WO2016171181A1 - Dérivés de pyrazole fusionnés substitués en position 2 - Google Patents

Dérivés de pyrazole fusionnés substitués en position 2 Download PDF

Info

Publication number
WO2016171181A1
WO2016171181A1 PCT/JP2016/062536 JP2016062536W WO2016171181A1 WO 2016171181 A1 WO2016171181 A1 WO 2016171181A1 JP 2016062536 W JP2016062536 W JP 2016062536W WO 2016171181 A1 WO2016171181 A1 WO 2016171181A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
substituted
compound
ring
same
Prior art date
Application number
PCT/JP2016/062536
Other languages
English (en)
Japanese (ja)
Inventor
英史 吉永
洋平 井熊
Original Assignee
大日本住友製薬株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 大日本住友製薬株式会社 filed Critical 大日本住友製薬株式会社
Publication of WO2016171181A1 publication Critical patent/WO2016171181A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to a condensed pyrazole derivative having a selective dopamine D 4 receptor agonistic action and a salt thereof, and a therapeutic agent for central nervous system diseases comprising the derivative as an active ingredient.
  • Dopamine D 4 receptors G-protein coupled receptors (G protein-coupled receptors: GPCRs ) is one of, since it is highly expressed in prefrontal cortex associated with attention behavior and cognitive function, dopamine D 4 Receptor agonists are expected as therapeutic agents for central nervous system diseases related to higher brain functions such as attention deficit hyperactivity disorder (ADHD).
  • ADHD is one of the developmental disorders that develop in childhood with inattention, hyperactivity, and impulsivity as core symptoms. Core symptoms persist even in adulthood. It is known to do.
  • the central nervous system stimulant methylphenidate is used as a first-line drug in ADHD drug therapy.
  • methylphenidate has the risk of drug dependence and abuse, and the risk of side effects on the cardiovascular system such as palpitation, tachycardia, and blood pressure fluctuations.
  • the selective noradrenaline reuptake inhibitor atomoxetine which is a non-central nervous stimulant, is selected as an ADHD therapeutic agent with small drug dependence formation.
  • atomoxetine requires a sufficient administration period before the therapeutic effect is exhibited. For these reasons, it is desired to develop an ADHD therapeutic agent that can reduce the risk of drug dependence and cardiovascular side effects and exhibits rapid onset of efficacy.
  • the ADHD patient the mutation of the dopamine transporter gene and the dopamine D 4 receptor gene is observed has been reported (e.g., see Non-Patent Document 1).
  • the child with a genetic polymorphism of seven repeat sequence of 48bp in the third exon of the dopamine D 4 receptor gene developmental delay of the cerebral cortex has been observed (for example, see Non-Patent Document 3).
  • dopamine D 4 receptors are highly expressed in prefrontal cortex associated with attention behavior and cognitive function (e.g., see Non-Patent Document 2). From these facts, dopamine D 4 receptor is considered to be related to attention / cognitive function.
  • dopamine D 4 receptors are known to be not expressed in the nucleus accumbens involved in drug dependence. Based on the above, a drug that selectively exhibits an agonistic action on the dopamine D 4 receptor is a therapeutic agent for central nervous system diseases involving dopaminergic nerves, particularly ADHD and drug dependence. It is expected as a therapeutic agent for ADHD with reduced side effects.
  • a compound represented by the following formula can regulate the activity of a metabotropic glutamate receptor (mGluR5), and is useful for the treatment, prevention, and / or management of various disorders such as neuropathy. It is disclosed.
  • R 1 is aryl, heteroaryl, etc .
  • R 2 is aryl, heteroaryl, etc .
  • R 3 and R 4 are each independently hydrogen, halogen, lower alkyl, etc .
  • L 1 is a bond, —O—, —CR 5 R 6 — and the like
  • L 2 is a bond, —O—, —CR 5 R 6 — and the like
  • X is C or N
  • Y is O, S, N, etc .
  • Z is O, S, N, etc .
  • R 5 and R 6 are each independently hydrogen, halogen, or lower alkyl, or CR 5 R 6 is C ⁇ O; or R 5 and R 6 are taken together with the carbon atom to which they are attached. May form 3 to 7 member
  • Patent Document 1 does not specifically disclose a condensed pyrazole derivative.
  • An object of the present invention is to provide a novel selective dopamine D 4 receptor agonist useful as a therapeutic agent for central nervous system diseases.
  • the present inventors have found that the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “the compound of the present invention” as necessary). Has been found to have an excellent selective dopamine D 4 receptor agonist activity, and the present invention has been completed.
  • the present invention is as follows.
  • n and m each independently represent 1 or 2; W 1 and W 2 each independently represent a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms); R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 alkyl group, or together with the carbon atom to which they are attached, a 3-membered May form a ⁇ 8 membered cycloalkane ring; R 3 represents a hydrogen atom, a halogen atom, a cyano group, or an optionally substituted C 1-6 alkyl group; Ring Q 1 represents an optionally substituted C 6-10 aryl group, or an optionally substituted 5- to 10-membered heteroaryl group; Ring Q 2 represents an optionally substituted 5-membered heteroaryl group, and the following compounds Or a pharmaceutically acceptable salt thereof.
  • n and m are each independently 1 or 2; W 1 and W 2 are each independently a single bond or a C 1-4 alkylene group (the group may be substituted with the same or different 1-2 halogen atoms); R 1 and R 2 are each independently a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types).
  • R 3 is a hydrogen atom, a halogen atom, a cyano group, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types);
  • Ring Q 1 is (1) a 5- to 10-membered heteroaryl group (the group is (A) a halogen atom, (B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups); (C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms), (D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types); (E) a cyano group, and (f)
  • Item [3] m is 1; The compound or a pharmaceutically acceptable salt thereof according to Item [1] or Item [2], wherein both W 1 and W 2 are a single bond.
  • n 1; The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [3], wherein R 1 and R 2 are both hydrogen atoms.
  • Ring Q 1 is a 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms
  • the group is (A) a halogen atom, (B) a C 1-6 alkyl group (the group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups); (C) a C 2-6 alkenyl group (the group may be substituted with the same or different 1 to 4 halogen atoms), (D) a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms of the same or different types); (E) a cyano group, and (f) an amino group (the group is substituted with one or two groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) May be substituted with 1 to 4 groups of the same or different types selected from the group consisting of, and when two substitution of
  • Ring Q 1 is represented by the following formula (2a) or (2b): Wherein X 1 represents N or CR 12 ; R 11 represents a halogen atom, a C 1-6 alkoxy group (the group may be substituted with 1 to 3 halogen atoms), or a C 1-6 alkyl group (the group includes a halogen atom and a hydroxy group). Which may be substituted with the same or different 1 to 3 groups selected from the group consisting of groups); R 12 , R 13 , R 14 and R 15 each independently represents a hydrogen atom, a halogen atom or a C 1-6 alkyl group (the group is substituted with 1 to 3 halogen atoms of the same or different types).
  • a C 2-6 alkenyl group (the group may be substituted with 1 to 4 halogen atoms of the same or different types), a C 1-6 alkoxy group (1 to 3 groups Or an amino group (the group may be substituted with the same or different 1 to 2 C 1-6 alkyl groups);
  • R 11 and R 12 , or R 11 and R 15 together with the carbon atom to which they are attached, are a 5- to 8-membered cycloalkane ring, a 5- to 8-membered saturated heterocycle, or 5 Membered to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocyclic ring, or 5-membered to 8-membered cycloalkene ring includes a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group) And may be substituted with 1 to 4 groups of the same or different types selected from the group consisting of:
  • Item [9] The compound or a pharmaceutically acceptable salt thereof according to any one of Items [6] to [8], wherein X 1 is CR 12 .
  • R 11 and R 12 , or R 11 and R 15 together with the carbon atom to which they are attached, are a 5 to 8 membered cycloalkane ring, a 5 to 8 membered saturated heterocycle, or a 5 to 8-membered cycloalkene ring (the cycloalkane ring, saturated heterocycle, or 5- to 8-membered cycloalkene ring is composed of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group. Or a compound thereof according to any one of items [6] to [9], which may be substituted with 1 to 4 groups of the same or different types selected from the group A pharmaceutically acceptable salt.
  • Item 11 The compound according to any one of Items [6] to [9] or a pharmaceutically acceptable salt thereof, wherein R 11 is a C 1-4 alkyl group optionally substituted with 1 to 3 fluorine atoms. Salt.
  • Ring Q 2 is The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types).
  • the oxazole group, isoxazole group, imidazole group, pyrazole group, oxadizazole group, triazole group, thiazole group, isothiazole group, or thiadiazole group that may be substituted with one or two groups of Item [11]
  • Ring Q 2 is The same or different selected from the group consisting of (a) a halogen atom, and (b) a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types).
  • Ring Q 2 is represented by the following formula (3a), (3b) or (3c): (In the formula, X 2 represents O or NR 23 (R 23 represents a hydrogen atom or a C 1-6 alkyl group (the group may be substituted with the same or different 1 to 3 halogen atoms).) Represents); R 21 and R 22 each independently represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group (the group may be substituted with 1 to 3 halogen atoms of the same or different types). To express. The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [13], which is a group represented by
  • Item [16] The compound or a pharmaceutically acceptable salt thereof according to Item [14] or Item [15], wherein X 2 is O.
  • Item [17] The compound or a pharmaceutically acceptable salt thereof according to any one of Items [14] to [16], wherein R 21 and R 22 are both hydrogen atoms.
  • Item [18] Item [1] to Item [17], wherein R 3 is a hydrogen atom or a C 1-6 alkyl group (this group may be substituted with the same or different 1 to 3 halogen atoms). Or a pharmaceutically acceptable salt thereof.
  • Item [19] The compound or a pharmaceutically acceptable salt thereof according to any one of Items [1] to [18], wherein R 3 is a C 1-4 alkyl group.
  • Item [22] A pharmaceutical comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item [23] Containing the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient, attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, A therapeutic agent for central nervous system diseases selected from the group consisting of mood disorders and cognitive impairments.
  • a therapeutic agent for attention deficit / hyperactivity disorder comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item [25] The therapeutic agent according to Item [24], wherein the attention deficit hyperactivity disorder is a disorder mainly caused by attention deficit (inattention).
  • Item [26] The therapeutic agent according to Item [24], wherein the attention deficit hyperactivity disorder is a disorder mainly having hyperactivity.
  • Item [28] A therapeutic agent for autism spectrum disorder, comprising the compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Item [29] The therapeutic agent according to Item [28], wherein the autism spectrum disorder is a disorder whose main symptom is a persistent defect in social communication and social interaction.
  • Item [30] The therapeutic agent according to Item [28], wherein the autism spectrum disorder is a disorder whose main symptom is a repeated behavior, interest, or activity pattern with limited autism spectrum disorder.
  • Item [31] Lack of attention, characterized by administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of items [1] to [21] or a pharmaceutically acceptable salt thereof
  • a method for treating a central nervous system disease selected from the group consisting of hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive impairment.
  • Item [32] Item [1] to Item [1] for producing a therapeutic agent for central nervous system disease selected from the group consisting of attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive dysfunction 21]
  • a therapeutic agent for central nervous system disease selected from the group consisting of attention deficit hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive dysfunction 21]
  • the present invention compounds exhibit strong agonistic effect on dopamine D 4 receptors.
  • bioavailability at the time of oral administration (bioavailability) is high, the ability to transfer to the brain is excellent, and the risk of hepatotoxicity is also low. Therefore, the compound of the present invention is highly safe and excellent in the treatment of central nervous system diseases (for example, lack of attention). It is useful as a therapeutic agent for hyperactivity disorder.
  • C 1-6 alkyl is synonymous with an alkyl group having 1 to 6 carbon atoms.
  • halogen atom include fluorine atom, chlorine atom, bromine atom or iodine atom.
  • C 1-6 alkyl group means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is a “C 1-4 alkyl group”. Specific examples of “C 1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.
  • C 2-6 alkenyl group means a linear or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms and containing 1 to 3 carbon-carbon double bonds.
  • a “C 2-4 alkenyl group” is preferable.
  • Specific examples of “C 2-6 alkenyl group” include, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like.
  • the “C 1-4 alkylene group” is a divalent saturated hydrocarbon containing a linear or branched saturated hydrocarbon group having 1 to 4 carbon atoms or a cyclic structure having 3 to 4 carbon atoms. Means group.
  • Specific examples of the linear or branched “C 1-4 alkylene group” include, for example, methylene, ethylene, propylene, butylene, 1-methylmethylene, 1-ethylmethylene, 1-propylmethylene, 1-methylethylene. 2-methylethylene, 1-ethylethylene and the like, preferably methylene and ethylene.
  • Specific examples of the “C 1-4 alkylene group” containing a cyclic structure include, for example, groups represented by the following groups.
  • C 1-6 alkoxy group refers to a “C 1-6 alkyl-O— group”, and the “C 1-6 alkyl” portion has the same meaning as the above “C 1-6 alkyl”.
  • a “C 1-4 alkoxy group” is preferable.
  • Specific examples of “C 1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
  • C 3-7 cycloalkyl group means a 3- to 7-membered monocyclic saturated or partially unsaturated hydrocarbon group.
  • Specific examples of “C 3-7 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and the like.
  • “3- to 8-membered cycloalkane ring” means a 3- to 8-membered monocyclic saturated hydrocarbon ring. A 5-membered or 6-membered saturated hydrocarbon ring is preferred. Specific examples of the “3- to 8-membered cycloalkane ring” include, for example, cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring and the like.
  • C 6-10 aryl group means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Preferred is “C 6 aryl group” (phenyl). Specific examples of “C 6-10 aryl group” include, for example, phenyl, 1-naphthyl, 2-naphthyl and the like.
  • the “C 6-10 aryl group” contains one or more (for example, 1 to 4) of the same or different heteroatoms selected from phenyl and 5- to 7-membered nitrogen, sulfur and oxygen atoms. Or a group condensed with a 5- to 7-membered saturated or partially unsaturated hydrocarbon ring (eg, cyclopentane, cyclopentene, cyclohexane, etc.). However, in the case of a polycyclic “C 6-10 aryl group” in which an aromatic ring and a non-aromatic ring are condensed, only the aromatic ring has a “group” bond. Specific examples of the group include groups represented by the following formulas.
  • heteroaryl group examples include a 5- to 10-membered monocyclic or polycyclic aromatic group, and the group is the same or selected from a nitrogen atom, a sulfur atom and an oxygen atom, 1 or more (for example, 1 to 4) heterogeneous heteroatoms are contained.
  • polycyclic heteroaryl group a bicyclic or tricyclic group is preferable, and a bicyclic group is more preferable.
  • the polycyclic heteroaryl group includes those in which the monocyclic heteroaryl group is condensed with an aromatic ring (benzene, pyridine, etc.) or a non-aromatic ring (cyclohexyl, piperidine, etc.).
  • Specific examples of the “heteroaryl group” include, for example, a group represented by the following formula.
  • the “5- to 10-membered heteroaryl group” in ring Q 1 is preferably a 5- to 10-membered heteroaryl group containing 1 to 3 nitrogen atoms, A group represented by the following formula is more preferable, A group represented by the following formula is more preferable.
  • the “5-membered heteroaryl group” in ring Q 2 include, for example, an oxazole group, an isoxazole group, a pyrrole group, an imidazole group, a pyrazole group, an oxadizazole, a triazole group, a thiazole group, an isothiazole group, a thiadiazole group, Examples include tetrazole groups, and oxazole groups, isoxazole groups, imidazole groups, and pyrazole groups are preferable, and oxazole groups are more preferable.
  • the bond across the ring in the above formula means that the “group” is bonded at a substitutable position in the ring.
  • the following formula In the case of the heteroaryl group, it means a 2-pyridyl group, a 3-pyridyl group or a 4-pyridyl group.
  • heteroaryl group is a polycyclic group, for example, the following formula In addition to 1-benzimidazolyl or 2-benzimidazolyl, 4-, 5-, 6- or 7-benzimidazolyl may be used.
  • the substituent in the group defined as “optionally substituted” can be substituted at a substitutable position within the substitutable number range.
  • the range of the number of substitutable substituents in the methyl group is 1 to 3.
  • the optionally substituted C 6-10 aryl group is a phenyl group
  • the number of substitutable substituents in the phenyl group ranges from 1 to 5.
  • there are a plurality of substituted groups they may be the same or different.
  • the description of each group also applies if the group is part of another group or a substituent.
  • Examples of the substituent in the “optionally substituted C 1-4 alkylene group” include a hydroxy group, a halogen atom, a C 3-7 cycloalkyl group, a C 1-6 alkoxy group, and the like, A fluorine atom is mentioned.
  • Examples of the substituent in the “optionally substituted C 1-6 alkyl group” include (1) a halogen atom, (2) a C 3-7 cycloalkyl group, (3) C 1-6 alkoxy group (this group may be substituted with 1 to 3 halogen atoms of the same or different types), (4) a cyano group, (5) Amino group (this group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) , (6) a hydroxy group, and (7) an aminocarbonyl group (the amino is a same or different 1-2 groups selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted).
  • Preferable examples include a fluorine atom, a hydroxy group, and a C 1-6 alkoxy group.
  • Examples of the substituent in the “optionally substituted aryl group” and “optionally substituted heteroaryl group” include (1) a halogen atom, (2) C 1-6 alkyl group (this group may be substituted with 1 to 3 groups of the same or different types selected from the group consisting of halogen atoms and hydroxy groups), (3) C 1-6 alkoxy group (this group may be substituted with 1 to 3 halogen atoms of the same or different types), (4) a cyano group, (5) Amino group (this group may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) , (6) a hydroxy group, and (7) an aminocarbonyl group (the amino is a same or different 1-2 groups selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted).
  • a halogen atom a C 1-6 alkyl group, a C 1-6 alkoxy group, a cyano group, an amino group (the group is selected from the group consisting of a C 1-6 alkyl group and a C 3-7 cycloalkyl group) And may be substituted with 1-2 groups of the same or different types.
  • R 1 and R 2 together with the carbon atoms to which they are bonded may form a 3- to 8-membered cycloalkane ring
  • R 1 and R 2 are the same carbon When attached to an atom and together with the carbon atom to which they are attached form a 3- to 8-membered spirocycloalkane ring, and (2) R 1 and R 2 are attached to an adjacent carbon atom. And the case where they form a 3- to 8-membered fused cycloalkane ring together with the carbon atom to which they are bonded.
  • ring Q 1 When two substituents of ring Q 1 are substituted by adjacent carbon atoms, they may be combined with the carbon atoms to which they are attached to form a 5- to 8-membered ring”. one of the substituents attached to two adjacent carbon atoms on the ring Q 1, if they form a ring of 5 to 8 membered together with partial ring Q 1 containing a carbon atom bonded Examples of the ring include a cycloalkane ring, a saturated heterocyclic ring, and a cycloalkene ring. Wherein heteroatom saturated heterocyclic ring derived from a hetero atom contained in the substituent of the ring Q 1 (the oxygen atom in the alkoxy group, such as a nitrogen atom in an amino group).
  • the cycloalkane ring, saturated heterocycle, or 5- to 8-membered cycloalkene ring is selected from the group consisting of a halogen atom, a hydroxy group, a C 1-6 alkyl group, and a C 1-6 alkoxy group. It may be substituted with 1 to 4 groups of the same or different types. Specific examples include “groups” represented by the following groups.
  • the compounds of the present invention may exist in the form of hydrates and / or solvates, solvates such as these hydrates or ethanol solvates are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.
  • Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) include, for example, hydrochloride, hydrobromide, sulfuric acid.
  • Inorganic acid salts such as salts, phosphates, nitrates; and acetates, propionates, oxalates, succinates, lactates, malates, tartrate, citrate, maleate, fumarate
  • organic acid salts such as methanesulfonate, p-toluenesulfonate, benzenesulfonate, and ascorbate.
  • the compound represented by the formula (1) may exist as a tautomer. Therefore, this invention compound also includes the tautomer of the compound represented by Formula (1).
  • the compound represented by formula (1) may have at least one asymmetric carbon atom. Accordingly, the compound of the present invention includes not only the racemic form of the compound represented by the formula (1) but also optically active forms of these compounds. When the compound represented by the formula (1) has two or more asymmetric carbon atoms, stereoisomerism may occur. Accordingly, the compounds of the present invention include stereoisomers of these compounds, mixtures thereof and isolated ones. In addition, a deuterium converter obtained by converting any one or two or more 1 H of the compound represented by the formula (1) into 2 H (D) is also included in the compound represented by the formula (1). .
  • Boc group tert-butoxycarbonyl group
  • Cbz group benzyloxycarbonyl group
  • Alloc group allyloxycarbonyl group
  • Fmoc group 9-fluorenylmethyloxycarbonyl group
  • DMF N, N-dimethylformamide
  • the compound of the present invention can be produced, for example, by the methods shown in the following production methods 1 to 9. These production methods can be improved as appropriate based on the knowledge of those skilled in organic synthesis.
  • the compounds used as raw materials may be used as salts as necessary.
  • the desired product can be obtained by protecting the points other than the reaction point as necessary and deprotecting after completion of the reaction or after a series of reactions.
  • Protecting groups are described in literature (T. W. Greene and P. G. M.
  • amino protecting groups include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl, and the like, and hydroxy groups
  • specific examples of the protection of can include, for example, trialkylsilyl, acetyl, benzyl and the like.
  • Manufacturing method 1 The compound represented by Formula (1) is manufactured by the method shown below, for example.
  • R 101 represents a Cbz group and a Boc group , Alloc group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group
  • LG represents a leaving group (for example, iodine atom, bromine atom, A chlorine atom, a substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like are represented.
  • R 101 represents a Cbz group and a Boc group , Alloc group, benzyl group, 4-methoxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group
  • LG represents a leaving group (for example, iodine
  • Step 1-1 Preparation process of Compound (1-2) (1-2), using the compound (1-1) as a starting material, the literature (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .) Etc.).
  • Step 1-2 Production Step of Compound (1)
  • Compound (1) is produced by reacting compound (1-2) with compound (1-3) in a suitable inert solvent.
  • the reaction may be performed in the presence of a base, if necessary, in the presence of a phase transfer catalyst.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium
  • phase transfer catalyst examples include, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether. Etc.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol, 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane
  • Lower alcohols such as methanol, ethanol, 2-propanol
  • Step 1-3 Production Step of Compound (1)
  • Compound (1) is reduced in a suitable inert solvent using compound (1-2) and an aldehyde represented by formula (1-4) and a reducing agent. It can also be produced by subjecting it to an amination reaction.
  • the reaction may be performed in the presence of a base, an acid, or other additives as necessary.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the reducing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • the reducing agent include, for example, lithium aluminum hydride, sodium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride, lithium tri (sec-butyl) borohydride, hydrogen Tri (sec-butyl) borohydride sodium, potassium tri (sec-butyl) borohydride, borane-dimethylsulfide complex, borane-tetrahydrofuran complex, lithium triethylborohydride, ammonium formate, palladium-carbon and palladium oxide
  • a metal catalyst such as
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide, potassium tert-butoxide, etc. It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphat
  • the acid examples include organic acids such as acetic acid, trifluoroacetic acid and methanesulfonic acid; inorganic acids such as hydrochloric acid and sulfuric acid.
  • additives include dehydrating agents such as tetramethyl orthosilicate and methyl orthoformate; zinc chloride, titanium tetrachloride, lanthanum sulfate, magnesium sulfate-pyridinium sulfate pyridinium, magnesium bromide, indium chloride, zirconium chloride,
  • dehydrating agents such as tetramethyl orthosilicate and methyl orthoformate
  • zinc chloride titanium tetrachloride, lanthanum sulfate, magnesium sulfate-pyridinium sulfate pyridinium, magnesium bromide, indium chloride, zirconium chloride
  • Lewis acids such as magnesium triflate, ytterbium (III) triflate, scandium triflate, alumina, copper sulfate, tetraisopropoxide titanate, and tetraethoxide titanate.
  • the solvent include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like.
  • Ether solvents halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • 1,2-dimethoxyethane 1, tetrahydrofuran, 1,4-dioxane and the like.
  • Ether solvents include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like.
  • Ether solvents alcohol solvents such as methanol
  • Step 1-4 Production Step of Compound (1-6)
  • Compound (1-6) is a compound represented by formula (1-5) in the presence of a condensing agent in an inert solvent. It is produced by reacting with a carboxylic acid.
  • the reaction may be further performed in the presence of a base.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • condensing agent examples include those described in Experimental Chemistry Course (edited by Chemical Society of Japan, Maruzen) Vol.
  • phosphate esters such as diethyl cyanophosphate and diphenylphosphoryl azide
  • carbodiimides such as 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (WSC ⁇ HCl) and dicyclohexylcarbodiimide (DCC); Triazol-1-yl-tris (dimethylamino) phosphonium hexafluorophosphide salt (BOP), benzotriazol-1-yl-N, N, N ′, N′-tetramethyluronium hexafluorophosphide salt ( And phosphates such as HBTU); diphenylphosphonyl diamide (DPPA); N, N-carbonyl diimidazole (CDI) and the like.
  • DPPA diphenyl
  • N-hydroxysuccinimide HSu
  • 1-hydroxybenzotriazole HBt
  • 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine HOOBt
  • the additive can be added to carry out the reaction.
  • the inert solvent include halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane, 1, Ether solvents such as 4-dioxane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; aprotic polarities such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide A solvent; a basic solvent such as pyridine; and a mixed solvent thereof.
  • halogenated hydrocarbons such as chloroform, dichloromethane and dichloroethane
  • aromatic hydrocarbons such as benzene and toluene
  • phase transfer catalyst can be added as necessary.
  • phase transfer catalyst include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
  • the compound (1-6) is obtained by adding a halogenating reagent (eg, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, pentachloride to the compound (1-5). It is also produced by reacting with a compound (1-2) in an inert solvent in the presence of a base as necessary.
  • a halogenating reagent eg, 1-chloro-N, N, 2-trimethylpropenylamine, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, pentachloride
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform , Halogenated hydrocarbon solvents such as dichloroethane; ester solvents such as ethyl acetate and isopropyl acetate; ketone solvents such as methyl ethyl ketone and acetone; non-solvents such as acetonitrile, N, N-dimethylformamide, dimethyl sulfoxide and hexamethylenephosphoamide A protic solvent is mentioned.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
  • hydrocarbon solvents such as
  • Examples of the base include N-methylmorpholine, triethylamine, diisopropylethylamine, tributylamine, 1,8-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [5.4.0] undec-7-ene. , Organic bases such as pyridine, dimethylaminopyridine, and picoline.
  • Step 1-5 Production Step of Compound (1)
  • Compound (1) can also be produced by reacting compound (1-6) with a reducing agent in an inert solvent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, reducing agent used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • the reducing agent examples include lithium aluminum hydride, sodium bis (2-methoxyethoxy) aluminum hydride, borane complex (borane-dimethylsulfide complex or borane-tetrahydrofuran complex) and the like.
  • the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane; and mixed solvents thereof.
  • the compound represented by the formula (2-4) is produced, for example, by the method shown below.
  • R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, 4- It represents a methoxybenzyl group, a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, or an Fmoc group.
  • Step 2-1 Step of producing compound (2-2)
  • Compound (2-2) is produced by the same method as in step 1-5, using compound (2-1).
  • Step 2-2 Production Step of Compound (2-4)
  • Compound (2-4) is produced in the same manner as in step 1-1, using compound (2-2).
  • Step 2-3 Preparation process of Compound (2-3) (2-3), using the compound (2-1), the literature (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.) Etc.).
  • Step 2-4 Step of producing compound (3-3) Compound (2-4) is produced by the same method as in step 1-5 using compound (2-3).
  • the compound represented by the formula (3-2) is produced, for example, by the method shown below.
  • LG represents a leaving group (for example, an iodine atom , Bromine atom, chlorine atom, substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like.
  • LG represents a leaving group (for example, an iodine atom , Bromine atom, chlorine atom, substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.) and the like.
  • Step 3-1 Production Step of Compound (3-1)
  • Compound (3-1) is produced by the same method as in Step 1-2, using Compound (2-3) and Compound (1-3) as raw materials. Is done.
  • Step 2-2 Production Step of Compound (2-3)
  • Compound (3-2) is produced in the same manner as in step 1-5 using compound (3-1).
  • the compound represented by formula (4-3) is produced, for example, by the method shown below.
  • R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, and a 4-methoxybenzyl group. , 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, or Fmoc group; both Z 1 and Z 2 represent a hydrogen atom, or Z 1 and Z 2 together represent a carbonyl group
  • R 3a represents a halogen atom
  • R 3b represents a C 1-6 alkyl group.
  • Step 4-1 Production Step of Compound (4-2)
  • Compound (4-2) is prepared by reacting Compound (4-1) with, for example, N-bromosuccinimide, N-chlorosuccinimide, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2] octane It is produced by reacting with a halogenating agent such as bis (tetrafluoroborate).
  • a halogenating agent such as bis (tetrafluoroborate).
  • the reaction temperature is usually in the range from ⁇ 20 ° C. to the boiling point of the solvent used. While the reaction time varies depending on the reaction temperature, the halogenating agent used, the raw materials, the solvent and the like, it is usually 10 minutes to 48 hours.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; dimethylformamide and N-methyl And aprotic polar solvents such as -2-pyrrolidinone; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane
  • aprotic polar solvents such as -2-pyrrolidinone
  • Step 4-2 Production Step of Compound (4-3)
  • Compound (4-3) is prepared by reacting compound (4-2) with, for example, dimethylzinc in an appropriate inert solvent in the presence of a transition metal catalyst. Or an organoboron compound such as trimethylboroxine.
  • the reaction can be performed in the presence of a ligand, a base, an additive, or the like as necessary.
  • the reaction temperature is usually in the range from ⁇ 10 ° C. to the boiling point of the solvent used. Although depending on conditions such as reaction temperature, reagents used, raw materials and solvent, it is usually 10 minutes to 48 hours.
  • transition metal examples include, for example, palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) Palladium chloride (II), dichlorobis (tri-O-tolylphosphine) palladium (II), bis (tri-tert-butylphosphine) palladium (0), and [1,1′-bis (diphenylphosphino) ferrocene] Examples include dichloropalladium (II).
  • ligand examples include, for example, triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1′-bis.
  • (Diphenylphosphino) ferrocene 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and the like.
  • the base include organic bases such as triethylamine and diisopropylethylamine; inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
  • organic bases such as triethylamine and diisopropylethylamine
  • inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
  • specific examples of the additive include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, copper (I) bromide, and the like.
  • compound (4-3) is obtained by reacting compound (4-2) with alkyllithium such as n-butyllithium in a suitable inert solvent and then reacting with alkyl halide such as methyl iodide. It is also produced by reacting.
  • alkyllithium such as n-butyllithium
  • alkyl halide such as methyl iodide
  • Step 5-1 Step of producing compound (5-4)
  • Compound (5-4) is compound (5-2) or compound (5-3) in a suitable inert solvent. It is manufactured by reacting with.
  • the reaction may be carried out in the presence of a base, if necessary, in the presence of a phase transfer catalyst.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium
  • phase transfer catalyst examples include, for example, quaternary ammonium salts such as tetrabutylammonium hydrogen sulfate, tetrabutylammonium iodide, tetrabutylammonium bromide, benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether. Etc.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol, 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane
  • Lower alcohols such as methanol, ethanol, 2-propanol
  • compound (5-4) is produced by carrying out Mitsunobu reaction according to a conventional method in a suitable inert solvent. Specifically, it can be carried out in the presence of triphenylphosphine and Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, or using a cyanomethylenephosphorane reagent.
  • Mitsunobu reaction according to a conventional method in a suitable inert solvent. Specifically, it can be carried out in the presence of triphenylphosphine and Mitsunobu reagent such as diethyl azodicarboxylate or diisopropyl azodicarboxylate, or using a cyanomethylenephosphorane reagent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; and mixed solvents thereof.
  • Step 5-2 Production Step of Compound (5-5)
  • Compound (5-5) is produced by reacting compound (5-4) with a reducing agent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on the reaction temperature, the reducing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
  • the reducing agent include, for example, lithium aluminum hydride, sodium borohydride, borane complex (borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, etc.) and the like.
  • the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, lower alcohols such as methanol, ethanol and 2-propanol, and mixed solvents thereof.
  • Step 5-3 Production Step of Compound (5-6)
  • LG has a methanesulfonyloxy group, a chloromethanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a benzenesulfonyloxy group, p-toluenemethane
  • the compound (5-5) in an inert solvent in the presence of a base, methanesulfonyl chloride, methanesulfonic anhydride, chloromethanesulfonyl chloride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, Produced by reacting with benzenesulfonyl chloride, benzenesulfonic anhydride, p-toluenesulfonyl chloride, or p-toluenesulfonic
  • the reaction temperature is usually in the range from about ⁇ 40 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, reagent, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • the base is not particularly limited as long as it is used as a base in a normal reaction.
  • Organic bases such as -ene, 1,4-diazabicyclo [5.4.0] undec-7-ene, pyridine, dimethylaminopyridine, picoline; sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium Bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, sodium-bis (trimethylsilyl) amide, lithium amide, n-butyllithium, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate And inorganic bases such as sodium hydroxide and sodium hydride.
  • the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; aprotic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, hexamethylenephosphoamide and the like, and a mixed solvent thereof may be used.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
  • hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene
  • dichloromethane chloroform And halogenated hydrocarbon solvents
  • the compound (5-5) is chlorinated by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989)
  • compound (5-6) can be produced.
  • the chlorinating reagent oxalyl chloride, thionyl chloride, phosphorus oxychloride, sulfuryl chloride, cyanuryl trichloride, carbon tetrachloride, or N-chlorosuccinimide is preferably used.
  • LG represents a bromine atom
  • bromination of the compound (5-5) by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989, etc.)
  • compound (5-6) can be produced.
  • the bromination reagent phosphorus tribromide, carbon tetrabromide, bromine, or N-bromosuccinimide is preferably used.
  • compound (5-5) is iodinated by a method similar to a known method (for example, Comprehensive Organic transformation, R. C. Lalock et al., VCH publisher Inc., 1989, etc.)
  • compound (5-6) can be produced.
  • the iodination reagent iodine, N-iodosuccinimide and the like are preferably used.
  • the compound (5-6) in which LG is halogen can also be produced by reacting the compound (5-6) in which LG is a substituted sulfonyloxy group with, for example, lithium bromide or lithium chloride in an inert solvent. Is done.
  • Step 5-4 Production Step of Compound (5-7)
  • Compound (5-7) is produced by reacting compound (5-6) with a base in a suitable inert solvent.
  • the reaction may be performed in the presence of a phase transfer catalyst as necessary.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.
  • organic bases such as triethylamine, diisopropylethylamine, pyridine
  • phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium
  • phase transfer catalyst examples include quaternary ammonium salts such as tetrabutylammonium bromide and benzyltriethylammonium bromide, and crown ethers such as 18-crown-6-ether.
  • the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide; and mixed solvents thereof.
  • halogenated hydrocarbons such as chloroform and dichloromethane
  • aromatic hydrocarbons such as benzene and toluene
  • ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane
  • Aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2
  • n and R 3 are as defined above in [1];
  • R 102 represents an optionally substituted C 1-4 alkyl group;
  • R 103 represents a benzyl group, a 4-methoxybenzyl group, Represents a 2,4-dimethoxybenzyl group or a 3,4-dimethoxybenzyl group;
  • Y represents —W 2 -ring Q 2 (W 2 , ring Q 2 has the same meaning as in the above [1]),
  • C 1-4 represents an alkoxycarbonyl group, a halogen atom, or a nitro group;
  • LG 1 and LG 2 are the same or different and are a leaving group (for example, an iodine atom, a bromine atom, a chlorine atom, a substituted sulfonyl group (for example, a methanesulfonyl group, p -Toluen
  • Step 6-1 Step for producing compound (6-3)
  • Compound (6-3) is compound (5-1) and compound (6-1) or (6-2), which is the same as step 5-1 It is manufactured by the method.
  • Step 6-2 Production Step of Compound (6-5)
  • Compound (6-5) is obtained by converting Compound (6-3) to Compound (6-) in an appropriate inert solvent and optionally in the presence of an additive. Produced by reacting with 4).
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.
  • additives can be added as necessary.
  • examples of the additive include potassium iodide, sodium iodide, tetrabutylammonium iodide and the like.
  • the inert solvent include, for example, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane; lower alcohols such as methanol, ethanol, 2-propanol; acetonitrile, acetone, methyl ethyl ketone, dimethylformamide.
  • aprotic polar solvents such as N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.
  • Manufacturing method 7 The compound represented by the formula (7-4) is produced, for example, by the method shown below. [Wherein, n, R 1 , R 2 , R 3 , and ring Q 2 have the same meanings as the above [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, and a 4-methoxybenzyl group.
  • X represents a halogen atom
  • A represents the following formula (a), (b), (c), (d) Or (e); (Wherein M + represents a potassium ion, a sodium ion, or an ammonium ion, and X ′ represents a halogen atom); Z 1 and Z 2 both represent a hydrogen atom; Alternatively, Z 1 and Z 2 together represent a carbonyl group.
  • Step 7-1 Production Step of Compound (7-2)
  • the production can be carried out by the following production method (i. Or ii.).
  • Compound (7-2) is produced by reacting iron and compound (7-1) in an inert solvent.
  • the inert solvent include water, acetic acid, or alcohol solvents such as methanol, ethanol, or 2-propanol, and a mixed solvent thereof may be used.
  • the reaction temperature is usually in the range from about 30 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, raw materials, and solvent, but is usually 10 minutes to 96 hours.
  • Compound (7-2) can be produced by hydrogenating compound (7-1) in the presence of palladium on carbon or palladium hydroxide in an inert solvent. Moreover, an acid can also be added as needed.
  • the reaction temperature is usually in the range from about 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, raw materials, and solvent, but is usually 10 minutes to 96 hours.
  • the acid include hydrochloric acid water, hydrogen bromide water, sulfuric acid water, acetic acid, trifluoroacetic acid and the like.
  • the inert solvent examples include ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane; hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene; dichloromethane, chloroform And halogenated hydrocarbon solvents such as dichloroethane; alcohol solvents such as ethanol, methanol and isopropanol, acetic acid and the like, and mixed solvents thereof may be used.
  • ether solvents such as tetrahydrofuran, diethyl ether, 1,4-dioxane, 1,2-dimethoxyethane
  • hydrocarbon solvents such as hexane, heptane, toluene, benzene, xylene
  • dichloromethane chloroform And halogenated hydrocarbon solvents
  • alcohol solvents such as ethanol,
  • Step 7-2 Production Step of Compound (7-3)
  • Compound (7-3) is compound (7-2) as a starting material, and literature (for example, Tetrahedron Letters 38, 7963 (1997), Bioorg. Med. Chem. Lett. 12, 543 (2002), Heterocycles 57, 123 (2002), Tetrahedron Letters 41, 9957 (2000) and Tetrahedron Letters 42, 2201 (2001)).
  • literature for example, Tetrahedron Letters 38, 7963 (1997), Bioorg. Med. Chem. Lett. 12, 543 (2002), Heterocycles 57, 123 (2002), Tetrahedron Letters 41, 9957 (2000) and Tetrahedron Letters 42, 2201 (2001)).
  • Step 7-3 Step of producing compound (7-4)
  • Compound (7-4) is prepared by mixing compound (7-3) with an appropriate transition metal catalyst and an appropriate ligand in an inert solvent as necessary. In the presence of a base, it is produced by reacting with compound (6-5) in a suitable inert solvent.
  • the reaction temperature is usually in the range from about ⁇ 20 ° C. to the boiling point of the solvent used.
  • the reaction time varies depending on conditions such as reaction temperature, reagents used, raw materials, and solvent, but is usually 10 minutes to 48 hours.
  • transition metal catalyst and the ligand include, for example, the transition metal catalyst and the ligand used in Step 4-2.
  • the base include organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium hydride, hydrogen Inorganic bases such as potassium iodide, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium phosphate, sodium methoxide, sodium tert-butoxide, potassium tert-butoxide, lithium diisopropylamide, lithium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) ), Organometallic reagents such as amide, sodium bis (trimethylsilyl) amide, lithium amide, n-butyllithium, and the like.
  • potassium carbonate or cesium carbonate is used.
  • the inert solvent include acetone, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane.
  • ether solvents such as tert-butyl methyl ether and cyclopentyl methyl ether, lower alcohols such as methanol, ethanol and isopropanol, and aprotic polar solvents such as N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide. These may be a mixed solvent.
  • toluene and N, N-dimethylformamide are used.
  • R 101 is a Cbz group, a Boc group, an Alloc group, a benzyl group, a 4-methoxybenzyl group, Represents a 2,4-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, or an Fmoc group
  • R 104 represents a C 1-4 alkyl group
  • LG represents a leaving group (for example, an iodine atom, a bromine atom, Represents a chlorine atom, a substituted sulfonyl group (eg, methanesulfonyl group, p-toluenesulfonyl group, etc.)
  • Z 1 and Z 2 both represent a hydrogen atom, or Z 1 and Z 2 together Represents a carbonyl group
  • Step 8-1 Preparation process of Compound (8-2) (8-2), the compound (8-1) a known method (for example, Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc .), Comprehensive Organic Transformation, RC Laroc et al., VCH publisher Inc., 1989 etc.).
  • Step 8-2 Production Step of Compound (8-3) Compound (8-3) is produced by the same method as in Step 1-4 using Compound (8-2) and Compound (8-8) as raw materials. Is done.
  • Step 8-3 Production Step of Compound (8-4) Compound (8-4) is produced in the same manner as in step 5-3 using compound (8-3).
  • Step 8-4 Production Step of Compound (8-5)
  • Compound (8-5) uses compound (8-4) as a starting material, and literature (for example, Tetrahedron Letters, 53, 4409 (2012), JACS, 126 15195 (2004), Tetrahedron 58, 9853 (2002), Tetrahedron Letters 50, 6252 (2009), Angewandte Chemie, International Edition 51, 6480 (2012), etc.).
  • Step 8-5 Production Step of Compound (8-6)
  • Compound (8-6) uses Compound (8-5) as a raw material, and literature (for example, Organic Letters 13, 6256 (2011), Organic Letters, 12 , 4686 (2010), Tetrahedron Letters 51, 1822 (2010), Tetrahedron Letters 44, 3133 (2003), Synthesis 11, 873 (1989), Journal of Medicinal Chemistry 47, 1969 (2004), Tetrahedron Letters 44, 3133 (2003 ), Bioorganic & Medicinal Chemistry Letters 22, 4955 (2012), etc.).
  • Manufacturing method 9 The compound represented by the formula (9-4) is produced, for example, by the method shown below. [Wherein n, R 1 and R 2 have the same meanings as defined in [1]; R 101 represents a Cbz group, a Boc group, an Alloc group, a benzyl group, a 4-methoxybenzyl group, and 2,4-dimethoxybenzyl.
  • R 104 represents a C 1-4 alkyl group
  • R 105 is a C 1-4 alkyl group, or two OR 105 together And may be bonded to form a ring
  • both Z 1 and Z 2 represent a hydrogen atom, or Z 1 and Z 2 together represent a carbonyl group.
  • Step 9-1 Production Step of Compound (9-2)
  • Compound (9-2) is obtained from compound (8-1) and compound (9-1) based on literature (for example, Organic Letters 16, 2018, (2014), etc. ) In the same manner as described in).
  • Step 9-2 Preparation process of Compound (9-3) (9-3) in the literature from a compound (9-2) (Protective Groups in Organic Synthesis 3 rd Edition (John Wiley & Sons, Inc.) , etc.) In the same manner as described in 1.
  • Step 9-3 Production Step of Compound (9-4)
  • Compound (9-4) is obtained from compound (9-3) in literature (for example, Journal of Medicinal Chemistry 45, 3905 (2002), Synlett 10, 1642 (1999). ), WO2012 / 168350, WO2004 / 113353, Organic Letters 4, 2665 (2002), Bioorg. Med. Chem. Lett. 21, 3404 (2011), Bioorg. Med. Chem. Lett. 24, 1681 (2014), etc.) In the same manner as described in 1.
  • the intermediates and target compounds in each of the above production methods are isolated by purification methods commonly used in organic synthetic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be purified.
  • each intermediate can be subjected to the next reaction without any particular purification.
  • the optically active form of the compound of the present invention can be produced by using optically active starting materials and intermediates, or by optically resolving the final racemate.
  • Examples of the optical resolution method include a physical separation method using an optically active column and a chemical separation method such as a fractional crystallization method.
  • the diastereomer of the compound of the present invention is produced, for example, by a fractional crystallization method.
  • the pharmaceutically acceptable salt of the compound represented by the formula (1) is, for example, a compound represented by the formula (1) and a pharmaceutically acceptable acid in a solvent such as water, methanol, ethanol, and acetone. It can be manufactured by mixing with.
  • the compound of the present invention is a dopamine D 4 receptor agonist, it is a central nervous disease that exhibits symptoms similar to ADHD, for example, autism spectrum disorder (diagnosis and statistical guide 5th edition of mental disorders (DSM- 5) Autism spectrum disorder in the conventional DSM-IV, which was classified as autism, Asperger syndrome, atypical pervasive developmental disorder, and childhood disintegrative disorder), ADHD-like It can be a therapeutic agent for schizophrenia, mood disorder, cognitive dysfunction and the like that show symptoms.
  • the compound of the present invention can be used in combination with a central nerve stimulant such as methylphenidate, a selective noradrenaline reuptake inhibitor such as atomoxetine, various schizophrenia therapeutic agents and the like.
  • One of the etiology hypotheses of autism spectrum disorder is the lack of neural network synchrony associated with the excitatory-inhibitory neurotransmitter imbalance in the cerebral cortex. It has been observed that amplification improves this imbalance.
  • Dopamine D 4 receptor agonists can be amplified ⁇ waves in the cerebral cortex it has been reported.
  • oxytocin a hormone produced in the hypothalamus, has been reported to be involved in social cognition, suggesting an association with autism. Since dopamine D 4 receptors are highly expressed in oxytocin-producing neurons expressed in the hypothalamic paraventricular nucleus, dopamine D 4 receptor agonists activate oxytocin-producing neurons and promote oxytocin release in the brain. It is expected. From the above, a dopamine D 4 receptor agonist can be a therapeutic agent for autism spectrum disorder through the ⁇ -wave amplification effect in the cerebral cortex and the oxytocin release promoting effect in the hypothalamus.
  • the compound of the present invention is ADHD (diagnosis name classified as attention deficit / hyperactivity disorder in conventional DSM-IV in ADHD in Diagnosis and Statistics Guide 5th Edition (DSM-5)) And preferably used for the treatment of autism spectrum disorder.
  • ADHD diagnosis name classified as attention deficit / hyperactivity disorder in conventional DSM-IV in ADHD in Diagnosis and Statistics Guide 5th Edition (DSM-5)
  • DSM-5 Diagnosis and Statistics Guide 5th Edition
  • autism spectrum disorder As a treatment for ADHD, it is particularly preferably used for ADHD whose main symptoms are attention, hyperactivity, and impulsivity.
  • the treatment of autism spectrum disorders includes, among other things, persistent deficits in social communication and social interaction, and autism spectrum disorders whose main symptoms are limited repetitive behaviors, interests and activities. Is preferably used.
  • the pharmaceutical compound After the pharmaceutical compound is taken into the living body, it undergoes metabolism to change its chemical structure, producing highly reactive intermediates, ie reactive metabolites, and toxicity (liver toxicity, allergy, tissue necrosis, mutagen) Sex, carcinogenicity, etc.).
  • One of the tests for easily evaluating the toxicity risk due to this reactive metabolite is a glutathione (GSH) trapping test using dansylated glutathione (dGSH).
  • GSH glutathione
  • dGSH dansylated glutathione
  • the compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal preparation, nasal preparation and the like.
  • topical administration agent examples include capsules, tablets, pills, powders, cachets, suppositories, and liquids.
  • injections include sterile solutions or suspensions.
  • topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.
  • the above-mentioned dosage form is formulated by a usual method together with pharmaceutically acceptable excipients and additives.
  • pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.
  • Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter Etc.
  • Capsules can be formulated by placing the compound of the present invention in a pharmaceutically acceptable carrier.
  • the compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachets can be produced in the same manner.
  • injection solutions include solutions, suspensions, and emulsions. Examples thereof include an aqueous solution and a water-propylene glycol solution.
  • the solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water.
  • a solution suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary.
  • a solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous.
  • the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
  • the dose varies depending on the individual compound and the patient's disease, age, weight, sex, symptom, route of administration, etc., but usually 0.1 to 1000 mg of the compound of the present invention for an adult (50 kg body weight). / Day, preferably 0.1 to 300 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to several weeks.
  • Example 1 5-[(5-Methylpyridin-2-yl) methyl] -2- (1,3-oxazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
  • the compound of Reference Example 1 (43.9 mg, 0.231 mmol), commercially available 2- (chloromethyl) -5-methylpyridine hydrochloride (41.1 mg, 0.231 mmol), tetrabutylammonium bromide (7.5 mg, 0 0.0231 mmol), 50% aqueous potassium carbonate (255 mg), and THF (2.0 mL) were stirred at 80 ° C. overnight.
  • reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (22.4 mg, 33%).
  • Example 2 5-Benzyl-2- (1-methyl-1H-imidazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
  • a mixture of the compound of Reference Example 7 (101 mg, 0.497 mmol), potassium carbonate (103 mg, 0.746 mmol), benzyl bromide (85 mg, 0.497 mmol), and acetonitrile (2 mL) was stirred at 50 ° C. overnight.
  • the reaction solution was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • Example 3 2- (1,3-oxazol-2-yl) -5- ⁇ [2- (trifluoromethyl) pyrimidin-5-yl] methyl ⁇ -4,5,6,7-tetrahydropyrazolo [1,5- a] Pyrazine
  • dichloromethane 2 mL
  • the compound of Reference Example 11 105 mg, 0.599 mmol
  • TFA 5.7 mg, 0.05 mmol
  • sodium triacetoxyborohydride 212 mg, 0.998 mmol
  • Examples 4-7 The compounds of Examples 4 to 7 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 2.
  • Examples 8-11 The compounds of Examples 8 to 11 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 3.
  • Examples 12-33 The compounds of Examples 12 to 36 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 1.
  • Examples 37-44 The compounds of Examples 37 to 44 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 3.
  • Examples 45-48 The compounds of Examples 45 to 48 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 1.
  • reaction solution was allowed to cool to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography to obtain the title compound (2.01 g, 59%).
  • the reaction solution was allowed to cool to room temperature, di-tert-butyl dicarbonate (10.99 g, 50.36 mmol) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (5.53 g, 49%).
  • Reference Example 7 2- (1-Methyl-1H-imidazol-2-yl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine
  • dichloromethane 15 mL
  • hydrochloric acid-1,4-dioxane 15 mL
  • potassium carbonate 1.38 g, 10 mmol
  • water 30 mL
  • reaction solution was allowed to cool to room temperature, and the solvent was concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the obtained residue was purified by silica gel column chromatography to obtain the title compound (2.09 g, 87%).
  • Reference Example 44 5- (2,4-Dimethoxybenzyl) -N-[(2S) -1-hydroxypropan-2-yl] -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] Pyrazine-2-carboxamide
  • a mixture of the compound of Reference Example 45 (515.6 mg, 1.435 mmol), L-alaninol (216 mg, 2.87 mmol), lanthanum trifluorosulfonate (84 mg, 0.143 mmol), and toluene (1 mL) was added at 70 ° C. for 24 hours. Stir for hours.
  • Reference Example 45 Ethyl 5- (2,4-dimethoxybenzyl) -4-oxo-4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxylate To a solution of the compound of Reference Example 46 (8.22 g, 25.12 mmol) in ethanol (6 mL) was added 2,4-dimethoxybenzylamine (4.62 g, 27.63 mmol) and potassium iodide (417 mg, 2.5 mmol). The mixture was stirred for 7 hours under heating and reflux. The reaction solution was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure.
  • Reference Example 49 tert-Butyl 3-methyl-2- (1,3-oxazol-2-yl) -6,7-dihydropyrazolo [1,5-a] pyrazine-5 (4H) -carboxylate
  • the compound of Reference Example 50 (1.10 g, 3.0 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (367 mg, 0.45 mmol), sodium carbonate (1.27 g, 12 mmol) ), And DMF (5 mL) were added 2,4,6-trimethylboroxine (940 mg, 7.50 mmol) in an ice bath. The reaction mixture was stirred at 100 ° C.
  • Reference Example 54 5- (2,4-Dimethoxybenzyl) -4-oxo-N- (2-oxoethyl) -4,5,6,7-tetrahydropyrazolo [1,5-a] pyrazine-2-carboxamide 1 mol / L hydrochloric acid (1.42 L) was added to an acetone (1.42 L) solution of the compound of Reference Example 55 (188.5 g, 0.423 mol), and the mixture was stirred at 65 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature and concentrated under reduced pressure.
  • Test Example 1 D 4 Evaluation of selectivity and agonist activity for the receptor Action of the compound of the present invention on the G protein-dependent pathway of the dopamine D 4 receptor
  • the G protein-dependent pathway is that G protein is activated by binding of G protein to guanosine triphosphate (GTP), It is a pathway that transmits signals into cells via second messengers.
  • GTP guanosine triphosphate
  • GPCRs When GPCRs are activated by a ligand, G protein binds to GPCRs, GTP binds to G ⁇ which is one of G protein subunits, and G ⁇ subunits dissociate.
  • the activated G ⁇ transmits a signal into the cell by adjusting intracellular cAMP concentration through activation and inhibition of adenylate cyclase and adjusting intracellular calcium concentration through activation of phospholipase C. Therefore, G protein-dependent pathway activity can be measured by measuring the amount of intracellular cAMP and the concentration of intracellular calcium. In this test, to measure the effect of the present invention compounds on G-protein-dependent pathway of dopamine D 4 receptors.
  • Expressing cell lines produced human brain-derived dopamine D 4 receptor gene (Gene Bank Accession No: NM_000797) , calcium-binding photoprotein aequorin, and G ⁇ 16 or to prepare a plasmid expressing a chimeric G protein such as Gqi5, these An expression cell line was prepared by introducing it into CHO cells (chinese hamster ovary cells) or HEK293 cells (human embryonic kidney 293 cells).
  • G protein-dependent agonist activity was measured as follows using intracellular calcium concentration as an index.
  • D 4 receptor gene was introduced was a CHO-K1 cell line or HEK293 cell lines were seeded in 384 well plates, 37 ° C. in a CO 2 incubator, after 24 hours of incubation, dissolved in DMSO to cells that have incorporated the pre coelenterazine The compound of the present invention was added, and the change in the amount of luminescence was measured with FDSS (manufactured by Hamamatsu Photonics).
  • the compound of the present invention is defined by setting the luminescence amount of a well not added with the compound of the present invention to 0% and the luminescence amount of a well added with 1 ⁇ M endogenous ligand (dopamine) instead of the compound of the present invention as 100%.
  • the maximum activity (Emax) was calculated.
  • the EC 50 value was calculated as a reaction concentration corresponding to 50% of the compound Emax of the present invention.
  • Test Example 2 Evaluation of bioavailability Rat PK Test
  • the pharmacokinetics of the compound of the present invention can be evaluated.
  • the SD compound or the WKY rat 7 weeks old is administered the compound of the present invention intravenously in a physiological saline solution or orally in a carboxymethylcellulose suspension or a methylcellulose suspension. Collected.
  • Intravenous administration 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration
  • Oral administration 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration
  • Plasma is obtained from the collected blood for 24 hours and the plasma drug concentration is measured by LC-MS. From this concentration transition, the area under the plasma concentration-time curve (AUC) was calculated and applied to the following formula to calculate the bioavailability.
  • Bioavailability (%) AUC after oral administration / AUC after intravenous administration ⁇ 100
  • Test Example 2 The results of Test Example 2 are shown in the table below.
  • Test Example 3 Evaluation of migration into the brain Rat Brain Translocation Test This test can evaluate the brain translocation of the compounds of the present invention.
  • the compound of the present invention is administered subcutaneously in a physiological saline solution or orally in a methylcellulose suspension solution to a SD or WKY 7-week-old rat, and plasma is administered 0.5 hour, 1 hour or 2 hours after administration. Then, brains were collected, and plasma and brain drug concentrations were measured by LC-MS. Serum and brain protein binding rates of the compounds of the present invention were measured using equilibrium dialysis.
  • Kp, uu, brain (Brain compound concentration ⁇ (100 ⁇ protein binding rate in brain (%)) / 100) / (plasma compound concentration ⁇ (100 ⁇ protein binding rate in plasma (%)) / 100)
  • Test Example 3 The results of Test Example 3 are shown in the table below.
  • Test Example 4 Evaluation of pharmacological action on hyperactive behavior in SHR rats SHR rats in early childhood are widely recognized as highly valid ADHD models.
  • the compound of the present invention was orally administered to 6- or 7-week-old SHR rats, and the spontaneous movement for 90 minutes was evaluated after 30 minutes.
  • the measurement was performed using an open field of 900 mm ⁇ 900 mm ⁇ 420 mm, and the momentum was analyzed using a behavior analysis system LimeLight (ACTIMETRICS). Based on the solvent administration group, the cumulative exercise amount (cm) every 30 minutes of the compound administration group of the present invention was compared.
  • the compounds of Example 19 (10 mg / kg administration) and Example 22 (10 mg / kg administration) suppressed the hyperactivity behavior exhibited by SHR rats.
  • Test Example 5 Evaluation of pharmacological action on attention function in SHR rats
  • SHR rats a low spontaneous alternation behavior rate is observed in the Y-shaped maze test compared to the background animals WKY rats. Therefore, the compound of the present invention was pretreated and the effect on attention function was evaluated.
  • a Y-shaped maze device made of black acrylic: 450 mm ⁇ 100 mm ⁇ 420 mm, Horikawa Seisakusho
  • the compound of the present invention was orally administered to 6- or 7-week-old SHR rats, and the spontaneous alternation behavior rate was measured for 8 minutes from 30 minutes later. Based on the spontaneous alternation behavior rate of the vehicle administration group, the spontaneous alternation behavior rate (%) of the compound administration group was compared.
  • the compounds of Example 19 (10 mg / kg administration) and Example 22 (10 mg / kg administration) showed a significant effect of improving the spontaneous alternation behavior rate.
  • Test Example 6 Evaluation of pharmacological action against social disorder in rats treated with fetal valproic acid
  • the compound of the present invention can be pretreated to evaluate the improvement effect on social cognition. Rats exposed to valproic acid at 12.5 days of gestation are widely recognized as a highly relevant model of autism. In this rat, social cognitive impairment is observed in the three-chamber test, which is a social evaluation test. In the experiment, a social cage (600 mm ⁇ 400 mm ⁇ 220 mm, Muromachi Kikai Co., Ltd.) is used. The compound of the present invention was orally administered to a 3-week-old gestational valproic acid-treated rat, and after 30 minutes, the approach time to the rat or a new object was measured for 10 minutes. The ratio of the approach time to the rat when the approach time to the new object is taken as 100% is calculated, and the improvement rate (%) based on the result of the vehicle administration group is evaluated.
  • the compound of the present invention is a dopamine D 4 receptor agonist, it is useful as a therapeutic agent for central nervous system diseases (for example, a therapeutic agent for attention deficit hyperactivity disorder, etc.).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des dérivés de pyrazole fusionnés et des sels pharmaceutiquement acceptables de ces derniers qui agissent avec une sélectivité élevée sur les récepteurs D4 de la dopamine et sont utilisables en tant qu'agents pour le traitement d'un trouble déficitaire de l'attention avec hyperactivité et similaire, les dérivés de pyrazole fusionnés comprenant un composé représenté par la formule (1) : [dans la formule, n et m représentent chacun indépendamment 1 ou 2 ; W1 et W2 représentent chacun indépendamment une simple liaison ou un groupe alkylène C1-4 éventuellement substitué ; R1 et R2 représentent chacun indépendamment un atome d'hydrogène, ou similaire ; R3 représente un atome d'hydrogène, un atome de la famille des halogènes, ou similaire ; le cycle Q1 représente un groupe aryle en C6-10 éventuellement substitué, ou similaire ; et le noyau Q2 représenu un sel pharmaceutiquement acceptable de ce dernier.te un groupe hétéroaryle à 5 chaînons éventuellement substitué] o
PCT/JP2016/062536 2015-04-21 2016-04-20 Dérivés de pyrazole fusionnés substitués en position 2 WO2016171181A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2015-086709 2015-04-21
JP2015086709 2015-04-21

Publications (1)

Publication Number Publication Date
WO2016171181A1 true WO2016171181A1 (fr) 2016-10-27

Family

ID=57143121

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2016/062536 WO2016171181A1 (fr) 2015-04-21 2016-04-20 Dérivés de pyrazole fusionnés substitués en position 2

Country Status (1)

Country Link
WO (1) WO2016171181A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110724151A (zh) * 2019-11-18 2020-01-24 成都睿智化学研究有限公司 一种（3,4-二氢-2H-吡喃并[2,3-b]吡啶-6-基）甲醇的合成方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012522793A (ja) * 2009-04-03 2012-09-27 大日本住友製薬株式会社 代謝型グルタミン酸受容体５介在障害の治療のための化合物、およびその使用方法
JP2013544891A (ja) * 2010-12-08 2013-12-19 ヴァンダービルト ユニバーシティー ｍＧＬＵＲ５受容体のアロステリック調節剤としての二環式ピラゾール化合物
JP2015059118A (ja) * 2013-09-20 2015-03-30 大日本住友製薬株式会社 テトラヒドロピラゾロピラジン誘導体
WO2015060348A1 (fr) * 2013-10-23 2015-04-30 大日本住友製薬株式会社 Dérivé de pyrazole fusionné

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012522793A (ja) * 2009-04-03 2012-09-27 大日本住友製薬株式会社 代謝型グルタミン酸受容体５介在障害の治療のための化合物、およびその使用方法
JP2013544891A (ja) * 2010-12-08 2013-12-19 ヴァンダービルト ユニバーシティー ｍＧＬＵＲ５受容体のアロステリック調節剤としての二環式ピラゾール化合物
JP2015059118A (ja) * 2013-09-20 2015-03-30 大日本住友製薬株式会社 テトラヒドロピラゾロピラジン誘導体
WO2015060348A1 (fr) * 2013-10-23 2015-04-30 大日本住友製薬株式会社 Dérivé de pyrazole fusionné

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110724151A (zh) * 2019-11-18 2020-01-24 成都睿智化学研究有限公司 一种（3,4-二氢-2H-吡喃并[2,3-b]吡啶-6-基）甲醇的合成方法
CN110724151B (zh) * 2019-11-18 2022-03-04 成都睿智化学研究有限公司 一种（3,4-二氢-2H-吡喃并[2,3-b]吡啶-6-基）甲醇的合成方法

Similar Documents

Publication Publication Date Title
KR102179599B1 (ko) 이환형 유도체
US8841299B2 (en) Substituted pyrrolo[1,2-a]pyrazines as tankyrase inhibitors
JP6800885B2 (ja) イミダゾピラジン及びピラゾロピリミジン、並びにａｍｐａ受容体調節物質としてのこれらの使用
JP2021193099A (ja) 置換４−アザインドール及びｇｌｕｎ２ｂ受容体調節因子としてのそれらの使用
KR20150126036A (ko) 오토탁신 억제제로서의 신규한 옥타하이드로-피롤로[3,4-c]-피롤 유도체 및 이의 유사체
TW201726675A (zh) M4毒蕈鹼乙醯膽鹼受體之異位調節劑6,7-二氫-5h-吡咯并[3,4-b]吡啶-5-酮
JPWO2007040166A1 (ja) 新規な縮合ピロール誘導体
JP2021512055A (ja) Ｔａｍファミリーキナーゼ／及びｃｓｆ１ｒキナーゼ阻害剤及びその用途
JP2024020396A (ja) 縮環ラクタム誘導体
KR20220140710A (ko) 트리아졸로피리다진 유도체, 이의 제조 방법, 약물 조성물 및 용도
CN112805063A (zh) 作为gabaa a5受体调节剂的双环衍生物
WO2015060348A1 (fr) Dérivé de pyrazole fusionné
JP2023134749A (ja) マクロライド誘導体、その製造方法および用途
WO2016171181A1 (fr) Dérivés de pyrazole fusionnés substitués en position 2
JP2016204374A (ja) 縮合ピラゾール誘導体からなる医薬
US10745401B2 (en) Condensed lactam derivative
JP6370294B2 (ja) 環状アミノメチルピリミジン誘導体
CA3191001A1 (fr) Synthese de composes de quinazoline
JP2013166727A (ja) ジヒドロイミダゾピラジノン誘導体
JP2022554385A (ja) Ｗｄｒ５阻害剤及び調節剤
WO2018079628A1 (fr) Dérivé de pyrrole à noyau fusionné et son utilisation pharmaceutique
JP2021119130A (ja) 縮環ラクタム誘導体からなる医薬
AU2015370697A1 (en) Novel heterocyclic compounds and the use thereof in medicine and in cosmetics

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16783202

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16783202

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP