Premature leakage, migraine, pain (eg, neurogenic pain), asthma which comprises administering an effective amount of the pharmaceutical composition of the present invention for use in the prevention or treatment of the present invention to a subject. It also relates to methods of preventing or treating diseases selected from rhinitis, diabetes, pruritus, and ischemic heart disease.
  • the present invention contains a compound of the present invention which is a histamine H 3 receptor agonist or a salt thereof, a compound of the present invention or a salt thereof for use as a histamine H 3 receptor agonist, a compound of the present invention or a salt thereof.
  • the compounds of the invention or salts thereof for the prevention or treatment of the disease, premature leakage, migraine, pain (eg, neurogenic pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • Premature leakage, migraine, pain (eg, neurogenic) consisting of administering to a subject an effective amount of the compound of the present invention or a salt thereof for use in the prevention or treatment of a disease, and the compound of the present invention or a salt thereof. Pain), asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • the "subject” is a human or other animal in need of its prevention or treatment, and in one embodiment, a human in need of its prevention or treatment.
  • the present invention also relates to a preventive or therapeutic agent for premature ejaculation containing histamine H 3 receptor agonist as an active ingredient.
  • histamine H 3 receptor agonist but it may be any compound having histamine H 3 receptor agonist activity as described above, as one aspect, a compound or its salt of the formula (I) be.
  • Histamine H 3 receptor agonist in particular, of the compounds of the above formula (I) have histamine H 3 receptor agonist action, the pharmaceutical compositions comprising them, use as a prophylactic or therapeutic agent for premature ejaculation It is expected that it can be done.
  • the change in the number of firings before and after intravenous administration of 0.5 mg / kg of Imetit in Test Example 3 is shown.
  • the change in the number of firings before and after intravenous administration of 1 mg / kg of Imetit in Test Example 3 is shown.
  • Ciproxifan was intravenously administered at a dose of 1 mg / kg and then Imetit was intravenously administered at a dose of 1 mg / kg, and Imetit was intravenously administered at a dose of 1 mg / kg without Ciproxifan.
  • the change in the number of firings in the administered group is shown.
  • premature ejaculation means that ejaculation is always or almost always before or within about 1 minute after insertion, and that ejaculation is delayed every time or almost every time during vaginal insertion.
  • Diseases characterized by inability and self-negative consequences such as distress, anxiety, frustration or avoidance of sexual intercourse, or ejaculation faster than desired before or shortly after vaginal insertion It refers to a disease that causes pain to the person or a partner (see, for example, Non-Patent Document 1).
  • alkyl group is a monovalent group among linear or branched saturated hydrocarbon groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl. , Tert-butyl, n-pentyl, n-hexyl and the like.
  • the “alkylene group” is a divalent group among linear or branched saturated hydrocarbon groups.
  • the linear alkylene may be referred to as a linear alkylene or "-(CH 2 ) m- ", “-(CH 2 ) n- ", etc. in the present specification.
  • Examples of the linear alkylene include methylene, ethylene, trimethylene, tetramethylene and the like.
  • m and n represent integers and represent the number of carbon atoms of the linear alkylene. For example, when m is 0, ⁇ (CH 2 ) m ⁇ indicates a single bond, and when m is 1, ⁇ (CH 2 ) m ⁇ indicates methylene.
  • alkoxy group is a monovalent group in which the "alkyl group” is bonded to oxygen.
  • methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy and the like can be mentioned.
  • the "cycloalkyl group” is a saturated hydrocarbon ring group. Therefore, the "C 3-8 cycloalkyl group” is a saturated hydrocarbon ring group having 3 to 8 ring members, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group. Group etc. can be mentioned.
  • One embodiment is a saturated hydrocarbon ring group (C 3-6 cycloalkyl group) having 3 to 6 ring members, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Is a cyclopropyl group.
  • the "aliphatic heterocycle” is a 3- to 11-membered aliphatic heterocycle containing 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms as ring-constituting atoms, and 3 to 8 members.
  • the nitrogen atom may be oxidized to form an oxide or a dioxide.
  • monocyclic aliphatic heterocycles include azetidine, pyrrolidine, piperidine, piperazine, azepane, diazepane (eg homopiperazin), morpholine, thiomorpholine, oxetane, tetrahydrofuran, tetrahydropyran, dioxolane, dioxane, or tetrahydrothiopyran. And so on.
  • the "aliphatic heterocyclic group” is a 3 to 11-membered aliphatic heterocyclic group containing 1 to 3 heteroatoms selected from oxygen atom, sulfur atom, and nitrogen atom as ring constituent atoms. Includes ⁇ 8-membered monocyclic saturated heterocyclic groups (also referred to as monocyclic aliphatic heterocyclic groups) and 7-11 membered bicyclic saturated heterocyclic groups (also referred to as bicyclic aliphatic heterocyclic groups).
  • a sulfur atom or a nitrogen atom, which is a ring atom may be oxidized to form an oxide or a dioxide.
  • bicyclic aliphatic heterocyclic groups include, for example. And so on.
  • Examples of the aliphatic heterocyclic group containing a nitrogen atom in the heterocyclic atom and the substitution site being the nitrogen atom contained in the aliphatic heterocyclic group include an azetidino group, a pyrrolidino group, a piperidino group, and a piperazino group. Homopiperazino group, morpholino group, thiomorpholino group and the like can be mentioned.
  • aromatic hydrocarbon group is an aromatic composed of 6 to 10-membered carbon, and may be monocyclic or bicyclic.
  • a phenyl group or a naphthyl group can be mentioned, preferably a phenyl group.
  • aromatic heterocyclic group refers to 1 to 5 (preferably 1 to 3, more preferably 1 to 2) heterocyclic atoms selected from sulfur atoms, oxygen atoms, and nitrogen atoms in addition to carbon atoms. It is a 5- to 10-membered aromatic heterocyclic group containing), and includes a monocyclic aromatic heterocyclic group and a bicyclic aromatic heterocyclic group.
  • examples of the monocyclic aromatic heterocyclic group include a 5- to 6-membered monocyclic aromatic heterocyclic group, and specifically, a pyrrolyl group, a furanyl group, a thienyl group, an imidazolyl group, a pyrazolyl group, and the like.
  • Examples thereof include an oxazolyl group, an isoxazolyl group, a thiazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridadinyl group, a thiazinyl group, or a triazinyl group.
  • examples of the bicyclic aromatic heterocyclic group include a 9 to 10-membered bicyclic aromatic heterocyclic group, and specifically, an indrill group, an isoindrill group, an indazolyl group, a benzoimidazolyl group, a benzothiazolyl group, and a benzofuranyl group.
  • examples thereof include a group, a quinolyl group, an isoquinolyl group, an imidazopyridyl group, a benzopyranyl group and the like.
  • the "aromatic heterocyclic group which may be partially hydrogenated” means that the "aromatic heterocyclic group" may contain a group which is partially reduced by hydrogen. For example, if the "aromatic heterocyclic group" is partially reduced by hydrogen, Can be mentioned.
  • halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • the halogen atom is a fluorine atom.
  • Boc tert-butoxycarbonyl Cbz: benzyloxycarbonyl Ms: methanesulfonyl Ts: p-toluenesulfonyl Tf: trifluoromethanesulfonyl
  • aromatic heterocyclic group or aliphatic heterocyclic group of the optionally substituted aromatic heterocyclic group or the optionally substituted aliphatic heterocyclic group in A includes nitrogen, oxygen, and sulfur.
  • aromatic heterocyclic groups or aliphatic heterocyclic groups containing 1 to 3 selected atoms preferably aromatic heterocyclic groups containing 1 to 2 atoms selected from nitrogen, oxygen, and sulfur.
  • it is an aliphatic heterocyclic group, preferably an aromatic heterocyclic group containing one sulfur atom and one or two nitrogen atoms, or one or two atoms selected from a nitrogen atom and an oxygen atom.
  • aliphatic heterocyclic group more preferably selected from aromatic heterocyclic group or tetrahydropyranyl group, azetidinyl group, pyrrolidinyl group, and piperidinyl group selected from pyridyl group, pyrimidinyl group, and thiazolyl group. It is an aliphatic heterocyclic group, particularly preferably a pyridyl group or a tetrahydropyranyl group.
  • the "aromatic heterocyclic group or aliphatic heterocyclic group" of the aromatic heterocyclic group which may be substituted or the aliphatic heterocyclic group which may be substituted in A has 1 to 3 substituents.
  • the substituent of the aromatic heterocyclic group or the aliphatic heterocyclic group is preferably substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a halogen atom, a hydroxy group, and a cyano group.
  • Examples of the aromatic heterocyclic group in A include an aromatic heterocyclic group having 1 to 3 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, preferably containing 1 sulfur atom. It is an aromatic heterocyclic group containing one or two nitrogen atoms, and is particularly preferably an aromatic heterocyclic group selected from a pyridyl group, a pyrimidyl group, and a thiazolyl group, and particularly preferably a pyridyl group. be.
  • the aromatic heterocyclic group in A is preferably a 5- to 8-membered aromatic heterocyclic group, more preferably a 5- to 7-membered aromatic heterocyclic group, and particularly preferably a 5- to 6-membered aromatic heterocyclic group. It is a group heterocyclic group.
  • the substituent of the aromatic heterocyclic group in A is preferably a substituent selected from amino groups which may be substituted with a halogen atom and an alkyl group, and more preferably an amino group.
  • Examples of the aliphatic heterocyclic group in A include an aliphatic heterocyclic group having 1 to 3 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and preferably selected from a nitrogen atom and an oxygen atom. It is an aliphatic heterocyclic group containing one or two atoms to be used, more preferably an aliphatic heterocyclic group selected from a tetrahydropyranyl group, an azetididinyl group, a pyrrolidinyl group, and a piperidinyl group, and particularly preferably. It is a tetrahydropyranyl group.
  • the aliphatic heterocyclic group in A is preferably a 3 to 8 member aliphatic heterocyclic group, more preferably a 5 to 7 member aromatic heterocyclic group, and particularly preferably a 5 to 6 member fat. It is a group heterocyclic group.
  • aromatic heterocyclic group or aliphatic heterocyclic group of the optionally substituted aromatic heterocyclic group or the optionally substituted aliphatic heterocyclic group in A may be, for example, substituted.
  • a ring group can be mentioned.
  • A is a tetrahydropyranyl group that may be substituted with a pyridyl group or a halogen atom.
  • the substituent of the aliphatic heterocyclic group in A is a substituent selected from a halogen atom, a hydroxy group, a cyano group, an alkyl group, and an amino group which may be substituted with an alkyl group, and more preferably amino. It is a group.
  • Partial structure of A in equation (1) Preferred include 2-azetidinel group, 3-pyrrolidinyl group, 4-piperidinyl group, 4-tetrahydropyranyl group, 5-thiazolyl group, 4-pyridyl group, and 4-pyrimidinyl group.
  • 4-tetrahydropyranyl group and 4-pyridyl group are mentioned.
  • a and b represent, for example, 1 to 3 independently of each other, preferably 1 or 2 independently of each other, and more preferably 2 of both.
  • B is preferably an aliphatic heterocyclic group or the following formula (II).
  • Ra represents an optionally substituted alkyl group.
  • the piperidine ring in formula (II) may be substituted.
  • the aliphatic heterocyclic group is an aliphatic heterocyclic group which may contain a double bond in a part of the ring and may be substituted.
  • the aliphatic heterocyclic group is a monocyclic aliphatic heterocyclic group (for example, a 3- to 7-membered monocyclic aliphatic heterocyclic group containing 1 to 3 nitrogen atoms) or is substituted.
  • bicyclic aliphatic heterocyclic group It is also a good bicyclic aliphatic heterocyclic group, and the bicyclic aliphatic heterocyclic group is It is an aliphatic heterocyclic group selected from, more preferably a monocyclic aliphatic heterocyclic group, and even more preferably a monocyclic aliphatic heterocyclic group containing 1 to 3 nitrogen atoms.
  • a monocyclic aliphatic heterocyclic group selected from an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, and a homopiperazinyl group is particularly preferable, and more preferably selected from a piperidinyl group and a piperazinyl group. It is a monocyclic aliphatic heterocyclic group.
  • Partial structure including B in equation (1) As preferably And more preferably, it is a partial structure selected from the following. More preferably, it is a partial structure selected from the following. Particularly preferably, a partial structure selected from the following, Is.
  • the "aliphatic heterocyclic group" of the optionally substituted aliphatic heterocyclic group in B or the piperidine ring in the formula (II) may have 1 to 3 substituents, preferably one. You may be doing it.
  • the substituent of the aliphatic heterocyclic group or the piperidine ring in the formula (II) is substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a halogen atom, a hydroxy group, and a cyano group.
  • an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an alkoxy group; and a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • Aminocarbonyl groups that may be substituted with an alkyl group that may be substituted include substituents that are selected from, preferably substituents that are selected from a halogen atom, a cyano group, a halogen atom, and an alkoxy group.
  • the aliphatic heterocyclic group is preferably a 3- to 11-membered aliphatic heterocyclic group, more preferably a 4- to 7 monocyclic aliphatic heterocyclic group, and further preferably a 5- to 6-membered single. It is a cyclic aliphatic heterocyclic group, and particularly preferably a 6-membered monocyclic aliphatic heterocyclic group.
  • Ra is preferably an alkyl group that may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and more preferably an alkyl group.
  • M and L are independent of each other and either single bond or exhibit a linear alkylene group, preferably M indicates a linear alkylene group and L indicates a single bond, or M indicates a single bond and L indicates a single bond. It represents a linear alkylene group, more preferably M represents a linear alkylene group and L represents a single bond.
  • M and L are preferably each M is-(CH 2 ) m- , L is-(CH 2 ) n- (In the formula, m and n indicate 0, 1 or 2 independently of each other.) Indicated by.
  • -MX'-L- is preferably-(CH 2 ) m- X'-(CH 2 ) n- , and more preferably-(CH 2 ) m- CR b R c- (CH). 2 ) n- or-(CH 2 ) m- NR b- (CH 2 ) n- .
  • n and n preferably indicate m 0 to 2, n indicates 0 to 1, more preferably m indicates 1, n indicates 0, or m indicates 0 and n indicates 1. Particularly preferably, m represents 1 and n represents 0.
  • Is-(CH 2 ) m -X'-(CH 2 ) n- , m and n represent 0, 1 or 2 independently of each other.
  • R b and R c form an oxo group together, or independently of each other, a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic heterocyclic group, or -COR d and-.
  • R b and R c preferably combine to form an oxo group or independently of each other.
  • Hydrogen atom (I) A carbonylamino group which may be substituted with an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group, (ii) a hydroxycarbonyl group and (iii) a halogen atom.
  • An alkoxy group optionally substituted with a substituent selected from a hydroxy group, a cyano group, and an aromatic hydrocarbon group, a (iv) oxo group, a halogen atom, a hydroxy group, and a substituent selected from a cyano group.
  • a group R d is (I) Substituent with a substituent selected from an aliphatic heterocyclic group, a halogen atom, a hydroxy group, and a cyano group, which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group. May be an alkyl group; (ii) a cycloalkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; (iii) selected from a halogen atom, a hydroxy group, and a cyano group.
  • An aromatic hydrocarbon group optionally substituted with a substituent, a halogen atom, a hydroxy group, a cyano group, and an alkoxy group optionally substituted with a substituent selected from an alkoxy group;
  • halogen atom An aromatic heterocyclic group optionally substituted with a substituent selected from a hydroxy group and a cyano group, a halogen atom, a hydroxy group, and a cycloalkyl group optionally substituted with a substituent selected from a cyano group.
  • It may be substituted with a substituent selected from an alkyl group and an aliphatic heterocyclic group; and (vi) may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group. It may be substituted with a substituent selected from an alkyl group, a halogen atom, a hydroxy group, and a cyano group. It may be substituted with an aminocarbonyl group, a halogen atom, a hydroxy group, and a substituent selected from a cyano group.
  • Good aromatic hydrocarbon groups selected from.
  • R b and R c together form an oxo group or are independent of each other and are substituted with a hydrogen atom; a hydroxycarbonyl group, a carbonylamino group which may be substituted with an alkyl group, an aromatic hydrocarbon group.
  • R d is (I) Alkyl group optionally substituted with an aliphatic heterocyclic group optionally substituted with a halogen atom; (ii) Cycloalkyl group optionally substituted with a halogen atom; (iii) Aromatic hydrocarbon An alkoxy group which may be substituted with a group; (iv) an aromatic heterocyclic group, a cycloalkyl group which may be substituted with a halogen atom, and a substituent selected from a halogen atom and a cycloalkyl group.
  • Amino group optionally substituted with a substituent selected from an alkyl group (v) substituted with a halogen atom and a substituent selected from an alkyl group optionally substituted with a halogen atom.
  • R b is preferably Together with R c to form an oxo group, or independently of each other, a hydrogen atom; Hydroxycarbonyl group, carbonylamino group optionally substituted with alkyl group, alkoxy group optionally substituted with aromatic hydrocarbon group, aliphatic heterocyclic group optionally substituted with oxo group, alkyl group An alkyl group optionally substituted with a substituent selected from an aromatic heterocyclic group, a halogen atom, a hydroxy group, and a cyano group which may be substituted; or selected from -COR d and -SO 2 R d.
  • R d is An alkyl group optionally substituted with an aliphatic heterocyclic group which may be substituted with a halogen atom; a cycloalkyl group optionally substituted with a halogen atom; an alkoxy optionally substituted with an aromatic hydrocarbon group.
  • Amino group which may be substituted an aliphatic heterocyclic group which may be substituted with a substituent selected from a halogen atom, a haloalkyl group and an alkyl group; and an aminocarbonyl group which may be substituted with an alkyl group.
  • Halogen atoms, and aromatic hydrocarbon groups optionally substituted with substituents selected from cyano groups;
  • R b and R c are groups independently selected from the group consisting of hydrogen atom and -COR d, respectively.
  • R d is It may be substituted with an amino group which may be substituted with an alkyl group which may be substituted with a halogen atom; and a substituent selected from a halogen atom and an alkyl group which may be substituted with a halogen atom. Selected from aliphatic heterocyclic groups;
  • R c preferably forms an oxo group with R b or exhibits a hydrogen atom, more preferably a hydrogen atom.
  • Examples of the alkyl group of the "optionally substituted alkyl group” in R b and R c include a methyl group.
  • the alkyl group of the "optionally substituted alkyl group” in R b and R c may have 1 to 3 substituents, preferably 1 substituent.
  • Examples of the substituent of the alkyl group include a hydroxycarbonyl group, an acetylamino group, a methoxy group, a benzyloxy group, a morpholino group, a 2-oxopiperidino group, a 4-methylpyrazol-1-yl group, a halogen atom and a hydroxy group. And a cyano group.
  • aromatic heterocyclic group as the substituent of the "optionally substituted alkyl group” in R b and R c , for example, 1 to 1 to an atom selected from a nitrogen atom, an oxygen atom, and a sulfur atom.
  • An aromatic heterocyclic group having three is mentioned, preferably an aromatic heterocyclic group having one or two nitrogen atoms, and more preferably a pyrazolyl group.
  • the aromatic heterocyclic group preferably includes a 5- to 6-membered aromatic heterocyclic group, and more preferably a 5-membered aromatic heterocyclic group.
  • aromatic heterocyclic group as the substituent of the "optionally substituted alkyl group” in R b and R c may have 1 to 3 substituents, preferably one. You may do it.
  • substituent of the aromatic heterocyclic group include a methyl group.
  • Examples of the "aromatic heterocyclic group" of the “optionally substituted aromatic heterocyclic group” in R b and R c include a pyrazolyl group. Examples of the substituent of the "optionally substituted aromatic heterocyclic group” in R b and R c include a methyl group.
  • the aromatic hydrocarbon group in R b and R c is preferably a phenyl group.
  • the "group selected from -COR d and -COR d " in R b and R c is preferably -COR d .
  • R d in "groups selected from -COR d and -COR d " in R b and R c include, for example. It may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group. It may be substituted with an aliphatic heterocyclic group, a halogen atom, a hydroxy group, and a substituent selected from a cyano group. Alkyl group; may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • Cycloalkyl group may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • An alkoxy group that may be substituted with a substituent selected from a good aromatic hydrocarbon group, halogen atom, hydroxy group, cyano group, and alkoxy group; a substituent selected from a halogen atom, hydroxy group, and cyano group.
  • Examples include a substituent selected from an aminocarbonyl group optionally substituted with, a halogen atom, a hydroxy group, and an aromatic hydrocarbon group optionally substituted with a substituent selected from the cyano group;
  • a substituent selected from an aminocarbonyl group optionally substituted with, a halogen atom, a hydroxy group, and an aromatic hydrocarbon group optionally substituted with a substituent selected from the cyano group Preferably, an alkyl group optionally substituted with an aliphatic heterocyclic group optionally substituted with a halogen atom; a cycloalkyl group optionally substituted with a halogen atom; substituted with an alkoxy group or an aromatic hydrocarbon group.
  • an alkoxy group which may be substituted an aromatic heterocyclic group, a cycloalkyl group which may be substituted with a halogen atom, and an alkyl group which may be substituted with a substituent selected from a halogen atom and a cycloalkyl group.
  • Amino groups optionally substituted with selected substituents aliphatic heterocyclic groups optionally substituted with substituents selected from halogen atoms, haloalkyl groups, and alkyl groups; and alkyl groups substituted.
  • Examples include substituents selected from aminocarbonyl groups, halogen atoms, and aromatic hydrocarbon groups optionally substituted with substituents selected from cyano groups; More preferably, amino, N-ethylamino, N- (2,2,2-trifluoroethyl) amino group, N-ethyl-N-methylamino group, N- (4,4-difluorocyclohexyl) amino group, 3,3-Difluoropyrrolidino group, piperidino group, 4-fluoropiperidino group, 4,4-difluoropiperidino group, 4-trifluoromethylpiperidino group, morpholino group, 2,2-dimethyl-morpholin -4-yl group, 4-tetrahydropyranyl group, and 4,4-difluorocyclohexyl group. More preferably, it is a 4,4-difluoropiperidino group, a morpholino group, and a 4,4-difluorocycl
  • the "aliphatic heterocyclic group" as R d in the "group selected from -COR d and -SO 2 R d " in R b and R c is selected from, for example, nitrogen atom, oxygen atom, and sulfur atom. Examples thereof include an aliphatic heterocyclic group having 1 to 3 atoms to be formed, preferably an aliphatic heterocyclic group having 1 to 2 atoms selected from nitrogen atom and oxygen, and more preferably a pyrrolidino group.
  • the aliphatic heterocyclic group preferably includes a 5- to 8-membered aliphatic heterocyclic group, more preferably a 5- to 6-membered monocyclic aliphatic heterocyclic group, and particularly preferably a 6-membered aliphatic heterocyclic group. It is a monocyclic aliphatic heterocyclic group.
  • the aromatic hydrocarbon group as R d in the "group selected from -COR d and -SO 2 R d " in R b and R c is preferably a phenyl group.
  • R d may be substituted with a "substituted group selected from a halogen atom, a hydroxy group, and a cyano group" as R d in "a group selected from -COR d and -SO 2 R d " in R b and R c.
  • Cycloalkyl groups optionally substituted with substituents selected from aromatic heterocyclic groups, halogen atoms, hydroxy groups, and cyano groups, as well as halogen atoms, hydroxy groups, cyano groups, and halogen atoms, hydroxy groups, and It may be substituted with a substituent selected from a cyano group. It may be substituted with a substituent selected from a cycloalkyl group.
  • aromatic heterocyclic group examples include an aromatic heterocyclic group having 1 to 3 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, and preferably 1 or 3 nitrogen atoms. It is an aromatic heterocyclic group containing two, and more preferably a pyrimidinyl group.
  • Y is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, or a group selected from a) to h).
  • a) an optionally substituted cycloalkyl group b) a group represented by -SO 2 R e, R e is an optionally substituted aliphatic heterocyclic group, an aromatic substituted Selected from heterocyclic groups and optionally substituted aromatic hydrocarbon groups, c) optionally substituted aromatic hydrocarbon groups, d) optionally substituted aromatic heterocyclic groups, e).
  • Y is preferably a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, or a group selected from a) to h).
  • a) Halogen atom; hydroxy group; cyano group; and alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; may be substituted with a substituent selected from.
  • Cycloalkyl group b) a group represented by -SO 2 R e, R e is halogen atom, hydroxy group, cyano group, and a halogen atom, may be substituted with a substituent selected from hydroxy group and a cyano group,
  • An aliphatic heterocyclic group optionally substituted with a substituent selected from an alkyl group; an aromatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and Selected from aromatic hydrocarbon groups optionally substituted with substituents selected from halogen atoms, hydroxy groups, and cyano groups;
  • An aromatic heterocyclic group that may be substituted with a substituent selected from the carbonyl group; the aromatic heterocyclic group may be partially hydrogenated.
  • An alkyl group optionally substituted with a substituent of choice; a cycloalkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a halogen atom, a hydroxy group, and a cyano group.
  • R f is substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • R g may be substituted with a substituent selected from (i) halogen atom, (ii) halogen atom, hydroxy group, and cyano group, (iii) halogen atom, hydroxy.
  • a substituent selected from (i) halogen atom, (ii) halogen atom, hydroxy group, and cyano group (iii) halogen atom, hydroxy.
  • an alkoxy group optionally substituted with a substituent selected from a group and a cyano group, (iv) a halogen atom, a hydroxy group, a cyano group, and a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • a good aromatic heterocyclic group and an alkyl group optionally substituted with a substituent selected from (vi) halogen atom, hydroxy group and cyano group; substitution selected from halogen atom, hydroxy group and cyano group.
  • a substituent selected from an aromatic hydrocarbon group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group Select from an amino group, which may be; an aliphatic heterocyclic group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and a halogen atom, a hydroxy group, and a cyano group.
  • an alkoxy group that may be substituted with a substituent selected from halogen atoms, hydroxy groups, and cyano groups.
  • a carbonylamino group which may be substituted with an alkyl group, which may be substituted with a substituent of choice, Is.
  • Y is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, or a group selected from a) to h).
  • a) Halogen atom; hydroxy group; cyano group; and alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; may be substituted with a substituent selected from.
  • Cycloalkyl group b) a group represented by -SO 2 R e, R e is halogen atom, hydroxy group, cyano group, and a halogen atom, may be substituted with a substituent selected from hydroxy group and a cyano group,
  • An aliphatic heterocyclic group optionally substituted with a substituent selected from an alkyl group; an aromatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and Selected from aromatic hydrocarbon groups optionally substituted with substituents selected from halogen atoms, hydroxy groups, and cyano groups;
  • An aromatic heterocyclic group that may be substituted with a substituent selected from the carbonyl group; the aromatic heterocyclic group may be partially hydrogenated.
  • Halogen atom e) Halogen atom; Hydroxy group; Cyano group; Oxo group;
  • An alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and an alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • a cycloalkyl group optionally substituted with a substituent selected from halogen atoms, hydroxy groups, and cyano groups
  • An alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group
  • An alkyl group represented by —SO 2 R f wherein R f may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and a halogen atom, a hydroxy group, and a cyano.
  • An aromatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group, and (v) a substituent selected from a halogen atom, a hydroxy group and a cyano group.
  • a substituent selected from a halogen atom, a hydroxy group and a cyano group selected from an alkyl group optionally substituted with, a halogen atom, a hydroxy group, and a cycloalkyl group optionally substituted with a substituent selected from a cyano group, and selected from a halogen atom, a hydroxy group, and a cyano group.
  • Amino group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may be substituted with a substituent, Selected from;
  • An aliphatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; and an aliphatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group.
  • Y is a hydrogen atom, a hydroxy group, or a group selected from a) to h).
  • a) A cycloalkyl group which may be substituted with a substituent selected from a halogen atom and an alkoxy group b) a group represented by -SO 2 R e, R e is an aliphatic optionally substituted with an alkyl heterocyclic group; aromatic heterocyclic group; optionally substituted with a cyano group aromatic Group hydrocarbon groups; selected from c) An aromatic hydrocarbon group which may be substituted with a substituent selected from a cyano group, a hydroxycarbonyl group, and an alkoxycarbonyl group.
  • halogen atoms represented by -SO 2 R f; halogen atom, hydroxy group, cyano group, and may be substituted with a substituent selected from alkoxy alkyl group; a cycloalkyl group; an alkoxy group; oxo group It is a group, even if R f is substituted with an alkyl group and an alkyl group selected from an amino group; a group represented by -COR g, R g is (i) alkyl groups, (ii) Selected from alkoxy groups, (iii) aromatic heterocyclic groups, and amino groups optionally substituted with substituents selected from (iv) alkyl groups, cycloalkyl groups, and aromatic hydrocarbon groups; fats An aliphatic heterocyclic group which may be substituted with a substituent selected from the group heterocyclic group; and the aromatic heterocyclic group; f) Alkoxy group, g) an aminocarbonyl group that may be substituted with an alkoxy al
  • Y is preferably the above d) and e).
  • Y is preferably d) Halogen atom; hydroxy group; cyano group; alkyl group optionally substituted with substituents selected from halogen atom, hydroxy group and cyano group; substitution selected from halogen atom, hydroxy group and cyano group Selected from an alkoxy group optionally substituted with a group; and an aminocarbonyl group optionally substituted with an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; It is an aromatic heterocyclic group that may be substituted with a substituent, and the aromatic heterocyclic group may be partially hydrogenated, or is a group represented by e) -SO 2 R f.
  • R f is a halogen atom; a halogen atom, a hydroxy group, a cyano group, and an alkyl optionally substituted with a substituent selected from an alkoxy group optionally substituted with a halogen atom, a hydroxy group, or a cyano group.
  • Group May be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • Cycloalkyl group May be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • R g is (i) a halogen atom.
  • Amino group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may be substituted with a substituent, Selected from;
  • An aliphatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; and an aliphatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group.
  • Aromatic heterocyclic groups which may be substituted with a substituent selected from And More preferably d) Substituent with a substituent selected from a halogen atom; an oxo group; a cyano group; an alkyl group optionally substituted with a halogen atom; an alkoxy group; and an aminocarbonyl group optionally substituted with an alkyl group; It may be an aromatic heterocyclic group, and the aromatic heterocyclic group may be a partially hydrogenated aromatic heterocyclic group selected from the following.
  • halogen atoms represented by -SO 2 R f; halogen atom, hydroxy group, cyano group, and may be substituted with a substituent selected from alkoxy alkyl group; a cycloalkyl group; an alkoxy group; oxo group It is a group, even if R f is substituted with an alkyl group and an alkyl group selected from an amino group; a group represented by -COR g, R g is (i) alkyl groups, (ii) Selected from alkoxy groups, (iii) aromatic heterocyclic groups, and amino groups optionally substituted with substituents selected from (iv) alkyl groups, cycloalkyl groups, and aromatic hydrocarbon groups; fats An aliphatic heterocyclic group which may be substituted with a substituent selected from the group heterocyclic group; and the aromatic heterocyclic group; Is.
  • Y is an aromatic heterocyclic group that may be substituted with a substituent selected from d) halogen atoms and alkoxy groups.
  • the aromatic heterocyclic group is a 5- to 6-membered monocyclic aromatic heterocyclic group containing 1 to 3 atoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom, or e. ) An aliphatic heterocyclic group that may be substituted with a halogen atom or an alkoxy group.
  • the "cycloalkyl group" of the "optionally substituted cycloalkyl group” in a) in Y is preferably a cyclohexyl group.
  • the "cycloalkyl group” of the “optionally substituted cycloalkyl group” in a) may have 1 to 3 substituents, preferably 1 to 2 substituents. May be.
  • substituent of the cycloalkyl group include a halogen atom and an alkoxy group.
  • R e substituted with preferably an aromatic heterocyclic group, optionally substituted with an alkyl group aliphatic heterocyclic group and cyano group
  • R e substituted with preferably an aromatic heterocyclic group, optionally substituted with an alkyl group aliphatic heterocyclic group and cyano group
  • examples thereof include a substituent selected from the aromatic hydrocarbon groups which may be substituted, and more preferably substituted with a pyridyl group, a piperazino group which may be substituted with an alkyl group, and a cyano group. It is a substituent selected from phenyl groups.
  • the aromatic hydrocarbon group in Y which may be substituted with c) is preferably a phenyl group.
  • the "aromatic hydrocarbon group" of the optionally substituted aromatic hydrocarbon group of c) in Y may have 1 to 3 substituents, preferably 1 substituent. You may.
  • the substituent of the aromatic hydrocarbon group is preferably a substituent selected from a cyano group, a hydroxycarbonyl group, and an alkoxycarbonyl group.
  • the aromatic heterocyclic group in Y which may be substituted with d) is preferably an aromatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom. , More preferably an aromatic heterocyclic group containing 1 to 2 nitrogen atoms, and even more preferably a pyridyl group, a pyrimidinyl group, a pyrazolyl group, and an imidazolyl group.
  • the aromatic heterocyclic group in which d) may be substituted in Y is preferably an aromatic heterocyclic group in which d) may be substituted in Y, which is a 5- to 6-membered aromatic heterocyclic group.
  • the "aromatic heterocyclic group" of the group may have 1 to 3 substituents, preferably 1 substituent.
  • the substituent of the aromatic heterocyclic group is preferably selected from a halogen atom, a cyano group, an alkyl group optionally substituted with a halogen atom, an alkoxy group, and an aminocarbonyl group optionally substituted with an alkyl group. It is a substituent to be used.
  • the aliphatic heterocyclic group in Y which may be substituted with e) is preferably an aliphatic heterocyclic group containing 1 to 2 atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom.
  • Examples include thiomorpholino groups and groups selected from the following: More preferably, a piperidino group, a morpholino group, and a group selected from the following can be mentioned.
  • the aliphatic heterocyclic group in Y which may be substituted with e) is preferably a 4- to 8-membered aliphatic heterocyclic group, and more preferably a 6 to 8-membered aliphatic heterocyclic group. ..
  • the "aliphatic heterocyclic group" of the aliphatic heterocyclic group in which e) may be substituted in Y may have 1 to 3 substituents, and preferably 1 to 2 substituents. You may have one.
  • the substituent of the aliphatic heterocyclic group is preferably halogen; oxo; an alkyl group that may be substituted with a substituent selected from a halogen atom and a hydroxy group; a cycloalkyl group; an alkoxy group; -COR g .
  • R g may be substituted with an alkyl group, an alkoxy group, and an amino group optionally substituted with a substituent selected from an alkyl group and an aromatic hydrocarbon group; indicated by SO 2 R f.
  • R f examples thereof include a substituent selected from an alkyl group and an amino group in which R f may be substituted with an alkyl group; an aliphatic heterocyclic group; and an aromatic heterocyclic group;
  • Examples of the "alkoxy group" in f) in Y include a methoxy group and an ethoxy group, preferably a methoxy group.
  • the alkoxy group may have 1 to 3 substituents, and preferably 1 to 2 substituents.
  • Examples of the substituent of the alkoxy group include a halogen atom, a hydroxy group, and a cyano group.
  • the aminocarbonyl group of g) in Y may have one or two substituents.
  • substituent of the aminocarbonyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like, and a methyl group is preferable.
  • the carbonylamino group of h) in Y may have one or two substituents, preferably one.
  • substituent of the carbonylamino group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and the like, and a methyl group is preferable.
  • A is an aromatic heterocyclic group or an aliphatic heterocyclic group
  • the aromatic heterocyclic group and the aliphatic heterocyclic group are both halogen atoms; hydroxy groups; cyano groups; alkyl groups which may be substituted with substituents selected from halogen atoms, hydroxy groups, and cyano groups;
  • the amino group may be substituted with an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; and may be substituted with a substituent selected from.
  • B is an aliphatic heterocyclic group which may contain a double bond in a part of the ring and may be substituted, or a substituent represented by the formula (II).
  • Ra is an alkyl group that may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • the aliphatic heterocyclic group and the piperidine ring in the formula (II) may all be substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; a halogen atom, a hydroxy group, and a cyano group.
  • An alkoxy group an alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, an alkoxy group, and a cyano group; and an alkyl group substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • M and L are independent of each other and either single bond or exhibit a linear alkylene group, and -X'-indicates -CR b R c- , -NR b- , or -O-.
  • R b and R c together to form an oxo group, or independently of each other, Hydrogen atom;
  • An alkoxy group optionally substituted with a substituent selected from a hydroxy group, a cyano group, and an aromatic hydrocarbon group, a (iv) oxo group, a halogen atom, a hydroxy group, and a substituent selected from a cyano group.
  • An aliphatic heterocyclic group optionally substituted with, (v) an aromatic complex optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • An alkyl group optionally substituted with a substituent selected from a ring group, a (vi) halogen atom, a (vii) hydroxy group, and a (viii) cyano group;
  • An aromatic heterocyclic group that may be substituted with an alkyl group that may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or selected from -COR d and -SO 2 R d.
  • a group R d is (I) Substituent with a substituent selected from an aliphatic heterocyclic group, a halogen atom, a hydroxy group, and a cyano group, which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group. May be an alkyl group; (ii) a cycloalkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; (iii) selected from a halogen atom, a hydroxy group, and a cyano group.
  • An aromatic hydrocarbon group optionally substituted with a substituent, a halogen atom, a hydroxy group, a cyano group, and an alkoxy group optionally substituted with a substituent selected from an alkoxy group;
  • halogen atom An aromatic heterocyclic group optionally substituted with a substituent selected from a hydroxy group and a cyano group, a halogen atom, a hydroxy group, and a cycloalkyl group optionally substituted with a substituent selected from a cyano group.
  • Alkyl may be substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • Amino group optionally substituted with a substituent selected from the group; (v) substituted with a halogen atom, a hydroxy group, a cyano group, and a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • An aliphatic heterocyclic group optionally substituted with a substituent selected from a good alkyl group; and (vi) an alkyl optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group. It may be substituted with a substituent selected from a group, a halogen atom, a hydroxy group, and a cyano group. It may be substituted with an aminocarbonyl group, a halogen atom, a hydroxy group, and a substituent selected from a cyano group.
  • Aromatic hydrocarbon groups selected from Y is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, or a group selected from a) to h), a) Halogen atom; hydroxy group; cyano group; and alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; may be substituted with a substituent selected from.
  • Cycloalkyl group b) a group represented by -SO 2 R e, R e is halogen atom, hydroxy group, cyano group, and a halogen atom, may be substituted with a substituent selected from hydroxy group and a cyano group,
  • An aliphatic heterocyclic group optionally substituted with a substituent selected from an alkyl group; an aromatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; and Selected from aromatic hydrocarbon groups optionally substituted with substituents selected from halogen atoms, hydroxy groups, and cyano groups;
  • An aromatic heterocyclic group that may be substituted with a substituent selected from the carbonyl group; the aromatic heterocyclic group may be partially hydrogenated.
  • Halogen atom Hydroxy group; Cyano group; Oxo group;
  • An alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, a cyano group, and a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
  • a cycloalkyl group optionally substituted with a substituent selected from halogen atoms, hydroxy groups, and cyano groups;
  • An alkoxy group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
  • An alkyl group represented by —SO 2 R f wherein R f may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group
  • An aromatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group, and (v) a substituent selected from a halogen atom, a hydroxy group and a cyano group.
  • a substituent selected from a halogen atom, a hydroxy group and a cyano group selected from an alkyl group optionally substituted with, a halogen atom, a hydroxy group, and a cycloalkyl group optionally substituted with a substituent selected from a cyano group, and selected from a halogen atom, a hydroxy group, and a cyano group.
  • Amino group which may be substituted with a substituent selected from aromatic hydrocarbon groups which may be substituted with a substituent, Selected from;
  • An aliphatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group; and an aliphatic heterocyclic group optionally substituted with a substituent selected from a halogen atom, a hydroxy group and a cyano group.
  • A is an aromatic heterocyclic group or an aliphatic heterocyclic group
  • the aromatic heterocyclic group and the aliphatic heterocyclic group are both substituted with a substituent selected from a halogen atom; a hydroxy group; a cyano group; an alkyl group; and an amino group optionally substituted with an alkyl group; May be Aliphatic heterocyclic group B may contain a double bond in a part of the ring and may be substituted, or formula (II).
  • Ra represents an alkyl group.
  • the aliphatic heterocyclic group and the piperidine ring in the formula (II) are both halogen atoms; cyano groups; alkyl groups which may be substituted with substituents selected from halogen atoms and alkoxy groups; and alkyl groups.
  • M and L are independent of each other and either single bond or exhibit a linear alkylene group, and -X'-indicates -CR b R c- , -NR b- , or -O-.
  • R b and R c combine to form an oxo group, or independently of each other, a hydrogen atom; substituted with a hydroxycarbonyl group, a carbonylamino group optionally substituted with an alkyl group, an aromatic hydrocarbon group.
  • an alkoxy group which may be substituted an aliphatic heterocyclic group which may be substituted with an oxo group, an aromatic heterocyclic group which may be substituted with an alkyl group, a halogen atom, a hydroxy group, and a cyano group.
  • An alkyl group that may be substituted with a substituent or a group selected from -COR d and -SO 2 R d.
  • R d is (I) Alkyl group optionally substituted with an aliphatic heterocyclic group optionally substituted with a halogen atom; (ii) Cycloalkyl group optionally substituted with a halogen atom; (iii) Aromatic hydrocarbon An alkoxy group optionally substituted with a group; (iv) substituted with an aromatic heterocyclic group, a cycloalkyl group optionally substituted with a halogen atom, and a substituent selected from a halogen atom and a cycloalkyl group.
  • halogen atoms represented by -SO 2 R f; halogen atom, hydroxy group, cyano group, and may be substituted with a substituent selected from alkoxy alkyl group; a cycloalkyl group; an alkoxy group; oxo group It is a group, even if R f is substituted with an alkyl group and an alkyl group selected from an amino group; a group represented by -COR g, R g is (i) alkyl groups, (ii) Selected from alkoxy groups, (iii) aromatic heterocyclic groups, and amino groups optionally substituted with substituents selected from (iv) alkyl groups, cycloalkyl groups, and aromatic hydrocarbon groups; fats An aliphatic heterocyclic group, which may be substituted with a substituent selected from the group heterocyclic group; and the aromatic heterocyclic group; f) Alkoxy group, g) an aminocarbonyl group optionally substituted with an alkoxy al
  • A is a pyridyl group or a tetrahydropyranyl group, and the tetrahydropyranyl group may be substituted with a halogen atom.
  • Both a and b are 2.
  • B is a piperidinyl group or a piperazinyl group, Is-(CH 2 ) m -X'-(CH 2 ) n- , m indicates 1 and n indicates 0, or m indicates 0 and n indicates 1.
  • -X'-indicates -CR b R c- or -NR b- R b and R c are groups independently selected from the group consisting of hydrogen atom and -COR d, respectively.
  • R d is It may be substituted with an amino group which may be substituted with an alkyl group which may be substituted with a halogen atom; and a substituent selected from a halogen atom and an alkyl group which may be substituted with a halogen atom.
  • the aromatic heterocyclic group is a 5- to 6-membered monocyclic aromatic heterocyclic group containing 1 to 3 atoms independently selected from an oxygen atom, a sulfur atom, and a nitrogen atom, or e.
  • An aliphatic heterocyclic group that may be substituted with a halogen atom or an alkoxy group.
  • A is a pyridyl group or a tetrahydropyranyl group, Both a and b are 2.
  • B is a piperidinyl group or a piperazinyl group, Is-(CH 2 ) m- CR b R c- (CH 2 ) n- or-(CH 2 ) m- NR b- (CH 2 ) n- .
  • R b and R c are each independently represented by a hydrogen atom; or -COR d , and are selected from an aliphatic heterocyclic group and a cycloalkyl group in which R d may be substituted with a halogen atom.
  • A is an aromatic heterocyclic group, Both a and b are 2.
  • B is a monocyclic aliphatic heterocyclic group, Is -MX'-L-, M and L are independent of each other and either single bond or exhibit a linear alkylene group.
  • An alkoxy group optionally substituted with a substituent selected from a hydroxy group, a cyano group, and an aromatic hydrocarbon group, a (iv) oxo group, a halogen atom, a hydroxy group, and a substituent selected from a cyano group.
  • An aliphatic heterocyclic group optionally substituted with, (v) an aromatic complex optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • An alkyl group optionally substituted with a substituent selected from a ring group, a (vi) halogen atom, a (vii) hydroxy group, and a (viii) cyano group;
  • An aromatic heterocyclic group that may be substituted with an alkyl group that may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; or selected from -COR d and -SO 2 R d.
  • a group R d is (I) Substituent with a substituent selected from an aliphatic heterocyclic group, a halogen atom, a hydroxy group, and a cyano group, which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • a substituent selected from an aliphatic heterocyclic group, a halogen atom, a hydroxy group, and a cyano group May be an alkyl group; may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; a cycloalkyl group may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • An alkoxy group optionally substituted with a substituent selected from an aromatic hydrocarbon group, a halogen atom, a hydroxy group, and a cyano group; a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • An aromatic heterocyclic group optionally substituted with, a cycloalkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group, and a halogen atom, a hydroxy group, a cyano group, and a It may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • Y is e) a halogen atom; a hydroxy group; a cyano group; an oxo group; a halogen atom, a hydroxy group, a cyano group, and an alkoxy group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • alkyl group which may be substituted with an alkyl group which may be substituted with an alkyl group which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group; at -COR g .
  • An aromatic complex optionally substituted with a substituent selected from a hydroxy group and a cyano group, an alkoxy group optionally substituted with a substituent selected from (iv) halogen atom, a hydroxy group, and a cyano group. It is substituted with a ring group and (v) a substituent selected from an alkyl group, a halogen atom, a hydroxy group, and a cyano group, which may be substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group.
  • the compound of [1] or a pharmaceutically acceptable salt thereof is mentioned.
  • A is an aromatic heterocyclic group, Both a and b are 2.
  • B is a monocyclic aliphatic heterocyclic group, Is -MX'-L-, M and L are independent of each other and either single bond or exhibit a linear alkylene group.
  • An alkyl group optionally substituted with a substituent selected from a halogen atom, a hydroxy group, and a cyano group;
  • Aromatic heterocyclic groups that may be substituted with alkyl groups; or groups selected from -COR d and -SO 2 R d.
  • R d is An alkyl group optionally substituted with an aliphatic heterocyclic group which may be substituted with a halogen atom; a cycloalkyl group optionally substituted with a halogen atom; an alkoxy optionally substituted with an aromatic hydrocarbon group.
  • R f is substituted with an alkyl group and an alkyl group selected from an amino group
  • a group represented by -COR g R g is (i) alkyl, ( Selected from ii) an alkoxy group, (iii) an aromatic heterocyclic group, and (iv) an amino group optionally substituted with a substituent selected from an alkyl group, a cycloalkyl group, and an aromatic hydrocarbon group.
  • An aliphatic heterocyclic group which may be substituted with a substituent selected from; an aliphatic heterocyclic group; and an aromatic heterocyclic group;
  • the compound of [1] or a pharmaceutically acceptable salt thereof is mentioned.
  • A is a pyridyl group Both a and b are 2.
  • B is a piperidinyl group or a piperazinyl group, Is-(CH 2 ) m- CR b R c- (CH 2 ) n- or-(CH 2 ) m- NR b- (CH 2 ) n- .
  • n indicates 0, and when m is 0, n indicates 1.
  • R b and R c independently represent a hydrogen atom or -COR d , respectively.
  • R d is an amino group that may be substituted with an alkyl group.
  • Y is selected from d) an aromatic heterocyclic group selected from pyridyl and pyrimidinyl groups, which may be substituted with a substituent selected from halogen atoms and alkoxy groups, or e) selected from halogen atoms and alkoxy groups.
  • Piperidino group, morpholino group, which may be substituted with a substituent examples thereof include the compound of [1], which is an aliphatic heterocyclic group selected from the above, or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of the formula (I) is A is a pyridyl group Both a and b are 2.
  • B is a piperidinyl group or a piperazinyl group, Is-(CH 2 ) m -CR b R c- (CH 2 ) n- , and m indicates 1, n indicates 0, Both R b and R c represent hydrogen atoms,
  • Y is d) A pyrimidinyl group that may be substituted with alkoxy, or e) An aliphatic heterocyclic group selected from a piperidino group and a morpholino group, which may be substituted with a halogen atom. Examples thereof include the compound of [1] or a pharmaceutically acceptable salt thereof.
  • A is a tetrahydropyranyl group, Both a and b are 2.
  • B is a piperidinyl group or a piperazinyl group, Is-(CH 2 ) m- CR b R c- (CH 2 ) n- or-(CH 2 ) m- NR b- (CH 2 ) n- .
  • m indicates 1, n indicates 0, R b and R c independently represent a hydrogen atom or -COR d , respectively.
  • R d is substituted with a substituent selected from a cycloalkyl group optionally substituted with a halogen atom; a cycloalkyl group optionally substituted with a halogen atom and an alkyl group optionally substituted with a halogen atom.
  • Y is selected from d) an aromatic heterocyclic group selected from pyridyl and pyrimidinyl groups, which may be substituted with a substituent selected from halogen atoms and alkoxy groups, or e) selected from halogen atoms and alkoxy groups.
  • a preferred embodiment of the formula (I) is A is a tetrahydropyranyl group, Both a and b are 2.
  • B is a piperidinyl group or a piperazinyl group, Is-(CH 2 ) m- CR b R c- (CH 2 ) n- or-(CH 2 ) m- NR b- (CH 2 ) n- .
  • m indicates 1, n indicates 0, R b and R c independently represent a hydrogen atom or -COR d , respectively.
  • a cycloalkyl group in which R d may be substituted with a halogen atom; an amino group optionally substituted with a substituent selected from an alkyl group optionally substituted with a halogen atom; and a halogen atom and a halogen.
  • Y is d) It may be substituted with a substituent selected from a halogen atom and an alkoxy group, an aromatic heterocyclic group selected from a pyridyl group and a pyrimidinyl group, or e) it may be substituted with a halogen atom, piperidino.
  • A is a tetrahydropyranyl group, Both a and b are 2.
  • B is a piperidinyl group or a piperazinyl group, Is-(CH 2 ) m- CR b R c- (CH 2 ) n- or-(CH 2 ) m- NR b- (CH 2 ) n- .
  • m indicates 1, n indicates 0,
  • R b and R c represent hydrogen atoms or -COR d independently of each other.
  • R d is selected from aliphatic heterocyclic groups and cycloalkyl groups which may be substituted with halogen atoms.
  • Y is d) A pyrimidinyl group that may be substituted with alkoxy, or e) An aliphatic heterocyclic group selected from a piperidino group and a morpholino group, which may be substituted with a halogen atom. Examples thereof include the compound according to [1] or a pharmaceutically acceptable salt thereof.
  • a preferred embodiment of the formula (I) is 4- [4- (2-Piperidin-1-ylethyl) piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 4- [4- (2-Morpholine-4-ylethyl) piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 4- [4- (2-Morpholine-4-ylethyl) piperazine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 4- [4- [4- [4- [2- (4-Methoxypiperidine-1-yl) ethyl] piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 1- (Pyridine-4-ylmethyl) -4- [4- [2- [3-oxa-6-azabicyclo [3.1.1
  • a preferred embodiment of the formula (I) is 4- [4- (2-Piperidin-1-ylethyl) piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 4- [4- (2-Morpholine-4-ylethyl) piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 4- [4- (2-Morpholine-4-ylethyl) piperazine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 4- [4- [4- [4- [2- (4-Methoxypiperidine-1-yl) ethyl] piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile, 1- (Pyridine-4-ylmethyl) -4- [4- [2- [3-oxa-6-azabicyclo [3.1.1
  • a preferred embodiment of the formula (I) is 4- [4-[(2S) -3- (4,4-difluoropiperidine-1-yl) -1-morpholine-4-yl-1-oxopropan-2-yl] piperazine-1-carbonyl] -1 -(Oxane-4-ylmethyl) piperidine-4-carbonitrile, N- [1- [4-Cyano-1- (oxane-4-ylmethyl) piperidine-4-carbonyl] piperidine-4-yl] -4,4-difluoro-N-[(2-methoxypyrimidine-5-yl) ) Methyl] cyclohexane-1-carboxyamide, 1- (Oxane-4-ylmethyl) -4- [4- [rel- (2R) -3- (4,4-difluoropiperidine-1-yl) -1-morpholin-4-yl-1-oxopropane- 2-Il] piperidine-1-
  • a pharmaceutical composition containing one or more of the compound of the present invention or a salt thereof as an active ingredient can be prepared by using a carrier usually used in the art, that is, a pharmaceutical excipient, a pharmaceutical carrier, or the like. It can be prepared by a commonly used method. Administration is oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or injections, suppositories, eye drops, eye ointments, transdermal liquids such as intra-articular, intravenous, intramuscular, etc. , Ointment, transdermal patch, transmucosal solution, transmucosal patch, parenteral administration with inhalant or the like.
  • a carrier usually used in the art that is, a pharmaceutical excipient, a pharmaceutical carrier, or the like. It can be prepared by a commonly used method.
  • Administration is oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or injections, sup
  • the solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active ingredients are mixed with at least one inert excipient.
  • the composition may contain an inert additive, such as a lubricant, a disintegrant, a stabilizer, or a solubilizing agent, according to conventional methods. Tablets or pills may be coated with a sugar-coated or gastrosoluble or enteric-coated film, if desired.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or elixirs, and are commonly used inert diluents such as purified. Contains water or ethanol.
  • the liquid composition may contain an auxiliary agent such as a solubilizer, a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, a fragrance agent, or a preservative in addition to the inert diluent.
  • an auxiliary agent such as a solubilizer, a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, a fragrance agent, or a preservative in addition to the inert diluent.
  • Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions.
  • aqueous solvent include distilled water for injection or physiological saline.
  • Non-aqueous solvents include alcohols such as ethanol.
  • Such compositions may further include tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or solubilizers. These are sterilized, for example, by filtration through a bacterial retention filter, formulation of a fungicide, or irradiation. In addition, these can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile injectable solvent before use.
  • the external preparation includes an ointment, a plaster, a cream, a jelly, a poultice, a spray, a lotion, an eye drop, an eye ointment, and the like.
  • the external preparation contains commonly used ointment bases, lotion bases, aqueous or non-aqueous liquids, suspensions, emulsions and the like.
  • the transmucosal agent such as an inhalant or a nasal agent
  • a solid, liquid or semi-solid one is used, and it can be produced according to a conventionally known method.
  • known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate.
  • a suitable device for inhalation or inhalation can be used.
  • a metered dose inhalation device or a nebulizer the compound is administered alone or as a powder of a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. be able to.
  • the dry powder inhaler or the like may be for single or multiple dose administration, and dry powder or powder-containing capsules can be used. Alternatively, it may be in the form of a pressurized aerosol spray or the like using a suitable propellant, for example a suitable gas such as chlorofluoroalkane or carbon dioxide.
  • a suitable propellant for example a suitable gas such as chlorofluoroalkane or carbon dioxide.
  • the daily dose that is, the effective amount is about 0.001 to 100 mg / kg, preferably 0.1 to 30 mg / kg, more preferably 0.1 to 10 mg / kg per body weight. kg is appropriate, and this is administered once or in 2 to 4 divided doses.
  • the daily dose is appropriately about 0.0001 to 10 mg / kg per body weight, and is administered once to multiple times a day.
  • the transmucosal agent about 0.001 to 100 mg / kg of body weight is administered once to a plurality of times a day. The dose is appropriately determined according to each individual case in consideration of symptoms, age, gender and the like.
  • the pharmaceutical composition of the present invention is 0.01 to 100% by weight, and in some embodiments 0.01 to 50% by weight, depending on the route of administration, dosage form, site of administration, or the type of excipient or additive. It contains one or more components of the present invention compound or a salt thereof.
  • compositions containing a histamine H 3 receptor agonists of the present invention as an active ingredient low histamine H 3 agonists useful diseases of the central transition, e.g., premature ejaculation, migraine, pain (e.g., neuropathic pain) , Asthma, rhinitis, diabetes, pruritus, and ischemic heart disease.
  • the disease selected is preferably a disease selected from premature ejaculation, migraine, pain, asthma, rhinitis, and pruritus, and more preferably a disease selected from premature ejaculation, migraine, and pain. Premature ejaculation is particularly preferred.
  • the prophylactic or therapeutic agent for premature ejaculation containing histamine H 3 receptor agonist as an active ingredient of the present invention is intended to extend the ejaculatory latency for example in premature ejaculation patients.
  • the ejaculation latency prolonging effect obtained as a result of taking the preventive or therapeutic agent is, for example, 1 times when calculated by the ratio of ejaculation latency before and after administration (ejaculation latency after administration ⁇ ejaculation latency before administration). (For example, 1 to 1.5 times, 1 to 2 times, 1 to 3 times, 1 to 5 times, or 1 to 10 times).
  • histamine H 3 receptor agonists of the present invention include histamine H 3 receptor selective agonist.
  • histamine H 3 receptor selective refers to Ki having the smallest binding inhibition constant (Ki) for histamine H 1 receptor, Ki for histamine H 2 receptor, and Ki for histamine H 4 receptor. divided by the Ki for the histamine H 3 receptor, refers to more than one times, preferably it refers to more than 10 times, more preferably refers to more than 100-fold, even more preferably greater than 1000-fold That is, especially preferably more than 5000 times.
  • histamine H 3 be a substance showing a receptor agonist activity antibody or low-molecular compound anything
  • histamine H 3 be a substance showing a receptor agonist activity antibody or low-molecular compound anything
  • histamine H 3 receptor agonist e.g., Nature, 1987, 327, p.117, Nature, 1983, 302, p.832, Journal of Pharmacology and Experimental Therapeutics, 1992, 263, p.304, Journal of Medicinal Chemistry, 1994, 37, p.332, and Journal of Medicinal Chemistry, 2004, 47, p.2414, etc.
  • the histamine H 3 receptor agonist is a compound or a salt thereof of the formula (I).
  • the compound of the present invention may have tautomers and geometric isomers depending on the type of substituent.
  • the compound of the present invention may be described in only one form of an isomer, but the present invention also includes other isomers, and separated isomers or mixtures thereof. Include.
  • the compound of the present invention may have an asymmetric carbon atom or an axial asymmetry, and an optical isomer based on this may exist.
  • the present invention also includes separated optical isomers of the compounds of the present invention, or mixtures thereof.
  • the present invention also includes pharmaceutically acceptable prodrugs of the compounds of the present invention.
  • a pharmaceutically acceptable prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like by solvolysis or under physiological conditions.
  • Examples of the groups forming prodrugs include the groups described in Prog. Med., 5, p.2157 (1985) and "Drug Development” (Hirokawa Shoten, 1990), Volume 7, Molecular Design p.163. Can be mentioned.
  • the salt of the compound of the present invention is a pharmaceutically acceptable salt of the compound of the present invention, and may form an acid addition salt or a salt with a base depending on the type of substituent.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, benzoic acid, oxalic acid, malonic acid, succinic acid, and fumal.
  • Organics such as acids, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyl tartaric acid, ditor oil tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid.
  • Acid addition salts with acids, salts with metal cations such as sodium, potassium, magnesium, and calcium
  • salts with organic bases such as methylamine, ethylamine, and ethanolamine, various types such as acetylleucine, lysine, and ornithine. Examples thereof include salts with amino acids and amino acid derivatives, ammonium salts and the like.
  • the present invention also includes various hydrates and solvates of the compounds of the present invention and salts thereof, and polymorphic substances.
  • the present invention also comprises compounds labeled with various radioactive or non-radioactive isotopes (eg, 2 H, 3 H, 13 C, 14 C, 15 N, 18 F, 32 P, 35 S, 125 I, etc.). Also includes.
  • the compound of the present invention and a salt thereof can be produced by applying various known synthetic methods by utilizing the characteristics based on the basic structure or the type of substituent. At that time, depending on the type of functional group, it is effective in terms of manufacturing technology to protect the functional group with an appropriate protecting group (a group that can be easily converted to the functional group) at the stage from the raw material to the intermediate. In some cases. Examples of such protecting groups include the protecting groups described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)" by PGM Wuts and TW Greene. , It may be appropriately selected and used according to these reaction conditions. In such a method, a desired compound can be obtained by introducing the protecting group, carrying out the reaction, and then removing the protecting group if necessary.
  • the prodrug of the compound of the present invention can be produced by introducing a specific group at the stage from the raw material to the intermediate, or by further reacting with the obtained Example compound, as in the case of the above-mentioned protecting group.
  • the reaction can be carried out by applying methods known to those skilled in the art, such as conventional esterification, amidation, and dehydration.
  • the compound of the present invention or a pharmacologically acceptable salt thereof can be produced, for example, as follows.
  • Synthesis method A [In the formula, A is an aromatic heterocyclic group which may be substituted or an aliphatic heterocyclic group which may be substituted, and B may contain a double bond in a part of the ring. , An aliphatic heterocyclic group which may be substituted, or the following formula (II).
  • R a represents alkyl which may be substituted.
  • Indicates, piperidine ring in formula (II) may be substituted, Is a single bond, -MX'-L- or -MX'-L-CH , where M and L are independent of each other, single bond or exhibit a linear alkylene group.
  • -X'-indicates -CR b R c- , -NR b- , or -O-, R b and R c indicate hydrogen atoms, optionally substituted alkyl groups, or groups selected from -COR d and -SO 2 R d, which form oxo together.
  • d is (i) an alkyl group which may be substituted; (ii) a cycloalkyl group which may be substituted; (iii) an alkoxy group which may be substituted; (iv) an amino group which may be substituted.
  • Y is a hydrogen atom, halogen atom, hydroxy group, cyano group, or A group selected from a) to h), a) an optionally substituted cycloalkyl group, b) a group represented by -SO 2 R e, R e is an optionally substituted aliphatic heterocyclic group, an aromatic substituted Selected from heterocyclic groups and optionally substituted aromatic hydrocarbon groups, c) optionally substituted aromatic hydrocarbon groups, d) optionally substituted aromatic heterocyclic groups, e).
  • LG represents a leaving group such as halogen atom, methanesulfonate, p-toluenesulfonate, and trifluoromethanesulfonate.
  • the compound represented by the general formula [Ia] can be produced, for example, as follows.
  • the compound represented by the general formula [c] is obtained by condensing the compound represented by [a-1] and the compound represented by the general formula [b].
  • the target product [Ia] can be produced by deprotecting this compound and subjecting the compound represented by the general formula [d] to the reductive amination of the compound [e] or the SN2 reaction with the compound [f]. can.
  • Condensation of compound [a-1] with compound [b] or a salt thereof is carried out according to a conventional method in a suitable solvent in the presence or absence of a base, in the presence of a condensing agent, in the presence of an activator or It can be carried out in the absence.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include ethers such as tetrahydrofuran, amides such as N, N-dimethylformamide, acetonitrile, and mixtures of two or more thereof.
  • the base include triethylamine, diisopropylethylamine, diazabicycloundecene and the like.
  • Examples of the condensing agent include O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU), 1-ethyl-3-. Examples thereof include (3-dimethylaminopropyl) carbodiimide hydrochloride, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride and the like.
  • Examples of the activator include 1-hydroxy-7-azabenzotriazole (HOAt), 1-hydroxybenzotriazole (HOBt), 4-dimethylaminopyridine and the like.
  • the amount of compound [a-1] used can be 1.0 to 10.0 equivalents, preferably 1.0 to 3.0 equivalents, in terms of molar ratio with respect to compound [b].
  • the amount of the base used can be 0 to 5.0 equivalents, preferably 0 to 2.0 equivalents, in terms of molar ratio with respect to compound [b].
  • the amount of the condensing agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in terms of molar ratio with respect to compound [a-1].
  • the amount of the activator used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.5 equivalents, in terms of molar ratio with respect to compound [a-1]. This reaction can be carried out at ⁇ 78 ° C. to room temperature, preferably 0 ° C. to room temperature.
  • Deprotection of compound [c] can be carried out according to a conventional method in a suitable solvent, in the presence or absence of an additive, and in the presence of an acid or a Lewis acid.
  • the solvent may be any solvent that does not affect this reaction, for example, ethers such as 1,4-dioxane and tetrahydrofuran, halogenated aliphatic hydrocarbons such as chloroform, and aromatic hydrocarbons such as toluene. , Acetonitrile, or mixtures of two or more of these.
  • the additive include water, tetraethylsilane, and the like.
  • Examples of the acid include hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, trifluoroacetic acid and the like.
  • Examples of the Lewis acid include triethylsilyl trifluoromethanesulfonate and the like.
  • the amount of the additive used can be 1.0 to 10.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [c].
  • the amount of the acid or Lewis acid used can be 1.0 to 10.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [c]. This reaction can be carried out at 0 ° C. to 80 ° C., preferably room temperature to 60 ° C.
  • Reductive amination of compound [d] or a salt thereof and compound [e] can be carried out according to a conventional method in a suitable solvent, for example, in the presence of a reducing agent and an acid or a Lewis acid.
  • the solvent may be any solvent that does not affect the reaction, for example, halogenated aliphatic hydrocarbons such as methylene chloride, alcohols such as methanol, ethers such as tetrahydrofuran, and aromatic hydrocarbons such as toluene. Types, or mixtures of two or more of these, and the like.
  • the reducing agent include sodium borohydride, sodium borohydride, hydrogen and a palladium catalyst (for example, a palladium catalyst supported on activated carbon) and the like.
  • Examples of the acid include acetic acid and the like.
  • Examples of the Lewis acid include titanium chloride (IV) and tetraisopropyl titanate.
  • the amount of compound [e] used can be 1 to 10 equivalents, preferably 1 to 5 equivalents, in terms of molar ratio with respect to compound [d].
  • the amount of the reducing agent used can be 1 to 10 equivalents, preferably 1 to 3 equivalents, in terms of molar ratio with respect to compound [d].
  • the amount of the acid or Lewis acid used can be 1 to 10 equivalents, preferably 1 to 3 equivalents, in terms of molar ratio with respect to compound [d]. This reaction can be carried out at ⁇ 10 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C.
  • the SN2 reaction between compound [d] or a salt thereof and compound [f] can be carried out in a suitable solvent, for example, in the presence or absence of a base, according to a conventional method.
  • the solvent may be any solvent that does not affect this reaction, for example, ethers such as tetrahydrofuran and 1,4-dioxane, aromatic hydrocarbons such as toluene, nitriles such as acetonitrile, water, or these. Two or more kinds of mixtures and the like can be mentioned.
  • Examples of the base include alkali metals such as hydrogen carbonate such as sodium hydrogen carbonate; alkali metals carbonate such as potassium carbonate, and inorganic bases such as alkali metals hydroxide such as sodium hydroxide; alkyl amines such as triethylamine and diisopropylethylamine. And pyridines such as pyridine and dimethylaminopyridine.
  • the amount of compound [f] used can be 1 to 10 equivalents, preferably 1 to 5 equivalents, in terms of molar ratio with respect to compound [d].
  • the amount of the base used can be 1 to 5 equivalents, preferably 2 to 3 equivalents, in terms of molar ratio with respect to compound [d].
  • This reaction can be carried out at room temperature to heating, for example, at room temperature to 100 ° C., preferably room temperature to 80 ° C.
  • the compound represented by the general formula [Ib] can be produced, for example, as follows.
  • the target product [Ib] can be produced by condensing the compound represented by the general formula [a] with the compound [b]. Condensation of compound [a] or a salt thereof with compound [b] or a salt thereof can be carried out in the same manner as the reaction of compound [a-1] and compound [b] in Synthesis Method A.
  • R 1 and R 2 together represent a cyclic amine, or independently represent a hydrogen atom, an alkyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group, respectively.
  • n represents 1 or 2
  • L represents the meaning described in the formula, and other symbols represent the same meanings as described above.
  • the compound represented by the general formula [Ic] can be produced, for example, as follows. First, among the compounds represented by the general formula [c] of the synthetic method A, the compound represented by the general formula [c-1] is halogenated or sulfonated with respect to the compound represented by the general formula [g]. The compound represented by the general formula [i] is obtained by the SN2 reaction with the compound [h]. This can be deprotected, converted to the compound represented by the general formula [j], and reductively aminated with the compound [e] to produce the target product [Ic].
  • the halogenated compound [g] can be produced by reacting compound [c-1] with a halogenating agent in a suitable solvent in the presence or absence of a phosphine derivative according to a conventional method.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include halogenated aliphatic hydrocarbons such as chloroform and dichloromethane.
  • the phosphine derivative include triarylphosphine such as triphenylphosphine and trialkylphosphine such as tributylphosphine.
  • the halogenating agent include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide and the like.
  • the amount of the phosphine derivative used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [c-1].
  • the amount of the halogenating agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [c-1]. This reaction can be carried out at 0 ° C. to 100 ° C., preferably room temperature.
  • the sulfonated compound [g] can be produced by reacting compound [c-1] with a sulfonylating agent in a suitable solvent in the presence of a base according to a conventional method.
  • the solvent may be any solvent that does not affect the reaction, for example, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane.
  • the base include alkylamines such as triethylamine and diisopropylethylamine, diazabicycloundecene, and pyridines such as pyridine and dimethylaminopyridine.
  • the sulfonylating agent examples include sulfonates such as methanesulfonic acid chloride and p-toluenesulfonic acid chloride, and sulfonic acid anhydrides such as methanesulfonic anhydride and trifluoromethanesulfonic anhydride. ..
  • the amount of the base used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [c-1].
  • the amount of the sulfonylating agent used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [c-1]. This reaction can be carried out at ⁇ 78 ° C. to 50 ° C., preferably ⁇ 30 ° C. to room temperature.
  • the SN2 reaction between the compound [g] and the compound [h] or a salt thereof can be carried out in the same manner as the reaction between the compound [f] and the compound [d] in the synthetic method A.
  • Deprotection of compound [i] can be carried out in the same manner as the reaction of compound [c] in synthesis method A.
  • the reductive amination of the compound [e] and the compound [j] or a salt thereof can be carried out in the same manner as the reaction of the compound [e] and the compound [d] in the synthetic method A.
  • R 3 and R 4 represent an alkyl group, an aryl group which may be substituted, or a heteroaryl group which may be substituted, and other symbols have the same meanings as described above. ]
  • the compound represented by the general formula [Id] can be produced, for example, as follows. First, among the compounds represented by the general formula [c] of the synthetic method A, the compound represented by the general formula [c-2] is represented by the general formula [l] by reductive amination with the compound [k]. The compound is obtained. This is N-acylated, converted to a compound represented by the general formula [m], and deprotected to obtain a compound represented by the general formula [n], which is the target product by reductive amination with the compound [e]. Ic] can be produced.
  • the reductive amination of the compound [c-2] and the compound [k] can be carried out in the same manner as the reaction of the compound [d] and the compound [e] in the synthetic method A.
  • the N-acyllation reaction of compound [l] can be carried out by reacting with an acylating agent in a suitable solvent in the presence of a base according to a conventional method.
  • Solvents include, for example, aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, nitriles such as acetonitrile, halogenation such as chloroform and dichloromethane.
  • Examples thereof include aliphatic hydrocarbons or a mixture of two or more of these.
  • the base include inorganic bases such as alkali metals hydrogen carbonate such as sodium hydrogen carbonate, alkali metals carbonate such as potassium carbonate, alkali metals hydroxide such as sodium hydroxide, and alkylamines such as triethylamine and diisopropylethylamine. Species, diazabicycloundecene, and organic bases such as pyridines such as pyridine and dimethylaminopyridine.
  • the acylating agent include acid chlorides such as chloride chloride and acid anhydrides such as acetate anhydride.
  • the amount of the acylating agent used can be 1.0 to 10.0 equivalents, preferably 1.5 to 2.5 equivalents, in terms of molar ratio with respect to compound [l].
  • the amount of the base used can be 1.0 to 10.0 equivalents, preferably 2.0 to 3.0 equivalents, in terms of molar ratio with respect to compound [l]. This reaction can be carried out at 0 ° C. to 50 ° C., preferably room temperature.
  • Deprotection of compound [m] can be carried out in the same manner as the reaction of compound [c] in synthesis method A.
  • the reductive amination of the compound [n] and the compound [e] can be carried out in the same manner as the reaction of the compound [d] and the compound [e] in the synthetic method A.
  • R 5 represents a protecting group such as an alkyl group
  • R 6 and R 7 represent a hydrogen atom or an alkyl group, and other symbols have the same meanings as described above.
  • the compound represented by the general formula [Ie] can be produced, for example, as follows. First, among the compounds represented by the general formula [c] of the synthetic method A, the compound represented by the general formula [c-3] is converted into the compound represented by the general formula [o] by intramolecular cyclization. The compound represented by the general formula [p] can be obtained by deprotection, and the target product [Ie] can be produced by reductive amination with the compound [e].
  • Intramolecular cyclization of compound [c-3] can be carried out in a suitable solvent in the presence of a base according to a conventional method.
  • the solvent may be any solvent that does not affect the reaction, for example, alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane. Examples thereof include amides such as dimethylformamide, nitriles such as acetonitrile, and mixtures of two or more of these.
  • Examples of the base include alkali metals carbonate such as potassium carbonate and cesium carbonate, alkali metals hydrides such as sodium hydride, and alkali metal alkoxides such as tert-butoxysodium and tert-butoxypotassium.
  • the amount of the base used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [c-3]. This reaction can be carried out at 0 ° C. to 50 ° C., preferably room temperature.
  • Deprotection of compound [o] can be carried out in the same manner as the reaction of compound [c] in synthesis method A.
  • the reductive amination of the compound [p] and the compound [e] can be carried out in the same manner as the reaction of the compound [d] and the compound [e] in the synthetic method A.
  • the compounds represented by the general formula [If-1] and the general formula [If-2] can be produced, for example, as follows. First, the compound represented by the general formula [d] of the synthetic method A and the general formula [q-1] or the general formula [q-2] are obtained by reductive amination of the compound [e-1] or the compound [e-2]. ], The target product [If-1] or the target product [If-2] can be produced by deprotection.
  • Reductive amination of compound [e-1] or compound [e-2] and compound [d] or a salt thereof is carried out in the same manner as the reaction of compound [e] and compound [d] in Synthesis Method A. be able to.
  • Deprotection of compound [q-1] or compound [q-2] can be carried out in the same manner as the reaction of compound [c] in synthesis method A.
  • Synthesis method G [In the formula, n indicates 0, 1, or 2, and other symbols have the same meanings as described above. ]
  • the compound represented by the general formula [Ig] can be produced, for example, as follows. First, among the compounds represented by the general formula [d] of the synthetic method A, the compound represented by the general formula [d-1] and the compound represented by the general formula [r] are obtained by reductive amination of the compound [e]. After being obtained, it can be converted into a compound represented by the general formula [s] by oxidation of an alcohol, and the target product [Ig] can be produced by reductive amination with the compound [h].
  • Reductive amination of compound [d-1] or a salt thereof and compound [e] can be carried out in the same manner as the reaction of compound [d] and compound [e] in synthesis method A.
  • the alcohol oxidation reaction of compound [r] can be carried out in a suitable solvent in the presence of an oxidizing agent according to a conventional method.
  • the solvent may be any solvent that does not affect this reaction, for example, halogenated aliphatic hydrocarbons such as methylene chloride, ethers such as tetrahydrofuran, aromatic hydrocarbons such as toluene, or 2 of these. Examples include more than one kind of mixture.
  • the oxidizing agent include Dess-Martin peryodinan (DMP) and o-iodoxybenzoic acid (IBX).
  • the amount of the oxidizing agent used can be 1 to 10 equivalents, preferably 1 to 3 equivalents, in terms of molar ratio with respect to compound [r]. This reaction can be carried out at ⁇ 10 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C.
  • the reductive amination of the compound [s] and the compound [h] or a salt thereof can be carried out in the same manner as the reaction of the compound [e] and the compound [d] in the synthetic method A.
  • Synthesis method H-1 [In the formula, P represents a protecting group such as a tert-butoxycarbonyl group (Boc) or a benzyloxycarbonyl group, and ring C represents an optionally substituted aromatic or aliphatic heterocycle. ]
  • the compound represented by the general formula [Ih] can be produced, for example, as follows. First, among the compounds represented by the general formula [Ib] of the synthetic method B, the compound represented by the general formula [t] can be obtained by deprotecting the compound represented by the general formula [Ib-1]. The target product [Ih] can be produced by reductive amination of this and the compound [u].
  • deprotection can be carried out by reacting in a suitable solvent in the presence of a catalyst and in a hydrogen atmosphere according to a conventional method. ..
  • the solvent may be any solvent that does not affect the reaction, for example, alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, and acetate. Examples thereof include esters such as ethyl, and mixtures of two or more of these.
  • the catalyst include palladium / carbon catalysts and the like.
  • the amount of the catalyst used can be 0.3 to 1.0, preferably 0.3, by weight with respect to the compound [Ib-1]. This reaction can be carried out at 0 ° C. to room temperature, preferably room temperature.
  • Reductive amination of compound [t] and compound [u] or a salt thereof can be carried out in the same manner as the reaction of compound [e] and compound [d] in synthesis method A.
  • the compound represented by the general formula [Ih] is obtained by reductive amination of the compound represented by the general formula [Ib-2] and the compound [v] among the compounds represented by the general formula [Ib] of the synthetic method B. It can also be manufactured.
  • Reductive amination of compound [Ib-2] and compound [v] or a salt thereof can be carried out in the same manner as the reaction of compound [e] and compound [d] in synthesis method A.
  • the compound [b] represented by the synthetic methods A and B can be produced by deprotecting the compound [A]. Deprotection of compound [A] can be carried out in the same manner as the reaction of compound [c] in synthesis method A.
  • the compounds represented by the general formula [A] in the intermediate synthesis method a are compound [B] and compound [C] or compound [D] and compound [ It can be produced by reducingly alkylating E].
  • Reductive amination of compounds [C] and [B] or salts thereof or compounds [D] and [E] or salts thereof is carried out in the same manner as the reaction of compounds [d] and compounds [e] in Synthesis Method A. can do.
  • R 8 represents a hydrogen atom, an alkyl group, or an optionally substituted carboxylamide group
  • Z 1 represents a nitrogen atom or C-R 9
  • R 9 is a hydroxyl group, an alkoxyl group, an alkyl group.
  • n represents 0 or 1
  • P represents a tert-butoxycarbonyl group, and other symbols represent the same meanings as described above.
  • the compound represented by the general formula [A-2] is subjected to reductive amination of the compound [F] and the compound [h].
  • the reductive amination of the compound [F] and the compound [h] or a salt thereof can be carried out in the same manner as the reaction of the compound [d] and the compound [e] in the synthetic method A.
  • the general formula [A-2] can also be produced by the SN2 reaction of compound [H] and compound [h] in which compound [G] is activated, or the SN2 reaction of compound [I] and compound [J].
  • Halogenation of compound [G] can be carried out in the same manner as the reaction of compound [c-1] in synthetic method C.
  • the sulfonate formation of the compound [G] can be carried out in the same manner as the reaction of the compound [c-1] in the synthetic method C.
  • the SN2 reaction between compound [H] and compound [h] or a salt thereof can be carried out in the same manner as the reaction between compound [d] and compound [f] in the synthetic method A.
  • the SN2 reaction between compound [I] and compound [J] or a salt thereof can be carried out in the same manner as the reaction between compound [d] and compound [f] in the synthetic method A.
  • the compound represented by the general formula [A] in the intermediate synthesis method a can be produced by sulfonamide formation of the compound [K] and the compound [L].
  • Sulfonamide formation of compound [K] or a salt thereof can be produced by reacting with a sulfonylating agent [L] in a suitable solvent in the presence of a base according to a conventional method.
  • the solvent may be any solvent that does not affect the reaction, for example, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, and ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane.
  • halogenated aliphatic hydrocarbons such as chloroform and dichloromethane
  • ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane.
  • Examples of the base include alkylamines such as triethylamine and diisopropylethylamine, diazabicycloundecene, and pyridines such as pyridine and dimethylaminopyridine.
  • the amount of the base used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [K].
  • the amount of compound [L] used can be 1.0 to 5.0 equivalents, preferably 1.0 to 2.0 equivalents, in terms of molar ratio with respect to compound [K]. This reaction can be carried out at ⁇ 78 ° C. to 50 ° C., preferably room temperature.
  • the compound represented by the general formula [A-4] can be produced by coupling the compound [K] and the compound [M].
  • Coupling of compound [K] or a salt thereof with compound [M] can be carried out according to a conventional method in a suitable solvent in the presence of a base, a ligand, and a catalyst.
  • the solvent may be any solvent that does not affect the reaction, for example, nitriles such as acetonitrile, aromatic hydrocarbons such as toluene and xylene, amides such as dimethylformamide, or two or more of these. Examples include mixtures.
  • the base include alkali metals carbonate such as potassium carbonate and cesium carbonate, and alkali metal alkoxides such as tert-butoxysodium and tert-butoxypotassium.
  • Examples of the ligand include bidentate phosphines such as Xantphos, BINAP, and BRETTPHOS.
  • Examples of the catalyst include palladium such as Pd (OAc) 2 , Pd 2 (dba) 3 , PdCl 2 (PPh 3 ) 2 , PdCl 2 (dppf) 2 , and Pd (PPh 3 ) 4 .
  • the amount of the base used can be 1.0 to 3.0 equivalents, preferably 1.2 equivalents, in terms of molar ratio with respect to compound [K].
  • the amount of compound [M] used can be 1.0 to 3.0 equivalents, preferably 1.2 equivalents, in terms of molar ratio with respect to compound [K].
  • the amount of the ligand used can be 0.1 to 1.0 equivalent, preferably 0.2 equivalent, in terms of molar ratio with respect to compound [K].
  • the amount of the catalyst used can be 0.05 to 0.5 equivalents, preferably 0.1 equivalents, in terms of molar ratio with respect to compound [K]. This reaction can be carried out at 50 ° C. to 120 ° C., preferably 80 ° C.
  • the compound represented by the general formula [A-5] can be produced by sulfonamide formation of the compound [N] and the compound [L].
  • Sulfonamide formation of compound [N] or a salt thereof and compound [L] can be carried out in a suitable solvent in the presence or absence of a base according to a conventional method.
  • the solvent may be any solvent that does not affect the reaction, for example, nitriles such as acetonitrile, halogenated aliphatic hydrocarbons such as chloroform and dichloromethane, tetrahydrofuran, 1,4-dioxane, and 1,2.
  • -Ethers such as dimethoxyethane, or a mixture of two or more of these can be mentioned.
  • Examples of the base include alkylamines such as triethylamine and diisopropylethylamine, diazabicycloundecene, and pyridines such as pyridine and dimethylaminopyridine.
  • the amount of the base used can be 1.0 to 5.0 equivalents, preferably 3 equivalents, in terms of molar ratio with respect to compound [N].
  • the amount of compound [L] used can be 1.0 to 5.0 equivalents, preferably 1.5 equivalents, in terms of molar ratio with respect to compound [N]. This reaction can be carried out at 0 ° C to 80 ° C, preferably at room temperature.
  • the compound represented by the general formula [A-6] can be produced by condensation of the compound [O] and the compound [h]. Condensation of compound [O] and compound [h] or a salt thereof can be carried out in the same manner as the reaction of compound [a-1] and compound [b] in Synthesis Method A.
  • R 10 represents a trifluoromethyl group, a methyl group, or a p-methylbenzyl group
  • L represents the meaning described in the formula
  • other symbols represent the same meanings as described above.
  • the compound represented by the general formula [A-7] is obtained by an epoxy ring-opening reaction between the compound [P] and the compound [h]. It can be produced by sulfonateizing the compound [Q] with the compound [L] and then reacting it with the compound [J] by SN2.
  • the epoxy cleavage reaction of compound [P] and compound [h] or a salt thereof can be carried out in a suitable solvent in the presence or absence of a base according to a conventional method.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include alcohols such as methanol, ethanol and isopropanol, nitriles such as acetonitrile, and a mixture of two or more of these.
  • the base include alkylamines such as triethylamine and diisopropylethylamine, and diazabicycloundecene.
  • the amount of the base used can be 1.0 to 3.0 equivalents, preferably 1.1 equivalents, in terms of molar ratio with respect to compound [P].
  • the amount of compound [h] used can be 1.0 to 3.0 equivalents, preferably 1.1 equivalents, in terms of molar ratio with respect to compound [P]. This reaction can be carried out at 0 ° C. to 100 ° C., preferably 80 ° C.
  • the sulfonate formation of the compound [Q] by the compound [L] can be carried out in the same manner as the reaction of the compound [c-1] in the synthetic method C.
  • the subsequent SN2 reaction with compound [J] or a salt thereof can be carried out in the same manner as the reaction between compound [d] and compound [f] in the synthetic method A.
  • the compound represented by the general formula [A] in the intermediate synthesis method a is obtained by an epoxy ring-opening reaction between the compound [R] and the compound [h].
  • the compound [S] is sulfonated with the compound [L] and then reacted with the compound [J] in SN2 to produce the compound [S].
  • the epoxy cleavage reaction of compound [R] and compound [h] or a salt thereof can be carried out in the same manner as the reaction of compound [P] and compound [h] in the intermediate synthesis method h.
  • the sulfonate formation of the compound [S] by the compound [L] can be carried out in the same manner as the reaction of the compound [c-1] in the synthetic method C.
  • the subsequent SN2 reaction with compound [J] or a salt thereof can be carried out in the same manner as the reaction between compound [d] and compound [f] in the synthetic method A.
  • the compound represented by the general formula [A-9] is obtained by an epoxy ring-opening reaction between the compound [R] and the compound [J]. It can be produced by sulfonaten the compound [T] with the compound [L] and then reacting it with the compound [h] by SN2.
  • the epoxy cleavage reaction of compound [R] and compound [J] or a salt thereof can be carried out in the same manner as the reaction of compound [P] and compound [h] in the intermediate synthesis method h.
  • the sulfonate formation of the compound [T] by the compound [L] can be carried out in the same manner as the reaction of the compound [c-1] in the synthetic method C.
  • the subsequent SN2 reaction with the compound [h] or a salt thereof can be carried out in the same manner as the reaction between the compound [d] and the compound [f] in the synthetic method A.
  • the compound represented by the general formula [A-10] is the compound [V] obtained by ⁇ -aminomethylation of the compound [U]. ] Is desorbed from E2, converted to compound [W], and then compound [h] or a salt thereof is added thereto.
  • ⁇ -Aminomethylation of compound [U] can be carried out according to a conventional method in a suitable solvent in the presence of a base and in the presence of an Eschenmoser reagent.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane.
  • the base include metal amides such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, and lithium tetramethylpiperidide.
  • the amount of the base used can be 1.0 to 3.0 equivalents, preferably 1.3 equivalents, in terms of molar ratio with respect to compound [U].
  • the amount of the Eschenmoser reagent used can be 1.0 to 3.0 equivalents, preferably 1.5 equivalents, in terms of molar ratio with respect to compound [U]. This reaction can be carried out at 0 ° C. to 100 ° C., preferably room temperature.
  • the ⁇ -methyleneation of compound [V] can be carried out according to a conventional method in a suitable solvent in the presence of iodomethane and a base.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include nitriles such as acetonitrile.
  • the base include alkali metals hydrogen carbonate such as sodium hydrogen carbonate, alkyl amines such as triethylamine and diisopropylethylamine, diazabicycloundecene, and a mixture of two or more thereof.
  • the amount of iodomethane used can be 1.0 to 3.0 equivalents, preferably 1.5 equivalents, in terms of molar ratio with respect to compound [V].
  • the amount of the base used can be 2.0 to 10.0 equivalents, preferably 3.5 equivalents, in terms of molar ratio with respect to compound [V].
  • This reaction can be carried out at 0 ° C. to 50 ° C., preferably room temperature.
  • the addition reaction of compound [W] and compound [h] or a salt thereof can be carried out according to a conventional method in a suitable solvent in the presence of a Lewis acid.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include halogenated aliphatic hydrocarbons such as chloroform, dichloromethane, and 1,2-dichloroethane.
  • the Lewis acid include lithium salts such as lithium chloride and lithium perchlorate.
  • the amount of compound [h] used can be 1.0 to 3.0 equivalents, preferably 1.5 equivalents, in terms of molar ratio with respect to compound [W].
  • the amount of the Lewis acid used can be 1.0 to 2.0 equivalents, preferably 1.0 equivalent, in terms of molar ratio with respect to compound [W].
  • This reaction can be carried out at 0 ° C. to 100 ° C., preferably 80 ° C.
  • the general formula [A-10] can also be produced by ⁇ -formylating compound [U] and reducing amination of the obtained compound [X] and compound [h].
  • the ⁇ -formylation of compound [U] can be carried out according to a conventional method in a suitable solvent in the presence of Brederek's reagent.
  • the solvent may be any solvent as long as it does not interfere with this reaction.
  • ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane
  • amides such as dimethylformamide, or two kinds thereof. Examples thereof include the above mixtures.
  • the amount of the Brederek reagent used can be 1.0 to 10.0 equivalents, preferably 3.0 equivalents, in terms of molar ratio with respect to compound [U]. This reaction can be carried out at room temperature to 120 ° C., preferably 100 ° C.
  • Reductive amination of compound [X] and compound [h] or a salt thereof can be carried out in the same manner as the reaction of compound [d] and compound [e] in synthesis method A.
  • the compound represented by the general formula [A-11] is a compound obtained by the aldol reaction of the compound [U] and the compound [Y]. It can be produced by sulfonating [Z], converting it to compound [AA], desorbing it from E2 to obtain compound [AB], and then hydrogenating it.
  • the aldol reaction of compound [U] and compound [Y] can be carried out according to a conventional method in a suitable solvent in the presence of a base.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane.
  • the base include metal amides such as lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, and lithium tetramethylpiperidide.
  • the amount of compound [Y] used can be 1.0 to 3.0 equivalents, preferably 1.1 equivalents, in terms of molar ratio with respect to compound [U].
  • the amount of the base used can be 1.0 to 3.0 equivalents, preferably 1.2 equivalents, in terms of molar ratio with respect to compound [U]. This reaction can be carried out at ⁇ 78 ° C. to room temperature, preferably ⁇ 78 ° C.
  • the sulfonated compound [Z] can be carried out in the same manner as the reaction of the compound [c-1] in the synthetic method C.
  • the ⁇ -methyleneation of compound [AA] can be carried out according to a conventional method in a suitable solvent in the presence of a base.
  • the solvent may be any solvent that does not affect this reaction, for example, aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane. Examples thereof include amides such as dimethylformamide, nitriles such as acetonitrile, or a mixture of two or more of these.
  • the base examples include alkali metals hydrogen carbonate such as sodium hydrogen carbonate, alkali metals carbonate such as potassium carbonate and cesium carbonate, alkali metals hydroxide such as sodium hydroxide, tert-butoxy sodium and tert-butoxy potassium.
  • alkali metal alkoxides such as alkylamines such as triethylamine and diisopropylethylamine, and diazabicycloundecene and the like.
  • the amount of the base used can be 1.0 to 3.0 equivalents, preferably 2.0 equivalents, in terms of molar ratio with respect to compound [AA]. This reaction can be carried out at 0 ° C. to 100 ° C., preferably 80 ° C.
  • Hydrogenation of compound [AB] can be carried out by reacting in a suitable solvent in the presence of a catalyst and in a hydrogen atmosphere according to a conventional method.
  • the solvent may be any solvent as long as it does not affect the reaction, for example, alcohols such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, and acetate. Examples thereof include esters such as ethyl, and mixtures of two or more of these.
  • the catalyst include a palladium / carbon catalyst, a Pearlman catalyst and the like.
  • the amount of the catalyst used can be 0.05 to 1.0, preferably 0.2 by weight, based on the compound [AB]. This reaction can be carried out at 0 ° C. to room temperature, preferably room temperature.
  • the compound represented by the general formula [a-2] is a compound obtained by reductive amination of the compound [AC] and the compound [e] [ It can be produced by hydrolyzing [AD].
  • Reductive amination of compound [AC] or a salt thereof and compound [e] can be carried out in the same manner as the reaction of compound [d] and compound [e] in synthesis method A.
  • Hydrolysis of compound [AD] can be carried out according to a conventional method in a suitable solvent in the presence of base and water.
  • the solvent may be any solvent that does not affect the reaction, for example, alcohols such as methanol, ethanol, and isopropanol, ethers such as tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane. Alternatively, a mixture of two or more of these may be mentioned.
  • the base include alkali metals hydroxide such as sodium hydroxide.
  • the amount of the base used can be 1.0 to 10.0 equivalents, preferably 1.0 to 3.0 equivalents, in terms of molar ratio with respect to compound [AC]. This reaction can be carried out at 0 ° C. to room temperature, preferably room temperature.
  • the compound represented by the general formula [a] in the synthetic method B is the compound [AG] obtained by the epoxy cleavage reaction of the compound [AE] and the compound [AF]. ] Can be produced by hydrolyzing.
  • the epoxy cleavage reaction of compound [AE] or a salt thereof and compound [AF] can be carried out in the same manner as the reaction of compound [P] and compound [h] in the intermediate synthesis method h.
  • Hydrolysis of compound [AG] can be carried out in the same manner as the reaction of compound [AD] in the synthetic method m.
  • the compound [AH] obtained by fluorination of the compound [AG] is hydrolyzed. Can be manufactured with.
  • Fluorination of compound [AG] can be carried out in a suitable solvent in the presence of a fluorinating agent according to a conventional method.
  • the solvent may be any solvent as long as it does not affect the reaction, and examples thereof include halogenated aliphatic hydrocarbons such as chloroform and dichloromethane.
  • the fluorinating agent include (diethylamino) sulfatrifluoride and the like.
  • the amount of the fluorinating agent used can be 1.0 to 5.0 equivalents, preferably 1.3 equivalents, in terms of molar ratio with respect to compound [AG]. This reaction can be carried out at ⁇ 78 ° C. to room temperature, preferably room temperature.
  • the raw material compound in the above method can be produced in the same manner as a known method and / or the method described in Examples described later.
  • the introduction of the protecting group into the functional group and the removal of the protecting group of the functional group are carried out by referring to a known method (PROTECTIVE GROUPS in ORGANIC SYNTHESIS (Theodora W. Greene, Peter GM Wuts, etc.)). be able to.
  • the compound of the present invention and the intermediate compound produced by the above method are further structurally converted into another target compound or an intermediate by the method described in Examples below and / or a known method or a combination thereof. can do. Specifically, the following methods can be mentioned.
  • N-Carbamate N-carbamate can be formed by reacting a nitrogen-containing compound with a carbamate agent.
  • N-carbamate can be formed by reacting with a carbamate agent (for example, methyl chloroformate) in a solvent (for example, chloroform or the like) and in the presence of a base (for example, N, N-diisopropylethylamine or the like).
  • a carbamate agent for example, methyl chloroformate
  • solvent for example, chloroform or the like
  • a base for example, N, N-diisopropylethylamine or the like.
  • N-Ureaization A nitrogen-containing compound can be converted to N-urea by reacting it with a urea agent.
  • N-urea can be formed by reacting with a urea agent (for example, isopropyl isocyanate) in a solvent (for example, chloroform or the like).
  • a urea agent for example, isopropyl isocyanate
  • a solvent for example, chloroform or the like
  • N-acyllation A nitrogen-containing compound can be N-acylated by reacting it with an acylating agent.
  • N-acyllation can be carried out by reacting with an acylating agent (for example, acetyl chloride) in a solvent (for example, chloroform or the like) and in the presence of a base (for example, N, N-diisopropylethylamine or the like).
  • an acylating agent for example, acetyl chloride
  • solvent for example, chloroform or the like
  • a base for example, N, N-diisopropylethylamine or the like.
  • N-Sulfonylation A nitrogen-containing compound can be N-sulfonylated by reacting it with a sulfonylating agent.
  • N-sulfonyl can be formed by reacting with a sulfonylating agent (eg, ethanesulfonic acid chloride, etc.) in a solvent (eg, chloroform, etc.) and in the presence of a base (eg, N, N-diisopropylethylamine, etc.).
  • N-alkylation A nitrogen-containing compound can be N-alkylated by reacting it with an alkylating agent.
  • N-alkylation can be carried out by reacting with an alkylating agent (for example, methyl iodide) in a solvent (for example, acetonitrile or the like) and in the presence of a base (for example, potassium carbonate or the like).
  • an alkylating agent for example, methyl iodide
  • solvent for example, acetonitrile or the like
  • a base for example, potassium carbonate or the like
  • the nitrogen-containing compound can be mixed with an aldehyde (eg, formaldehyde) in a solvent (eg, dichloromethane, etc.), in the presence of a base (eg, N, N-diisopropylethylamine, etc.), in the presence of a reducing agent (eg, sodium triacetoxyborohydride, etc.). By reacting, it can be N-alkylated.
  • a solvent eg, dichloromethane, etc.
  • a base eg, N, N-diisopropylethylamine, etc.
  • a reducing agent eg, sodium triacetoxyborohydride, etc.
  • N-Sulfamoylation can be achieved by reacting a nitrogen-containing compound with a sulfamoylating agent.
  • N-sulfamoylation can be achieved by reacting with a sulfamoylizing agent (eg, methylsulfamoyl chloride, etc.) in a solvent (for example, dichloromethane, etc.) in the presence of a base (for example, N, N-diisopropylethylamine, etc.).
  • a sulfamoylizing agent eg, methylsulfamoyl chloride, etc.
  • a solvent for example, dichloromethane, etc.
  • a base for example, N, N-diisopropylethylamine, etc.
  • N-aryllation (sulfamoylamine)
  • the nitrogen-containing compound can be converted to N-aryl by reacting with a compound having a halogen atom on the aryl.
  • a compound having a halogen atom on the aryl For example, in the presence of solvents (eg 1,4-dioxane, etc.), bases (eg, potassium phosphate, etc.), ligands (eg, Tetramethyl tBuXPhos), catalysts (eg, Pd 2 (dba) 3 ), aryl halides (eg, 2). It can be N-aryllated by reacting with -bromopyridine).
  • solvents eg 1,4-dioxane, etc.
  • bases eg, potassium phosphate, etc.
  • ligands eg, Tetramethyl tBuXPhos
  • catalysts eg, Pd 2 (dba) 3
  • aryl halides eg
  • ester can be converted to a tertiary alcohol by reacting with a nucleophile.
  • a compound having a corresponding tertiary alcohol can be produced by reacting a starting compound having an ester with a nucleophile (for example, a grineer reagent such as methylmagnesium bromide) in a solvent (for example, tetrahydrofuran). ..
  • ester can be converted to alcohol by reacting it with a reducing agent.
  • a compound having a corresponding alcohol can be produced by reacting a starting compound having an ester with a reducing agent (for example, lithium aluminum hydride) in a solvent (for example, tetrahydrofuran).
  • a reducing agent for example, lithium aluminum hydride
  • a solvent for example, tetrahydrofuran
  • a starting compound having a hydroxy group can be reacted by reacting it with an alkylating agent (for example, a methylating agent such as methyl iodide) in a solvent (for example, dichloromethane or the like) in the presence of a base (for example, sodium hydride or the like).
  • an alkylating agent for example, a methylating agent such as methyl iodide
  • a solvent for example, dichloromethane or the like
  • a base for example, sodium hydride or the like
  • a compound having a halogen atom can be converted to a corresponding cyano group by reacting it with a cyanating agent.
  • a compound having a corresponding cyano group can be produced by reacting a starting compound having a halogen atom with a cyanating agent (for example, sodium cyanide) in a solvent (for example, N, N-dimethylamide, etc.). ..
  • a compound having a halogen atom can be converted to a corresponding azide group by reacting it with an azizing agent.
  • a compound having a corresponding azido group can be produced by reacting a starting compound having a halogen atom with an azizing agent (for example, sodium azide) in a solvent (for example, N, N-dimethylamide, etc.). ..
  • a compound having a corresponding amino group can be produced by reacting a starting compound having an azide group with a reducing agent (for example, triphenylphosphine or the like) in a solvent (for example, a mixture of tetrahydrofuran and water).
  • a reducing agent for example, triphenylphosphine or the like
  • a solvent for example, a mixture of tetrahydrofuran and water
  • Examples 2-43 The corresponding raw material compound was treated in the same manner as in Example 1 to obtain the compounds shown in Table 1 below.
  • reaction mixture was subjected to solid-phase extraction with pora pack TM (20 cc, supported by methanol, eluted with 1 M ammonia methanol solution), the solvent was evaporated under reduced pressure, and 4- [4- (2-morpholine-4-ylethyl) piperazine was added. A crude product of -1-carbonyl] piperidine-4-carbonitrile was obtained.
  • Examples 45-101 The corresponding raw material compounds were treated in the same manner as in Example 44 to obtain the compounds shown in Table 2 below.
  • reaction mixture was subjected to solid-phase extraction with pora pack TM (20 cc, supported by methanol, eluted with 1 M ammonia methanol solution), and the solvent was evaporated under reduced pressure to 4- [4- (2-pyrrolidin-1-ylethyl)-.
  • TM pora pack
  • a crude product of 1,4-diazepan-1-carbonyl] piperidine-4-carbonitrile was obtained.
  • Examples 105-144 The corresponding raw material compounds were treated in the same manner as in Example 104 to obtain the compounds shown in Table 3 below.
  • reaction mixture was diluted with methanol, and the reaction mixture was subjected to solid-phase extraction with pora pack TM (20 cc, supported by methanol, eluted with 1 M ammonia methanol solution), and the solvent was evaporated under reduced pressure to form N, N-dimethyl-3.
  • a crude product of -morpholin-4-yl-2-piperazin-1-ylpropanamide (45.1 mg) was obtained.
  • Examples 146-183 The corresponding raw material compound was treated in the same manner as in Example 145 to obtain the compounds shown in Table 4 below.
  • HATU hexafluorophosphate
  • Examples 186-206 The corresponding raw material compounds were treated in the same manner as in Example 185 to obtain the compounds shown in Table 5 below.
  • Example 207 4- [4-[(2S) -1-morpholin-4-yl-3- (2-oxopiperidine-1-yl) propan-2-yl] piperazine-1-carbonyl] -1- (oxane-4- Production of ylmethyl) piperidine-4-carbonitrile (1) Of benzyl 4-[(2S) -1-chloro-3-morpholine-4-ylpropan-2-yl] piperazine-1-carboxylate (193 mg) and N, N-dimethylformamide (4 mL) Potassium tert-butoxide (170 mg) and 2-piperidone (60 mg) were added to the mixture, and the mixture was stirred at 100 ° C. for 17 hours.
  • Examples 211-224 By dividing the racemic mixture or diastereomer mixture produced in each of the above examples by chiral high performance liquid chromatography (chiral HPLC) or chiral supercritical fluid chromatography (chiral SFC), the compounds shown in Table 8 below can be obtained. Obtained.
  • Examples 226-260 The corresponding raw material compounds were treated in the same manner as in Example 225 to obtain the compounds shown in Table 9 below.
  • Example 261 Production of 4- [4- [2- (2-cyclopropylmorpholine-4-yl) ethyl] piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile hydrochloride (1) Acetate in a mixture of 4- [4- (2-oxoethyl) piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile (100 mg) and chloroform (2 mL). (15 ⁇ L) and 2-cyclopropylmorpholine (68 mg) were added and stirred at room temperature for 5 minutes, and sodium triacetoxyborohydride (113 mg) was added and stirred at room temperature for 2.5 hours.
  • a saturated aqueous potassium carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with chloroform.
  • the organic layer was separated by Phase-separator (registered trademark), and then the solvent was evaporated under reduced pressure.
  • a crude product of -yl) ethyl] piperidine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile was obtained.
  • Examples 263-270 The corresponding raw material compounds were treated in the same manner as in Example 262 to obtain the compounds shown in Table 10 below.
  • Example 271 (60.9 mg, yield 18%) was obtained as a colorless powder
  • Example 272 (104.4 mg, yield 30%) was obtained as a colorless powder.
  • HATU hexafluorophosphate
  • 2- (4,4-difluoropiperidine-1-yl) acetic acid 69 mg
  • N, N-diisopropylethylamine 186 ⁇ L
  • o- (7-azabenzotriazole-1-yl) -N, N , N', N'-tetramethyluronium hexafluorophosphate 167 mg
  • Examples 274-278 The corresponding raw material compounds were treated in the same manner as in Example 273 to obtain the compounds shown in Table 13 below.
  • Examples 280-283 The corresponding raw material compounds were treated in the same manner as in Example 279 to obtain the compounds shown in Table 14 below.
  • Examples 285-289 The corresponding raw material compounds were treated in the same manner as in Example 284 to obtain the compounds shown in Table 15 below.
  • Example 290 4-[[[1- [4-Cyano-1- (pyridin-4-ylmethyl) piperidine-4-carbonyl] piperidine-4-yl] -propanoylamino] methyl] production of benzoic acid tert-Butyl 4-[[[1- [4-cyano-1- (pyridin-4-ylmethyl) piperidine-4-carbonyl] piperidine-4-yl] -propanoylamino] methyl] benzoato (83.3 mg) To a mixture of dichloromethane (0.7 mL) and trifluoroacetic acid (0.3 mL) was added, and the mixture was stirred at room temperature for 1 hour.
  • Example 291 The corresponding raw material compounds were treated in the same manner as in Example 290 to obtain the compounds shown in Table 16 below.
  • Examples 293-298 The corresponding raw material compound was treated in the same manner as in Example 292 to obtain the compounds shown in Table 17 below.
  • reaction mixture was subjected to solid-phase extraction with pora pack TM (20 cc, supported by methanol, eluted with 1 M ammonia methanol solution), and the solvent was evaporated under reduced pressure to 4- [4- [2- [3-oxa-6-].
  • TM pora pack
  • a crude product of azabicyclo [3.1.1] heptan-6-yl] ethyl] piperidine-1-carbonyl] piperidine-4-carbonitrile was obtained.
  • a saturated aqueous potassium carbonate solution is added to the reaction mixture, the aqueous layer is extracted three times with chloroform, the organic layer is filtered through a Phase-separator (registered trademark), and the solvent is distilled off under reduced pressure to obtain tert-butyl N- [. 4-[[4-Cyano-4- [4- [2- [3-oxa-6-azabicyclo [3.1.1] heptane-6-yl] ethyl] piperidine-1-carbonyl] piperidine-1-yl ] Methyl] pyridine-2-yl] A crude product of carbamate was obtained.
  • Example 300 Production of 4- [4-[(4-methylmorpholine-3-yl) methyl] piperazine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile 37% formaldehyde in a mixture of 4- [4- (morpholine-3-ylmethyl) piperazine-1-carbonyl] -1- (pyridin-4-ylmethyl) piperidine-4-carbonitrile (147 mg) and methanol (3 mL) An aqueous solution (174 ⁇ L) was added and the mixture was stirred at room temperature for 10 minutes, and sodium triacetoxyborohydride (58 mg) was added and the mixture was stirred at room temperature for 6 hours.
  • the solvent of the reaction mixture was distilled off under reduced pressure, and acetonitrile (3 mL) and N-[[1- (4-cyanopiperidine-4-carbonyl) piperidine-4-yl] methyl] -N-methylmorpholine-4 were added to the residue.
  • -Sulfonamide (100 mg) and sodium carbonate (76.9 mg) were added, and the mixture was stirred at 50 ° C. for 22.5 hours.
  • a 10% aqueous potassium carbonate solution was added to the reaction mixture, and the aqueous layer was extracted 3 times with chloroform.
  • Trifluoroacetic acid (2 mL) was added to a mixture of the product (766 mg) and chloroform (4 mL), and the mixture was stirred at room temperature for 1 hour. By distilling off the solvent of the reaction mixture under reduced pressure, 4- [4-fluoro-4- (2-piperidine-1-ylethyl) piperidine-1-carbonyl] piperidine-4-carbonitrile 2,2,2-tri A crude product of fluoroacetate was obtained.
  • Example 303 (132 mg, yield 5 steps 14%) was obtained as a colorless powder.
  • Examples 307-333 The corresponding raw material compounds were treated in the same manner as in Example 306 to obtain the compounds shown in Table 22 below.
  • Reference examples 2-10 The corresponding raw material compounds were treated in the same manner as in Reference Example 1 to obtain the compounds shown in Table 23 below.
  • Reference Examples 12-18 The corresponding raw material compounds were treated in the same manner as in Reference Example 24 to obtain the compounds shown in Table 24 below.
  • Reference example 20-33 The corresponding raw material compounds were treated in the same manner as in Reference Example 19 to obtain the compounds shown in Table 25 below.
  • Reference example 35-97 The corresponding raw material compounds were treated in the same manner as in Reference Example 34 to obtain the compounds shown in Table 26 below.
  • Reference example 99-135 The corresponding raw material compounds were treated in the same manner as in Reference Example 98 to obtain the compounds shown in Table 27 below.
  • Reference example 137-169 The corresponding raw material compounds were treated in the same manner as in Reference Example 136 to obtain the compounds shown in Table 28 below.
  • Reference example 172 to 187 The corresponding raw material compound was treated in the same manner as in Reference Example 171 to obtain the compounds shown in Table 29 below.
  • Reference example 194-206 The corresponding raw material compound was treated in the same manner as in Reference Example 193 to obtain the compounds shown in Table 31 below.
  • Carbonyl-4-cyanopiperidine-4-carboxylic acid (50.5 mg), chloroform (1.5 mL), N, N-diisopropylethylamine (103 ⁇ L), and o- (7-azabenzotriazole-1-).
  • (Il) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) (90.6 mg) was added, and the mixture was stirred at room temperature for 16 hours.
  • Reference example 208-219 The corresponding raw material compounds were treated in the same manner as in Reference Example 207 to obtain the compounds shown in Table 32 below.
  • Reference example 221 The corresponding raw material compounds were treated in the same manner as in Reference Example 220 to obtain the compounds shown in Table 33 below.
  • Reference example 223 The corresponding raw material compounds were treated in the same manner as in Reference Example 222 to obtain the compounds shown in Table 34 below.
  • Reference example 225 The corresponding raw material compounds were treated in the same manner as in Reference Example 224 to obtain the compounds shown in Table 35 below.
  • Triazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) (209.6 mg) was added, and the mixture was stirred at room temperature for 19 hours, and tert-butyl 4-cyano- A solution containing 4- [7- (4-cyanophenyl) sulfonyl-2,7-diazaspiro [3.5] nonane-2-carbonyl] piperidin-1-carboxylate was obtained.
  • the tert-butyl 4-cyano-4- [7- (4-cyanophenyl) sulfonyl-2,7-diazaspiro [3.5] nonan-2-carbonyl] piperidin-1- obtained in (2).
  • Reference example 227 The corresponding raw material compounds were treated in the same manner as in Reference Example 226 to obtain the compounds shown in Table 36 below.
  • Reference Examples 229, 230 The corresponding raw material compounds were treated in the same manner as in Reference Example 228 to obtain the compounds shown in Table 37 below.
  • Reference example 232-273 The corresponding raw material compounds were treated in the same manner as in Reference Example 231 to obtain the compounds shown in Table 38 below.
  • Reference example 274 Production of tert-butyl 4-[(2S) -2-morpholin-4-yl-3-phenylmethoxypropyl] piperazine-1-carboxylate N, N-diisopropylethylamine (2.48 mL) was added to a solution of (2R) -1-morpholine-4-yl-3-phenylmethoxypropan-2-ol (1.50 g) in dichloromethane (25 mL). It was cooled at ⁇ 78 ° C. Trimethylsilyl trifluoromethanesulfonate (1.77 g) was gradually added, and the mixture was stirred at ⁇ 78 ° C. for 1 hour.
  • Reference example 275-285 The corresponding raw material compound was treated in the same manner as in Reference Example 274 to obtain the compounds shown in Table 39 below.
  • Reference example 287: 288 The corresponding raw material compounds were treated in the same manner as in Reference Example 286 to obtain the compounds shown in Table 40 below.
  • Reference example 290-309 The corresponding raw material compounds were treated in the same manner as in Reference Example 289 to obtain the compounds shown in Table 41 below.
  • Reference Examples 311 to 314 The corresponding raw material compounds were treated in the same manner as in Reference Example 310 to obtain the compounds shown in Table 42 below.
  • Reference example 317-330 The corresponding raw material compounds were treated in the same manner as in Reference Example 316 to obtain the compounds shown in Table 43 below.
  • Reference example 332, 333 The corresponding raw material compounds were treated in the same manner as in Reference Example 331 to obtain the compounds shown in Table 44 below.
  • Reference example 335-338 The corresponding raw material compounds were treated in the same manner as in Reference Example 335 to obtain the compounds shown in Table 45 below.
  • Reference example 340 The corresponding raw material compounds were treated in the same manner as in Reference Example 339 to obtain the compounds shown in Table 46 below.
  • Reference example 347 4- [Azetidine-3-ylmethyl (methyl) sulfamoyl] -N, N-Dimethylbenzamide production
  • tert-Butyl 3- (methylaminomethyl) azetidine-1-carboxylate (100.0 mg) was dissolved in chloroform (3 mL), and N, N-diisopropylethylamine (0.216 mL) and 4- Chlorosulfonylbenzoic acid (132.2 mg) was added, and the mixture was stirred at room temperature for 3 hours.
  • Reference example 349 The corresponding raw material compounds were treated in the same manner as in Reference Example 348 to obtain the compounds shown in Table 47 below.
  • Reference example 350 Production of tert-butyl 4- [1-methoxy-3- (oxane-4-yl) -1-oxopropan-2-yl] piperidine-1-carboxylate (1)
  • a 1.6 M n-butyllithium hexane solution (18.9 mL) was added dropwise to a solution of N, N-diisopropylethylamine (4.23 mL) in tetrahydrofuran (100 mL) at ⁇ 78 ° C. under an argon atmosphere. After stirring at ⁇ 78 ° C.
  • tert-butyl 4- (2-oxo-2-phenylmethoxyethyl) piperidine-1-carboxylate 8.37 g was dissolved in tetrahydrofuran (50 mL) and added dropwise. Added while. After stirring for another 20 minutes, 4-formyltetohydropyran (3.16 g) was dissolved in tetrahydrofuran (20 mL), added dropwise, and stirred at ⁇ 78 ° C. for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate.
  • the reaction solution was diluted with methanol, solid-phase extracted with pora pack TM (20 cc, supported by methanol, eluted with 1 M ammonia methanol solution), and then the solvent was distilled off under reduced pressure to obtain benzyl 4-[(2R)-.
  • a crude product of 1-amino-3-morpholin-4-ylpropan-2-yl] piperazine-1-carboxylate was obtained.
  • Dichloromethane (2 mL) was prepared as a crude product of benzyl 4-[(2R) -1-amino-3-morpholine-4-ylpropan-2-yl] piperazine-1-carboxylate obtained in (1).
  • Reference example 352 The corresponding raw material compounds were treated in the same manner as in Reference Example 351 to obtain the compounds shown in Table 48 below.
  • Reference example 356 Production of tert-butyl 4- (1-ethoxy-1,3-dioxopropan-2-yl) piperidine-1-carboxylate Dissolve tert-butyl 4- (2-ethoxy-2-oxoethyl) piperidine-1-carboxylate (3.12 g) in N, N-dimethylformamide (55 mL) and add Brederic reagent (7.12 mL). In addition, the mixture was stirred at 80 ° C. for 23 hours. Brederic reagent (7 mL) was added, the temperature was raised to 100 ° C., and the mixture was further stirred for 24 hours.
  • Trifluoromethanesulfonic acid 2,2,2-trifluoroethyl 0.054 mL
  • N, N-diisopropylethylamine 0.15 mL
  • the solvent of the reaction mixture was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform.
  • the organic layer was washed with water and saturated brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure.
  • the pharmacological activity of the compound of the present invention was confirmed by the following test.
  • Test Example 1 Evaluation Test of human histamine H 3 receptor agonist activity (1) human histamine H 3 receptor expression vector construct human histamine H 3 receptor gene (GenBank Accession No.: NM_007232.1) the expression vector pcDNA3.1 Introduced in (+) (registered trademark). (2) Construction human histamine H 3 receptor expression vectors for human histamine H 3 receptor stably expressing cell, CHO-K1 cells (ATCC No.: CCL-61) was introduced into. The introduction was carried out using the gene transfer reagent Lipofectoamine (registered trademark) 2000 reagent according to the attached instructions.
  • Drug-resistant cells were cultured in Dulbecco's Modified Eagle Medium (DMEM) containing 10% fetal bovine serum, 1% penicillin streptomycin, and 1.0 mg / mL Geneticin® at 37 ° C for 8 weeks at 5% CO 2. Obtained a clone. (3) Measurement of cAMP production using a 384-well plate The cells obtained in (2) above were used in 10% fetal bovine serum, 1% penicillin streptomycin, 0.5 mg / mL Geneticin®, and 4 mM L.
  • DMEM Dulbecco's Modified Eagle Medium
  • Assay buffer (Hanks balance salt solution, 20 mM 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid (HEPES, Sigma-Aldrich), 1 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma-) Aldrich), pH 7.4), dissolved in dimethyl sulfoxide (DMSO, Kanto Kagaku), and diluted with assay buffer (final concentration 3.1 pM to 0.1 ⁇ M, evaluation concentration selected suitable concentration for each compound , Common ratio 2,16 concentration) or histamine (Sigma-Aldrich, model number H7125, final concentration 3.1 pM to 0.1 ⁇ M, common ratio 2,16 concentration) was added.
  • BioCoat® Collagen I 96-well White Plate (Corning, model number 356699) to 1000 cells / well to 37 ° C, 5% CO 2 .
  • the medium was assay buffer (Hanks balance salt solution, 20 mM 4- (2-hydroxyethyl) -1-piperazine ethanesulfonic acid (HEPES, Thermo Fisher Scientific), 1 mM 3-isobutyl-1-methylxanthine (IBMX, Sigma-).
  • the reaction was then removed and cells were lysed with a 0.2% Triton X-100 (Sigma-Aldrich) -containing phosphate buffered saline (PBS) solution.
  • the amount of cAMP in the cytolytic solution was measured using the LANCE (registered trademark) Ultra cAMP Kit (PerkinElmer). That is, Eu-cAMP tracer solution and ULight (registered trademark) -anti-cAMP solution were added, and the mixture was allowed to stand at room temperature for about 1 hour.
  • EnVision® PerkinElmer
  • the fluorescence intensities of two wavelengths of 665 nm and 615 nm were measured, and the cAMP concentration in the solution was calculated from the fluorescence intensity ratio using the calibration curve method.
  • Agonist activity was calculated for efficacy (EC 50 (nM)) by the Sigmoid-Emax model nonlinear regression method.
  • Example 2 Evaluation of Example Compounds in Male Rat Mating Behavior Test
  • the one-hour mating behavior was filmed in video (HC-VX985M, Panasonic) night mode (infrared light) and recorded on a BD disc. The images recorded after the experiment were analyzed.
  • Table 50 shows changes in ejaculatory latency when some of the compounds of the present invention were administered.
  • the compounds of the present invention was confirmed to have histamine H 3 receptor agonist activity in in vitro, also latency prolongation in vivo as well was confirmed. Therefore, the compound of the present invention is useful as a preventive or therapeutic agent for premature ejaculation.
  • Ignition by brush stimulation of the penis was defined as induced ignition.
  • the induced ignition was determined by stimulating with a brush for 10 seconds and averaging two or more responses.
  • (3) Administration of test compound Imetit (Imetit dihydrobromide, Sigma-Aldrich) was used as the test compound. Imetit was dissolved in saline. The doses were 0.5 mg / kg and 1 mg / kg, which are equivalent to the free form.
  • the test compound was administered intravenously through a catheter placed in the femoral vein at a volume of 1 mL / kg.
  • Data analysis Data acquisition and analysis were performed using Spike2 (Cambridge Electro design). Brush stimulation-induced ignition before and after administration of the test compound was evaluated.
  • the average value of the number of brush stimulation-induced firings before administration of the test compound was set to 100%, and the change in the number of firings after administration of the test compound was compared by Student's t-test. The significance level was 5% on both sides. The number of cases per group was 12 to 14.
  • FIGS. 1 and 2 The changes in the number of firings before and after administration of the test compound are shown in FIGS. 1 and 2.
  • the number of inflammation induced by brush stimulation after administration of the test compound was significantly reduced.
  • the histamine H 3 receptor agonist inhibits peripheral nerves firing during penile stimulation, it can be said that results in a prolongation of the ejaculatory latency.
  • Micro1401-3 (Cambridge Electro design) was used for the interface.
  • a catheter (BD Intramedic Polyethylene Tubing PE 50, Becton, Dickinson) was inserted into the femoral vein and used for administration of the test compound.
  • Measurement parameters Ignition by brush stimulation of the penis was defined as induced ignition. The induced ignition was determined by stimulating with a brush for 10 seconds and averaging two or more responses.
  • test compounds were dissolved in physiological saline, adjusted to a dose equivalent to 1 mg / kg in a free form, and intravenously administered in a volume of 1 mL / kg from a catheter placed in the femoral vein. rice field.
  • the administration of the test compound was divided into two doses (administration 1 and administration 2) as shown below.
  • administration 1 and administration 2 physiological saline was administered as administration 1 and then physiological saline was administered as administration 2.
  • administration 1 physiological saline was administered as administration 1
  • physiological saline was administered as administration 1
  • Imetit was administered as administration 2.
  • Ciproxifan + Imetit group Ciproxifan was administered as administration 1 and then Imetit was administered as administration 2.
  • Test Example 6 a known H 3 receptor agonist assessment of the impact of Ciproxifan for efficacy of Imetit in male rats mating behavior test Imetit (Journal of Pharmacology and Experimental Therapeutics , 1992, 263, p.304) with known H 3 receptor A body antagonist, Ciproxifan (Journal of Pharmacology and Experimental Therapeutics, 1998, 287, p.658), was used to test the prolongation of ejaculation latency.
  • a group was provided in which intraperitoneal administration was performed before, and a solution prepared by dissolving Imetit in a solvent (0.5% aqueous solution of methyl cellulose (Shinetsu Chemical Industry)) was orally administered in a volume of 5 mL / kg 50 minutes before the start of the test. Calculate the geometric mean value of the first ejaculation latency ratio (Post / Pre ratio) between the 6th (Pre) and 7th and subsequent compound evaluations (Post) for each individual in each administration group (9 to 10 cases). bottom.
  • the dose was 3 mg / kg for Ciproxifan and 3 mg / kg for Imetit, which was equivalent to the free form.
  • the histamine H 3 receptor agonist may, in its H 3 receptor agonist activity, inhibit peripheral nerve firing at penis stimulation, it can be said that results in a prolongation of the ejaculatory latency.
  • Central transferability evaluation test refers to the total brain concentration (hereinafter referred to as C brain ) and plasma total concentration (hereinafter referred to as C plasma, t ) of the test compound. It has been reported that the brain-plasma concentration ratio (meaning the value represented by C brain / C plasma, t , hereinafter referred to as K p, brain ), which is the ratio, can be shown as an index (Journal). of Pharmacology and Experimental Therapeutics, 2008, 325, p.349). The test compound was orally administered to rats, and plasma and brain were collected 3 or 4 hours later. 80% acetonitrile solution and acetonitrile containing an internal standard substance were added to the collected plasma.
  • the collected brain was homogenized by adding twice the volume of physiological saline, and 80% acetonitrile solution and acetonitrile containing an internal standard substance were added to the prepared brain homogenate. These samples were centrifuged, and the supernatant was measured by LC-MS / MS to obtain C brain and C plasma, t of the test compound.
  • Table 51 shows the central transferability at the time of administration of some of the compounds of the present invention.
  • the K p, brain (brain-plasma concentration ratio) of some of the compound examples was less than 1, confirming that the central transferability was low.
  • the compound of the present invention has low central transferability and is particularly useful as a preventive or therapeutic agent for premature ejaculation.
  • the present invention compound or a salt thereof are useful as histamine H 3 receptor agonist
  • pharmaceutical compositions may be used for example as the active ingredient of the pharmaceutical composition for preventing or treating premature ejaculation.

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Abstract

La présente invention concerne un composé utile en tant que principe actif d'une composition pharmaceutique pour la prévention ou le traitement de l'éjaculation précoce. Plus particulièrement, l'invention concerne un composé représenté par la formule (I) ci-dessous [dans la formule, A est un groupe aromatique hétérocyclique ou similaire qui peut avoir un substituant ; a et b représentent chacun indépendamment 1, 2 ou 3 ; B représente un groupe aliphatique hétérocyclique ou similaire qui peut comprendre une double liaison constituant une partie de l'anneau et peut comporter un substituant, et --------ｘ- - - - - - est une liaison simple ou similaire ; et Y est un atome d'hydrogène ou similaire] ou un sel pharmaceutiquement acceptable de celui-ci.
PCT/JP2021/011242 2020-03-19 2021-03-18 Composé hétérocyclique carbonylé à fonction cyano en alpha contenant de l'azote WO2021187605A1 (fr)

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066948A1 (fr) * 2004-12-20 2006-06-29 Schering Aktiengesellschaft Derives de piperidine utilises comme antagonistes des recepteurs aux cc chimiokines ccr1 et utilisation de ceux-ci comme agents anti-inflammatoires
WO2007001975A1 (fr) * 2005-06-20 2007-01-04 Schering Corporation Dérivés de la pipéridine utiles comme antagonistes du récepteur h3 de l'histamine
WO2010011653A1 (fr) * 2008-07-23 2010-01-28 Schering Corporation Dérivés d'hétérocycles tricycliques utilisés comme antagonistes de l'histamine h3
WO2010027567A2 (fr) * 2008-07-23 2010-03-11 Schering Corporation Dérivés spirocycliques tricycliques et leurs procédés d’utilisation
WO2014089379A1 (fr) * 2012-12-07 2014-06-12 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs d'atr kinase
WO2018213632A1 (fr) * 2017-05-17 2018-11-22 Denali Therapeutics Inc. Inhibiteurs de kinase et leurs utilisations

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006066948A1 (fr) * 2004-12-20 2006-06-29 Schering Aktiengesellschaft Derives de piperidine utilises comme antagonistes des recepteurs aux cc chimiokines ccr1 et utilisation de ceux-ci comme agents anti-inflammatoires
WO2007001975A1 (fr) * 2005-06-20 2007-01-04 Schering Corporation Dérivés de la pipéridine utiles comme antagonistes du récepteur h3 de l'histamine
WO2010011653A1 (fr) * 2008-07-23 2010-01-28 Schering Corporation Dérivés d'hétérocycles tricycliques utilisés comme antagonistes de l'histamine h3
WO2010027567A2 (fr) * 2008-07-23 2010-03-11 Schering Corporation Dérivés spirocycliques tricycliques et leurs procédés d’utilisation
WO2014089379A1 (fr) * 2012-12-07 2014-06-12 Vertex Pharmaceuticals Incorporated Composés utiles en tant qu'inhibiteurs d'atr kinase
WO2018213632A1 (fr) * 2017-05-17 2018-11-22 Denali Therapeutics Inc. Inhibiteurs de kinase et leurs utilisations

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Title
DE LERA RUIZ, M. ET AL.: "Bicyclic and tricyclic heterocycle derivatives as histamine H3 receptor antagonists for the treatment of obesity", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 23, no. 21, 2013, pages 6004 - 6009, XP028732599, DOI: 10.1016/j.bmcl. 2013.08.01 3 *

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