WO2012147890A1 - Nouveau dérivé d'azole - Google Patents

Nouveau dérivé d'azole Download PDF

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WO2012147890A1
WO2012147890A1 PCT/JP2012/061288 JP2012061288W WO2012147890A1 WO 2012147890 A1 WO2012147890 A1 WO 2012147890A1 JP 2012061288 W JP2012061288 W JP 2012061288W WO 2012147890 A1 WO2012147890 A1 WO 2012147890A1
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ring
alkyl
alkoxy
membered
hydroxy
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石川　誠
淳 灰谷
直人 小菅
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Mochida Pharmaceutical Co Ltd
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Mochida Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an azole compound useful as an effective phosphodiesterase 10 (PDE10) inhibitor.
  • PDE10 phosphodiesterase 10
  • the invention further relates to pharmaceutical compositions comprising such compounds and the use of such compounds in methods of treating certain central nervous system (CNS) disorders or other disorders.
  • CNS central nervous system
  • the invention also relates to methods of treating neurodegenerative and psychiatric disorders, such as schizophrenia and disorders involving cognitive deficits as symptoms.
  • Phosphodiesterase is one type of intracellular enzyme involved in the hydrolysis of nucleotide cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to each nucleotide monophosphate.
  • the cyclic nucleotides cAMP and cGMP are synthesized by adenylyl cyclase and guanylyl cyclase, respectively, and serve as second messengers in various cellular pathways.
  • CAMP and cGMP function as intracellular second messengers that regulate many intracellular processes, particularly in neurons of the central nervous system. In neurons, this includes activation of cAMP and cGMP-dependent kinases, as well as the subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission and neuronal differentiation and survival.
  • the complexity of cyclic nucleotide signaling is suggested by the molecular diversity of the enzymes involved in the synthesis and degradation of cAMP and cGMP. There are at least 10 adenylyl cyclase families, 2 guanylyl cyclases, and 11 phosphodiesterases.
  • various different types of neurons are known to express each of these classes of multiple isozymes, and there is ample evidence for compartmentalization and functional specificity of the various different isozymes within a given neuron. is there.
  • the primary mechanism for regulating cyclic nucleotide signaling is by phosphodiesterase-catalyzed cyclic nucleotide catabolism.
  • PDE families encoded by 21 different genes. Each gene typically results in multiple splice variants that further contribute to the diversity of isozymes.
  • the PDE family is functionally distinguished based on cyclic nucleotide substrate specificity, regulatory mechanisms, and sensitivity to inhibitors.
  • PDE is specifically expressed throughout the body including the central nervous system. As a result of these specific enzyme activities and localization, a variety of different PDE isozymes can perform specific physiological functions. Further, compounds that can selectively inhibit specific PDE families or isozymes can provide specific therapeutic effects, fewer side effects, or both.
  • PDE10 is identified as a unique family based on primary amino acid sequence and specific enzyme activity. Homology screening of the EST database revealed mouse PDE10A as the first member of the PDE10 family of PDEs (Fujishige et al., J. Biol. Chem. 274: 18438-18445, 1999; Loughney, K. et al., Gene. 234: 109-117, 1999). This mouse homologue has also been cloned (Soderling, S. et al., Proc. Natl. Acad. Sci. USA 96: 7071-7076, 1999), and N-terminal splice variants of both rat and human genes have been identified. (Kotera, J.
  • Mouse PDE10A is a 779 amino acid protein that hydrolyzes both cAMP and cGMP to AMP and GMP, respectively.
  • Vmax is about 5 times greater in cGMP than cAMP, suggesting that PDE10 is a unique cAMP-inhibiting cGMPase (Fujishige et al., J. Biol. Chem. 274: 18438-18445, 1999).
  • PDE10 family polypeptides exhibit low sequence homology compared to previously identified PDE families and are insensitive to certain inhibitors known to be specific for other PDE families It has been shown. Reference is made to US Pat. No. 6,350,603 as part of this specification.
  • PDE10 is also uniquely localized in mammals compared to other PDE families.
  • PDE10 mRNA is highly expressed only in the testis and brain (Fujishige, K. et al., Eur J Biochem. 266: 1118-1127, 1999; Soderling, S. et al., Proc. Natl. Acad. Sci. 96: 7071. ⁇ 7076, 1999; Loughney, K. et al., Gene 234: 109-117, 1999).
  • These early studies show that in the brain, PDE10 expression is highest in the striatum (caudate nucleus and putamen), nucleus accumbens, and olfactory nodule.
  • PDE10 mRNA Seeeger, TF et al., Abst. Soc. Neurosci. 26: 345.10, 2000
  • PDE10 protein PDE10 protein
  • Patent Document 1 International Publication No. 2009/152825
  • Patent Document 2 International Publication No. 2010/027097
  • Patent Document 3 International Publication No. 2010/030027.
  • Pamphlet patent document 3
  • international publication 2010/145668 pamphlet patent document 4
  • international publication 2011/036127 pamphlet patent document 5
  • international publication 2011/072694 pamphlet patent document 6
  • International Publication No. 2011/072695 Patent Document 7
  • Patent Document 8 International Publication No. 2011/072696
  • Patent Document 9 International Publication No.
  • Patent Document 10 2010/030027 Pamphlet
  • Psychiatric disorders are serious mental illnesses that greatly impair everyday life.
  • the symptoms of schizophrenia can be divided into two parts. In the acute phase, it is dominated by hallucinations and delusions called positive symptoms. When the excitement period weakens, so-called negative symptoms become conspicuous. These include cognitive impairment, social phobia, reduced attention, indifference and impaired language learning and memory, language fluency and impaired motor function.
  • EPS extrapyramidal symptoms
  • Clozapine has emerged as a benchmark to treat and recover positive, negative and cognitive symptoms of schizophrenia but shows granulocytopenia as a potential fatal side effect (Capuano et al., 2002). Moreover, there are still many treatment-resistant cases (Lindenmayer et al., 2002).
  • PDE10 inhibitors there are always comprehensive problems in the development of these drugs, and they have not yet been put on the market. More specifically, for compounds having PDE10 inhibitory activity, for example, poor solubility, low metabolic stability and difficulty in systemic exposure by oral administration, and pharmacokinetics such as absorption and persistence. Inhibiting activity of hERG (human ether-a-go-related gene) channels that are not good or may cause arrhythmia, inducing or inhibiting activity of drug metabolizing enzymes (eg, cytochrome P450) There are problems of usefulness and safety such as showing high protein binding rate. There are also issues that can be identified at the clinical trial stage. There is a need to solve these problems as much as possible and find highly effective compounds.
  • hERG human ether-a-go-related gene
  • the present inventors have conducted extensive studies to obtain a PDE10 inhibitor that is highly safe and / or excellent in effectiveness.
  • the formula (I) and the formula (I -A) a derivative having the azole structure represented by formula (I-1), formula (I-2), formula (I-3), formula (I-4), formula (I-5), etc.
  • PDE10 inhibitory action The compound of the present invention has an excellent PDE10 inhibitory action and a strong ameliorating action for schizophrenia-like symptoms.
  • the present invention relates to a compound having the azole structure represented by formula (I) or a salt thereof or a solvate thereof, and the compound or a pharmaceutically acceptable salt thereof. It is a pharmaceutical composition characterized by containing these solvates as active ingredients.
  • the compound of the present invention increases the nerve firing and promotes the activation of the striatum by inhibiting the cAMP degradation of the striatal GABA nerve by inhibiting the PDE10-inhibiting compound or PDE10 In other words, it has an ameliorating effect on schizophrenia.
  • a pharmaceutical composition containing the compound of the present invention as an active ingredient can be administered orally and is expected as a therapeutic agent for schizophrenia.
  • the compound group of the present invention has a strong PDE10 inhibitory activity in an in vitro test, good solubility, high metabolic stability, excellent oral absorbability, and excellent brain migration. It has high usefulness because it has at least one characteristic such as having a hERG channel inhibitory action, an in vivo test, and a spontaneous momentum suppressing action.
  • the present invention includes a compound having the azole structure represented by the formula (I) represented by the following embodiment or a salt thereof or a solvate thereof, and containing them as an active ingredient.
  • the present invention includes the following embodiment [1].
  • cyclopropane ring or cyclobutane ring may be formed,
  • the cyclopropane ring or cyclobutane ring may be substituted with 1-2 halogen atoms or C1-6 alkyl,
  • R1 is a hydrogen atom, halogen, cyano, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 3-6 membered aliphatic ring, 1-2 carbons
  • R1 may be bridged with phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 3-6 membered aliphatic ring, 1-2 carbon atoms
  • Each ring in a good 4-10 membered heteroaliphatic ring is halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, hydroxy, C1-6 alkoxycarbonyl, NR4'R5 ', C1-6 alkylsulfonyl, C1- 6 alkoxy C1-6 alkyl, C2-6 alkanoyl, COR7, CONR8R9 or C1-6 alkoxy may be independently substituted with 1-2, each ring being substituted with 1-2 oxo May be replaced,
  • the 4- to 10-membered heteroaliphatic ring which may be bridged with 1 to 2 carbon atoms in R1 is further composed of a total of 3 to 6-membered aliphatic rings or
  • Each alkyl part of the C1-6 alkyl, C1-6 alkylsulfonyl, and C1-6 alkoxy in R1 is further independently 1-3 of halogen, oxo, hydroxy, phenyl, C1-6 alkoxy, and —NR4′R5 ′. May be replaced
  • R4 and R5 in NR4R5 in R1 are each independently a hydrogen atom, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, condensed heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylsulfonyl, Phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, phenyl C1-6 alkyl, 5-6 membered heteroaryl in the R4 or R5
  • Each ring in C1-6 alkyl is halogen, cyano, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl, hydroxy C1-6 al
  • the sulfonyl or C1-6 alkoxy may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, —NR4′R5 ′,
  • Each alkyl part of C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkoxy C1-6 alkyl, or C1-6 alkoxy in R4 or R5 is further halogen, oxo, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, phenyl, C1-6 alkylaminocarbonyl, -NR4'R5 ', 4-10 membered heteroaliphatic ring, or 5-6 membered heteroaryl, each independently 1-3 substituted Often, In the C1-6 alkyl in R4 or R5, when two alkyl groups or alkoxy groups at the geminal position are substituted, these are bonded to each other to form a 3-6 membered cyclocycle or a 4-10 membered heterofatty acid. May
  • R6 in the OR6 in R1 represents phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 alkyl, or a hydrogen atom
  • the phenyl in R6, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring is halogen, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl or C1 -6 alkoxy may be independently substituted with 1-2, and each ring may be substituted with 1-2 oxo if possible, and the C1-6 alkyl, C1 -6 alkylsulfonyl or C1-6 alkoxy may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, -NR4'R5 ',
  • the C1-6 alkyl in OR6 may be further independently substituted
  • R7 in the COR7 in each ring in R1 and R1 is phenyl, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring, C1-6 alkyl, C1-6 alkoxy, Or represents hydroxy
  • the phenyl in R7, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring is halogen, oxo, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl Or C1-6 alkoxy may be independently substituted by 1-2, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in each ring is further halogen, oxo, hydroxy, C1-6 Each may be independently substituted with 1-3 of alkoxy and -NR4'R5 ',
  • R8 and R9 in CONR8R9 in each ring in R1 and R1 are each independently a hydrogen atom, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, C1-6 alkyl, or C1-6 Represents alkylsulfonyl,
  • the phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring in R8 and R9 are independently halogen, C1-6 alkyl, hydroxy, NR4′R5 ′, C1-6 alkylsulfonyl or C1-6 alkoxy.
  • each ring may be substituted with 1-2 oxo groups if possible, C1-6 alkyl and C1-6 alkylsulfonyl in R8 and R9 may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′,
  • R2 represents a 4-7 membered heteroaliphatic ring, 5-6 membered heteroaryl, phenyl, NR4 '' R5 '', or OR6 ', Each ring of 4-7 membered heteroaliphatic ring, 5-6 membered heteroaryl and phenyl in R2 is halogen, cyano, hydroxy, C1-6 alkoxy, NR4'R5 ', COR7', C1-6 alkyl, C1-6 1-2 may be substituted with alkylsulfonyl, and each ring may be substituted with 1-2 oxo if possible, R7 ′ in COR7 ′ in each ring of R2 represents phenyl, 4-6 membered heteroaliphatic ring, C1-6 alkyl, C1-6 alkoxy, or hydroxy, and the C1-6 alkoxy in each ring of R2, C1 -6 alkyl may be further substituted 1-3 by halogen, hydroxy, cyano, oxo, C
  • R4 ′ ′ and R5 ′ ′ in NR4′′R5 ′ ′ in R2 are each independently a hydrogen atom, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic Represents a ring, C1-6 alkyl, or C1-6 alkylsulfonyl;
  • phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring is halogen, hydroxy, NR4′R5 ′, C1-6 alkyl, C1 -6 alkylsulfonyl or C1-6 alkoxy may be independently substituted with 1-2, and each ring may be substituted with oxo if it can be substituted,
  • the C1-6 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy may be further independently substituted with
  • C1-6 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy in the R4 ′ ′ or R5 ′ ′ is independently independently halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′. -3 may be replaced, However, R4 ′ ′ and R5 ′ ′ in R2 are not hydrogen atoms at the same time,
  • R6 ′ in the OR6 ′ in R2 represents phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, or 3-6 membered aliphatic ring, Each of the phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring in R6 ′ in R2 is halogen, hydroxy, NR4′R5 ′, C1-6 alkyl, C1 -6 alkylsulfonyl or C1-6 alkoxy may be independently substituted with 1-2, and each ring may be substituted with oxo if it can be substituted, The C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in each ring is further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′.
  • R6 '' in the OR6 '' in R3 is phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 alkyl, C2-6 represents an alkanoyl or hydrogen atom
  • the phenyl in R6 '', 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, condensed heteroaryl, 3-6 membered aliphatic ring is halogen, hydroxy, NR4'R5 ', C1-6 It may be independently substituted with 1-2 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy, and each ring may be substituted with 1-2 oxo if it can be substituted.
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in the ring may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′.
  • Each substituent of the C1-6 alkyl or C2-6 alkanoyl in R6 '' is further independently halogen, oxo, hydroxy, C1-6 alkoxy, phenyl, 5-6 membered heteroaryl, -NR4'R5 ' 1-3 may be substituted,
  • the phenyl and 5-6-membered heteroaryl are each independently substituted with 1-3 of hydroxy and C1-6 alkoxy.
  • X2, X3 and X4 in the hetero condensed ring containing ring A each independently represent C, CH, NH or N, and the condensed ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • R4 ′ and R5 ′ in NR4′R5 ′ each independently represent a hydrogen atom, C1-6 alkyl, or a 4-6 membered heteroaliphatic ring.
  • a pharmaceutically acceptable salt or solvate thereof, a PDE10 inhibitor or a pharmaceutically acceptable salt or solvate thereof, a PDE10 inhibitor.
  • formula (Ia) preferred examples of X1, X2, X3, X4, X5, L1, L2, hetero condensed ring containing ring A, R1 to R10 and the like are described in the following formula (I) and the like. This is the same as the preferred example of the present invention.
  • a preferred embodiment of the present invention is expressed as follows, for example.
  • cyclopropane ring or cyclobutane ring may be formed,
  • the cyclopropane ring or cyclobutane ring may be substituted with 1-2 halogen atoms or C1-6 alkyl,
  • CH1 and CH2 in each of L1 and L2 may be substituted with 1 to 2 of C1-6 alkyl, C1-6 haloalkyl, oxo, hydroxy, C1-6 alkoxy, and two alkyl groups are bonded to each other. May form a 3-6 membered cyclo ring, or may be substituted 1-4 with halogen, Or you may form the cyclopropane ring shown below, The cyclopropane ring may be substituted with 1-2 halogen atoms,
  • R1 is a hydrogen atom, halogen, cyano, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 3-6 membered aliphatic ring, 1-2 carbons
  • R1 is a hydrogen atom, halogen, cyano, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 3-6 membered aliphatic ring, 1-2 carbons
  • R1 may be bridged with phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 3-6 membered aliphatic ring, 1-2 carbon atoms
  • Each ring in a good 4-10 membered heteroaliphatic ring is halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, hydroxy, C1-6 alkoxycarbonyl, NR4'R5 ', C1-6 alkylsulfonyl, C1- 6 alkoxy C1-6 alkyl, C2-6 alkanoyl, COR7, CONR8R9 or C1-6 alkoxy may be independently substituted with 1-2, each ring being substituted with 1-2 oxo May be replaced,
  • the 4- to 10-membered heteroaliphatic ring which may be bridged with 1 to 2 carbon atoms in R1 is further composed of a total of 3 to 6-membered aliphatic rings or
  • Each alkyl part of the C1-6 alkyl, C1-6 alkylsulfonyl, and C1-6 alkoxy in R1 is further independently 1-3 of halogen, oxo, hydroxy, phenyl, C1-6 alkoxy, and —NR4′R5 ′. May be replaced,
  • R4 and R5 in NR4R5 in R1 are each independently a hydrogen atom, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, condensed heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylsulfonyl, Phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, phenyl C1-6 alkyl, 5-6 membered heteroaryl in the R4 or R5
  • Each ring in C1-6 alkyl is halogen, cyano, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl, hydroxy C1-6 al
  • the sulfonyl or C1-6 alkoxy may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, —NR4′R5 ′,
  • Each alkyl part of C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkoxy C1-6 alkyl, or C1-6 alkoxy in R4 or R5 is further halogen, oxo, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, phenyl, C1-6 alkylaminocarbonyl, -NR4'R5 ', 4-10 membered heteroaliphatic ring, or 5-6 membered heteroaryl, each independently 1-3 substituted Often, In the C1-6 alkyl in R4 or R5, when two alkyl groups or alkoxy groups at the geminal position are substituted, these are bonded to each other to form a 3-6 membered cyclocycle or a 4-10 membered heterofatty acid. May
  • R6 in the OR6 in R1 represents phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 alkyl, or a hydrogen atom
  • the phenyl in R6, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring is halogen, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl or C1 -6 alkoxy may be independently substituted with 1-2, and each ring may be substituted with 1-2 oxo if possible, and the C1-6 alkyl, C1 -6 alkylsulfonyl or C1-6 alkoxy may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, -NR4'R5 ',
  • the C1-6 alkyl in OR6 may be further independently substituted
  • R7 in the COR7 in each ring in R1 and R1 is phenyl, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring, C1-6 alkyl, C1-6 alkoxy, Or represents hydroxy
  • the phenyl in R7, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring is halogen, oxo, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl Or C1-6 alkoxy may be independently substituted by 1-2, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in each ring is further halogen, oxo, hydroxy, C1-6 Each may be independently substituted with 1-3 of alkoxy and -NR4'R5 ',
  • R8 and R9 in CONR8R9 in each ring in R1 and R1 are each independently a hydrogen atom, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, C1-6 alkyl, or C1-6 Represents alkylsulfonyl,
  • the phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring in R8 and R9 are independently halogen, C1-6 alkyl, hydroxy, NR4′R5 ′, C1-6 alkylsulfonyl or C1-6 alkoxy.
  • each ring may be substituted with 1-2 oxo groups if possible, C1-6 alkyl and C1-6 alkylsulfonyl in R8 and R9 may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′,
  • R1 Hydrogen atom, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 4-10 membered heteroaliphatic optionally bridged with 1-2 carbon atoms
  • Each ring in the ring is halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, hydroxy, C1-6 alkoxycarbonyl, NR4'R5 ', C1-6 alkylsulfonyl, C1-6 alkoxy C1-6 alkyl
  • a 7-12 membered spiro ring which may be substituted with 1-2 halogens or C1-6 alkyl, Alternatively, preferably as R1, Hydrogen atom, NR4R5, OR6, halogen, cyano, phenyl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, 5-6 membered heteroaryl, C1-6 alkyl, C1-6 alkylsulfonyl, C1- 6 represents alkoxy, COR7, or CONR8R9,
  • the ring in R1, phenyl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, and 5-6 membered heteroaryl are each halogen, oxo, C1-6 alkyl, hydroxy, NR4'R5 ', C1 Optionally substituted with 1-2 alkylsulfonyl, C1-6 alkoxy, cyano, C2-6 alkanoyl, COR7, or
  • R4 and R5 in NR4R5 in R1 are each independently a hydrogen atom, phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, Represents C1-6 alkyl, or C1-6 alkylsulfonyl,
  • phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring are halogen, oxo, hydroxy, NR4′R5 ′, C1 -6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy may be independently 1-2 substituted, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further substituted with halogen, oxo , Hydroxy, C1-6 alkoxy, and -NR4'R5
  • R6 in OR6 in R1 represents phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, or C1-6 alkyl
  • the phenyl in R6, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring is halogen, oxo, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl
  • C1-6 alkoxy may be independently substituted with 1-2, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further halogen, oxo, hydroxy, C1-6 alkoxy,-
  • Each of NR4′R5 ′ may be independently substituted 1-3, C1-6 alkyl in OR6 in R1 may be further independently substituted
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′.
  • the phenyl and 5-6 membered heteroaryl in R8 and R9 are independently substituted with 1-2 halogen, oxo, C1-6 alkyl, hydroxy, NR4′R5 ′, C1-6 alkylsulfonyl or C1-6 alkoxy.
  • C1-6 alkyl and C1-6 alkylsulfonyl in R8 and R9 may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′,
  • R1 more preferably represents a 4- to 10-membered heteroaliphatic ring, NR4R5, or OR6, which may be bridged with 1-2 carbon atoms
  • the 4- to 10-membered heteroaliphatic ring in R1 may be independently substituted with 1-2 halogen, cyano, C1-6 alkyl, C2-6 alkanoyl, COR7, CONR8R9, hydroxy, NR4'R5 '
  • the 4- to 10-membered heteroaliphatic ring which may be bridged with 1 to 2 carbon atoms in R1 is further composed of a total of 3 to 6-membered aliphatic rings or oxygen-containing 4 to 6-membered aliphatic rings. May form a 7-12 membered spiro ring, which may be substituted with 1-2 halogens or C1-6 alkyl,
  • R2 represents a 4-7 membered heteroaliphatic ring, 5-6 membered heteroaryl, phenyl, NR4 '' R5 '', or OR6 ', Each ring of 4-7 membered heteroaliphatic ring, 5-6 membered heteroaryl and phenyl in R2 is halogen, cyano, hydroxy, C1-6 alkoxy, NR4'R5 ', COR7', C1-6 alkyl, C1-6 1-2 may be substituted with alkylsulfonyl, and each ring may be substituted with 1-2 oxo if possible, R7 ′ in COR7 ′ in each ring of R2 represents phenyl, 4-6 membered heteroaliphatic ring, C1-6 alkyl, C1-6 alkoxy, or hydroxy, and the C1-6 alkoxy in each ring of R2, C1 -6 alkyl may be further substituted 1-3 by halogen, hydroxy, cyano, oxo, C
  • R4 ′ ′ and R5 ′ ′ in NR4′′R5 ′ ′ in R2 are each independently a hydrogen atom, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic Represents a ring, C1-6 alkyl, or C1-6 alkylsulfonyl;
  • phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring is halogen, hydroxy, NR4′R5 ′, C1-6 alkyl, C1 -6 alkylsulfonyl or C1-6 alkoxy may be independently substituted with 1-2, and each ring may be substituted with oxo if it can be substituted,
  • the C1-6 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy may be further independently substituted with
  • C1-6 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy in the R4 ′ ′ or R5 ′ ′ is independently independently halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′. -3 may be replaced, However, R4 ′ ′ and R5 ′ ′ in R2 are not hydrogen atoms at the same time,
  • R6 ′ in the OR6 ′ in R2 represents phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, or 3-6 membered aliphatic ring
  • Each of the phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring in R6 ′ in R2 is halogen, hydroxy, NR4′R5 ′, C1-6 alkyl, C1 -6 alkylsulfonyl or C1-6 alkoxy may be independently substituted with 1-2, and each ring may be substituted with oxo if it can be substituted,
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in each ring is further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′.
  • R2 Represents a 4-7 membered heteroaliphatic ring
  • the 4-7 membered heteroaliphatic ring is 1-2 substituted with halogen, cyano, oxo, hydroxy, C1-6 alkoxy, NR4′R5 ′, C1-6 alkylsulfonyl, COR7 ′, C1-6 alkyl.
  • R7 ′ in COR7 ′ in the 4-7 membered heteroaliphatic ring represents C1-6 alkyl, C1-6 alkoxy, or hydroxy
  • Each ring of 4-6 membered heteroaliphatic ring and 5-6 membered heteroaryl in R2 is substituted with 1-2 halogen, oxo, hydroxy, C1-6 alkoxy, NR4'R5 ', COR7', C1-6 alkyl
  • the C1-6 alkoxy, C1-6 alkyl may be substituted with 1-2 halogen, hydroxy, cyano
  • R7 ′ in the COR7 ′ in R2 represents phenyl, a 4-6 membered heteroaliphatic ring, C1-6 alkyl, C1-6 alkoxy, or hydroxy, R6 ′ in the
  • R10 represents halogen, cyano, hydroxy, C1-6 alkoxy, NR4′R5 ′, COR7 ′ ′, hydroxy C1-6 alkyl, or C1-6 alkyl
  • R7 ′ ′ in the COR7 ′ ′ is C1-6 alkyl , C1-6 alkoxy, hydroxy C1-6 alkyl, or hydroxy
  • R4 ′ and R5 ′ in NR4′R5 ′ each independently represent a hydrogen atom, C1-6 alkyl, a 4-6 membered heteroaliphatic ring
  • R6 ′ ′ in the OR6 ′ ′ in R3 is phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 alkyl, C2-6 represents an alkanoyl or hydrogen atom
  • the phenyl in R6 ′ ′, 4-6 membered heteroaliphatic ′ is C
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in the ring may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′.
  • Each substituent of the C1-6 alkyl or C2-6 alkanoyl in R6 ′ ′ is further independently halogen, oxo, hydroxy, C1-6 alkoxy, phenyl, 5-6 membered heteroaryl, or —NR4′R5 ′.
  • 1-3 may be substituted,
  • the phenyl and 5-6-membered heteroaryl are each independently substituted with 1-3 of hydroxy and C1-6 alkoxy.
  • R6 ′ ′ in the OR6 ′ ′ in R3 preferably represents a 5-6 membered heteroaryl, a 4-6 membered heteroaliphatic ring, C1-6 alkyl, or C2-6 alkanoyl, and the 5- 6-membered heteroaryl, 4-6-membered heteroaliphatic ring may be independently 1-2 substituted with C1-6 alkoxy, and each ring may be substituted with oxo if 1-2
  • the C1-6 alkoxy in each ring may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, —NR4′R5 ′, and R6 ′.
  • Each substituent of the C1-6 alkyl or C2-6 alkanoyl in ' is further independently halogen, oxo, hydroxy, C1-6 alkoxy, phenyl, 5-6 membered heteroaryl, or -NR4'R5'.
  • R6 ′ ′ in the OR6 ′ ′ in R3 represents a 4-6 membered heteroaliphatic ring, C1-6 alkyl, or C2-6 alkanoyl, and the 4-6 membered heteroaliphatic ring in R6 ′ ′.
  • X2, X3 and X4 in the hetero condensed ring containing ring A each independently represent C, CH, NH or N, and the condensed ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced, Also preferably, the fused ring is selected from the group consisting of: Each 6-membered ring A site or adjacent nitrogen-containing 5-membered ring may be substituted with 1-2 C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy. )
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • R4 ′ and R5 ′ in NR4′R5 ′ in the above each independently represent a hydrogen atom, C1-6 alkyl, a 4-6 membered heteroaliphatic ring, Preferably, R4 ′ and R5 ′ each independently represent a hydrogen atom or C1-6 alkyl. ), Or a pharmaceutically acceptable salt or solvate thereof,
  • the present invention provides a nitrogen-containing compound represented by the above formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the present invention also has the following embodiments.
  • CH1 and CH2 in each of L1 and L2 may be substituted with 1 to 2 of C1-6 alkyl, C1-6 haloalkyl, oxo, hydroxy, C1-6 alkoxy, and two alkyl groups are bonded to each other.
  • the cyclopropane ring may be substituted with 1-2 halogen atoms or C1-6 alkyl,
  • -CH CH-
  • -CH CH- preferably represents E-form
  • the following cyclopropane ring may be formed.
  • a preferable heterofused ring containing the ring A is, for example, as follows: Expressed.
  • X2, X3 and X4 in the hetero condensed ring containing ring A each independently represent C, CH, NH or N, and the condensed ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • the fused ring is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • R 1 is expressed, for example, as follows.
  • Formula (I) (Where X1, X2, X3, X4, X5, R2, L1, L2, and the linker (-L1-L2-site) are the same as defined in Embodiment [1-1],
  • R1 is Hydrogen atom, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 4-10 membered heteroaliphatic optionally bridged with 1-2 carbon atoms
  • the phenyl in R1 phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 4-10 membered heteroaliphatic optionally bridged with 1-2 carbon atoms
  • Each ring in the ring is halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, hydroxy, C1-6 alkoxycarbonyl, NR4'R5 ', C1-6 alkylsulfonyl, C1-6 alkoxy C1-6 alky
  • R1 is Represents a 4-10 membered heteroaliphatic ring, NR4R5, or OR6, optionally bridged with 1-2 carbon atoms
  • the 4- to 10-membered heteroaliphatic ring in R1 may be independently substituted with 1-2 halogen, cyano, C1-6 alkyl, C2-6 alkanoyl, COR7, CONR8R9, hydroxy, NR4'R5 '
  • the 4- to 10-membered heteroaliphatic ring which may be bridged with 1 to 2 carbon atoms in R1 is further composed of a total of 3 to 6-membered aliphatic rings or oxygen-containing 4 to 6-membered aliphatic rings.
  • R4 to R9, R4 ′, and R5 ′ in R1 are the same as defined in Embodiment [1-1]. ).
  • R 2 is expressed, for example, as follows.
  • Formula (I) (Where The hetero-fused ring containing ring A, X1, X2, X3, X4, X5, R1, L1, L2, and the linker (-L1-L2-site) are the same as defined in embodiment [1-1].
  • R2 is Represents a 4-7 membered heteroaliphatic ring
  • the 4-7 membered heteroaliphatic ring may be substituted with 1-2 halogen, cyano, hydroxy, C1-6 alkoxy, NR4′R5 ′, COR7 ′, C1-6 alkyl, R7 ′ in COR7 ′ in the 4-7 membered heteroaliphatic ring represents C1-6 alkyl, C1-6 alkoxy, or hydroxy,
  • R2 is And R10 represents halogen, cyano, hydroxy, C1-6 alkoxy, NR4′R5 ′, COR7 ′ ′, hydroxy C1-6 alkyl, or C1-6 alkyl, and R7 ′ ′ in the COR7 ′ ′ is C1-6 alkyl , C1-6 alkoxy, hydroxy, R4 ′, R5 ′, and R7 ′ in R2 are the same as defined in Embodiment [1-1]. ).
  • R 3 is expressed, for example, as follows.
  • Formula (I) (Wherein the hetero condensed ring including ring A, X2, X3, X4, R1, R2, L1, L2, and the linker (-L1-L2- moiety) are the same as defined in the embodiment [1-1].
  • X1 and X5 each independently represent CR3 or N
  • R3 represents a hydrogen atom, halogen, C1-6 alkyl
  • OR6 ′ ′, R6 ′ ′ in OR6 ′ ′ in R3 represents phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 Represents an alkyl, a C2-6 alkanoyl, or a hydrogen atom
  • the phenyl in R6 ′ ′, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, condensed heteroaryl, 3-6 membered aliphatic ring is halogen, hydroxy, NR4′R5 ′, C1-6 It may be independently substituted with 1-2 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy, and each ring may be substituted with 1-2 oxo
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in the ring may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′.
  • Each substituent of the C1-6 alkyl or C2-6 alkanoyl in R6 ′ ′ is further independently halogen, oxo, hydroxy, C1-6 alkoxy, phenyl, 5-6 membered heteroaryl, or —NR4′R5 ′.
  • 1-3 may be substituted,
  • the phenyl and 5-6-membered heteroaryl are each independently substituted with 1-3 of hydroxy and C1-6 alkoxy.
  • R6 ′ ′ in the OR6 ′ ′ in R3 preferably represents a 5-6 membered heteroaryl, a 4-6 membered heteroaliphatic ring, C1-6 alkyl, or C2-6 alkanoyl, and the 5- 6-membered heteroaryl, 4-6-membered heteroaliphatic ring may be independently 1-2 substituted with C1-6 alkoxy, and each ring may be substituted with oxo if 1-2
  • the C1-6 alkoxy in each ring may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, —NR4′R5 ′, and R6 ′.
  • Each substituent of the C1-6 alkyl or C2-6 alkanoyl in ' is further independently halogen, oxo, hydroxy, C1-6 alkoxy, phenyl, 5-6 membered heteroaryl, or -NR4'R5'.
  • R6 ′ ′ in the OR6 ′ ′ in R3 represents a 4-6 membered heteroaliphatic ring, C1-6 alkyl, or C2-6 alkanoyl, and the 4-6 membered heteroaliphatic ring in R6 ′ ′.
  • a preferable embodiment is expressed as follows, for example.
  • Formula (I) (Wherein, X1 and X5 are the same as defined in the embodiment [1-1], X2 represents CH, NH or N; X3 and X4 represent C or N,
  • -CH CH-
  • -CH CH- preferably represents E-form, Or you may form the cyclopropane ring shown below,
  • R1 is Hydrogen atom, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 4-10 membered heteroaliphatic optionally bridged with 1-2 carbon atoms
  • the phenyl in R1 phenyl C1-6 alkyl, 5-6 membered heteroaryl, 5-6 membered heteroaryl C1-6 alkyl, 4-10 membered heteroaliphatic optionally bridged with 1-2 carbon atoms
  • Each ring in the ring is halogen, C1-6 alkyl, C1-6 haloalkyl, cyano, hydroxy, C1-6 alkoxycarbonyl, NR4'R5 ', C1-6 alkylsulfonyl, C1-6 alkoxy C1-6 alky
  • R1 Represents a 4-10 membered heteroaliphatic ring, NR4R5, or OR6, optionally bridged with 1-2 carbon atoms
  • the 4- to 10-membered heteroaliphatic ring in R1 may be independently substituted with 1-2 halogen, cyano, C1-6 alkyl, hydroxy, C2-6 alkanoyl, COR7, CONR8R9, NR4'R5 '
  • the 4- to 10-membered heteroaliphatic ring which may be bridged with 1 to 2 carbon atoms in R1 is further composed of a total of 3 to 6-membered aliphatic rings or oxygen-containing 4 to 6-membered aliphatic rings. May form a 7-12 membered spiro ring, which may be substituted with 1-2 halogens or C1-6 alkyl,
  • R2 Represents a 4-6 membered heteroaliphatic ring
  • the 4-6 membered heteroaliphatic ring may be substituted with 1-2 halogen, cyano, hydroxy, C1-6 alkoxy, NR4′R5 ′, COR7 ′, C1-6 alkyl, R7 ′ in COR7 ′ in the 4-6 membered heteroaliphatic ring represents C1-6 alkyl, C1-6 alkoxy, or hydroxy,
  • R10 represents halogen, cyano, hydroxy, C1-6 alkoxy, NR4′R5 ′, COR7 ′ ′, or C1-6 alkyl
  • R7 ′ ′ in the COR7 ′ ′ is C1-6 alkyl, C1-6 alkoxy, Represents hydroxy C1-6 alkyl, or hydroxy
  • the hetero-fused ring containing ring A is selected from the group consisting of: 6-membered ring A site in each, or adjacent nitrogen-containing 5-membered ring is 1-3 by C1-6 alkyl, C2-6 alkenyl, halogen, cyano, C1-6 haloalkyl, -NR4'R5 ', C1-6 alkoxy May be replaced,
  • R4 ′ and R5 ′ in NR4′R5 ′ in the above each independently represent a hydrogen atom, C1-6 alkyl, a 4-6 membered heteroaliphatic ring, R4 to R9 in the above are the same as defined in the embodiment [1-1]. Or a pharmaceutically acceptable salt or solvate thereof.
  • R10 represents halogen, cyano, hydroxy, C1-6 alkoxy, NR4′R5 ′, COR7 ′ ′, hydroxy C1-6 alkyl, or C1-6 alkyl
  • R7 ′ ′ in the COR7 ′ ′ is C1-6 alkyl
  • C1-6 alkoxy, hydroxy, R4 ′ and R5 ′ in the above are the same as defined in the embodiment [1-1].
  • a preferable embodiment is expressed as follows, for example.
  • the following formula (I-2) (Where Heterocondensed ring containing ring A, X1, X2, X3, X4, X5, R1 is the same as defined in the embodiment [1-1],
  • R10 represents halogen, cyano, hydroxy, C1-6 alkoxy, NR4′R5 ′, COR7 ′ ′, hydroxy C1-6 alkyl, or C1-6 alkyl, and R7 ′ ′ in the COR7 ′ ′ is C1-6 alkyl , C1-6 alk
  • the present invention includes the following aspect [4-3].
  • CH1 and CH2 in each of L1 and L2 may be substituted by C1-6 alkyl, C1-6 haloalkyl, C1-6 alkenyl, oxo, hydroxy, halogen, or NR4′R5 ′, and the C1- 6 alkyl may further be independently substituted with 1-3 hydroxy, oxo, NR4′R5 ′, NH in each of L1, L2 may be substituted with C1-6 alkyl, the C1- 6 alkyl may be further substituted with 1-2 oxo, hydroxy, R1 is a hydrogen atom, NR4R5, OR6, halogen, cyano, phenyl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, 5-6 membered heteroaryl, C1-6 alkyl, C1-6 alkylsulfonyl , C1-6 alkoxy, COR7, or CONR8R9, The ring in R1, phenyl, 4-6 membere
  • R4 and R5 in NR4R5 in R1 are each independently a hydrogen atom, phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, Represents C1-6 alkyl, or C1-6 alkylsulfonyl,
  • phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring are halogen, oxo, hydroxy, NR4′R5 ′, C1 -6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy may be independently 1-2 substituted, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further substituted with halogen, oxo , Hydroxy, C1-6 alkoxy, and -NR4'R5 'each independently may be substituted 1-3, C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in R4 or R5 is further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′. You may, However, R4 and R5 in R1
  • R6 in OR6 in R1 represents phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, or C1-6 alkyl
  • the phenyl in R6, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring is halogen, oxo, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl
  • C1-6 alkoxy may be independently substituted with 1-2, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further halogen, oxo, hydroxy, C1-6 alkoxy,-
  • Each of NR4′R5 ′ may be independently substituted 1-3
  • C1-6 alkyl in OR6 in R1 may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alk
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′.
  • R8 and R9 in CONR8R9 in each ring in R1 and R1 each independently represent a hydrogen atom, phenyl, 5-6 membered heteroaryl, C1-6 alkyl, or C1-6 alkylsulfonyl,
  • the phenyl and 5-6 membered heteroaryl in R8 and R9 are independently substituted with 1-2 halogen, oxo, C1-6 alkyl, hydroxy, NR4′R5 ′, C1-6 alkylsulfonyl or C1-6 alkoxy.
  • C1-6 alkyl and C1-6 alkylsulfonyl in R8 and R9 may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′
  • R2 represents a 4-6 membered heteroaliphatic ring, NR4′′R5 ′ ′, OR6 ′, phenyl, or 5-6 membered heteroaryl
  • Each ring of 4-6 membered heteroaliphatic ring and 5-6 membered heteroaryl in R2 is substituted with 1-2 halogen, oxo, hydroxy, C1-6 alkoxy, NR4'R5 ', COR7', C1-6 alkyl
  • the C1-6 alkoxy, C1-6 alkyl may be substituted with 1-2 halogen, hydroxy, cyano,
  • R7 ′ in the COR7 ′ in R2 represents phenyl, a 4-6 membered heteroaliphatic ring, C1-6 alkyl, C1-6 alkoxy, or hydroxy
  • R6 ′ in the OR6 ′ in R2 represents phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, or 3-6 membered aliphatic ring
  • Each of the phenyl, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, 3-6 membered aliphatic ring in R6 ′ is halogen, oxo, hydroxy, NR4′R5 ′, C1-6 alkyl, C1 -6 alkylsulfonyl or C1-6 alkoxy may be independently substituted with 1-2, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further halogen, oxo, hydroxy, C1- Each may be independently substituted
  • Phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring and 3-6 membered aliphatic ring in the R4 ′ ′ or R5 ′ ′ are halogen, oxo, hydroxy, NR4′R5 ′, C1-6 alkyl , C1-6 alkylsulfonyl or C1-6 alkoxy may be independently 1-2 substituted, and the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy is further halogen, oxo, hydroxy, Each may be independently substituted with 1-3 of C1-6 alkoxy and -NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in the R4 ′ ′ or R5 ′ ′ is further independently halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′. 3 may be replaced, However, R4 ′ ′
  • X1 represents CR3 or N
  • R3 represents a hydrogen atom
  • R6 ′ ′ in the OR6 ′ ′ in R3 is phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, C1-6 alkyl, C2-6 represents an alkanoyl or hydrogen atom
  • the phenyl in R6 ′ ′, 4-6 membered heteroaliphatic ring, 5-6 membered heteroaryl, condensed heteroaryl, 3-6 membered aliphatic ring is halogen, hydroxy, NR4′R5 ′, C1-6 It may be independently substituted with 1-2 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy, and each ring may be substituted with 1-2 oxo if it can be substituted.
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in the ring may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′.
  • Each substituent of the C1-6 alkyl or C2-6 alkanoyl in R6 ′ ′ is further independently halogen, oxo, hydroxy, C1-6 alkoxy, phenyl, 5-6 membered heteroaryl, or —NR4′R5 ′.
  • 1-3 may be substituted,
  • the phenyl and 5-6-membered heteroaryl are each independently substituted with 1-3 of hydroxy and C1-6 alkoxy.
  • R4 ′ and R5 ′ in —NR4′R5 ′ in the above each independently represent a hydrogen atom or C1-6 alkyl
  • X2, X3 and X4 each independently represent C, CH or N in the hetero condensed ring containing ring A
  • the condensed ring is selected from the group consisting of:
  • Each 6-membered ring A site or adjacent nitrogen-containing 5-membered ring may be substituted with 1-2 C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy.
  • Example 1 Compound (E) -2- (2- (6- (azetidin-1-yl) pyridin-2-yl) vinyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine
  • Example 2 Compound 2- (2- (6- (azetidin-1-yl) pyridin-2-yl) ethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine (Example 3) Compound) (E) -5,8-dimethyl-2- (2- (6- (pyrrolidin-1-yl) pyridin-2-yl) vinyl)-[1,2,4] triazolo [1,5-a] pyrazine
  • Example 4 Compound 5,8-Dimethyl-2- (2- (6- (pyrrolodin-1-yl) pyridin-2-yl) ethyl
  • Example 5 Compound (R, E) -2- (2- (6- (3-Fluoropyrrolidin-1-yl) pyridin-2-yl) vinyl) -5,8-dimethyl- [1,2,4] triazolo [1, 5-a] pyrazine (Compound of Example 6) (R, E) -2- (2- (6- (2- (methoxymethyl) pyrrolidin-1-yl) pyridin-2-yl) vinyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine (Compound of Example 7) (E) -5,8-dimethyl-2- (2- (6- (3-methylazetidin-1-yl) pyridin-2-yl) vinyl)-[1,2,4] triazolo [1,5 -A] pyrazine (Compound of Example 8) (E) -2- (2- (4-Chloro-6- (pyrrolidin-1-yl) pyridin
  • Example 9 Compound (E) -2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (pyrrolidin-1-yl)- N- (Tetrahydrohydro-2H-pyran-4-yl) -pyrimidin-4-amine (Compound of Example 10) 2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) -N- (tetrahydro Hydro-2H-pyran-4-yl) pyrimidin-4-amine (Compound of Example 11) (E) -4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (pyrrolidine-1- Yl) pyrimidin-4-yl) morpholine
  • Example 13 Compound (E) -2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -N, N-diethyl-6- (pyrrolidine -1-yl) -pyrimidin-4-amine (Compound of Example 14) (E)-(5,8-Dimethyl-2- (2- (4- (piperidin-1-yl) -6- (pyrrolidin-1-yl) -pyrimidin-2-yl) vinyl- [1,2, 4] Triazolo [1,5-a] pyrazine (Compound of Example 15) (E) -2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -N- (pyridin-2-yl)- 6- (Pyrrolidin-1-yl) pyrimidin-4-amine
  • Example 16 Compound (E) -2- (2- (4- (4-Fluorophenyl) -6- (pyrrolidin-1-yl) pyrimidin-2-yl) vinyl) -5,8-dimethyl [1,2,4] triazolo [1,5-a] pyrazine (Compound of Example 17) (E) -2- (2- (4- (4-Fluorophenoxy) -6- (pyrrolidin-1-yl) -pyrimidin-2-yl) vinyl) -5,8-dimethyl [1,2,4] Triazolo [1,5-a] pyrazine (Example 18 compound) (E) -5,8-dimethyl-2- (2- (4- (pyrrolidin-1-yl) -6-((tetrahydro-2H-pyran-4-yl) oxy) pyrimidin-2-yl) vinyl) [1,2,4] triazolo [1,5-a] pyrazine
  • Example 1P Compound (4- (2- (azetidin-1-yl) -6- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -1- Methoxyethyl) pyrimidin-4-yl) morpholine)
  • Example 2P Compound (1- (6- (azetidin-1-yl) -4-morpholinopyridin-2-yl) -2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] Pyrazin-2-yl) ethanol)
  • Example 3P Compound (4- (2- (azetidin-1-yl) -6- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -1- Fluoroethyl) pyridin-4-yl) morpholine)
  • Example 4 Compound (4- (2- (azeti
  • Example 14P Compound (4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -2,2-difluoroethyl) -6- (pyrrolidine -1-yl) pyrimidin-4-yl) morpholine)
  • Example 15P Compound ((E) -5,8-dimethyl-2- (2- (4-methylsulfonyl) -6- (pyrrolidin-1-yl) -pyrimidin-2-yl) vinyl)-[1,2,4] triazolo [1,5-a] pyrazine)
  • Example 16P Compound ((E) -2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (pyrrolidin-1-yl) Pyrimidine-4-carboxylic acid)
  • Example 17P Compound ((E) -2- (2-
  • Example 21P Compound (5,8-Dimethyl-2- (2- (4- (methylsulfonyl) -6- (pyrrolidin-1-yl) pyrimidin-2-yl) ethyl- [1,2,4] triazolo [1,5- a] pyrazine)
  • Example 22P Compound (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) pyrimidine-4- carboxylic acid)
  • Example 23P Compound (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) pyrimidine-4- Yl) methanol)
  • Example 24P Compound (2- (2- (5,8-Dimethyl- [1,2,4] triazolo
  • Example 28P Compound (N- (6- (azetidin-1-yl) -4-((tetrahydro-2H-pyran-4-yl) oxy) pyridin-2-yl) -N, 5,8-trimethyl- [1,2, 4] Triazolo [1,5-a] pyrazine-2-carboxamide)
  • Example 30P Compound (4- (2- (azetidin-1-yl) -6-((5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) methoxy) pyridine-4 -Il) Morpholine)
  • Example 31P Compound (6- (azetidin-1-yl) -N-((5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) methyl) -N-methyl-4 -((Tetrahydro-2H-pyran-4-yl) oxy) pyr
  • * represents an asymmetric center
  • Hal represents a halogen atom, or a salt or solvate thereof.
  • [6-1] A pharmaceutical composition for treating schizophrenia, delusional disorder, and drug-induced central disease; anxiety disorder, movement disorder, mood disorder, neurodegenerative disorder, obesity, and drug addiction, said disorder or condition
  • a pharmaceutical composition comprising an amount of a compound according to embodiments [1] to [5-3] effective to be treated.
  • [6-2] A method of treating a disorder selected from schizophrenia, delusional disorder, and drug-induced central disease; anxiety disorder, movement disorder, mood disorder, obesity, and neurodegenerative disorder, wherein the disorder is treated A method comprising administering an effective amount of a compound according to embodiment [1] to embodiment [5-3] to a subject in need of treatment for said disorder.
  • the disorder is dementia, Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumor or brain trauma, cognition associated with Huntington's disease or Parkinson's disease Or AIDS-related dementia; delirium; amnesia disorder; post-traumatic stress disorder; mental retardation; learning disorders such as reading disorders, math disorders, or written expression disorders; attention deficit / hyperactivity disorder; Sexual cognitive decline, mild, moderate, or severe major depression episodes; mania or mixed mood episodes; mild mood episodes; depression episodes with atypical features; depression episodes with melancholic features; Depressive episodes with features; mood episodes with postpartum onset; poststroke depression; major depressive disorder; mood modulation Harm; minor depressive disorder; premenstrual dysphoric disorder; post-schizophrenic depressive disorder; major depressive disorder associated with central disorder including delusional disorder or schizophrenia; bipolar I disorder; Bipolar type II disorder, bipolar disorder including mood circulation disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease, dementia,
  • [6-4] A method of treating schizophrenia, paranoid disorders, and drug-induced central diseases; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, obesity, and drug addiction, effective for inhibiting PDE10 A method comprising administering an amount of the compound according to embodiment [1] to embodiment [5-3].
  • treatment includes not only treatment of a disease or symptom, but also improvement, prevention or prevention of recurrence of the disease or symptom.
  • the pharmaceutically acceptable salt is also referred to.
  • the compound of the present invention may have an asymmetric carbon, and the compound of the present invention includes a mixture of various stereoisomers such as geometric isomers, tautomers, optical isomers, and isolated compounds. It is. Isolation and purification of such stereoisomers can be carried out by those skilled in the art through conventional techniques through preferential crystallization, optical resolution using column chromatography or asymmetric synthesis.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid , Acetic acid, propionic acid, butyric acid, valeric acid, enanthic acid, capric acid, myristic acid, palmitic acid, stearic acid, lactic acid, sorbic acid, mandelic acid and other aliphatic monocarboxylic acids, benzoic acid, salicylic acid and other aromatic monocarboxylic acids Carboxylic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, malic acid, aliphatic dicarboxylic acid such as tartaric acid, aliphatic tricarboxylic acid such as citric acid, cinnamic acid, glycolic acid, pyruvic acid, oxylic acid, Organic carboxylic acids such as salicylic acid and N-acetylcysteine; aliphatic s
  • salts can be obtained by a conventional method, for example, by mixing an appropriate amount of the compound of the present invention with a solution containing the desired acid or base, and collecting the desired salt by filtration or distilling off the solvent. Moreover, this invention compound or its salt can form solvates with solvents, such as water, ethanol, and glycerol.
  • the salt of the compound of the present invention includes a mono salt, a di salt and a tri salt.
  • the compound of the present invention can form both an acid addition salt and a base salt at the same time depending on the side chain substituent.
  • the present invention includes hydrates of the compounds represented by the formula (I) of the present invention, various pharmaceutically acceptable solvates, crystal polymorphs, and the like.
  • this invention is not limited to the compound described in the below-mentioned Example, All the compounds or the pharmaceutically acceptable salt represented by the formula (I) of this invention are included. Is.
  • Suitable base salts are formed from bases that form non-toxic salts. Examples include, but are not limited to, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, cesium and zinc salts. Is done.
  • Acid and base hemi-salts such as hemisulfate and hemi-calcium salts can also be formed.
  • compositions of formula (I) can be prepared by one or more of the following three methods.
  • (Ii) by removing the acid or base labile protecting group from the appropriate precursor of the compound of formula (I) by reacting the compound of formula (I) with the desired acid or base, Or by conversion to another salt using the desired acid or base, by reaction with a suitable acid or base, or by a suitable ion exchange column.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization of the resulting salt may vary from fully ionized to nearly non-ionized.
  • the compound of the present invention can exist in a continuous solid state from completely amorphous to completely crystalline.
  • amorphous refers to a state in which the material lacks long-range order at the molecular level and can exhibit solid or liquid physical properties depending on temperature. Typically such materials do not exhibit a characteristic X-ray analysis pattern and are more formally considered liquid while exhibiting solid properties. Heating causes a change from solid to liquid properties, which is characterized by a state change that is typically second order ("glass transition").
  • crystalline refers to a solid phase in which the material has a regular X-ray analysis pattern with a regular ordered internal structure at the molecular level and with distinct peaks. Such materials also exhibit liquid properties when fully heated, but the change from solid to liquid is typically characterized by a phase change that is first order ("melting point").
  • solvate is used to describe a molecular complex comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules, such as ethanol.
  • solvent such as ethanol
  • hydrate is used.
  • Isolated site hydrates are those in which water molecules are each isolated from direct contact with each other through the intervention of organic molecules.
  • channel hydrates water molecules are present in lattice channels where the water molecules are adjacent to each other.
  • metal ion coordination hydrate water molecules are bound to metal ions.
  • the complex When the solvent or water is strongly bound, the complex will have a well-defined stoichiometry independent of humidity. However, when the solvent or water binding is weak, such as channel solvates and hygroscopic compounds, the water / solvent content depends on humidity and drying conditions. In such cases, non-stoichiometry is the standard.
  • the compounds of the present invention can also exist in an intermediate state (intermediate phase or liquid crystal) when subjected to appropriate conditions.
  • the intermediate state is intermediate between the true crystalline state and the true liquid state (molten or solution).
  • the intermediate form resulting from the temperature change is called “thermotropic” and the result of the addition of a second component such as water or other solvent is called “lyotropic”.
  • Compounds with the potential to form lyotropic mesophases are called “amphiphilic” and are ionic (such as —COO—Na +, —COO—K +, or —SO 3 —Na +) or nonionic (—N—N + (CH 3 And 3)) consisting of a molecule having a polar head group.
  • ionic such as —COO—Na +, —COO—K +, or —SO 3 —Na +
  • nonionic —N—N + (CH 3 And 3)
  • the compounds of the present invention include compounds of formula (I) as defined above, including all polymorphs and crystal habits thereof, and prodrugs and isomers (optical, geometric and tautomeric forms) as defined below. And isotope-labeled compounds of formula (I).
  • prodrugs of the compounds of formula (I) are also within the scope of the present invention.
  • certain derivatives of compounds of formula (I) that may themselves have little or no pharmacological activity have the desired activity when administered in or on the body, for example by hydrolysis It can be converted to a compound of formula (I).
  • Such derivatives are referred to as “prodrugs”.
  • Pro-drugs see Pro-drugs as Novell Delivery Systems, Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella), as well as Bioreversible Carriers in Drug Design, Pergamon Press, 1987 (edited by E. B. Roche, AmericanAmericaPrice).
  • Prodrugs according to the present invention may be, for example, suitable functional groups present in compounds of formula (I), such as Design of Products, H.P. Can be generated by substitution with certain substituents known to those skilled in the art as protecting groups, as described in Bundgaard (Elsevier, 1985).
  • prodrugs according to the present invention include, but are not limited to: (I) When the compound of formula (I) contains a carboxylic acid functional group (—COOH), its ester, for example, the hydrogen of the carboxylic acid functional group of the compound of formula (I) is replaced by (C1-C8) alkyl.
  • —COOH carboxylic acid functional group
  • its ester for example, the hydrogen of the carboxylic acid functional group of the compound of formula (I) is replaced by (C1-C8) alkyl.
  • the ether for example, the hydrogen of the alcohol function of the compound of formula (I) is (C2 to C6)
  • the compound substituted with alkanoyloxymethyl and (iii) the compound of formula (I) contains a primary or secondary amino functional group (—NH 2 or —NHR (where R ⁇ H))
  • An amide thereof for example a compound in which one or both hydrogens of the amino function of the compound of formula (I) are optionally substituted with (C2-C10) alkanoyl.
  • metabolites of the compound of formula (I), that is, compounds formed in vivo upon administration of the drug are also encompassed within the scope of the present invention.
  • Some examples of metabolites according to the present invention include, but are not limited to: (I) when the compound of formula (I) contains a methyl group, its hydroxymethyl derivative (—CH 3 —> CH 2 OH), (ii) when the compound of formula (I) contains an alkoxy group, its hydroxy derivative (-OR->-OH), (iii) when the compound of formula (I) contains a tertiary amino group, its secondary amino derivative (-NR1R2->-NHR1 or -NHR2), (iv) When the compound of formula (I) contains a secondary amino group, its primary derivative (-NHR1->-NH2), (v) when the compound of formula (I) contains a phenyl moiety, its phenol Derivatives (-Ph->-PhOH), and (vi) when the compound of formula (I) contains an
  • the compound of formula (I) containing one or more asymmetric carbon atoms can exist as two or more stereoisomers.
  • a compound of formula (I) contains an alkenyl or alkenylene group
  • geometric cis / trans (or Z / E) isomers are possible.
  • Tautomerism (“tautomerism”) can occur when structural isomers are interconvertible by a low energy barrier. This can take the form of proton tautomerism in compounds of formula (I) containing, for example, an imino, keto, or oxime group, or so-called valence tautomerism in compounds containing aromatic moieties. . As a result, a single compound can exhibit multiple types of isomerism.
  • Cis / trans isomers can be separated by conventional techniques well known to those skilled in the art, such as chromatography and fractional crystallization.
  • the olefin is also referred to as Z-form / E-form.
  • the racemate (or racemic precursor) is converted to a suitable optically active compound, such as an alcohol, or a base such as 1-phenylethylamine or tartaric acid if the compound of formula (I) contains an acidic or basic moiety.
  • a salt with an acid can be used.
  • the resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereomers can be converted to the corresponding pure enantiomers by means well known to those skilled in the art. it can.
  • the chiral compounds of the present invention can be synthesized from 0 to 50% by volume isopropanol, eg 2% to 20%, and 0 to 5% by volume alkylamine using chromatography, typically HPLC.
  • chromatography typically HPLC.
  • the enriched mixture is obtained by concentration of the eluent.
  • the first type is the racemic compound described above (true racemate) in which one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts.
  • the second type is a racemic mixture or conglomerate in which two forms of crystals each containing a single enantiomer are produced in equimolar amounts.
  • Racemic mixtures can be separated by conventional techniques known to those skilled in the art, for example, Stereochemistry of Organic Compounds, E.I. L. Eliel and S.M. H. See Wilen (Wiley, 1994).
  • the present invention relates to all pharmaceuticals in which one or more atoms have been replaced with atoms having the same atomic number but having an atomic mass or mass number different from the atomic mass or mass number found primarily in nature.
  • isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2H and 3H, isotopes of carbon, such as 11C, 13C and 14C, isotopes of chlorine, 36Cl and the like, Isotopes of fluorine, such as 18F, isotopes of iodine, such as 123I and 125I, isotopes of nitrogen, such as 13N and 15N, isotopes of oxygen, such as 15O, 17O and 18O, isotopes of phosphorus, 32P etc., and Sulfur isotopes such as 35S are included.
  • isotopes of hydrogen such as 2H and 3H
  • isotopes of carbon such as 11C, 13C and 14C
  • Isotopes of fluorine such as 18F
  • isotopes of iodine such as 123I
  • isotopically-labelled compounds of formula (I), such as those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies.
  • the radioactive isotopes tritium, ie 3H, and carbon-14, ie 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • Substitution with heavy isotopes such as deuterium, ie 2H, may provide certain therapeutic benefits due to higher metabolic stability, eg, increased in vivo half-life, or reduced dosage requirements And therefore may be preferred in certain situations.
  • heavy isotopes such as deuterium, ie 2H
  • positron emitting isotopes such as 11C, 18F, 15O, and 13N
  • PET Positron Emission Topography
  • Isotopically-labelled compounds of formula (I) can be obtained from unlabeled reagents previously used by conventional techniques known to those skilled in the art or by methods analogous to those described in the Examples and Preparations below. Can be generally prepared using a suitable isotope labeling reagent instead of
  • the pharmaceutically acceptable solvate according to the present invention includes solvates in which the solvent for crystallization may be isotopically substituted, such as D2O, d6-acetone, d6-DMSO.
  • Certain embodiments of the present invention include compounds exemplified in the following examples, and pharmaceutically acceptable salts, complexes, solvates, polymorphs, stereoisomers, metabolites, prodrugs thereof, and Includes those other derivatives.
  • the invention also encompasses certain central disorders and conditions such as schizophrenia, paranoid disorders, and drug-induced central diseases; anxiety disorders such as panic disorder and obsessive compulsive disorder; and Parkinson's disease and Huntington's disease Relates to a pharmaceutical composition comprising an amount of a compound of formula (I) effective to inhibit PDE10.
  • the present invention also includes central disorders and conditions such as schizophrenia, paranoid disorders, and drug-induced central diseases; anxiety disorders such as panic disorder and obsessive compulsive disorder; and Parkinson's disease and Huntington It relates to a pharmaceutical composition for treating movement disorders including diseases, comprising a certain amount of a compound of formula (I) effective to treat said disorder or condition.
  • central disorders examples include, but are not limited to, eg, delusional, dismantled, strained, indistinguishable, or residual schizophrenia; Schizophrenia-like disorders; for example, paranoid or depressive schizophrenic disorder; paranoid disorders; substance-induced central disorders such as alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine Included are induced central disease; delusional personality disorder; and schizophrenic personality disorder.
  • Examples of movement disorders that can be treated according to the present invention include, but are not limited to, Huntington's disease, and aberrant motility associated with dopamine agonist therapy, Parkinson's disease, restless leg syndrome, and essential tremor. Is included.
  • the invention is a method of treating an anxiety disorder or condition in a mammal, wherein said mammal is administered an amount of a compound of formula (I) effective to inhibit PDE10. Relates to a method comprising:
  • the present invention also provides a method of treating an anxiety disorder or condition in a mammal comprising administering to said mammal an amount of a compound of formula (I) effective to treat said disorder or condition.
  • a method of including is provided.
  • anxiety disorders examples include, but are not limited to, panic disorder; agoraphobia; specific phobia; social phobia; obsessive compulsive disorder; Disorders include: acute stress disorder; and generalized anxiety disorder.
  • the present invention further provides a method of treating drug addiction, such as alcohol, amphetamine, cocaine, or opium addiction, in mammals, including humans, wherein the mammal is an amount effective to treat drug addiction
  • a method comprising administering a compound of formula (I):
  • the invention also provides a method of treating drug addiction, such as alcohol, amphetamine, cocaine, or opium addiction, in mammals, including humans, wherein the mammal has an amount effective to inhibit PDE10.
  • drug addiction such as alcohol, amphetamine, cocaine, or opium addiction
  • drug addiction means an abnormal desire for a drug and is generally characterized by a motivational disorder such as an impulsive compulsion to take a desired drug and an episode of intense drug craving.
  • the invention further provides a method of treating a disorder, including a lack of attention and / or cognition as a symptom, in a mammal, including a human, wherein the mammal has an amount effective to treat the disorder.
  • a method comprising administering a compound of formula (I).
  • the present invention also provides a method of treating a disorder or condition comprising a lack of attention and / or cognition as a symptom in a mammal, including a human, wherein the mammal is an amount effective to inhibit PDE10.
  • a method comprising administering a compound of formula (I):
  • the present invention is also a method of treating a disorder or condition that includes a lack of attention and / or cognition as a symptom in a mammal, including a human, and is effective for treating said disorder or condition in said mammal.
  • a method comprising administering an amount of a compound of formula (I).
  • the phrase “lack of attention and / or cognition” as used herein for “disorders involving attention and / or lack of cognition as a symptom” refers to a particular individual compared to other individuals of the same age population Refers to subnormal functioning of one or more cognitive aspects such as memory, intelligence, or learning and logic ability. “Lack of attention and / or cognition” also refers to a decline in function in any particular individual of one or more cognitive aspects, such as occurs with age-related cognitive decline.
  • disorders that include as a symptom a lack of attention and / or cognition that can be treated according to the present invention include dementia such as Alzheimer's disease, multiple cerebral infarction, alcoholic or other drug-related dementia, intracranial tumors Or dementia related to brain trauma, dementia related to Huntington's disease or Parkinson's disease, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; learning disorder such as reading disorder, arithmetic disorder Or written disability; attention deficit / hyperactivity disorder; and age-related cognitive decline.
  • dementia such as Alzheimer's disease, multiple cerebral infarction, alcoholic or other drug-related dementia, intracranial tumors Or dementia related to brain trauma, dementia related to Huntington's disease or Parkinson's disease, or AIDS-related dementia
  • delirium amnestic disorder
  • post-traumatic stress disorder dementia
  • mental retardation learning disorder such as reading disorder, arithmetic disorder Or written disability
  • attention deficit / hyperactivity disorder and age-related cognitive decline.
  • the present invention is also a method of treating a mood disorder or mood episode in a mammal, including a human, wherein the mammal has an amount of Formula (I) effective to treat the disorder or episode.
  • a method comprising administering a compound is provided.
  • the present invention is also a method of treating mood disorders or mood episodes in mammals, including humans, wherein said mammal is administered an amount of a compound of formula (I) effective to inhibit PDE10.
  • Providing a method comprising:
  • mood disorders and mood episodes that can be treated according to the present invention include, but are not limited to, mild, moderate, or severe forms of major depression episodes, mania or mixed mood episodes, hypomania mood Episodes; Depressive episodes with atypical features; Depressive episodes with melancholic features; Depressive episodes with tension-type features; Mood episodes with postpartum onset; Depression after stroke; Major depression Disorder; mood modulation disorder; minor depression disorder; premenstrual dysphoric disorder; depressive disorder after schizophrenia; major depressive disorder associated with central disorder such as delusional disorder or schizophrenia; Bipolar disorders such as bipolar I disorder, bipolar type II disorder, and mood circulatory disorder are included.
  • the present invention is further a method of treating a neurodegenerative disorder or condition in mammals, including humans, wherein the mammal has an amount of formula (I) effective to treat the disorder or condition.
  • a method comprising administering a compound is provided.
  • the present invention is further a method of treating a neurodegenerative disorder or condition in mammals, including humans, wherein said mammal is administered an amount of a compound of formula (I) effective to inhibit PDE10.
  • Providing a method comprising:
  • neurodegenerative disorder or condition refers to a disorder or condition resulting from neuronal dysfunction and / or death in the central nervous system. Treatment of these disorders and conditions prevents dysfunction or death of neurons at risk in these disorders or conditions and / or compensates for loss of function due to dysfunction or death of neurons at risk As such, it can be facilitated by administration of agents that can enhance the function of damaged or normal neurons.
  • neurotrophic agent refers to a substance or agent that has some or all of these properties.
  • neurodegenerative disorders and conditions that can be treated according to the present invention include, but are not limited to, Parkinson's disease; Huntington's disease; dementia such as Alzheimer's disease, multiple cerebral infarction dementia, AIDS-related Dementia and frontotemporal dementia; neurodegeneration associated with brain trauma; neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction; hypoglycemia-induced neurodegeneration; neurodegeneration associated with epileptic seizures; Neurodegeneration associated with poisoning; and multiple system atrophy.
  • Parkinson's disease Huntington's disease
  • dementia such as Alzheimer's disease, multiple cerebral infarction dementia, AIDS-related Dementia and frontotemporal dementia
  • neurodegeneration associated with brain trauma neurodegeneration associated with stroke, neurodegeneration associated with cerebral infarction
  • hypoglycemia-induced neurodegeneration neurodegeneration associated with epileptic seizures
  • Neurodegeneration associated with poisoning and multiple system atrophy.
  • the neurodegenerative disorder or condition comprises neurodegeneration of striatal medium spiny neurons in mammals, including humans.
  • the neurodegenerative disorder or condition is Huntington's disease.
  • the present invention also provides a pharmaceutical composition for treating central disorder, delusional disorder, and drug-induced central disease; anxiety disorder, movement disorder, mood disorder, neurodegenerative disorder, and drug addiction, said disorder Or a pharmaceutical composition comprising an amount of a compound of formula (I) effective to treat the condition.
  • the present invention also provides a method of treating a disorder selected from central disorder, delusional disorder, and drug-induced central disease; anxiety disorder, movement disorder, mood disorder, and neurodegenerative disorder, wherein said disorder is treated
  • a method comprising administering an effective amount of a compound of formula (I) to a subject in need of treatment for said disorder.
  • the invention also relates to dementia, Alzheimer's disease, multiple cerebral infarction dementia, alcoholic dementia or other drug-related dementia, dementia associated with intracranial tumors or brain trauma, Huntington's disease or Parkinson's disease Dementia, or AIDS-related dementia; delirium; amnestic disorder; post-traumatic stress disorder; mental retardation; learning disorders such as reading disorders, math disorders, or written expression disorders; attention deficit / hyperactivity disorder; Age-related cognitive decline, mild, moderate, or severe major depression episodes; mania or mixed mood episodes; mild mood episodes; depression episodes with atypical features; depression episodes with melancholic features; tension Depressive episode with type characteristics; mood episode with postpartum episode; poststroke depression; major depressive disorder; mood change Minor depressive disorder; premenstrual dysphoric disorder; post-schizophrenic depressive disorder; major depressive disorder associated with central disorder including delusional disorder or schizophrenia; bipolar type I disorder Bipolar type II disorder, bipolar disorder including mood circulation disorder, Parkinson's disease; Huntington's disease; dementia, Alzheimer's disease
  • the present invention also provides a method of treating central disorders, delusional disorders, and drug-induced central diseases; anxiety disorders, movement disorders, mood disorders, neurodegenerative disorders, and drug addiction, for inhibiting PDE10.
  • a method comprising administering an effective amount of a compound of formula (I) to a subject in need of said treatment.
  • C 1-6 means that the number of constituent carbon atoms is 1 to 6, and unless otherwise specified, represents a linear, branched or cyclic group, A linear or branched group substituted with a group, or a cyclic group substituted with a linear or branched group.
  • C2-6 means 2 to 6 carbon atoms, and unless otherwise specified, represents a linear, branched or cyclic group, which is a linear or branched group substituted with a cyclic group. It includes a branched group, or a cyclic group substituted with a linear or branched group.
  • halogen examples include fluorine atom, chlorine atom, bromine atom and iodine atom.
  • Examples of the “5-6-membered heteroaryl” include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 , 3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl , Pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, 2H-1,2,3-thiadiazinyl, 4H-1,2,4-thiadiazinyl 6H-1,3,
  • heteroaryl includes indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1 , 2-Benzisothiazolyl, 1H-benzimidazolyl, 1H-indazolyl, 1H-benzotriazolyl, 2,1,3-benzothiadiazinyl, chromenyl, isochromenyl, 4H-1,4-benzoxazinyl, 4H-1,4-benzothiazinyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, benzoxazepinyl, benzoazepinyl, benzodiazepinyl, naphthyrid
  • “4-10 membered heteroaliphatic ring” refers to a 4-10 membered saturated or partially unsaturated non-aromatic heterocycle. These rings include at least one heteroatom (preferably 1 to 3) arbitrarily selected from N, O and S in addition to the carbon atom.
  • the term “4-10 membered heteroaliphatic ring optionally bridged with 1 to 2 carbon atoms” as used herein refers to any 4-10 membered saturated or partially unsaturated heterocyclic ring. This represents a ring in which a carbon atom or a nitrogen atom may be bridged with methylene or ethylene. When this is treated as a substituent, it can be formed by removing any hydrogen atom from the 4- to 10-membered heteroaliphatic ring. Represents a valent group.
  • the heteroaliphatic ring includes at least one heteroatom (preferably 1 to 3) arbitrarily selected from N, O, and S in addition to the carbon atom.
  • the heteroaliphatic ring includes at least one heteroatom (preferably 1 to 3) arbitrarily selected from N, O, and S in addition to the carbon atom.
  • the “4-6 membered heteroaliphatic ring” represents a 4-6 membered saturated or partially unsaturated non-aromatic heterocycle. These rings include at least one heteroatom (preferably 1 to 3) arbitrarily selected from N, O and S in addition to the carbon atom.
  • Oxygen-containing 4-6-membered aliphatic ring refers to a 4-6-membered saturated or partially unsaturated oxygen-containing 4-6-membered ring. Represents a monovalent group formed by removing the hydrogen atom. For example, oxetanyl, tetrahydrofuryl, tetrahydropyranyl, etc. are mentioned.
  • 3-6 membered aliphatic ring refers to a saturated or partially unsaturated carbon monocycle of a 3-6 membered ring, and when this is treated as a substituent, excluding any hydrogen atom Represents a monovalent group that can be formed. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 1-cyclopropylethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-methylcyclopropyl, and the like. In the present specification, it is also described as “3-6 membered cyclo ring”.
  • the spiro ring having 7 to 12 members represents, for example, the following partial structure as a specific example.
  • aryl group means a monocyclic or condensed C6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, acenaphthyl, etc., or (1-, 2-, 4- Or, 5-) partially hydrogenated fused aryl groups such as indanyl, indenyl, tetrahydronaphthyl and the like.
  • Phenyl C1-6 alkyl is a C1-C6 linear, branched or cyclic alkyl group bonded with a phenyl group, and examples thereof include benzyl, phenethyl, phenylhexyl and the like.
  • C7-11 aralkyl is a group in which the above “aryl group” is substituted with a linear or branched alkyl group of “C1-6 alkyl group”, such as benzyl, phenethyl, 3-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl, 2- (1-naphthyl) ethyl, 2- (2-naphthyl) ethyl, 1-indanylmethyl, 2-indanylmethyl, 1,2,3,4-tetrahydronaphthalene -1-ylmethyl, 1,2,3,4-tetrahydronaphthalen-2-ylmethyl and the like.
  • 5-6 membered heteroaryl C1-6 alkyl is a C1-C6 linear, branched or cyclic alkyl group bonded to a 5-6 membered heteroaryl group, for example, pyridinomethyl, pyridinoethyl, furani Examples include ruhexyl.
  • C1-6 alkoxy C1-6 alkyl is a C1-C6 linear, branched or cyclic alkyl group bonded to a C1-C6 alkoxy group, for example, methoxymethyl, ethoxymethyl, methoxyethyl , Ethoxyethyl, n-propoxymethyl, n-propoxyethyl, n-propoxypropyl, cyclopropoxymethyl, n-butoxymethyl, cyclobutoxymethyl, n-pentyloxymethyl, cyclopentyloxymethyl, n-hexyloxymethyl, cyclohexyloxy Methyl, and the like.
  • C1-6 alkyl refers to a C1-C6 linear, branched or cyclic alkyl group such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1 -Dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1 , 2-trimethyl
  • C 1-6 haloalkyl represents a group in which the “C 1-6 alkyl group” is optionally substituted with 1 to 5 halogen atoms. Examples include trifluoromethyl, trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl and the like.
  • C2-6 alkenyl refers to a C2-C6 straight, branched or cyclic alkenyl group such as vinyl, allyl, isopropenyl, 2-methylallyl, butenyl, pentenyl, hexenyl, 1-cyclopropene-1- Yl, 2-cyclopropen-1-yl, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 1-cyclohexen-1-yl 2-cyclohexen-1-yl, 3-cyclohexen-1-yl, 2,4-cyclopentadien-1-yl, 2,5-cyclohexadien-1-yl, and the like.
  • C1-6 alkoxy represents a C1-C6 linear, branched or cyclic alkoxyl group.
  • “Hydroxy C1-6 alkyl” represents a group in which a hydroxyl group is bonded to the above-described — (C1-C6) -alkyl. Examples thereof include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxycyclopropyl, 4-hydroxycyclohexyl and the like.
  • C1-6 alkylthio represents a group in which — (C1-C6) -alkyl described above is bonded to S.
  • C 1-6 alkylamino means an amino group in which one hydrogen atom of an amino group is substituted with the above “C 1-6 alkyl group”. For example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, pentylamino, isopentylamino, hexylamino, isohexylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, 1- And cyclopropylmethylamino, 1-cyclobutylmethylamino, 1-cyclopentylmethylamino, 1-cyclohexylmethylamino, and the like.
  • C1-6 alkylaminocarbonyl means a group in which the “C1-6 alkylamino” group is bonded to a carbonyl group.
  • C2-6 alkanoyl represents a group in which — (C1-C6) -alkyl described above is bonded to a carbonyl group. Examples include acetyl, propionyl (propanoyl), butyryl, izobutyryl, valeryl, isovaleryl, pivaloyl, cyclopropylcarbonyl, cyclobutylcarbonyl, and cyclopentylcarbonyl.
  • C1-6 alkoxycarbonyl means a group in which the “C1-6 alkoxy” group is bonded to a carbonyl group.
  • C1-6 alkylsulfonyl means a group in which the “C1-6 alkyl” group and a sulfonyl group are bonded. Examples include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, cyclopropylmethylsulfonyl, 2-methylcyclopropylsulfonyl, and the like. “Substituted silyl” means a protecting group for a substituent such as an alcohol group, a phenol group, a carboxyl group, an amino group, an imino group, or a carbon atom.
  • Examples include trimethylsilyl, dimethylphenylsilyl, triisopropylsilyl, dimethylmethoxysilyl, dimethyl-t-butylsilyl, diphenylmethylsilyl, triphenylsilyl, and the like.
  • R4 and R5 are each independently a hydrogen atom, phenyl, phenyl C1-6 alkyl, 5-6 membered heteroaryl, condensed heteroaryl, 5-6 membered heteroaryl C1-6 alkyl Represents a 4-6 membered heteroaliphatic ring, a 3-6 membered aliphatic ring, C1-6 alkyl, C1-6 alkoxy, C1-6 alkyl, C1-6 alkoxy, or C1-6 alkylsulfonyl, Phenyl, 5-6 membered heteroaryl, condensed heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered aliphatic ring, phenyl C1-6 alkyl, 5-6 membered heteroaryl in the R4 or R5
  • Each ring in C1-6 alkyl is halogen, cyano, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 alkylsulfonyl, hydroxy
  • the sulfonyl or C1-6 alkoxy may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, —NR4′R5 ′,
  • Each alkyl part of C1-6 alkyl, C1-6 alkylsulfonyl, C1-6 alkoxy C1-6 alkyl, or C1-6 alkoxy in R4 or R5 is further halogen, oxo, cyano, hydroxy, C1-6 alkyl, C1-6 alkoxy, phenyl, C1-6 alkylaminocarbonyl, -NR4'R5 ', 4-10 membered heteroaliphatic ring, or 5-6 membered heteroaryl, each independently 1-3 substituted Often, In the C1-6 alkyl in R4 or R5, when two alkyl groups or alkoxy groups at the geminal position are substituted, these are bonded to each other to form a 3-6 membered cyclocycle or a 4-10 membered heterofatty acid.
  • R4 and R5 in R1 are not hydrogen atoms at the same time.
  • R4 ′ ′ and R5 ′ ′ each independently represent a hydrogen atom, phenyl, 5-6 membered heteroaryl, 4-6 membered heteroaliphatic ring, 3-6 membered fat.
  • C1-6 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy in the R4 ′ ′ or R5 ′ ′ is independently independently halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′. -3 may be replaced, However, R4 ′ ′ and R5 ′ ′ in R2 are not hydrogen atoms at the same time.
  • R4 ′R5 ′ each independently represent a hydrogen atom, C1-6 alkyl, or a 4-6 membered heteroaliphatic ring.
  • OR6 in R1 represents phenoxy, 5-6 membered heteroaryloxy, 4-6 membered heteroaliphatic ring oxy, 3-6 membered aliphatic ring oxy, C1-6 alkoxy, or hydroxyl group;
  • the phenoxy, 5-6 membered heteroaryloxy, 4-6 membered heteroaliphatic ring oxy, 3-6 membered aliphatic ring oxy is halogen, hydroxy, NR4′R5 ′, C1-6 alkyl, C1-6 alkylsulfonyl or 1-2 independently substituted with C1-6 alkoxy, and if each ring is substitutable, 1-2 may be substituted with oxo, the C1-6 alkyl in each ring, C1-6 alkylsulfonyl or C1-6 alkoxy may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, —NR4′R5 ′,
  • the C1-6 alkoxy in OR6 may be further independently
  • the phenyl and the 5-6 membered heteroaryl may be independently substituted with 1-3 of hydroxy and C1-6 alkoxy, respectively.
  • "OR6 '" in R2 represents phenoxy, 5-6 membered heteroaryloxy, 4-6 membered heteroaliphatic ring oxy, or 3-6 membered aliphatic ring oxy,
  • Each ring of the phenoxy, 5-6 membered heteroaryloxy, 4-6 membered heteroaliphatic ring oxy, 3-6 membered aliphatic ring oxy is halogen, hydroxy, NR4'R5 ', C1-6 alkyl, C1-6 May be independently substituted with 1-2 alkylsulfonyl or C1-6 alkoxy, and each ring may be substituted with 1-2 oxo if possible,
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in each ring is further independently substituted with 1-3 of halogen, o
  • OR6 ′ ′ in R3 is phenoxy, 5-6 membered heteroaryloxy, condensed heteroaryloxy, 4-6 membered heteroaliphatic ring oxy, 3-6 membered aliphatic ring oxy, C1-6 alkyl Represents oxy, C2-6 alkanoyloxy, or hydroxyl,
  • the phenoxy, 4-6 membered heteroaliphatic ring oxy, 5-6 membered heteroaryloxy, condensed heteroaryloxy, 3-6 membered aliphatic ringoxy are halogen, hydroxy, NR4'R5 ', C1-6 It may be independently substituted with 1-2 alkyl, C1-6 alkylsulfonyl, or C1-6 alkoxy, and each ring may be substituted with 1-2 oxo if it can be substituted.
  • the C1-6 alkyl, C1-6 alkylsulfonyl or C1-6 alkoxy in the ring may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, or —NR4′R5 ′.
  • Each substituent of the C1-6 alkyl or C2-6 alkanoyl in R6 ′ ′ is further independently halogen, oxo, hydroxy, C1-6 alkoxy, phenyl, 5-6 membered heteroaryl, or —NR4′R5 ′.
  • CONR8R9 is a carbamoyl group (R8 and R9 are each independently a hydrogen atom, phenyl, 5-6 membered heteroaryl, C1-6 alkyl) or a sulfonylcarbamoyl group (R8 is a C1-6 alkylsulfonyl)
  • R9 represents a hydrogen atom, phenyl, 5-6 membered heteroaryl, C1-6 alkyl, or R8 and R9 may be reversed.
  • Heteroaryl may be independently 1-2 substituted with halogen, oxo, C1-6 alkyl, hydroxy, NR4′R5 ′, C1-6 alkylsulfonyl or C1-6 alkoxy; C1-6 alkyl and C1-6 alkylsulfonyl in R8 and R9 may be further independently substituted with 1-3 of halogen, oxo, hydroxy, C1-6 alkoxy, and —NR4′R5 ′.
  • Neurotoxin poisoning refers to poisoning caused by neurotoxin.
  • a neurotoxin is any chemical or substance that can cause neuronal death and thus neurological damage.
  • An example of a neurotoxin is alcohol, which, when abused by pregnant women, can result in alcoholism and neurological damage known as fetal alcohol syndrome in newborns.
  • neurotoxins examples include, but are not limited to, kainic acid, domoic acid, and achromelic acid; certain pesticides, such as DDT; certain insecticides, such as organophosphates; Volatile organic solvents such as hexacarbon (eg toluene); heavy metals (eg lead, mercury, arsenic and phosphorus); aluminum; certain chemicals used as weapons such as agent orange or nerve gas; and Neurotoxic antitumor agents are included.
  • certain pesticides such as DDT
  • certain insecticides such as organophosphates
  • Volatile organic solvents such as hexacarbon (eg toluene)
  • heavy metals eg lead, mercury, arsenic and phosphorus
  • aluminum certain chemicals used as weapons such as agent orange or nerve gas
  • Neurotoxic antitumor agents are included.
  • a compound of formula (I) includes all pharmaceutically acceptable salts thereof.
  • the term “selective PDE10 inhibitor” refers to a substance, such as an organic molecule, that effectively inhibits PDE10 family enzymes to a greater extent than PDE1-9 family or PDE11 family enzymes.
  • the selective PDE10 inhibitor is a substance having a Ki for inhibition of PDE10, eg, an organic molecule, that is about 1/10 or less of the Ki that the substance has for inhibition of any other PDE enzyme.
  • the substance inhibits PDE10 activity to the same extent at a concentration of about 1/10 or less than that required for any other PDE enzyme.
  • IC50 value of about 1 ⁇ M, or about 300 nM or less, preferably about 100 nM, more preferably about 10 nM or less, and most preferably about 1 nM or less, it is considered to effectively inhibit PDE10 activity.
  • a “selective PDE10 inhibitor” can be identified, for example, by comparing the ability of a substance to inhibit PDE10 activity with the ability to inhibit PDE enzymes of other PDE families. For example, substances are analyzed for their ability to inhibit PDE10 activity in addition to PDE1A, PDE1B, PDE1C, PDE2, PDE3A, PDE3B, PDE4A, PDE4B, PDE4C, PDE4D, PDE5, PDE6, PDE7, PDE8, PDE9, and PDE11 be able to.
  • treating refers to the progression of the disorder to which such term applies, or to ameliorate, alleviate or inhibit the symptoms of one or more of the disorder. To do. As used herein, this term also refers to the prevention of a disorder, including preventing the onset of the onset of the disorder or any symptom associated with the disorder, as well as the disorder or any Also included is reducing the severity of symptoms. As used herein, “treating” also refers to preventing the recurrence of a disorder.
  • treating schizophrenia, or schizophrenia-like disorder or schizophrenic emotional disorder refers to one or more symptoms (positive, negative, and other related features) of the disorder. It also includes treating, for example treating the associated delusions and / or hallucinations.
  • Other examples of schizophrenia and symptoms of schizophrenia-like disorders and schizophrenic emotional disorders include disorganized conversations, flattening of emotions, allergies, loss of pleasantness, disproportionate feelings, discomfort (eg, depression, anxiety) Or forms of anger), and some signs of cognitive impairment.
  • the compounds of the present invention can be administered either alone or in combination with a pharmaceutically acceptable carrier, either single or multiple doses.
  • suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents.
  • the pharmaceutical composition thereby formed can then be easily administered in various dosage forms such as tablets, powders, lozenges, liquid preparations, syrups, injection solutions and the like.
  • These pharmaceutical compositions can optionally contain additional ingredients such as flavoring agents, binders, excipients and the like.
  • the compounds of the present invention can be used for oral, buccal, nasal, parenteral (eg, intravenous, intramuscular, or subcutaneous), transdermal (eg, patch), or rectal administration, or by inhalation or insufflation.
  • parenteral eg, intravenous, intramuscular, or subcutaneous
  • transdermal eg, patch
  • rectal administration or by inhalation or insufflation.
  • a drug used in combination with the compound of the present invention may be a separate preparation or a combination. Moreover, in separate preparations, both can be taken simultaneously or can be administered at different times.
  • the medicament of the present invention is administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention only needs to contain at least one compound represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable additive.
  • excipients eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch
  • binders eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbo Cymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg; celluloses,
  • Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir.
  • Oral subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.
  • the compounds of the present invention can be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
  • injectable formulations may be presented as unit dosage forms, for example, in ampoules or multi-dose containers, with the addition of preservatives.
  • These formulations can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and contain formulation agents such as suspending, stabilizing, and / or dispersing agents. be able to.
  • the active ingredient can be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
  • the product solution is isolated in water (or other aqueous medium) in an amount sufficient to produce a solution of the strength required for oral or parenteral administration to the patient. It can be produced by dissolving the complex.
  • These compounds can be formulated into rapidly dispersed dosage forms (fddf) that are designed to release the active ingredient in the oral cavity. These formulations are often formulated using a matrix based on fast dissolving gelatin. These dosage forms are well known and can be used to deliver a wide range of drugs. Most rapid dispersion dosage forms utilize gelatin as a carrier or structure-forming agent. Gelatin is typically used to give a dosage form sufficient strength to prevent breakage when removed from the package, but once in the mouth, gelatin allows the dosage form to break down immediately. . Alternatively, various starches are used to achieve the same effect.
  • the compounds of the invention can also be formulated in rectal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may be administered in the form of a solution or suspension from a pump spray container which is squeezed or pumped by the patient, or a suitable propellant such as dichloromethane.
  • a suitable propellant such as dichloromethane.
  • the dosage unit can be determined by providing a valve that delivers a metered amount.
  • a pressurized container or nebulizer can contain a solution or suspension of the active compound.
  • Capsules and cartridges for use in an inhaler or insufflator should be formulated containing a mixed powder of a compound of the invention and a suitable powder base such as lactose or starch. Can do.
  • Aerosol formulations for treating the aforementioned conditions (eg, migraine) in the average adult preferably each metered dose or “puff” of the aerosol contains from about 20 mg to about 1000 mg of the compound of the invention. Is set as follows.
  • the total daily dose with an aerosol will be within the range of about 100 mg to about 10 mg.
  • Administration can be several times daily, for example 2, 3, 4 or 8 times, for example 1, 2 or 3 doses each time.
  • Proposed daily doses of the compounds of the invention administered orally, parenterally, rectally, or buccally to the average adult to treat the above conditions are, for example, units that can be administered 1 to 4 times daily From about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg, of the active ingredient of formula (I) per dose.
  • the compound represented by the formula (I) which is the compound of the present invention and a salt thereof can be easily produced from a commercially available compound or a commercially available compound by a method known in the literature, etc. and produced according to the production method shown below. Can do. Further, the present invention is not limited to the manufacturing method described below.
  • the production method of the compound represented by the formula (I) of the present invention is shown below.
  • Method for producing compound of the present invention The compound represented by formula (I) and related compounds used in the present invention can be obtained by the production method shown below. Hereinafter, each reaction process will be described.
  • the reaction conditions in the production method are as follows unless otherwise specified.
  • the reaction temperature is in the range of ⁇ 78 ° C. to 250 ° C.
  • the reaction time is the time for which the reaction proceeds sufficiently.
  • solvent inert to the reaction examples include aromatic hydrocarbon solvents such as toluene, xylene and benzene, alcoholic solvents such as methanol and ethanol and 2-propanol, N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile.
  • Polar solvents such as water, basic solvents such as triethylamine and pyridine, organic acid solvents such as acetic acid, halogen solvents such as chloroform, dichloromethane and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane It is a system solvent or a mixed solvent thereof, and is appropriately selected depending on the reaction conditions.
  • the base is an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, sodium hydrogen carbonate, or triethylamine, diethylamine, pyridine, N, N-dialkylaniline,
  • Organic bases such as N, N-diisopropylethylamine (hunig base), lithium diisopropylamide, lithium bis (trimethylsilyl) amide
  • acids are inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfone Acids, and organic acids such as p-toluenesulfonic acid.
  • it is not necessarily limited to what was described above.
  • the protecting group can be removed at an appropriate stage.
  • Such a method for introducing / removing a protecting group is appropriately performed depending on the group to be protected or the kind of the protecting group. For example, as described in Green et al. [Protective Groups in Organic Synthesis 4th Edition, 2007, John Wiley & Sons]. The method can be carried out by a method that can be appropriately selected by those skilled in the art.
  • amino-protecting groups include formyl group, C1-6 alkyl-carbonyl group, C1-6 alkoxy-carbonyl group, benzoyl group, C7-10 aralkyl-carbonyl group (eg, benzylcarbonyl), C7-14 aralkyl.
  • Oxy-carbonyl groups eg, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl
  • trityl groups phthaloyl groups
  • phthaloyl groups N, N-dimethylaminomethylene groups
  • substituted silyl groups eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl
  • C2-6 alkenyl groups eg, 1-allyl
  • These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C1-6 alkoxy group and a nitro group.
  • Examples of the protecting group for carboxy group include C1-6 alkyl group, C7-11 aralkyl group (eg, benzyl), phenyl group, trityl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- Butyldimethylsilyl, tert-butyldiethylsilyl), C2-6 alkenyl groups (eg, 1-allyl) and the like.
  • C1-6 alkyl group C7-11 aralkyl group (eg, benzyl), phenyl group, trityl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert- Butyldimethylsilyl, tert-butyldiethylsilyl), C2-6 alkenyl groups (eg, 1-allyl) and the like.
  • Examples of the protecting group for hydroxy group include C1-6 alkyl group, phenyl group, trityl group, C7-10 aralkyl group (eg, benzyl), formyl group, C1-6 alkyl-carbonyl group, benzoyl group, C7-10 Aralkyl-carbonyl group (eg, benzylcarbonyl), 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl) ), A C2-6 alkenyl group (eg, 1-allyl) and the like. These groups may be substituted with 1 to 3 substituents selected from a halogen atom, a C1-6 alkyl group, a C1-6 alkoxy group and a nitro group.
  • alcohols include methanol, ethanol, 1-propanol, 2-propanol, tert-butyl alcohol, and the like.
  • ethers include diethyl ether, diisopropyl ether, diphenyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like.
  • esters include ethyl acetate, methyl acetate, tert-butyl acetate and the like.
  • hydrocarbons examples include benzene, toluene, xylene, cyclohexane, normal hexane, pentane and the like.
  • amides examples include N, N-dimethylformamide, N, N-dimethylacetamide, N, N-dimethylaniline, hexamethylphosphoric triamide and the like.
  • halogenated hydrocarbons examples include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethylene, chlorobenzene and the like.
  • nitriles for example, acetonitrile, propionitrile and the like are used.
  • ketones for example, acetone, 2-butanone and the like are used.
  • organic acids include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and the like.
  • organic bases include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid and the like.
  • aromatic amines include pyridine, 2,6-lutidine, quinoline and the like.
  • aliphatic amines include triethylamine, N, N, diisopropylethylamine and the like.
  • sulfoxides include dimethyl sulfoxide.
  • the compound represented by the formula (I) can be produced by the following production method.
  • X1, X2, X3, X4 and X5 are the above-mentioned embodiments [1] [1-1] [1-2] [1-3] [2-1] [2-2] unless otherwise specified. [2-3] [3-1] [4-1] [4-2] [4-3] [4-4] [4-5] Same definitions as described above.
  • Y1, Y2, and X represent leaving groups such as halogen, OTf, Ms, and Ts groups unless otherwise specified.
  • ⁇ 1-1 to 1-2 step> represents a description of a process for producing the compound (1-2) using the compound (1-1) in the figure as a raw material.
  • “When Y1 (meaning when Y1 is Japanese)” in the figure has a leaving group Y1 in the process of producing the compound in the description of the substituent (R1 or Y1) in the figure When synthesized as a product, a process in which the final compound (I) is produced by replacing Y1 with R1 by Suzuki coupling or the like or a substitution reaction is shown.
  • the target compound of formula (I) can be produced by introducing R1 by an appropriate method, and the method depends on the type of R1. Is different. The same applies to the substituent (R2 or Y2).
  • reaction, reduction, base, hydrolysis, scondensation, cyclization, key intermediate, coupling, chlorination, etc. are reaction, reduction, base, hydrolysis, Represents chemical terms such as condensation, cyclization, key intermediate, coupling, chlorination and the like.
  • the wavy line in the figure indicates that the olefin is a mixture of E-form and Z-form, or is E-form or Z-form.
  • the phosphonium salt (1-2) can be prepared by a method known to those skilled in the art.
  • the phosphate ester (1-3) can be prepared by reacting P (OEt) 3 with a compound represented by the formula (1-1) by a method known to those skilled in the art.
  • a solvent inert such as aromatic hydrocarbon solvents such as ethylene, toluene, xylene, etc., or a mixed solvent thereof.
  • aromatic hydrocarbon solvents such as ethylene, toluene, xylene, etc., or a mixed solvent thereof.
  • HWE in the figure represents the Horner-Emmons reaction known to those skilled in the art.
  • ⁇ 4-4 to P-1 step> and ⁇ 4-4 to P-2 step> Using the compound of formula (4-4) as a raw material, the compound of formula (P-1) or (P- The compound of 2) can be produced.
  • ⁇ P-1 to 1-4 step> and ⁇ P-2 to 1-4 step> Using a compound of formula (P-1) or a compound of formula (P-2) and an aldehyde compound of formula (6-1-1), ⁇ 1-2 to 1-4 step> and ⁇ 1-3 to 1-
  • the compound of formula (1-4) can be produced in the same manner as in 4 step>.
  • ⁇ 1-4 to 1-5 step> Reduction with a metal catalyst such as palladium in the presence of a suitable hydrogen source such as hydrogen gas or ammonium formate can produce a compound of formula (1-5).
  • R1 is a 3-7-membered nitrogen-containing heteroaliphatic ring and a 3-7-membered nitrogen-containing heteroaliphatic ring compound having a secondary amine is used, the formula (1-4) or (1-5)
  • a substitution reaction between the represented compound and a 3-7-membered nitrogen-containing heteroalicyclic compound for example, piperidine, piperazine, morpholine, thiomorpholine is performed.
  • Halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide, etc.
  • ether solvents such as diethyl ether, tetrahydrofuran and dioxane
  • aromatic hydrocarbon solvents such as toluene and benzene
  • polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide, etc.
  • R1 is aryl or heteroaryl
  • a coupling reaction of a compound represented by formula (1-4) or formula (1-5) and an aryl boronic acid represented by ArB (OH) 2 is performed.
  • a compound represented by formula (1-4) or formula (1-5) a method known in the literature, for example, [Experimental Chemistry Course 5th edition 18 Synthesis of organic compounds VI-Organic synthesis using metals-327- 352, 2004, Maruzen], and [Journal of Medicinal Chemistry, 48 (20), 6326-6339, 2005].
  • phosphine reagents such as biphenyl and organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine and potassium phosphate
  • phosphine reagents such as biphenyl and organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine and potassium phosphate
  • a non-participating solvent or a mixed solvent thereof reacting at a temperature at which the solvent is refluxed from 0 ° C. to produce a compound of formula (I) (1-6) or a compound of formula (1-7) Can do.
  • it can be produced by a similar method using tetramethylammonium chloride, tetrabutylammonium chloride or the like instead of the phosphine reagent.
  • R1 is NR4R5
  • a substitution reaction of the compound represented by formula (1-4) or formula (1-5) and the amine compound represented by formula HN-R4R5 is performed.
  • a method known in the literature for example, [Tetrahedron, 63 (25), 5394-5405, 2007], triethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene (described as DBU in the scheme, the same applies hereinafter), carbonic acid, In the presence or absence of a base such as sodium, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and benzene, N, N-dimethyl In a solvent that does not participate in the reaction, such as a
  • R1 is OR6, a compound represented by formula (1-4) or formula (1-5) is used, and a method known in the literature, that is, (Experimental Chemistry Course 5th Edition, 14 Synthesis of Organic Compounds II Alcohol Amine, pages 239-249, 2004, Maruzen) can be used to produce the target compound. That is, in the presence of an alcohol represented by R6OH, in the presence of an organic or inorganic base such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • an organic or inorganic base such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, etc.
  • the reaction is carried out at a temperature at which the solvent is refluxed from 0 ° C. to give a compound of formula (I) (1-6) or a compound of formula (1-7) Can be manufactured.
  • Production method B-1) Production method of key intermediate A method for producing the compounds of formula (P-1) and (P-2) and the compound of formula (4-3), which are key intermediates.
  • the phosphonium salt of (P-1) can be prepared by a method known to those skilled in the art using the compound of formula (4-4).
  • the phosphate ester (P-2) is prepared by reacting P (OR) 3 (R represents C1-6 alkyl) and the compound represented by formula (4-4) by a method known to those skilled in the art. I can do it. Details of the method for producing a compound in which the condensed ring containing A ring is triazolopyrazine are described in Reference Examples 1 to 4, and can be appropriately applied to various A rings.
  • Aldehyde (4-3) which is a key intermediate, is obtained by subjecting a compound of formula (4-4) to acetate with sodium acetate by a method known to those skilled in the art, followed by hydrolysis to hydroxylate the compound of formula (4-2)
  • the aldehyde represented by the formula (4-3) can be produced by obtaining the alcohol represented by the formula (1) and then oxidizing with an oxidizing agent such as a desmartin reagent.
  • the aldehyde represented by the formula (4-3) can be produced from the compound represented by the formula (4-4) by direct oxidation using NMO (N-methylmorpholine N-oxide) or the like. Details of the method for producing a compound in which the condensed ring containing A ring is triazolopyrazine are described in Reference Examples 1 to 4, and can be appropriately applied to various A rings.
  • the method to manufacture the compound of Formula (2-1) which is a key intermediate is shown.
  • the compound of the formula (2-1) can be produced according to a known method shown in WO2010 / 145668 scheme 1. That is, dimethylchloropyrazine (2-3-1) is azidated with sodium azide and then reduced, and the resulting aminopyrazine derivative (3-1) is reacted with hydroxylamine having a leaving group such as tosylhydroxyamine. And then treated with chloromethylacetic acid to produce the desired compound of formula (2-1).
  • the compound of formula (3-1) can be synthesized directly from the compound of formula (2-3-1) using ammonium water.
  • the compound of formula (2-1) can directly obtain the key intermediate of formula (2-1) in the presence of a base from the following sulfonate produced by a known method shown in WO2010 / 145668, scheme 1. .
  • the compound of formula 2-7 can be produced by the following production method according to the method described in European Patent Publication EP2060572 A1.
  • the intermediate compound of formula 2-2 can be produced by the production method shown below. Details of the technique are described in Reference Example 35.
  • the compound of the following (2-2) can be produced via the following sulfonates and analogs thereof known from WO2009 / 152825, page 44.
  • aldehyde compound (2-3-3) described below is a hydrogen atom in the presence of a palladium base via an acetal compound (2-3-1) in the presence of a strong base from the following sulfonates shown in WO2009 / 152825. Hydrogenation known to those skilled in the art can be performed under an atmosphere to obtain an aldehyde compound (2-3-3) under acidic conditions.
  • Manufacturing method C The manufacturing method of a pyrimidine type compound The method to manufacture the compound shown by the formula (I) which has a pyrimidine structure in the method described in the manufacturing method A is explained in full detail below.
  • the compound represented by the formula (I) can be produced according to a method known in the literature such as the method described in WO2009 / 152825.
  • the compound represented by the formula (5-1) is a compound known from WO2010 / 30027 or Chem. Sox. C, 1968, No. 17, page 2188. ⁇ 5-1 to 5-2 step>
  • the compound of the formula (5-1) having a leaving group Cl can be produced by introducing R2 by an appropriate method that varies depending on the starting compound used. The method differs depending on the type of R2. 1.
  • R2 is NR4 ′′ R5 ′′
  • a substitution reaction of the compound represented by Formula (5-1) and the amine compound represented by Formula HN-R4 ′′ R5 ′′ is performed.
  • halogen solvents such as dichloromethane and chloroform
  • ether solvents such as diethyl ether, tetrahydrofuran and dioxane
  • aromatic hydrocarbon solvents such as toluene and benzene
  • N, N-dimethylformamide acetonitrile
  • R2 is OR6 ′
  • a method known in the literature that is, (Experimental Chemistry Course 5th Edition, 14 Synthesis of Organic Compounds II Alcohol Amines, 239-249, 2004, Maruzen
  • the compound of formula (5-2) can be produced in the same manner according to the method described in the above.
  • the compound of the formula (5-2) can be produced by carrying out the reaction at a temperature at which the solvent is refluxed from 0 ° C. using a solvent that does not participate in the reaction, or a mixed solvent thereof.
  • R2 is an aryl group
  • a coupling reaction of the compound represented by the formula (5-1) and the phenylboronic acid represented by ArB (OH) 2 is performed.
  • a compound represented by the formula (5-1) a method known in the literature, for example, [Experimental Chemistry Course 5th Edition 18 Synthesis of Organic Compounds VI-Organic Synthesis Using Metals-327-352, 2004, Maruzen And a compound represented by the formula (5-3) according to the method described in [Journal of Medicinal Chemistry, 48 (20), 6326-6339, 2005].
  • organic phosphine reagents and organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, etc.
  • organic or inorganic bases such as triethylamine, N, N-diisopropylethylamine, potassium phosphate, etc.
  • the reaction can be carried out at a temperature at which the solvent is refluxed from 0 ° C. to produce a compound represented by the formula (5-2).
  • it can be produced by a similar method using tetramethylammonium chloride, tetrabutylammonium chloride or the like instead of the phosphine reagent.
  • R1 is a 3-7-membered nitrogen-containing heteroaliphatic ring
  • R2 is a 3-7-membered nitrogen-containing heteroaliphatic ring
  • a 3-7-membered nitrogen-containing heteroaliphatic ring compound having a secondary amine is used as a reaction reagent
  • a substitution reaction between the compound represented by the formula (5-1) and a 3-7 membered nitrogen-containing heteroalicyclic compound for example, piperidine, piperazine, morpholine, thiomorpholine
  • the 3-7-membered nitrogen-containing heteroaliphatic ring compound is described as nitrogen containing 3-7 membered recycled ring, which is a chemical term known to those skilled in the art.
  • Halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbon solvents such as toluene and benzene, polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide, etc.
  • ether solvents such as diethyl ether, tetrahydrofuran and dioxane
  • aromatic hydrocarbon solvents such as toluene and benzene
  • polar solvents such as N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide, etc.
  • ⁇ 5-2 to 5-3 step> When a compound of formula (5-2) is reacted with triethyl phosphite by heating in the presence of a reagent known in the literature, such as Bu4NI, detailed in the literature WO2010 / 30027, formula (5-3) Of phosphonate. That is, it is manufactured according to Reference Example 4.
  • a reagent known in the literature such as Bu4NI, detailed in the literature WO2010 / 30027
  • formula (5-3) Of phosphonate That is, it is manufactured according to Reference Example 4.
  • ⁇ 5-2 to 6-1 step> According to the method of production method B-1, compounds represented by the formula (6-1) having various substituents R2 can be produced.
  • ⁇ 5-3 to 5-4 step> A method known in the literature using a compound of formula (5-3) and an aldehyde compound of formula (4-3), such as (Experimental Chemistry Course 4th Edition 19, Organic Synthesis I, Hydrocarbon / Halogen Compounds, pp.
  • ⁇ 5-4 to 5-5 step> Reduction with a metal catalyst such as palladium in the presence of a suitable hydrogen source such as hydrogen gas or ammonium formate can produce a compound of formula (5-5). That is, using a compound of formula (5-4), a method known in the literature, for example, (Experimental Chemistry Course 4th Edition 26, Organic Synthesis VIII, Asymmetric Synthesis / Reduction / Sugar / Labeled Compound, pp. 251-266, 1992) In accordance with the method described in J. Maruzen), palladium-carbon (Pd-C), Raney nickel (Raney-Ni), platinum oxide (PtO2), palladium fibroin (Wako Chemical, code No. 167-22181 or 163).
  • a catalyst such as methanol, ethanol and 2-propanol, halogen solvents such as dichloromethane and chloroform, ether solvents such as diethyl ether and tetrahydrofuran, ethyl acetate, Solvents that do not participate in reactions such as polar solvents such as acetonitrile, aromatic hydrocarbon solvents such as toluene and benzene, and acid solvents such as acetic acid. Or a mixed solvent thereof, by addition of hydrogen gas at a temperature the solvent from room temperature to reflux, can be prepared a compound of formula (5-5).
  • the compound of formula (5-6) can be synthesized in the same manner as in ⁇ 5-1 to 5-2 step> using the compound of formula (5-5) as a raw material.
  • a compound of formula (5-6) can be synthesized in the same manner as in ⁇ 5-1 to 5-2 step> using the compound of formula (5-4) as a raw material.
  • ⁇ P-1 to 5-6 step> Using a compound of formula (P-1) and a compound of formula (6-2) as raw materials, a Wittig reaction known to those skilled in the art can be performed to synthesize a compound of formula (5-6).
  • ⁇ 5-2 to 6-1 step> Using the compound of formula (5-2) as a raw material, the compound of formula (6-1) can be synthesized by the same method described in Production Method B-1.
  • ⁇ 6-1 to 6-2 step> The compound of formula (6-2) can be synthesized by the same method as described in ⁇ 5-1 to 5-2 step> using the compound of formula (6-1) as a raw material.
  • ⁇ 5-6 to compound I step> Using the compound of formula (5-6) as a raw material, the compound of formula (I) can be synthesized by the same method as in ⁇ 5-4 to 5-5 step>.
  • ⁇ 7-1 to 8-1 step> Using the compound of formula (P-1) or formula (P-2) and the compound of formula (7-1) as a raw material, ⁇ 5-3 to 5-4 step> or ⁇ P-1 to 5-4 step>
  • the olefin compound of the formula (8-1) can be synthesized by the same method.
  • ⁇ 7-1 to 7-2 step> Using compounds of formula (7-1) as raw materials, methods known in the literature, for example (Experimental Chemistry Course 5th edition 14 Synthesis of organic compounds II Alcohol amines, pages 182-189, 2.1.3. Synthesis of phenols by oxidation In 2004, Maruzen), the compound of the formula (7-2) can be produced by substitution with borane and oxidation with Oxone.
  • the olefin compound of the formula (8-2) can be synthesized by the same method.
  • the olefin compound of the formula (8-3) can be synthesized by the same method.
  • ⁇ 7-4 to 8-4 step> Using the compound of formula (P-1) or formula (P-2) and the compound of formula (7-4) as a raw material, ⁇ 5-3 to 5-4 step> or ⁇ P-1 to 5-4 step>
  • the olefin compound of the formula (8-4) can be synthesized by the same method.
  • ⁇ 8-1 to 8-2 step> Using compounds of formula (8-1) as raw materials, methods known in the literature, for example (Experimental Chemistry Course 5th edition 14 Synthesis of organic compounds II Alcohol amines, pages 182-189, 2.1.3. Synthesis of phenols by oxidation In 2004, Maruzen), the compound of formula (8-2) can be produced by substitution with borane and oxidation with Oxone.
  • the compound of formula (8-3) can be synthesized by the same method as Production Method C, ⁇ 5-1 to 5-2 step>. The method differs depending on the type of R2. ⁇ 8-3 to 9-3 step> Using the compound of formula (8-3) as a raw material, according to a method known in the literature, for example, (Experimental Chemistry Course 5th Edition 14 Synthesis of Organic Compounds II Alcohol Amine, 255-256, 2004, Maruzen) A compound of formula (9-3) can be produced by carrying out Mitsunobu reaction known to those skilled in the art using —OH and DEAD (diethyl azodicarboxylate).
  • ⁇ 8-3 to 9-1 step> Using the compound of formula (8-3) as a raw material, the reaction is performed at low temperature using a solvent that does not participate in the reaction, such as a halogen-based solvent, in the presence of an appropriate base such as Tf2O, TEA (triethylamine), and hunig base (diisopropylethylamine).
  • a solvent that does not participate in the reaction such as a halogen-based solvent
  • an appropriate base such as Tf2O, TEA (triethylamine), and hunig base (diisopropylethylamine).
  • Tf2O triethylamine
  • hunig base diisopropylethylamine
  • ⁇ 10-1 to 10-2 step> Using a compound of formula (P-1) or formula (P-2) and a compound of formula (10-1) which can be appropriately synthesized by the method described above or commercially available, as a raw material, production method C, ⁇ 5-3 to
  • the olefin compound of the formula (10-2) can be synthesized by conducting Wittig reaction or Horner-Emmons reaction in the same manner as in 5-4 step> or ⁇ P-1 to 5-4 step>.
  • ⁇ 10-2 to compound I> The compound of formula (I) can be synthesized by performing a reduction reaction in the same manner as in Production Method C, ⁇ 5-4 to 5-5 step> using the compound of formula (10-2) as a raw material.
  • ⁇ 11-2 to 11-3 step> Using the compound of formula (11-2) as a raw material, ester hydrolysis under alkaline conditions by a method known to those skilled in the art to obtain a carboxylic acid, the following production method H, ⁇ 16-4 to 16-6 step> The compound of the formula (11-3) can be produced by the same method. ⁇ 11-3 to 11-4 step> The compound of the formula (11-4) can be produced by using the compound of the formula (11-3) as a raw material in the same manner as in Production Method B-1, ⁇ 4-2 to 4-3 step>.
  • ⁇ 11-4 to 11-5 step> Using the compound of formula (11-4) as a raw material, the compound of formula (11-5) can be produced by a method similar to Production Method C, ⁇ 5-1 to 5-2 step>. ⁇ 11-5 to 11-6 step> Using the compound of formula (11-5) as a raw material, the compound of formula (11-6) can be produced by the same method as ⁇ 19-4 to 19-5 step> shown in Production Method I.
  • ⁇ 11-5 to 11-7 step> In the compound represented by the formula (11-5), when the substituent on the pyrimidine ring is the leaving group Y2, R2 is introduced by an appropriate method, whereby the production method C, ⁇ 5-1 to 5
  • the compound (11-7), which is the compound of formula (I), can be produced by the same method as in step -2 step>. The method differs depending on the type of R2.
  • ⁇ 11-5 to 11-8 step> The compound of the formula (11-8) can be produced by using the compound of the formula (11-5) as a raw material in the same manner as in Production Method C, ⁇ 5-4 to 5-5 step>.
  • a compound represented by the formula (4-4) and a compound represented by the formula (12-1) a method known in the literature, for example, (Experimental Chemistry Course 5th Edition, 14 Synthesis of Organic Compounds II Alcohol / Amine 151-159, 1.4.4. Reaction of carbonyl compound and organometallic reagent, Grignard reagent section, 2004, Maruzen) etc., to produce the compound of formula (12-2) be able to.
  • a compound of formula (13-1) can be produced in the same manner using C1-6-alkyl-MgBr as a raw material of the compound of formula (12-1).
  • DAST diethyl trifluoride trisulfate
  • formula (12-2) or formula (12-3) DAST (diethyl trifluoride trisulfate) is used as a raw material from the compound represented by formula (12-2) or formula (12-3), and the method known in the literature, that is, (Experimental Chemistry Course 5th Edition 14 Organic Synthesis of compound I Carrying out the compound of formula (12-5) according to the method described in Carbohydrate / halide, p. 350-353, d. Substituting hydroxy group with fluorine (2004, Maruzen), etc. Can do.
  • the compound represented by the formula (12-6) can be similarly produced using the compound represented by the formula (12-3) as a raw material.
  • the compound represented by the formula (13-3) is a Wittig reaction or Horner-Emmons reaction described in the production method C using the compound represented by the formula (13-2) and the formula (P-1) or the formula (P-2) as a raw material. Can be produced by appropriately selecting.
  • the compound represented by the formula (12-7) is obtained from the compound represented by the formula (12-4) as a raw material by a method known in the literature, that is, (Experimental Chemistry Course 5th Edition 14 Synthesis of Organic Compounds I , Page 1-3, 1.1.1 cyclopropane derivative 2004, Maruzen) and the like.
  • the compound represented by the formula (13-3) is selected from the compound represented by the formula (13-2) and the formula (P-1) or (P-2) as a raw material, and a Horner-Emmons reaction or a Wittig reaction is appropriately selected. Can be manufactured.
  • the compound represented by the formula (13-4) can be produced by reducing the compound represented by the formula (13-3) by a method known to those skilled in the art.
  • the compound represented by the formula (12-8) can be produced by conducting an ether synthesis reaction of an alcohol compound represented by the formula (12-2) by a method known to those skilled in the art.
  • the compound represented by the formula (12-3) or the compound represented by the formula (13-2) is known to those skilled in the art as the compound represented by the formula (12-2) or the compound represented by the formula (13-1), respectively. It can manufacture by oxidizing by the method produced.
  • the compounds represented by formulas (12-8), (12-5), (12-3), (12-6), (12-4), (12-7), (13-4) When produced as having a leaving group Y2, by introducing R2 by an appropriate method, the target formula (I) of the same method as in Production Method C, ⁇ 5-4 to 5-6 step> Can be produced. The method differs depending on the type of R2.
  • the alcohol form (15-4) is obtained by reacting with the aldehyde (15-3). After that, it was expressed by the formulas (15-5), (15-6), (15-7), (15-8) through oxidation, methylation, halogenation, etc. in the same way as the method shown in Production Method E.
  • a compound can be produced.
  • R1 and R2 can be introduced in the final step after producing a ketone body, an alkoxy body, a difluorine body, a fluorine body, or the like through the above-described process while either one is in a chloro or halogen form, and ⁇ step 5 It is also possible to introduce R1 or R2 in the same manner as -1 to 5-2>. The outline is shown as an example below.
  • the compound represented by the formula (16-1) which is a halogen form is directly represented by the formula (16-4) which is a carboxylic acid form by a method known to those skilled in the art in the presence of a palladium catalyst in a carbon monoxide atmosphere.
  • a compound can be obtained.
  • the carboxylic acid can be converted into an amide (16-5) or hydroxyl (16-6) through amidation by condensation known to those skilled in the art or reduction with borane.
  • the amide body (16-5) can also be reduced to the amine body (16-8).
  • the hydroxyl form (16-6) can be converted to the amine form (16-7) by a method known to those skilled in the art by chlorination, azidation and subsequent reduction.
  • a compound represented by the formula (16-8) can be obtained by reductive alkylation.
  • the olefin compounds represented by these formulas (16-4), (16-5), (16-6), (16-7), (16-8) are the same as ⁇ step 1-4 to 1-5>
  • the compounds represented by the formulas (17-1), (17-2), (17-3), (17-4), and (17-5) can be obtained by reducing to
  • ⁇ 8-2-1 to 18-1 step> Using a compound of formula (8-2-1), trifluoromethanesulfonic anhydride, trifluoromethanesulfonic acid chloride and the like, a method known in the literature, for example, Synthesis, (4), 547-550, 2005
  • a base such as triethylamine, N, N-diisopropylethylamine, pyridine or the like
  • a halogen solvent such as dichloromethane or chloroform, diethyl ether, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane
  • the reaction is carried out at a temperature at which the solvent is refluxed from ⁇ 78 ° C. using a solvent that does not participate in the reaction, such as an ether solvent such as benzene, toluene, or an aromatic hydrocarbon solvent such as benzene, toluene, and the like.
  • ⁇ 8-2-1 to 18-2 step> Using the compound of formula (8-2-1) as a raw material, the compound of formula (18-2) can be produced in the same manner as in Production Method D, ⁇ 8-3 to 9-3 step>. ⁇ 18-1 to 18-2 step>, ⁇ 18-1 to 18-3 step>, ⁇ 18-1 to 18-4 step>
  • the compound (18-1) having a leaving group OTf As a raw material and appropriately utilizing the method shown in Production Method C, ⁇ 5-1 to 5-2 step>, Formula (18-2), Formula (18- 3)
  • a compound represented by the formula (18-4) can be produced.
  • ⁇ 19-2 to 19-3 step> When the compound of the formula (19-2) is reacted with triethyl phosphite by heating in the presence of a reagent known in the literature detailed in the literature WO2010 / 30027, for example, a reagent such as Bu4NI, the formula (19-3) Of phosphonate.
  • a reagent such as Bu4NI
  • the detailed manufacturing method is also detailed in Reference Example 4.
  • the compound of the formula (19-4) can be produced by using the compound of the formula (19-3) as a raw material in the same manner as in Production Method C, ⁇ 5-3 to 5-4 step>.
  • ⁇ 19-4 to 19-5 step> According to a method known in the literature using a compound of the formula (19-4), for example, a method described in WO2008 / 035049 and the like, trimethylsulfoxonium iodide (Me3SO + I-), potassium t-butoxide (KOtBu), etc. In the presence of a base in a polar solvent such as DMSO, a compound of the formula (19-5) can be produced.
  • ⁇ 19-5 to 19-6 step> The compound of the formula (19-6) can be produced from the compound of the formula (19-5) as a raw material in the same manner as in Production Method C, ⁇ 5-4 to 5-6 step>.
  • the linker (-L1-L2-site) is -NH-CH2-, -O-CH2-, -S-CH2- compound (22-3), (22-5) And a method for producing the compound of (22-7).
  • the compound which has a various linker (-L1-L2- part) in the compound represented by Formula (I) can be manufactured.
  • ⁇ 21-1 to 21-3 step> Using the compound of formula (21-1) as a raw material, the compound of formula (21-2) obtained after azidation with sodium azide can be reduced to produce the compound of formula (21-3) .
  • ⁇ 21-3 to 22-2 step> Using the compound of formula (21-3) and the compound of formula (19-1), the reaction is carried out in the presence of a base such as sodium hydride in DMF, which is a polar solvent not involved in the reaction, from 0 ° C. at a temperature at which the reaction is completed. And the compound of formula (22-2) can be produced.
  • ⁇ 21-1 to 21-4 step> A compound of the formula (21-1) can be produced by subjecting the compound of the formula (21-1) to acetate by a method known to those skilled in the art and then hydrolyzing to hydroxylate. Or the compound of formula (21-1) is described in Bulletin of the Chemical Society of Japan, 1977, Vol. 50, No. 5, pp.
  • 1184 to 1190 Can be hydroxylated under alkaline conditions to produce the compound of formula (21-4).
  • ⁇ 21-4 to 22-4 step> Using the compound of formula (21-4) and the compound of formula (19-1), a compound of formula (22-4) is produced in the same manner as in Production Method B-1, ⁇ 4-1 to 5-2 step> be able to.
  • ⁇ 21-1 to 21-5 step> A method known in the literature using a compound of the formula (21-1) and a sulfur-containing compound, for example (Experimental Chemistry Course 4th Edition 24 Organic Synthesis VI Heteroelement / Typical Metal Element Compound, pages 344-345, 2004, Maruzen)
  • the compound of the formula (21-5) can be produced by performing the substitution reaction in the presence of a base described in the above in a solvent that does not participate in the reaction.
  • ⁇ 21-5 to 22-6 step> The compound of formula (21-5) is used as a raw material, and debenzylated by hydrogenation by a method known to those skilled in the art to produce the compound of formula (21-6), followed by formula (23-3) Using the compound and the compound of formula (19-1), in the presence of a base such as sodium hydride, the reaction is carried out at a temperature at which the reaction is completed from 0 ° C. using DMF, which is a polar solvent not involved in the reaction, as a solvent.
  • the compound of (22-6) can be produced.
  • the compound represented by the formula (22-7) is obtained by oxidizing the thioether moiety by using mCPBA, H2O2, Oxone or the like by a method known to those skilled in the art, so that the linker (-L1-L2-site) becomes -CH2- Compounds represented by SO-, -CH2- SO2- can be appropriately synthesized.
  • the linker (-L1-L2-site) is -CH2-NH-, -CH2-O-, -CH2-S-compound (24-2), (24-4) And a method for producing the compound of (24-6).
  • the compound which has a various linker (-L1-L2- part) in the compound represented by Formula (I) can be manufactured.
  • ⁇ 23-1 to 23-3 step> Using the compound of formula (23-1) as a raw material, the compound of formula (23-2) obtained after azidation with sodium azide can be reduced to produce the compound of formula (23-3) .
  • ⁇ 23-3 to 24-1 step> Using the compound of formula (23-3) and the compound of formula (5-1), the reaction is carried out in the presence of a base such as sodium hydride in DMF, which is a polar solvent not involved in the reaction, from 0 ° C. at a temperature at which the reaction is completed. And the compound of formula (24-1) can be produced.
  • ⁇ 23-1 to 23-4 step> A compound of the formula (23-1) can be produced by acetation by a method known to those skilled in the art and then hydroxylated by hydrolysis to produce a compound of the formula (23-4). Or the compound of formula (23-1) is described in Bulletin of the Chemical Society of Japan, 1977, 50, No. 5, pp.
  • the compound of formula (23-4) can be produced by hydroxylation by a simple method. ⁇ 23-4 to 24-3 step> Using the compound of formula (23-4) and the compound of formula (5-1), the compound of formula (24-3) can be produced in the same manner as in ⁇ 23-3 to 24-1 step>.
  • ⁇ 23-1 to 23-5 step> A method known in the literature using a compound of formula (23-1) and a sulfur-containing compound, for example (Experimental Chemistry Course 4th Edition 24 Organic Synthesis VI Heteroelement / Typical Metal Element Compound, pages 344-345, 2004, Maruzen)
  • the compound of the formula (23-5) can be produced by performing the substitution reaction in the presence of a base described in the above in a solvent that does not participate in the reaction.
  • ⁇ 23-5 to 24-5 step> The compound of formula (23-5) is used as a raw material and debenzylated by hydrogenation by a method known to those skilled in the art to produce the compound represented by (23-6), followed by ⁇ 23-3 to 24-1
  • the compound of formula (24-5) can be produced using the compound of formula (5-1).
  • the compound represented by the formula (24-6) is obtained by oxidizing the thioether moiety by using mCPBA, H2O2, Oxone or the like by a method known to those skilled in the art, so that the linker (-L1-L2-site) becomes -SO- Compounds represented by CH2- and -SO2-CH2- can be appropriately synthesized.
  • (Production method N) A method for producing a compound of formula (I) in which the linker (-L1-L2-site) has a cyclobutane ring.
  • a compound represented by the formula (28-1) was prepared as a Grignard reagent by a method known to those skilled in the art in a solvent that does not participate in the reaction, such as an ether solvent, and an ester represented by the formula (28-2) was used.
  • the compound of the formula (28-3) can be produced by reacting at 78 ° C. to room temperature according to a method known in the literature, for example, the method described in Example 1, Step 1 of WO2010 / 085528.
  • a compound represented by the formula (28-7) is obtained through hydrolysis, condensation using polyphosphoric acid (denoted as PPAA in the figure), and subsequent cyclization reaction. Thereafter, any of the substitution reaction, Mitsunobu reaction, and coupling reaction as shown in production method C and the like are appropriately selected, and R1 is also introduced as appropriate in the same manner as in production method C, ⁇ step 5-1 to 5-2>.
  • a compound represented by formula (28-8), which is a compound of (I), can be produced.
  • a base such as an aliphatic amine such as triethylamine or Hunig base
  • sodium hydride, butyllithium lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate or potassium carbonate
  • a palladium catalyst for example, 1, 1-bis (diphenylphosphino) relhocenepalladium (II) dichloride / dichloromethane complex, etc.
  • copper catalysts eg copper (I) iodide
  • the compound of the formula (29-2) can be produced by carrying out the reaction at a temperature at which the solvent is refluxed from 0 ° C. using an inert solvent or a mixed solvent thereof.
  • the subsequent substitution reaction is as shown in (Production method C)
  • the compound represented by the formula (29-3), which is the target compound of the formula (I) can be produced by appropriately selecting the Mitsunobu reaction and the coupling reaction and introducing R1 by an appropriate method. it can. The method differs depending on the type of R1.
  • the compound represented by the formula (29-3) can also be produced from the compound represented by the formula (29-5) and the formula (29-8).
  • (Production method P) A method for producing a compound of formula (I) in which the linker (-L1-L2-site) has a difluorocyclopropane ring at the linker (-L1-L2-site).
  • the compound represented by the formula (30-2) is obtained by using a compound of the formula (1-4), which is an olefin, as a raw material, in a method known in the literature, for example, Journal of Fluorine Chemistry, 125, According to the method described in 459-469, 2004, it can manufacture by selecting suitably the reaction reagent shown by method A to method F.
  • ⁇ 32-1 to 32-2 step> Using the compound of formula (32-1) as a raw material, the compound of formula (32-2) can be produced by a method similar to Production Method H, ⁇ 16-4 to 16-6 step>. ⁇ 32-2 to 32-3 step> Using the compound of formula (32-2) as a raw material, the compound of formula (32-3) can be produced in the same manner as in Production Method B-1, ⁇ 4-2 to 4-3 step>. ⁇ 32-3 to 32-4 step> Using the compound of formula (32-3) and the compound of formula (P-2) as raw materials, the compound of formula (32-4) is produced in the same manner as in Production Method A, ⁇ 1-3 to 1-4 step> be able to.
  • ⁇ 32-4 to 32-6 step>, ⁇ 32-5 to 32-7 step> The compound of formula (32-4) or formula (32-5) is used as a raw material, and the formula (32-6) or formula (32-7) is prepared in the same manner as in Production Method I, ⁇ 19-4 to 19-5 step> Can be produced.
  • ⁇ 32-4 to 32-5 step>, ⁇ 32-6 to 32-7 step> The compound of formula (32-4) or formula (32-6) is used as a raw material, and the formula (32-5) or formula (32-7) is prepared in the same manner as in Production Method C, ⁇ 5-1 to 5-2 step> Can be produced.
  • the method differs depending on the type of R2.
  • linker (-L1-L2- moiety) is ethylene
  • a compound having a substituent at the ethylene moiety can be synthesized based on the scheme shown above.
  • Carbonyl Compounds The compound of the formula (P1-3) can be produced according to the method described in the reaction of organometallic reagents with Grignard reagents, 2004, Maruzen).
  • DAST diethylaminosulfur trisulfate
  • a compound of formula (3P) can be prepared.
  • the compound represented by the formula (5P) can be similarly produced using the compound represented by the formula (4P) obtained by oxidizing the compound represented by the formula (2P) as a raw material using the fluorinating agent. .
  • the compound represented by the formula (6P) can be produced by appropriately selecting the Horner-Emmons reaction, not limited to the Wittig reaction or the reagent shown in the figure, using the compound represented by the formula (4P) as a raw material.
  • the compound represented by the formula (7P) is prepared from a compound represented by the formula (6P) as a raw material by a method known in the literature, that is, (Experimental Chemistry Course 5th Edition 14 Synthesis of Organic Compounds I Carbohydrates / halides, 1-3 Page, 1.1.1 cyclopropane derivatives, 2004, Maruzen) and the like.
  • the compound represented by the formula (1P) can be produced by subjecting the compound represented by the formula (2P) to an ether synthesis reaction by a method known to those skilled in the art.
  • the linker (-L1-L2-site) is ethylene
  • a compound having a substituent at the ethylene site can be synthesized based on the scheme shown above.
  • Carbonyl compounds After obtaining the alcohol form according to the method described in the reaction of organometallic reagent with Grignard reagent, 2004, Maruzen), etc., it is oxidized by using an oxidizing agent such as Dessmartin reagent.
  • the compound of (P2-2) can be produced.
  • the compound represented by the formula (8-P) can be produced by the Horner Emmons reaction using the compound represented by the formula (P2-2) as a raw material.
  • the compound represented by the formula (9P) can be produced by reducing the compound represented by the formula (8P) by a method known to those skilled in the art.
  • the key intermediate (15-3) in production method P-5 is prepared from the haloalkyl compounds of key intermediates (2-1) to (2-14) as raw materials according to the method described in (production method B-1) key intermediate.
  • Compounds of formula (15-3) having various structures can be produced and used as starting materials for production method P-5. That is, 27P and 28P compounds having various condensed ring structures can be produced.
  • the formula (2-6-1) prepared from the following raw material (2-6) according to the production method B-1 is used. 27P-1,28P-1 compounds can be produced.
  • Compounds of formula (4-2) having various structures can be prepared and used as starting materials for production method P-6. That is, 30P, 31P, and 32P compounds having various condensed ring structures can be produced.
  • the formula (P6-4-2-1) prepared according to the production method B from the following raw material (2-6) Can be used to produce 30P-1,31P-1,32P-1 compounds.
  • Step 2> Using the compound represented by the formula (S-II), the compound represented by the formula (S-III) can be produced by a method similar to (Production C) ⁇ 5-2 to 5-3 step>.
  • Step 3> Using the compound represented by the formula (S-III) and the aldehyde represented by the formula (15-3), a method similar to (Production C) ⁇ 5-3 to 5-4 step> The compound represented by these can be manufactured.
  • Step 4> Cyclopropanation is carried out using a compound of the formula (S-IV). Methods known from the literature, such as “Organic Synthesis, Coll. Vol.
  • Step 6> Using the compound represented by the formula (S-VI), the compound represented by the formula (S-IX) [the absolute configuration is (S) in the same manner as (Production C) ⁇ 5-4 to 5-6 step> , S), (S, R), (R, S), or (R, R)].
  • ⁇ Step 7> Using the compound represented by the formula (S-IV), the compound represented by the formula (S-VII) can be produced by a method similar to (Production C) ⁇ 5-4 to 5-6 step>.
  • Step 8> Using the compound represented by the formula (S-VII), the compound represented by the formula (S-VIII) can be produced by the same method as in (Production S) ⁇ Step 4>.
  • Step 9> Using the compound represented by the formula (SV), the compound represented by the formula (S-VIII) can be produced by a method similar to (Production C) ⁇ 5-4 to 5-6 step>.
  • Step 10> Using a compound represented by the formula (S-VIII), a compound represented by the formula (S-IX) [absolute configuration is (S, S), (S , R), (R, S), or (R, R)] can be manufactured.
  • C1-6 alkyl, C7-11 aralkyl group eg, benzyl
  • phenyl group, trityl group substituted silyl group (eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl)
  • silyl group eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl
  • C2-6 alkenyl group for example, 1-allyl
  • Step 3> Using a compound represented by the formula (T-VI), which is known per se (can be purchased) or can be derived from the formula (TV) by the Horner Emmons-Wittig reaction, (Production Method S) ⁇ Step 4 > Can be used to produce a heteroarylcyclopropane ester derivative represented by the formula (T-III). ⁇ Step 4> Hydrolysis of the heteroarylcyclopropane ester derivative represented by the formula (T-III) is carried out.
  • a compound represented by the formula (T-IV) can be produced by performing a reaction using an acid such as hydrochloric acid or trifluoroacetic acid.
  • R C1-6 alkyl, C7-11 aralkyl groups (eg, benzyl), phenyl groups, trityl groups, substituted silyl groups) (Eg, trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert- Tildiethylsilyl), C2-6 alkenyl groups (eg, 1-allyl) and the like) and methods known in the literature, such as “Bioorganic & Medicinal Chemistry”, 19 (12), 3709-3716, 2011 ”, a metal catalyst (for example, a copper catalyst represented by the formula (U-II)) and an asymmetric ligand (for example, the formula (UI)
  • Example 1P-34P compounds can be produced by appropriately combining the above reactions. Solvents and reagents used in the reaction are not limited to those described, but can be appropriately produced under conditions that can be selected by those skilled in the art.
  • the compound names represented below are based on English names obtained according to the compound name naming program of CambridgeSoft ChemBioDraw Ultra 12.0.2.1076.
  • Example 1P Compound (4- (2- (azetidin-1-yl) -6- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ) -1-Methoxyethyl) pyrimidin-4-yl) morpholine)
  • Example 2 P Compound (1- (6- (azetidin-1-yl) -4-morpholinopyridin-2-yl) -2- (5,8-dimethyl- [1,2,4] triazolo [1, 5-a] pyridin-2-yl) ethanol)
  • Example 3P Compound (4- (2- (azetidin-1-yl) -6- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ) -1-Fluoroethyl) pyridin-4-yl) morpholine)
  • Example 4P Compound (1- (6- (azetidin-1-yl) -4-morpholinepyridin-2-yl) -2- (5,8-dimethyl- [1,2,4] triazolo [1,5 -A] pyrazin-2-yl) ethanone)
  • Example 5P Compound (4- (2- (azetidin-1-yl) -6- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ) -1,1-difluoroethyl) pyridin-4-yl) morpholine)
  • Example 6P Compound (4- (2- (azetidin-1-yl) -6- (3- (5,8-dimethyl- [1,2,4] -triazolo [1,5-a] pyrazine-2- Yl) prop-1-en-2-yl) pyridin-4-yl) morpholine)
  • Example 7P Compound (4- (2- (azetidin-1-yl) -6- (1-((5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine-2- Yl) methyl) cyclopropyl) pyridin-4-yl) morpholine)
  • Example 8P Compound ((E) -4- (2- (azetidin-1-yl) -6- (1- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine) -2-yl) prop-1-en-2-yl) pyridin-4-yl) morpholine)
  • Example 9P Compound (4- (2- (azetidin-1-yl) -6- (1- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ) Propan-2-yl) pyridin-4-yl) morpho
  • Example 10P Compound (1- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -2- (4-morpholino-6- (pyrrolidine-1- Yl) pyrimidin-2-yl) ethanol)
  • Example 11P Compound (4- (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -2-fluoroethyl) -6- (Pyrrolidin-1-yl) pyrimidin-4-yl) morpholine)
  • Example 12P Compound (4- (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -2-methoxyethyl) -6- (Pyrrolidin-1-yl) pyrimidin-4-yl) morpholine)
  • Example 13P Compound (1- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -2- (4-morpholino-6- (pyrrolidine-1- Ill) pyrimidin-2-yl) ethanone)
  • Example 14P Compound (4- (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -2,2-difluoroethyl)- 6- (pyrrolidin-1-yl) pyrimidin-4-yl) morpholine)
  • Example 15P Compound ((E) -5,8-Dimethyl-2- (2- (4-methylsulfonyl) -6- (pyrrolidin-1-yl) -pyrimidin-2-yl) vinyl)-[1,2 , 4] triazolo [1,5-a] pyrazine)
  • Example 16P Compound ((E) -2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (pyrrolidine- 1-yl) pyrimidine-4-carboxylic acid)
  • Example 17P Compound ((E) -2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (pyrrolidine- 1-yl) pyrimidin-4-yl) methanol)
  • Example 18P Compound ((E) -2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -N, N-dimethyl -6- (pyrrolidin-1-yl) pyrimidine-4-carboxamide)
  • Example 19P Compound ((E) -2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (pyrrolidine- 1-yl) pyrimidin-4-yl) methanoamine)
  • Example 20P Compound ((E) -1- (2- (2- (5,8-d
  • Example 21P Compound (5,8-Dimethyl-2- (2- (4- (methylsulfonyl) -6- (pyrrolidin-1-yl) pyrimidin-2-yl) ethyl- [1,2,4] triazolo [ 1,5-a] pyrazine)
  • Example 22P Compound (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) Pyrimidine-4-carboxylic acid)
  • Example 23P Compound (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) Pyrimidin-4-yl) methanol)
  • Example 24P Compound (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5
  • Example 26P Compound (1- (2- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidine-1 -Yl) pyrimidin-4-yl) -N-methylmethanamine)
  • Example 27P Compound (N- (6- (azetidin-1-yl) -4-morpholinopyridin-2-yl) -N, 5,8-trimethyl- [1,2,4] triazolo [1,5- a] pyrazine-2-carboxamide)
  • Example 28P Compound (N- (6- (azetidin-1-yl) -4-((tetrahydro-2H-pyran-4-yl) oxy) pyridin-2-yl) -N, 5,8-trimethyl- [ 1,2,4] triazolo [1,5-a] pyrazine-2-carboxamide)
  • Example 30P Compound (4-
  • Example 31P Compound (6- (azetidin-1-yl) -N-((5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) methyl) -N -Methyl-4-((tetrahydro-2H-pyran-4-yl) oxy) pyridin-2-amine
  • Example 32P Compound (6- (azetidin-1-yl) -N-((5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) methyl) -N -Methyl-4-morpholinopyridin-2-amine)
  • Example 33P Compound (4- (2-azetidin-1-yl) -6- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) Cyclopropyl) pyridin-4-yl) morpholine
  • Example 34P Compound (4- (2-((1- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) methyl) -6- (Pyrrolidin-1-yl) pyrimidin-4-yl) morpholine))
  • an example compound having a pyridine ring can be synthesized by simultaneously combining the example compounds having a pyrimidine ring as appropriate, and vice versa. Examples are given below.
  • Example 1P compound having a pyrimidine ring On the other hand, the following Example compounds having a pyridine ring can also be synthesized by following the above production method and appropriately selecting raw materials.
  • compound (I) When compound (I) is obtained as a free compound, it can be converted to the target salt by a method known per se or a method analogous thereto, and conversely when it is obtained as a salt, a method known per se or It can be converted into a free form or other desired salt by a method equivalent thereto.
  • Examples of the salt of compound (I) include metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like.
  • Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N′-di Mention may be made of salts with benzylethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • pharmaceutically acceptable salts are preferred.
  • inorganic salts such as alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, barium salts, etc.)
  • a salt with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and acetic acid, phthalic acid, fumaric acid
  • salts with organic acids such as oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • the compound (I) of the present invention may be used as a prodrug, and such a prodrug means a compound that is converted into the compound (I) as a result of reaction with an enzyme, gastric acid or the like under physiological conditions in vivo. . That is, the compound is converted into compound (I) by enzymatic oxidation, reduction, hydrolysis or the like or by hydrolysis with gastric acid or the like.
  • a prodrug of compound (I) a compound obtained by subjecting the amino group of compound (I) to acylation, alkylation or phosphorylation (eg, the amino group of compound (I) is eicosanoylated or alanylated.
  • Pentylaminocarbonylation (5-methyl-2-oxo-1-, 3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, ter t-
  • a compound obtained by subjecting to a butylation a compound obtained by subjecting the hydroxyl group of the compound (I) to acylation, alkylation, phosphorylation and boration (eg, the hydroxyl group of the compound (I) to acetyl , Palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation, alanylation, Compounds obtained by subjecting to dimethylaminomethylcarbonylation); compounds obtained by subjecting the carboxyl group of compound (I) to esterification or amidation (eg, the carboxyl group of compound (I) to ethyl ester) , Phenyl esterification, carboxymethyl-
  • prodrugs of Compound (I) can be obtained under physiological conditions as described in Hirokawa Shoten 1990 “Drug Development”, Volume 7 (Molecular Design), pages 163 to 198. It may be a compound converted into
  • the medicament of the present invention is administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition of the present invention only needs to contain at least one compound represented by the formula (I) of the present invention, and is prepared in combination with a pharmaceutically acceptable additive.
  • excipients eg; lactose, sucrose, mannitol, crystalline cellulose, silicic acid, corn starch, potato starch
  • binders eg; celluloses (hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC)), crystalline cellulose, saccharides (lactose, mannitol, sucrose, sorbitol, erythritol, xylitol), starches (corn starch, potato starch), pregelatinized starch, dextrin, polyvinylpyrrolidone (PVP), macrogol, polyvinyl Alcohol (PVA)), lubricant (eg; magnesium stearate, calcium stearate, talc, carboxymethylcellulose), disintegrant (eg; starches (corn starch, potato starch), carbo Cymethyl starch sodium, carmellose, carmellose calcium, croscarmellose sodium, crospovidone), coating agent (eg; celluloses,
  • Various dosage forms include tablets, capsules, granules, powders, pills, aerosols, inhalants, ointments, patches, suppositories, injections, lozenges, liquids, spirits, suspensions, Examples include extract and elixir.
  • Oral subcutaneous administration, intramuscular administration, intranasal administration, transdermal administration, intravenous administration, intraarterial administration, perineural administration, epidural administration, intradural administration, intraventricular administration, intrarectal administration It can be administered to a patient by inhalation or the like.
  • the dose of the compound of the present invention is usually 0.005 mg to 3.0 g, preferably 0.05 mg to 2.5 g, more preferably 0.1 mg to 1.5 g per day for an adult. Can be increased or decreased as appropriate.
  • the entire amount can be divided into 1 or 2-6 doses, orally or parenterally, or can be administered continuously by intravenous infusion.
  • Formulation Example 1 Tablet Compound of Example 6 100 g 137g of lactose Crystalline cellulose 30g Hydroxypropylcellulose 15g Carboxymethyl starch sodium 15g Magnesium stearate 3g Weigh the above ingredients and mix uniformly. This mixture is compressed into tablets having a weight of 150 mg.
  • Formulation Example 2 Film Coating Hydroxypropylmethylcellulose 9g Macrogol 6000 1g Titanium oxide 2g After weighing the above components, hydroxypropylmethylcellulose and macrogol 6000 are dissolved in water and titanium oxide is dispersed. This liquid is film-coated on 300 g of the tablet of Preparation Example 1 to obtain film-coated tablets.
  • Example 3 Capsule Compound of Example 11 50g Lactose 435g Magnesium stearate 15g The above ingredients are weighed and mixed uniformly. The mixture is filled into an appropriate hard capsule in an amount of 300 mg in a capsule encapsulator to form a capsule.
  • Formulation Example 4 Capsule Compound of Example 15 100 g Lactose 63g Corn starch 25g Hydroxypropylcellulose 10g Talc 2g After weighing the above components, the compound of Example 15, lactose and corn starch are uniformly mixed, an aqueous solution of hydroxypropylcellulose is added, and granules are produced by wet granulation. Talc is uniformly mixed with the granules, and 200 mg each is filled into a suitable hard capsule to form a pushell.
  • Formulation Example 5 Powder 200 g of the compound of Example 16 790 g of lactose Magnesium stearate 10g After weighing each of the above components, they are mixed uniformly to form a 20% powder.
  • Formulation Example 6 Granules, Fine Granules Compound of Example 18 100 g Lactose 200g Crystalline cellulose 100g Partially pregelatinized starch 50g Hydroxypropylcellulose 50g After weighing the above components, the compound of Example 18, lactose, crystalline cellulose, and partially pregelatinized starch were added and mixed uniformly, an aqueous solution of hydroxypropylcellulose (HPC) was added, and granules or fine granules were obtained by wet granulation. Manufacturing. The granules or fine granules are dried to obtain granules or fine granules.
  • HPC hydroxypropylcellulose
  • Pharmacological experiment example 1 In vitro compound evaluation Enzyme inhibitory activity evaluation IMAP TR-FRET Phosphosterase Evaluation Assay Kit (Molecular device) was used for measurement. 10 ⁇ L of each concentration of test compound diluted in 384 well plate (Corning) and enzyme dilution solution (25 mM Tris-HCl, pH 8.0, 100 mM NaCl, 0.05% Tween-20, 30% glycerol, 3 mM DTT) 100 5 ⁇ L of PDE10 enzyme (BPA bioscience) diluted to ⁇ g / mL was added and preincubated for 5 minutes at room temperature. As a substrate, 5 ⁇ L of cAMP substrate attached to the kit was added and reacted at room temperature for 60 minutes.
  • Binding Buffer attached to the kit was added and allowed to stand for 3 hours or more, and then 5′-AMP produced by measuring fluorescence intensity at an excitation wavelength of 340 nm, an emission wavelength of 490 nm and 520 nm with ARVO SX (PerkinElmer). The amount of was calculated.
  • the inhibitory activity of each test compound was calculated by setting the count of wells to which a solvent was added instead of the test compound to 0% and the count of wells to which no cAMP substrate was added to 100%.
  • PDE10 inhibitory activity (IC50 value) was measured for all Example compounds. The IC50 values of all these example compounds were generally in the range of 0.01 nmol / L to 300 nmol / L.
  • the compound of the present invention having an IC50 value of 10 nmol / L or more and less than 100 nmol / L is defined as +
  • the compound of the present invention having an IC50 value of 1 nmol / L or more and less than 10 nmol / L is represented as ++
  • the IC50 value is less than 1 nmol / L.
  • Pharmacological experiment example 2 In vivo test example Animals Male Sprague-Dawley rats were purchased from Nihon Charles River Co., Ltd. (Japan). After arriving at the breeding facility, the animals were used for experiments with an acclimatization period of at least one week. Animals were housed under a 12 hour light / dark cycle in a laboratory with controlled temperature and humidity, and were allowed free access to food and water. Drug Administration The test compound was suspended in 0.5 w / v% methylcellulose 400 solution (Wako Pure Chemical Industries, Ltd., Japan) and orally administered (po).
  • (+)-MK-801 hydrogen maleate ((5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo [a, d] cycloheptene-5,10-imine maleic acid hydrogen salt, (Sigma Aldrich, St. Louis, MO) was dissolved in saline and administered subcutaneously (sc). The test compound was administered to rats at a volume of 5 mL / kg body weight, and MK-801 was administered at a volume of 1 mL / kg body weight.
  • Antagonism against MK-801-induced increased locomotor activity Evaluation of increased locomotor activity by psychostimulants (eg, amphetamine, cocaine, methamphetamine, MK-801 and phencyclidine) in rodents is an animal model of schizophrenia Widely used (Schizophrenia Bulletin 2010, vol. 36: 1066-1072; Psychopharmacology 1999, vol. 145: 237-250).
  • the test compound was tested for antagonism against MK-801-induced increased locomotor activity in rats. Until the test, male Sprague-Dawley rats (approximately 300 g) were acclimated to the room in which the measurements were performed in the housing cage for at least 60 minutes.
  • DMSO Precipitation Solubility (Kinetic Solubility) A 10 mM DMSO solution of the compound of the present invention is added to a 50 mM phosphate buffer (pH 7.4) to a final concentration of 100 ⁇ M. The solution was incubated at 600 rpm with stirring at room temperature for 1.5 hours, filtered through a filter plate (4 ⁇ m, MultiScreen Solidity filter plate (Millipore)), and then using a plate reader (Powerscan HT (Dainippon Pharmaceutical)). The absorbance of the filtrate is measured at the maximum absorption wavelength.
  • each standard solution absorbance is measured using a solution containing a test compound having a known concentration (1, 3, 10, 30, 100 ⁇ M) as a calibration curve standard solution, and a calibration curve is created.
  • the solubility ( ⁇ M) of the compound is calculated from the absorbance values of the filtrate and standard solution.
  • the reaction solution is subjected to centrifugal filtration using a filter plate (MultiScreen HTS-HV plate (Millipore)), and the test compound in the filtrate is measured using high performance liquid chromatogram / mass spectrometry. Similarly, a sample with a reaction time of 0 minutes is measured as a control, and a metabolic rate and a degradation rate (%) are calculated from the ratio of the microsome reaction sample and the control.
  • a filter plate MultiScreen HTS-HV plate (Millipore)
  • hERG-HEK human ether-a-go-related gene
  • a depolarizing pulse is periodically applied while maintaining the membrane potential at ⁇ 80 mV. After the generated current has stabilized, the test compound is added. The effect of the test compound on the hERG channel is confirmed by a change in tail current induced by a -40 mV, 0.5 second depolarizing pulse followed by a -40 mV, 0.5 second repolarizing pulse.
  • the Stimulation is performed once every 10 seconds. The measurement is performed at room temperature.
  • the hERG channel inhibition rate is calculated as a reduction rate (inhibition rate) of the tail current 2 minutes after application with respect to the maximum tail current before application of the test compound. By calculating this suppression rate, the possibility of inducing QT prolongation by drugs and subsequent fatal side effects (such as ventricular tachycardia and sudden death) is shown.
  • the compound of the present invention has an excellent PDE10 inhibitor blocking activity.
  • the effects of schizophrenia drugs in an in vivo schizophrenia model are shown.
  • the preferred compound of the present invention has a 50% inhibitory activity of hERG (human ether-a-go-go related gene) channel not lower than 10 ⁇ M.
  • the compounds of the present invention are selective PDE10 inhibitors, as well as certain psychiatric disorders and conditions such as schizophrenia, paranoid disorders, and drug-induced diseases; anxiety such as panic disorder and obsessive-compulsive disorder It is expected to be used as a preventive or therapeutic agent for disorders; and movement disorders including Parkinson's disease and Huntington's disease.
  • ⁇ Step 2> Synthesis of 5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine-2-carboxaldehyde Reference Example 2 1 of 2- (chloromethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine (2.0 g) obtained in ⁇ Step 1> , 4-Dioxane (68 ml), N-methylmorpholine N-oxide (3.6 g) and potassium bromide (1.6 g) were sequentially added, and the reaction solution was heated to reflux for 2.5 hours under a nitrogen atmosphere. .
  • reaction solution was cooled to room temperature, N-methylmorpholine N-oxide (0.58 g) was added, and the reaction solution was further heated to reflux under a nitrogen atmosphere for 1.5 hours.
  • the reaction solution was cooled to room temperature, filtered through celite, and washed with 1,4-dioxane (50 ml).
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), and washed with 0.1N hydrochloric acid (30 ml), water (20 ml), and saturated brine (20 ml).
  • the organic phase was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
  • Step 2 Synthesis of 4- (azetidin-1-yl) -6-chloropyrimidine-2-carboxaldehyde 4- (azetidin-1-yl) -6-chloro-2- (chloromethyl) pyrimidine (75 mg) obtained in Reference Example 5 (Step 1) or the same method as Reference Example 2 (Step 2), or Was used to give the title compound (55 mg) as a white solid.
  • N, N-dimethylformamide (0.77 ml) was added dropwise to the reaction solution at the same temperature over 10 minutes, and the mixture was stirred at the same temperature for 2 hours and then warmed to room temperature.
  • the reaction solution was quenched by addition of 0.5N aqueous hydrochloric acid (20 ml), and extracted with ethyl acetate (50 ml, 20 ml). The organic phase was washed with saturated brine (20 ml), dried over anhydrous sodium sulfate (10 g), and the solvent was distilled off under reduced pressure.
  • N-methylmorpholine (22 ⁇ l) and isobutyl chloroformate (26 ⁇ l) were added, and the mixture was stirred at the same temperature for 15 minutes.
  • the solvent was distilled off under reduced pressure, and sodium borohydride (7.7 mg) was added to a methanol (3 ml) solution of the obtained crude product under ice cooling, followed by stirring at 40 ° C. for 12 hours.
  • Water (1 ml) was added to the reaction solution, and the solvent was distilled off under reduced pressure.
  • ⁇ Step 4> Synthesis of 4-morpholino-6- (pyrrolidin-1-yl) pyrimidine-2-carbaldehyde (Reference Example 9) 4- (2- (dimethoxymethyl) -6- (pyrrolidine-) obtained in ⁇ Step 3>
  • Water (8 ml) and concentrated hydrochloric acid (16 ml) were sequentially added to a solution of 1-yl) pyrimidin-4-yl) morpholine (390 mg) in acetone (8 ml), and the mixture was stirred at room temperature for 21 hours.
  • Ethyl acetate (150 ml) and water (100 ml) were added to the reaction solution, and then sodium hydrogen carbonate was added for neutralization.
  • ⁇ Step 5> Synthesis of 7-chloro-2- (chloromethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-c] pyrimidine (Reference Example 10) 3 obtained in ⁇ Step 4> -Using amino-6-chloro-2,5-dimethylpyrimidine-4 (3H) -iminium 2,4,6-trimethylbenzenesulfonate according to the method described in [WO2009 / 152825 pamphlet, page 48] The title compound was synthesized.
  • Step 6 Synthesis of diethyl ((7-chloro-5,8-dimethyl- [1,2,4] triazolo [1,5-c] pyrimidin-2-yl) methyl) phosphonate ⁇ Reference Example 10) Obtained in ⁇ Step 5> 7-chloro-2- (chloromethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-c] pyrimidine obtained by the same method as in (Reference Example 4), or The title compound was synthesized according to the method described above.
  • the reaction solution was diluted with ice water (100 g) and stirred for 10 minutes, and then the precipitate was collected by filtration and washed 5 times with water (10 ml).
  • the obtained solid was dissolved in methylene chloride (10 ml), dried with sodium sulfate, and then added to a methylene chloride solution (10 ml) of 3,6-dimethylpyridin-2-amine (0.61 g) synthesized according to a method known in the literature.
  • the solution was added dropwise at 15 ° C. or lower under ice cooling. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours.
  • Step 2 Synthesis of 2- (chloromethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyridine (Reference Example 11) 1-obtained in ⁇ Step 1> Amino-3,6-dimethylpyridine-2 (1H) -iminium 2,4,6-trimethylbenzenesulfonate (1.2 g) and potassium carbonate (2.3 g) were suspended in acetonitrile (35 ml), Stir for hours. The mixture was cooled to 5 ° C.
  • ⁇ Step 3> Synthesis of diethyl ((5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyridin-2-yl) methyl) phosphonate in the presence of tetrabutylammonium iodide (28 mg).
  • the mixture was stirred with triethyl acid (0.66 ml) at 120 ° C. for 3 hours.
  • Tris (dibenzylideneacetone) dipalladium (0.53 g), 2- (dicyclohexylphosphino) -2 ′, 4 ′, 6′-triisopropylbiphenyl (X-Phos, 0.28 g) was added under a nitrogen atmosphere. Reflux for 2 hours, then And the mixture was stirred at room temperature night. The solvent was distilled off under reduced pressure, water (150 ml) and diisopropyl ether (150 ml) were added, and the mixture was filtered through Celite. Ammonium chloride (30 g) was added to the filtrate, and the mixture was extracted with ethyl acetate (200 ml).
  • Triethylamine (90 ⁇ l) and trifluoromethanesulfonic anhydride (50 ⁇ l) were added, and the mixture was stirred at the same temperature for 110 minutes.
  • Water (30 ml) and dichloromethane (40 ml) were added for liquid separation, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate (30 ml) and saturated brine (20 ml), and dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure to obtain the title compound (0.24 g) as a brown solid.
  • the extract was washed with water (20 ml) and saturated brine (20 ml) and then dried over anhydrous sodium sulfate.
  • the solvent was distilled off under reduced pressure.
  • optical purity and retention time were determined under the following conditions. (Column: CHIRALPAK OJ-H (0.46 cm ⁇ 25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent: ethanol (0.1% diethylamine), flow rate: 0.7 ml / min, UV: 254 nm detection, column temperature: 40 ° C).
  • ⁇ Step 2> Synthesis of 2- (dimethoxymethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-c] pyrimidine (Reference Example 16) 7-Chloro-2- obtained in ⁇ Step 1> From (dimethoxymethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-c] pyrimidine (2.9 g), the title compound (1.2 g) was prepared in the same manner as in Example 2.
  • ⁇ Step 2> Synthesis of (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyridin-2-yl) methanol (Reference Example 17) (5,8-dimethyl) obtained in ⁇ Step 1> -[1,2,4] triazolo [1,5-a] pyridin-2-yl) methyl acetate (0.2 g) was dissolved in methanol (2 ml), cesium carbonate (3 mg) was added, and then at room temperature. Stir overnight. The reaction mixture was concentrated under reduced pressure to obtain the title compound (0.15 g) as a brown white solid.
  • ⁇ Step 3> Synthesis of 5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyridine-2-carbaldehyde (Reference Example 17) obtained in ⁇ Step 2> (5,8 -Dimethyl- [1,2,4] triazolo [1,5-a] pyridin-2-yl) methanol (135 mg) in methylene chloride (5 ml) under ice-cooling, 1,1,1-triacetoxy- 1,1-dihydro-1,2-benziodoxol-3 (1H) -one (Dess-Martin periodinane: 646 mg) was added, and the mixture was stirred at room temperature for 1 hour.
  • the reaction solution was stirred at room temperature for 80 minutes, and then heated and stirred at 50 to 60 ° C. for an additional 70 minutes to return the reaction solution to room temperature.
  • the reaction solution was diluted with water (100 ml), ethyl acetate (150 ml) was added, and the insoluble material was removed with celite.
  • the obtained filtrate was extracted twice with ethyl acetate (50 ml) and dried over sodium sulfate.
  • ⁇ Step 2> Synthesis of 6-chloro-3-methylpyridine aldehyde (Reference Example 24) To a solution of (6-chloro-3-methylpyridin-2-yl) methanol (150 mg) obtained in ⁇ Step 1> in dichloromethane (7 ml) Under ice-cooling, 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3 (1H) -one (Dess-Martin periodinane: 480 mg) was added, and 3 Stir for hours. To the reaction solution were added saturated aqueous sodium hydrogen carbonate solution (1 ml) and aqueous sodium thiosulfate solution (1 ml), and the mixture was extracted with methylene chloride.
  • ⁇ Step 2> Synthesis of 1- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethanone (Reference Example 28) obtained in ⁇ Step 1> , 1- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethanol (100 mg) in dichloromethane (3 ml) at room temperature with manganese dioxide (140 mg ) Was added and stirred for 48 hours. The reaction solution was filtered through celite and washed with dichloromethane.
  • ⁇ Step 2> Synthesis of (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) methanamine (Reference Example 30) 2- (azidomethyl)-obtained in ⁇ Step 1>
  • methanol 10 ml
  • 10% palladium-carbon 20 mg
  • the reaction solution was filtered through Celite, and the filtrate was concentrated to obtain the title compound (0.16 g) as a pale yellow solid.
  • Step 3> 4-Chloro-N-((5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) methyl) -6- (pyrrolidin-1-yl) pyrimidine-2 Synthesis of amine (Reference Example 30) of (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) methanamine (98 mg) obtained in ⁇ Step 2> To a solution of ethanol (5 ml), (Reference Example 29) 2,4-dichloro-6- (pyrrolidin-1-yl) pyrimidine (0.12 g) and diisopropylethylamine (0.19 ml) obtained in ⁇ Step 1> were added.
  • the mixture was heated and stirred at 80 ° C. for 65 hours and at 100 ° C. for 23 hours.
  • the mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), washed with water (20 ml) and saturated brine (20 ml), and dried over anhydrous sodium sulfate.
  • ⁇ Step 2> Synthesis of 2- (chloromethyl) -5,8-dimethylimidazo (1,2-a) pyridine (Reference Example 36) 3,6-dimethylpyridin-2-amine (0.80 g) obtained in ⁇ Step 1> ) And 1,3-dichloropropan-2-one (0.87 g) were suspended in 1,2-dimethoxyethane (6.5 ml) and stirred at 40 ° C. for 16 hours. The reaction solution was cooled to room temperature, and the solid was collected by filtration and washed with 1,2-dimethoxyethane (2 ml). The obtained solid was suspended in ethanol (4.9 ml) and heated to reflux for 3 hours.
  • reaction solution was cooled to room temperature and concentrated under reduced pressure.
  • the resulting residue was suspended in ethyl acetate (10 ml), and 1N aqueous sodium hydroxide solution (8 ml) was added to dissolve the solid.
  • the organic layer was separated, washed with water (10 ml), dried over sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.0 g) as a brownish white solid.
  • the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was suspended in ethyl acetate (10 ml), and the insoluble material was filtered and washed 4 times with ethyl acetate (5 ml).
  • Step 4 2- (2- (3-Methoxy-6- (pyrrolidin-1-yl) pyridin-2-yl) cyclopropyl) -5,8-dimethyl- [1,2,4] triazolo [1, Synthesis of 5-a] pyrazine (Reference Example 39) 2- (2- (6-Bromo-3-methoxypyridin-2-yl) cyclopropyl)-(5,8-dimethyl-) obtained in (Step 3) Using [1,2,4] triazolo [1,5-a] pyrazine (900 mg) in the same manner as in (Example 21.026) or a method analogous thereto, the corresponding amine (1.00 ml ) Gave the title compound (481.1 mg) as a yellow solid.
  • Example 2 Synthesis of 2- (2- (6- (azetidin-1-yl) pyridin-2-yl) ethyl) -5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine
  • E -2- (2- (6- (azetidin-1-yl) pyridin-2-yl) vinyl) -5,8-dimethyl- [1,2,4] obtained in Example 1
  • To a solution of triazolo [1,5-a] pyrazine (40 mg) in methanol (10 ml) was added 10% palladium-carbon (17 mg), and the mixture was stirred under a hydrogen atmosphere for 4 hours.
  • reaction solution was filtered through celite and washed with methanol.
  • the solvent was evaporated under reduced pressure to give the title compound (25 mg) was obtained as a white solid.
  • Example 4 Synthesis of 5,8-dimethyl-2- (2- (6- (pyrrolidin-1-yl) pyridin-2-yl) ethyl)-[1,2,4] triazolo [1,5-a] pyrazine (E) -5,8-dimethyl-2- (2- (6- (pyrrolidin-1-yl) pyridin-2-yl) vinyl)-[1,2,4] triazolo [Example 3] obtained in Example 3 1,5-a] pyrazine was used in the same manner as in (Example 2) or a method analogous thereto.
  • Example 10 2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) -N- (tetrahydro -2H-pyran-4-yl) pyrimidin-4-amine
  • E 2--2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (obtained in Example 9
  • To a solution of pyrrolidin-1-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrimidin-4-amine (30 mg) in methanol (7.2 ml) was added 10% palladium-carbon (9.1 mg).
  • the mixture was stirred for 2.5 hours under a hydrogen atmosphere.
  • the reaction solution was filtered through celite and washed with methanol.
  • Example 12 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) pyrimidine- Synthesis of 4-yl) morpholine (E) -4- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) vinyl) -6- (obtained in Example 11 Using pyrrolidin-1-yl) pyrimidin-4-yl) morpholine, it was synthesized in the same manner as in (Example 10) or a method analogous thereto.
  • reaction solution was cooled to room temperature, 4-fluorophenylboronic acid (18 mg), bis (triphenylphosphine) palladium (II) dichloride (5.9 mg) and dimethoxyethane (0.5 ml) were added and heated for 14 hours. Refluxed.
  • the reaction solution was cooled to room temperature, filtered through celite, and washed with methanol. The filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by LC / MS to obtain the title compound (8.2 mg) as a light brown solid.
  • reaction solution was diluted with N, N-dimethylformamide (1 ml), filtered through a membrane filter (DISMIC (registered trademark) -13JP), and fractionated and purified by LC / MS to give the title compound (5 mg) as a light brown solid.
  • DISMIC registered trademark
  • iodomethane (17 ⁇ l) was added to the reaction solution, and the mixture was stirred at 40 ° C. for 4 hours and 30 minutes.
  • Sodium hydride (11 mg) and iodomethane (17 ⁇ l) were added to the reaction solution, and the mixture was stirred at 40 ° C. for 60 minutes.
  • the reaction solution was filtered and washed with tetrahydrofuran (30 ml). The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative LC / MS to obtain the title compound (2 mg) as a brown solid.
  • the solvent was distilled off under reduced pressure, and the residue was triturated with ethyl acetate.
  • the obtained solid was dissolved in a mixed solution of dichloromethane (2 ml) and ethanol (3 ml), and then the solvent was distilled off under reduced pressure.
  • the obtained residue was azeotroped with ethanol (3 ml), and the obtained residue was dried under reduced pressure to obtain the title compound (80 mg).
  • First fraction (20 mg, pale yellow solid, optical purity> 99% ee, retention time 12.4 minutes, enantiomer A: Example 21.095)
  • Second fraction 22 mg, pale yellow solid, optical purity> 99% ee, retention time 19.2 minutes, enantiomer B: Example 21.996)
  • reaction solution was cooled to room temperature, methyl iodide (0.10 ml) and potassium carbonate (0.22 g) were added, and the mixture was heated and stirred at 80 ° C. for 5 hours.
  • the reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml), washed twice with water (20 ml), saturated brine (20 ml), and dried over anhydrous sodium sulfate.
  • Example 21.102 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidin-1-yl) pyrimidine 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo) obtained by the synthesis of -4-yl) -1-methylpiperazin-2-one (Example 21.085) [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidin-1-yl) pyrimidin-4-yl) piperazin-2-one (25 mg) N, N-dimethylformamide (1 ml) To the solution, 60% sodium hydride (7 mg) was added at room temperature and stirred for 20 minutes.
  • Example 21.104 4- (6- (pyrrolidin-1-yl) -2- (2- (5,7,8-trimethyl- [1,2,4] triazolo [1,5-c] pyrimidin-2-yl) cyclopropyl ) Pyrimidin-4-yl) morpholine (E) -4- (6- (pyrrolidin-1-yl) -2- (2- (5,7,8) obtained in Example 19.054) Using trimethyl- [1,2,4] triazolo [1,5-c] pyrimidin-2-yl) vinyl) pyrimidin-4-yl) morpholine, a method similar to (Example 21.090), Alternatively, the title compound was synthesized by a method analogous thereto.
  • Example 21.105 4- (2- (2- (5,8dimethyl- [1,2,4] triazolo [1,5-a] pyridin-2-yl) cyclopropyl) -6- (pyrrolidin1-yl) pyrimidine-4 Synthesis of -yl) morpholine (Reference Example 17) 2- (2- (4-Chloro-6- (pyrrolidin-1-yl) pyrimidin-2-yl) cyclopropyl) -5 obtained in ⁇ Step 5> , 8-dimethyl- [1,2,4] triazolo [1,5-a] pyridine (50 mg) and morpholine (59 ⁇ l) in the same manner as in Example 19.022, the title compound (37 mg )
  • First fraction (4.2 mg, white amorphous,> 99% ee, retention time 5.9 minutes (enantiomer A: Example 21.106)
  • First fraction (4.3 mg, white amorphous,> 99% ee, retention time 7.4 minutes (enantiomer B: Example 21.107)
  • the optical purity and retention time were determined under the following conditions. (Column: CHIRALPAK AY-H (0.46 cm ⁇ 25 cm) manufactured by Daicel Chemical Industries, Ltd., eluent: ethanol, flow rate: 0.8 ml / min, UV: 254 nm detection, column temperature: 40 ° C.).
  • reaction solution was cooled to room temperature, diluted with methanol (1.5 ml), filtered through a membrane filter (DISMIC (registered trademark) -13JP), and then fractionated and purified by LC / MS.
  • DISMIC registered trademark
  • -13JP membrane filter
  • the obtained crude product was purified by silica gel preparative TLC (developing layer: ethyl acetate 100%) to obtain the title compound (3 mg) as a colorless oily substance.
  • Example 21.111 ((2R) -1- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6-morpholinopyrimidine- 4-yl) pyrrolidin-2-yl) Methanol (Example 21.110)
  • the title compound was synthesized in a similar manner or a method analogous thereto using the corresponding amine.
  • Example 22.001 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidin-1-yl) pyridine Synthesis of -4-yl) morpholine (Reference Example 20) 2- (2- (4-Chloro-6- (pyrrolidin-1-yl) pyridin-2-yl) cyclopropyl obtained in ⁇ Step 5> ) -5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine and morpholine, (Reference Example 20) The same method as in ⁇ Step 3> or a method analogous thereto The title compound was synthesized.
  • Example 23.002 6- (2- (5,8-Dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -2- (pyrrolidin-1-yl) -N- ( 2-chloro-6- (2- (5,8-dimethyl- [1,2,4]) obtained by synthesis of tetrahydro-2H-pyran-4-yl) pyrimidin-4-amine
  • the title compound (6 mg) was obtained in the same manner as in Example 19.056) or a method analogous thereto.
  • Example 25.010 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) -2-methoxyethyl) -6- (pyrrolidine-1- 1- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazine-, obtained by the synthesis of (yl) pyrimidin-4-yl) morpholine (Example 25.0101) 2-Iyl) -2- (4-morpholino-6- (pyrrolidin-1-yl) pyrimidin-2-yl) ethanol (10 mg) in tetrahydrofuran (1 ml) was added to 60% sodium hydride (1.
  • Example 26.017 1- (4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) ethyl) -6- (pyrrolidin-1-yl) 5,8-Dimethyl-2- (2- (4- (piperidin-4-yl) -6 obtained in Example 26.016) Synthesis of) pyrimidin-4-yl) piperidin-1-yl) ethanone To a solution of-(pyrrolidin-1-yl) pyrimidin-2-yl) ethyl)-[1,2,4] triazolo [1,5-a] pyrazine hydrochloride (10 mg) in pyridine (1 ml) was added acetic anhydride (4 ⁇ l ) And N, N-dimethyl-4-amino
  • Example 30.001 The compounds of (Example 30.001) to (Example 30.006) were synthesized in the same manner as in (Example 21.036) or a method analogous thereto, using each corresponding amine.
  • Example 30.001 2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -N- (5-methylpyridin-3-yl)- 6- (Pyrrolidin-1-yl) pyrimidin-4-amine
  • Example 30.002 2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -N- (5-methoxypyridin-3-yl)- 6- (Pyrrolidin-1-yl) pyrimidin-4-amine
  • Example 30.003 N- (5-chloropyridin-3-yl) -2- (2- (5,
  • Example 30.010 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidin-1-yl) pyrimidine -4-yl) -2,2-dimethylmorpholine (Example 30.111) 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidin-1-yl) pyrimidine -4-yl) -1-methylpiperazin-2-one (Example 3 0.012) 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidin-1-yl) pyrimidine -4-yl) -2,6-dimethylmorpho
  • Example 30.19 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6-((S) -2-methyl Pyrrolidin-1-yl) pyrimidin-4-yl) morpholine
  • Example 30.020 4- (2- (2- (5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6-((S) -3-fluoro Pyrrolidin-1-yl) pyrimidin-4-yl) morpholine 2- (2- (4-Chloro-6- (pyrrolidin-1-yl) pyrimidine-2) obtained in (Reference Example 14) from the compound of (Example 30.021) to (Example 30.023).
  • Second fraction (31.6 mg, pale yellow solid, optical purity 97% ee, retention time 8.2 minutes, diastereomer B: Example 30.029)
  • the optical purity and retention time were determined under the following conditions.
  • Methyl magnesium bromide (0.13 ml) was added to the reaction solution under water cooling, and the mixture was stirred at the same temperature for 30 minutes. Furthermore, methylmagnesium bromide (0.065 ml) was added to the reaction solution under water cooling, and the mixture was warmed to room temperature and stirred for 1 hour. To the reaction solution was added saturated aqueous ammonium chloride solution (20 ml), and the mixture was extracted with methylene chloride (50 ml). After drying the organic layer with sodium sulfate, the solvent was distilled off under reduced pressure.
  • Second fraction (30.2 mg, white solid, optical purity 92.7% ee, retention time 30.14 min, enantiomer B: Example 30.035)
  • Undec-7-ene (DBU: 1,21 ml) was added, and the mixture was stirred at 150 ° C. for 3 hours. After cooling to room temperature, water (5 ml) was added to the reaction solution, and the pH was adjusted to 4 with a 2N aqueous hydrochloric acid solution. Extraction was performed with an isopropanol / methylene chloride mixed solution (20:80, 30 ml and 20 ml), and the organic layers were combined and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product (1.58 g) of the title compound.
  • DBU Undec-7-ene
  • reaction solution was added with sodium triacetoxyborohydride (48.1 mg) and stirred for 15 hours and 30 minutes, and the reaction solution was added with saturated aqueous sodium hydrogen carbonate solution (20 ml). Extracted three times with ethyl (20 ml) The organic layers were combined, washed with saturated brine (20 ml) and dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was converted to L. / Prep purified by MS, to give the title compound (41.9 mg) as an orange solid.
  • Second fraction (9 mg, optical purity 95.8% ee, retention time 18.5 minutes, enantiomer B: Example 31.007)
  • the optical purity and retention time were determined under the following conditions.
  • Example 31.010 and (Example 31.010) 5,8-dimethyl-2- (2- (6- (pyrrolidin-1-yl) -4-(((S) -tetrahydrofuran-3-yl) oxy) pyridin-2-yl) cyclopropyl)-[1 , 2,4] Triazolo [1,5-a] pyrazine resolution 5,8-Dimethyl-2- (2- (6- (pyrrolidin-1-yl) -4-(((S) -tetrahydrofuran-3-yl) oxy) obtained in Example 31.09) Pyridin-2-yl) cyclopropyl)-[1,2,4] triazolo [1,5-a] pyrazine (100 mg) was subjected to preparative chromatography (column: manufactured by Daicel Chemical Industries, Ltd.
  • First fraction (29.7 mg, white solid, optical purity 100% ee, retention time 14.8 minutes, enantiomer A: Example 32.001)
  • Second fraction (29.5 mg, white solid, optical purity 100% ee, retention time 21.4 minutes, enantiomer B: Example 32.002)
  • First fraction (66 mg, optical purity 99.9% ee, retention time 9.9 minutes, enantiomer A: Example 32.004)
  • Second fraction (68.8 mg, pale yellow solid, optical purity 99.9% ee, retention time 12.9 minutes, enantiomer B: Example 32.005)
  • the optical purity and retention time were determined under the following conditions.
  • Example 33.015) to (Example 33.018) was synthesized using the corresponding amine in the same manner as in Example (33.014) or a method analogous thereto.
  • Example 34.001 4- (2- (2- (6- (5-Chloro-5,8-dimethyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidine-1 Synthesis of -yl) pyrimidin-4-yl) morpholine Reference Example 40 1-amino-5-chloro-3,6-dimethylpyrazine-2 (1H) -iminium 2,4,6-trimethylbenzenesulfonate (40 mg) obtained in ⁇ Step 2> Triethylamine (22.4 ⁇ l) was added to an acetonitrile (0.5 ml) solution, and the mixture was stirred at 20 ° C. for 30 minutes.
  • First fraction (1 mg, optical purity 100% ee, retention time 6.0 minutes, enantiomer A: Example 34.003) Second fraction (4 mg, pale yellow solid, optical purity 99% ee, retention time 8.0 minutes, enantiomer B: Example 34.004)
  • Example 35.002 4- (2- (2- (8-methoxy-5-methyl- [1,2,4] triazolo [1,5-a] pyrazin-2-yl) cyclopropyl) -6- (pyrrolidin-1-yl) Synthesis of) pyrimidin-4-yl) morpholine 4- (2- (2- (6-Bromo-8-methoxy-5-methyl- [1,2,4] triazolo [1,5-a] pyrazine-2 obtained in Example 35.001) To a solution of -yl) cyclopropyl) -6- (pyrrolidin-1-yl) pyrimidin-4-yl) morpholine (48 mg) in methanol (3 ml) was added 10% palladium-carbon (5 mg) and 25% under a hydrogen atmosphere.
  • Second fraction (6.7 mg, pale yellow solid, optical purity 97.4% ee, retention time 9.3 minutes, enantiomer B: Example 35.004)
  • the optical purity and retention time were determined under the following conditions.
  • the obtained residue was diluted with toluene (10 ml), 1N aqueous hydrochloric acid solution (3 ml) was added to the solution, and the mixture was stirred for 10 minutes. The organic layer was separated and washed with water (3 ml). Silica layer After mixing with gel (1 g) and washing with organic solvent, the filtrate was concentrated, 1N aqueous sodium hydroxide solution (2.5 ml) was added to a solution of the residue in methanol (2.5 ml), and the reaction solution was stirred overnight. The solvent was distilled off under reduced pressure, the resulting residue was diluted with ethyl acetate (5 ml), and the organic layer was extracted with 0.5 N aqueous sodium hydroxide solution (2 ml).
  • the precipitated insoluble material was removed by filtration, and the filtrate was diluted with 1N aqueous sodium hydroxide solution (2 ml) and extracted with ethyl acetate (5 ml). The organic layer was washed with a 10% aqueous citric acid solution and a saturated aqueous sodium hydrogen carbonate solution and then dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product (50 mg, 98% ee). The obtained crude product was dissolved in ethyl acetate (1 ml), and 4N hydrochloric acid-ethyl acetate (0.1 ml) was added.
  • LC-Mass was measured by one of the following methods.
  • a Waters FractionLynx MS system manufactured by Waters
  • a column manufactured by Waters and a SunFire column 4 mm ⁇ 5 cm, 5 ⁇ m

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Abstract

La présente invention concerne un composé aromatique azoté de formule (I), qui est un inhibiteur efficace de la phosphodiestérase 10 (PDE 10). La présente invention concerne également une composition pharmaceutique contenant ce type de composé et l'utilisation de ce type de composé dans des méthodes de traitement de certains types de troubles du système nerveux central (SNC) et d'autres troubles. La présente invention concerne également une méthode de traitement des troubles neurodégénératifs, des troubles mentaux tels que les troubles schizophréniques et des troubles dont le symptôme est une déficience cognitive.
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WO2014078220A1 (fr) * 2012-11-15 2014-05-22 Merck Sharp & Dohme Corp. Triazoles substitués par un alcool secondaire en tant qu'inhibiteurs de pde10
WO2014078217A1 (fr) * 2012-11-15 2014-05-22 Merck Sharp & Dohme Corp. Cyclopropylimidazopyridine utilisable en tant qu'inhibiteur de pde10
JP2015520238A (ja) * 2012-06-19 2015-07-16 スノビオン プハルマセウトイカルス インコーポレイテッド ヘテロアリール化合物及びその使用方法
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