JP5531066B2 - Pyrazolopyrimidine compounds and their use as PDE10 inhibitors - Google Patents

Description

  The present invention relates to a novel pyrazolopyrimidine compound having excellent phosphodiesterase 10 (PDE10) inhibitory activity and useful as a pharmaceutical, a method for preparing such a compound, and use thereof.

  The cyclic nucleotide phosphodiesterase (hereinafter referred to as phosphodiesterase or PDE) is a cyclic nucleotide such as cAMP (adenosine 3 ′, 5′-cyclic monophosphate) or cGMP (guanosine 3 ′, 5′-cyclic monophosphate) as a substrate. It is an enzyme that hydrolyzes the phosphodiester bond of to produce nucleotides such as 5′AMP (adenosine 5′-monophosphate) or 5′GMP (guanosine 5′-monophosphate).

  Cyclic nucleotides such as cAMP and cGMP are involved in the control of many functions in vivo as secondary messengers of intracellular signal transduction. The intracellular concentrations of cAMP and cGMP change in response to extracellular signals, and the enzymes involved in the synthesis of cAMP and cGMP (adenylate cyclase and guanylate cyclase) and PDEs involved in the hydrolysis of such enzymes It is controlled by balance.

  Regarding mammalian PDEs, many types of PDEs have been isolated and identified in mammals, and these have been divided into multiple families due to amino acid sequence homology, biochemical properties, properties due to inhibitors, etc. It is classified (Francis et al., Prog. Nucleic Acid Res., Vol.65, pp.1-52, 2001).

  Among such mammalian PDE families, phosphodiesterase 10 (PDE10) [more specifically, phosphodiesterase 10A (PDE10A)] recognizes both cAMP and cGMP as substrates. PDE10 has been reported to have a higher affinity for cAMP. In addition, human, mouse and rat PDE10A cDNAs have been isolated and identified. The presence of PDE10 protein has also been revealed (Fujishige et al., J. Biol. Chem., Vol. 274, pp. 18438-18445, 1999; Kotera et al., Biochem. Biophys. Res. Commun. , vol.261, pp.551-557, 1999; Soderling et al., Proc. Natl. Acad. Sci. USA, vol.96, pp.7071-7076, 1999; and Loughley et al., Gene, vol. 234, pp. 109-117, 1999).

  Regarding the PDE10 inhibitory compound (PDE10 inhibitor), that is, a compound having an inhibitory action on the enzyme activity of PDE10, the following compounds have been reported.

  For example, EP1250923 (Pfizer) and WO2005 / 082883 (Pfizer) disclose various aromatic heterocyclic compounds such as papaverine and quinazoline and isoquinazoline compounds as PDE10 inhibitors.

In addition, PDE10 inhibitor
Psychiatric disorders:
For example, schizophrenia, schizophrenia-like disorder,
Delusional disorder, schizophrenic emotional disorder, substance-induced psychotic disorder, paranoia or schizophrenic personality disorder, etc .;
Anxiety disorder:
For example, panic disorder, agoraphobia, specific phobia, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, etc .;
Movement disorders:
For example, Huntington's disease, dyskinesia associated with dopamine agonist treatment, Parkinson's disease, restless legs syndrome, etc .;
Drug addiction:
For example, addiction to alcohol, amphetamine, cocaine or opium;
Disorders including symptoms of cognitive impairment:
For example, dementia (including Alzheimer's disease, multiple cerebral infarction dementia, etc.), delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, learning disorder, attention deficit hyperactivity disorder (ADHD), age-related Cognitive decline, etc .; and mood disorders:
For example, major depressive disorder, dysthymic disorder, minor depressive disorder, bipolar disorder (including bipolar I disorder, bipolar II disorder), mood circulatory disorder, etc .; or mood episodes:
For example, it is disclosed that it is useful for the treatment or prevention of diseases or conditions such as major depression episodes, mania or mixed episodes, hypomania episodes and the like.

  It is further disclosed that PDE10 inhibitors are useful for the treatment or prevention of neurodegenerative disorders such as Parkinson's disease and Huntington's disease.

  In Menniti et al. [Menniti et al., Curr. Opin. Investig. Drugs., 2007, 8 (1): 54-59], PDE10 inhibitors have potential as antipsychotics and are integrated. It has been disclosed to have the potential to improve cognitive symptoms in ataxia.

  WO2003 / 000693 (Bayer) discloses imidazotriazine compounds as PDE10 inhibitors. It is also disclosed that PDE10 inhibitors are useful for the treatment or prevention of neurodegenerative disorders, particularly Parkinson's disease.

  WO2003 / 014117 (Bayer) discloses various pyrroloisoquinoline compounds as PDE10 inhibitors. It is also disclosed that these compounds having an inhibitory action on PDE10 activity exhibit a growth-suppressing action and are useful for the treatment of cancer. Furthermore, it has been disclosed that these compounds are useful for treating pain conditions and / or reducing body temperature in fever conditions.

  WO2005 / 12485 (Bayer) discloses that PDE10 inhibitors are useful for stimulating insulin release from pancreatic cells. In addition, PDE10 inhibitors may be used for diabetes and related diseases such as type 1 or type 2 diabetes, young adult-onset diabetes (MODY), adult latent autoimmune diabetes (LADA), impaired glucose tolerance (IGT). It is disclosed that it is useful for the treatment or prevention of abnormal fasting blood glucose level (IGF), gestational diabetes mellitus, metabolic syndrome X and the like.

  See also WO2005 / 120514 (Pfizer), which discloses PDE10 inhibitors that are said to be useful for reducing body weight and / or body fat in the treatment of obese patients. Furthermore, it has been disclosed that these PDE10 inhibitors are useful for the treatment of non-insulin dependent diabetes mellitus (NIDDM), metabolic syndrome and impaired glucose tolerance.

  Here, regarding the pyrazolopyrimidine compound, the following compounds are known.

  WO2007 / 076055 (Entremed Inc.) discloses a pyrazolopyrimidine compound having an action as a proteinase-activated receptor antagonist. However, they are clearly different from the compounds of the invention in terms of pharmacological action and structure.

  The present invention provides novel compounds having excellent PDE10 inhibitory activity, methods for preparing such compounds, uses of the compounds, pharmaceutical compositions containing the compounds, and the like.

  The present inventors have found a novel pyrazolopyrimidine compound having excellent PDE10 inhibitory activity, and have completed the present invention.

[式中、
Ｒ^１は、水素、ハロゲン、低級アルキル又はシアノであり；
環Ａは、場合により置換されている複素環基であり；
環Ｂは、場合により置換されている３〜６員単環式基であり；そして
Ｙは、場合により置換されているアミノ、
場合により置換されている環状アミノ、
場合により置換されている脂肪族３〜６員モノシクリルオキシ、
場合により置換されている低級アルキル又は
場合により置換されている低級アルキル−Ｏ−である]
で表される化合物又はその薬理的に許容しうる塩に関する。 That is, the present invention relates to the formula [I]:

[Where
R ¹ is hydrogen, halogen, lower alkyl or cyano;
Ring A is an optionally substituted heterocyclic group;
Ring B is an optionally substituted 3-6 membered monocyclic group; and Y is an optionally substituted amino,
Optionally substituted cyclic amino,
Optionally substituted aliphatic 3-6 membered monocyclyloxy,
Optionally substituted lower alkyl or optionally substituted lower alkyl-O-]
Or a pharmaceutically acceptable salt thereof.

  The present invention also provides a method for treating or treating a disease, comprising administering an effective amount of a compound represented by the formula [I] or a pharmacologically acceptable salt thereof to a patient in need of treatment or prevention of the disease. It relates to a method for prevention.

  Furthermore, the present invention relates to a pharmaceutical composition comprising a compound represented by the formula [I] or a pharmacologically acceptable salt thereof as an active ingredient, and the use of the compound for producing a medicament.

  Furthermore, the present invention relates to a method for producing a compound represented by the formula [I] or a pharmacologically acceptable salt thereof.

  The compound represented by the formula [I] or a pharmacologically acceptable salt thereof according to the present invention has excellent PDE10 inhibitory activity (that is, inhibitory activity on the enzyme activity of phosphodiesterase 10).

INDUSTRIAL APPLICABILITY The compound of the present invention and the pharmaceutical composition containing it as an active ingredient can be used for diseases or conditions that are expected to be improved by inhibiting PDE10 activity (ie, inhibiting the enzyme activity of phosphodiesterase 10) [for example, , Schizophrenia, anxiety disorder, drug addiction, diseases with symptoms of cognitive impairment, mood disorders and mood episodes, etc.].

  In the present invention, the following terms have the following meanings unless otherwise specified.

The lower alkyl, including “lower alkyl” such as lower alkylamino or di-lower alkylamino, has 1 to 6 carbon atoms (C _1-6 ), preferably 1 to 4 carbon atoms (C _{1- 4} ) or a straight chain or branched chain group. Specific examples of the lower alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, sec-butyl and the like.

Lower cycloalkyl includes cyclic groups having 3 to 8 carbon atoms (C _3-8 ), preferably 3 to 6 carbon atoms (C _3-6 ). Moreover, what has 1-2 lower alkyl substituents in the cyclic part is also mentioned. Specific examples of the lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The lower cycloalkane includes a ring having 3 to 8 carbon atoms (C _3-8 ), preferably 3 to 6 carbon atoms (C _3-6 ). Moreover, what has 1-2 lower alkyl substituents in the cyclic part is also mentioned. Specific examples of the lower cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

Lower alkoxy includes those having 1 to 6 carbon atoms (C _1-6 ), preferably 1 to 4 carbon atoms (C _1-4 ). Moreover, both lower alkyl-O- or lower cycloalkyl-O- are included. Specific examples of lower alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, sec-butoxy and the like.

Lower alkanoyl includes straight or branched chain groups having 2 to 7 carbon atoms (C _2-7 ), preferably 2 to 5 carbon atoms (C _2-5 ). Moreover, both lower alkyl-CO- or lower cycloalkyl-CO- are included. Specifically, examples of lower alkanoyl include formyl, acetyl, propanoyl, butanoyl, isobutanoyl, pivaloyl and the like.

Lower alkylene includes straight-chain or branched-chain groups having 1 to 6 carbon atoms (C _1-6 ), preferably 1 to 4 carbon atoms (C _1-4 ).

Lower alkenyl and lower alkenylene include those having 2 to 7 carbon atoms (C _2-7 ), preferably 2 to 5 carbon atoms (C _2-5 ) and at least one double bond. It is done.

Lower cycloalkenyl includes cyclic groups having 3 to 8 carbon atoms (C _3-8 ), preferably 3 to 6 carbon atoms (C _3-6 ). In addition, examples of the lower cycloalkenyl include those having 1 to 2 lower alkyl substituents in the cyclic portion.

  Examples of halogen include fluorine, chlorine, bromine or iodine. Halo includes fluoro, chloro, bromo or iodo.

  Halo lower alkyl includes lower alkyl substituted with halogen (usually 1 to 5, preferably 1 to 3). Specific examples of the halo lower alkyl include fluoroalkyl, difluoroalkyl, trifluoroalkyl, perfluoroalkyl and the like. More specifically, fluoromethyl, difluoromethyl, trifluoromethyl and the like can be mentioned.

  Halo lower alkoxy includes lower alkoxy substituted with halogen (usually 1 to 5, preferably 1 to 3). Specific examples of the halo lower alkoxy include fluoroalkoxy, difluoroalkoxy, trifluoroalkoxy, perfluoroalkoxy and the like. More specific examples include difluoromethoxy and trifluoromethoxy.

Aryl includes a C _6-14 monocyclic, bicyclic or tricyclic aromatic hydrocarbon group, preferably a C _6-10 monocyclic or bicyclic aromatic hydrocarbon group. Specific examples of aryl include phenyl, naphthyl, phenanthryl, anthryl and the like.

  Substituted amino includes mono- or disubstituted acyclic amino.

  Examples of cyclic amino include 1-pyrrolidinyl, 1-piperidyl, 1-piperazinyl, morpholin-4-yl and the like.

  Secondary hydroxy is hydroxy bonded to a carbon atom bonded to one hydrogen and two carbon atoms.

  Tertiary hydroxy is hydroxy bonded to a carbon atom bonded to three carbon atoms.

In the compound represented by the formula [I] of the present invention, examples of R ¹ include hydrogen, halogen, lower alkyl, and cyano, with hydrogen being preferred.

  The heterocyclic moiety of the “optionally substituted heterocyclic group” represented by ring A is preferably “monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as heteroatoms. Or a group having an aliphatic 5- to 6-membered ring condensed therewith. As the “aliphatic 5- to 6-membered ring” to be condensed, a 5- to 6-membered cycloalkane and an aliphatic 5 to 6-membered heterocyclic ring (preferably an aliphatic 5 to 6-membered heterocyclic ring includes an oxygen atom, a nitrogen atom, and a sulfur atom. For example, cyclohexane, tetrahydropyran and the like.

[式中、
Ｘ^ａは、Ｎ又はＣＨであり；そして
環Ｘ^ｂは、ベンゼン環、ピリジン環もしくは脂肪族５〜６員環であるか、又は存在しない]
で表される構造を有する。 Specific examples of the heterocyclic moiety include pyridyl, pyrazinyl, quinolyl, quinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazinyl, pyrido [3,4-b] pyrazinyl, pyrazolo [1,5-a] pyrimidinyl and the like. Among them, pyrazinyl, quinolyl, quinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazinyl, pyrido [3,4-b] pyrazinyl and Pyrazolo [1,5-a] pyrimidinyl is preferred, and pyrazinyl and quinoxalinyl are particularly preferred. Furthermore, the heterocyclic moiety is preferably of the formula [II]:

[Where
X ^a is N or CH; and Ring X ^b is a benzene ring, a pyridine ring, an aliphatic 5- to 6-membered ring, or is not present]
It has the structure represented by these.

  Specific examples of the heterocyclic moiety include pyridin-2-yl, pyrazin-2-yl, quinolin-2-yl, quinoxalin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7, 8-Dihydro-6H-pyrano [2,3-b] pyrazin-2-yl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl, pyrido [3,4-b] Examples include pyrazin-2-yl and pyrido [3,4-b] pyrazin-3-yl. Among them, pyrazin-2-yl, quinolin-2-yl, quinoxalin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7,8-dihydro-6H-pyrano [2,3-b Pyrazin-2-yl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl, pyrido [3,4-b] pyrazin-2-yl and pyrido [3,4-b Pyrazin-3-yl and the like are preferable, and pyrazin-2-yl and quinoxalin-2-yl are particularly preferable.

The “optionally substituted heterocyclic group” represented by ring A may be unsubstituted or one or more (for example, 1 to 6, preferably 1 to 3) which are the same or different. ) May have a substituent. Examples of such substituents include
Lower alkyl;
Lower cycloalkyl;
halogen;
Halo lower alkyl;
Hydroxy;
Lower alkoxy;
Halo lower alkoxy;
Optionally substituted amino (e.g. optionally having 1 or 2 identical or different substituents selected from lower alkyl, halogen, etc.); and optionally substituted cyclic amino (e.g. And optionally having 1 to 3 substituents which are the same or different and are selected from lower alkyl, halogen and the like. Of these, lower alkyl, cycloalkyl, halogen, halo lower alkyl, optionally substituted amino and optionally substituted cyclic amino are preferred. In particular, lower alkyl and halogen are preferable.

[式中、Ｘ^ｃは、ベンゼン環、ピリジン環又は脂肪族５〜６員環であり、それぞれが、低級アルキル；シクロアルキル；ハロゲン；ハロ低級アルキル；低級アルキル及びハロゲンから選択される同一又は異なる１〜２個の置換基により場合により置換されているアミノ；ならびに、低級アルキル及びハロゲンから選択される同一又は異なる１〜３個の置換基により場合により置換されている環状アミノから選択される１〜２個の置換基により場合により置換されており；
Ｒ^４ａは、水素又は低級アルキル、特に、メチルであり；
Ｒ^４ｂは、水素又は低級アルキル、特に、メチルであり；
Ｒ^４ｃ及びＲ^４ｄは、低級アルキル；シクロアルキル；ハロゲン；ハロ低級アルキル；低級アルキル及びハロゲンから選択される同一又は異なる１〜２個の置換基により場合により置換されているアミノ；ならびに、低級アルキル及びハロゲンから選択される同一又は異なる１〜３個の置換基により場合により置換されている環状アミノから独立して選択される]
で表される基が挙げられる。 Preferred ring A includes formula [VI] or [VII]:

[Wherein, X ^c is a benzene ring, a pyridine ring or an aliphatic 5- to 6-membered ring, each of which is the same or different selected from lower alkyl; cycloalkyl; halogen; halo lower alkyl; lower alkyl and halogen. Amino optionally substituted by 1 to 2 substituents; and 1 selected from cyclic amino optionally substituted by 1 to 3 identical or different substituents selected from lower alkyl and halogen Optionally substituted by ~ 2 substituents;
R ^4a is hydrogen or lower alkyl, especially methyl;
R ^4b is hydrogen or lower alkyl, especially methyl;
R ^4c and R ^4d are lower alkyl; cycloalkyl; halogen; halo lower alkyl; amino optionally substituted with one or two identical or different substituents selected from lower alkyl and halogen; and lower alkyl And independently selected from cyclic amino optionally substituted by 1 to 3 identical or different substituents selected from halogen]
The group represented by these is mentioned.

Examples of the “aliphatic 5- to 6-membered ring” in X ^b or X ^c include a 5- to 6-membered cycloalkane and an aliphatic 5 to 6-membered heterocyclic ring (preferably an aliphatic 5 to 6-membered heterocyclic ring is an oxygen atom. , Heteroatoms selected from nitrogen and sulfur atoms, especially oxygen atoms).

As a specific example of ring A,
3-methylpyrazin-2-yl;
3,6-dimethylpyrazin-2-yl;
3,5,6-trimethylpyrazin-2-yl;
3-methylpyridin-2-yl;
3,6-dimethylpyridin-2-yl;
3-methylquinoxalin-2-yl;
3-ethylquinoxalin-2-yl;
4-ethylquinoxalin-2-yl;
3-trifluoromethylquinoxalin-2-yl;
3,6-dimethylquinoxalin-2-yl;
3,7-dimethylquinoxalin-2-yl;
3,8-dimethylquinoxalin-2-yl;
7-fluoro-3-methylquinoxalin-2-yl;
3-methyl-7-trifluoroquinoxalin-2-yl;
3,6,7-trimethylquinoxalin-2-yl;
5-fluoro-3,7-dimethylquinoxalin-2-yl;
3-methylquinolin-2-yl;
4-methylquinolin-2-yl;
3-methyl-5,6,7,8-tetrahydro-quinoxalin-2-yl;
3-methyl-5-propylpyrazin-2-yl;
2-methyl-5-propylpyrazin-3-yl;
2,6-dimethyl-5-propylpyrazin-3-yl;
5-isobutyl-2-methylpyrazin-3-yl;
2,6-dimethyl-5-isobutylpyrazin-3-yl;
2,6-dimethyl-5-cyclopropylpyrazin-3-yl;
2-methyl-pyrido [3,4-b] pyrazin-3-yl;
3-methyl-pyrido [3,4-b] pyrazin-2-yl;
2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl;
3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl; and 6-methyl-pyrazolo [1,5-a] pyrimidin-5-yl;
In particular, mention may be made of 3-methylquinoxalin-2-yl; and 7-fluoro-3-methylquinoxalin-2-yl.

  The monocyclic moiety of the “optionally substituted 3-6 membered monocyclic group” represented by ring B includes “4-6 membered monocyclic nitrogen-containing heterocyclic group” and “3-6 membered”. A monocyclic hydrocarbon group ”. Among these, “4- to 5-membered monocyclic nitrogen-containing aliphatic heterocycle” and “3- to 5-membered monocyclic aliphatic hydrocarbon group” are preferable. “4- to 5-membered monocyclic nitrogen-containing aliphatic heterocyclic group having a bond on the nitrogen atom of the cyclic group” is more preferable.

、１−ピラゾールなど）がより好ましく、１−ピロリジニル及び１−アゼチジニルがさらに好ましく、１−ピロリジニルが特に好ましい。 Specific examples of “4- to 6-membered monocyclic nitrogen-containing heterocyclic group” include pyrrolidinyl, azetidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and unsaturated monocycles that are partially or completely unsaturated. And a formula group. Of these, pyrrolidinyl, azetidinyl, pyrazolidinyl and unsaturated monocyclic groups in which part or all of them are unsaturated are preferable. Among them, 1-pyrrolidinyl, 1-azetidinyl, 1-pyrazolidinyl and its unsaturated monocyclic group that is partially or completely unsaturated (for example,

1-pyrazole and the like, more preferably 1-pyrrolidinyl and 1-azetidinyl, and particularly preferably 1-pyrrolidinyl.

Examples of “3-6 membered monocyclic hydrocarbon groups” include C _3-6 cycloalkyl, some of which are optionally unsaturated. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like. Of these, cyclopentyl, cyclopentenyl (1-cyclopentenyl and the like) and the like are preferable.

  Examples of “3 to 6-membered monocyclic group” include 1-pyrrolidinyl, 1-azetidinyl, 1-pyrazolyl, cyclopropyl, cyclopentyl, cyclopenten-1-yl and the like.

The “optionally substituted 3-6 membered monocyclic group” represented by ring B may be unsubstituted, or one or more (eg, 1 to 3) substitutions that are the same or different. It may have a group. Examples of such substituents include
halogen;
Oxo;
Hydroxy;
Optionally substituted lower alkyl (e.g. optionally having the same or different 1-2 substituents selected from hydroxy, lower alkoxy, etc.);
Lower alkoxy;
Lower alkylsulfonyloxy;
And optionally substituted amino (for example, it may have 1 or 2 identical or different substituents selected from lower alkyl and the like). Among them, halogen; hydroxy; optionally substituted lower alkyl (for example, optionally having 1 or 2 substituents selected from hydroxy, lower alkoxy and the like) are preferable, halogen, In particular, fluorine is particularly preferable.

Preferred examples of Y include the following formula [III]:
-ZR ² [III]
[Where
Z is —N (R ³ ) —, —O— or C _1-2 alkylene;
R ³ is hydrogen; lower alkyl optionally substituted with one or two identical or different substituents selected from hydroxy and lower alkoxy; or lower cycloalkyl; and R ² is
(1) 1 to 3 identical or different substitutions selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, hydroxy substituted lower cycloalkyl, halo lower alkyl and mono- or di-lower alkylamino A lower alkyl optionally substituted by a group; or (2) an optionally substituted aliphatic 3-6 membered monocyclic group]
The group represented by these is mentioned.

Z is preferably —N (R ³ ) — or —O—, and more preferably —N (R ³ ) —.

R ³ is preferably hydrogen or lower alkyl (eg methyl), more preferably hydrogen.

1 to 3 identical or different R ² selected from the group consisting of “hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, hydroxy-substituted lower cycloalkyl, halo lower alkyl and mono- or di-lower alkylamino” “Lower alkyl optionally substituted with a substituent” is preferably a hydroxy-substituted lower alkyl optionally substituted with a halo lower alkyl. The hydroxy of the “hydroxy substituted lower alkyl” of R ² is preferably secondary or tertiary hydroxy, especially tertiary hydroxy.

By 1 to 3 identical or different substituents selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, hydroxy substituted lower cycloalkyl, halo lower alkyl and mono- or di-lower alkylamino Specific examples of “optionally substituted lower alkyl” include
2-hydroxypropan-1-yl;
2-hydroxy-2-methylpropan-1-yl;
1,1,1-trifluoro-2-hydroxypropan-3-yl; and 3-hydroxy-3-methylbutan-1-yl.

The monocyclic moiety of the “optionally substituted aliphatic 3 to 6 membered monocyclic group” represented by R ² is preferably 1 to 2 selected from an oxygen atom, a nitrogen atom and a sulfur atom. 4-6 membered (preferably 5-6 membered) aliphatic monocyclic heterocyclic group containing 1 hetero atom; _C3-6 (preferably _C5-6 ) cycloalkyl; etc. are mentioned. .

Specific examples of monocyclic moieties include tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, tetrahydrothiopyranyl, tetrahydrothienyl, thietanyl, piperidyl, C _3-6 cycloalkyl (cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl), etc. Is mentioned. Of these, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, C _3-6 cycloalkyl and the like are preferable. Of these, tetrahydropyranyl, cyclohexyl and the like are particularly preferable.

Further specific examples of monocyclic moieties include 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3- or 4-tetrahydrothiopyranyl, 3-tetrahydrothienyl, 3-thietanyl, 4-piperidyl, C _3-6 cycloalkyl and the like can be mentioned. Among these, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3-tetrahydrothienyl, 4-piperidyl, C _3-6 cycloalkyl and the like are preferable. Of these, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, cyclohexyl and the like are more preferable.

The “optionally substituted aliphatic 3- to 6-membered monocyclic group” represented by R ² may be unsubstituted, or one or more (for example, 1 to 3) that are the same or different You may have the substituent of. Examples of such substituents include: halogen; oxo; hydroxy, lower alkanoyl, lower alkoxy and optionally substituted lower alkyl, etc. (eg, the same or different 1-2 selected from hydroxy, lower alkoxy, etc.) May be substituted). Even more preferred are lower alkyl optionally substituted by 1-2 identical or different substituents selected from halogen; oxo; hydroxyl, lower alkanoyl, lower alkoxy, hydroxy and lower alkoxy.

[式中、
Ｘ^３は、−Ｏ−、−Ｓ−、−Ｃ（Ｒ^２ｃ）（Ｒ^２ｄ）−又は−ＳＯ_２−であり；
ｓ及びｔは、互いに独立して、１、２、３又は４であり；
ｓ＋ｔは、２、３、４又は５であり；そして
Ｒ^２ａ、Ｒ^２ｂ、Ｒ^２ｃ、Ｒ^２ｄは、同一又は異なって、それぞれ、独立して、水素、ハロゲン；オキソ；ヒドロキシ、低級アルカノイル、低級アルコキシ、又は、ヒドロキシ及び低級アルコキシから選択される同一又は異なる１〜２個の置換基により場合により置換されている低級アルキルである]
で表される基である。 The “optionally substituted aliphatic 3- to 6-membered monocyclic group” represented by R ² is preferably represented by the following formula [IV]:

[Where
X ³ is —O—, —S—, —C (R ^2c ) (R ^2d ) — or —SO ₂ —;
s and t are independently of each other 1, 2, 3 or 4;
s + t is 2, 3, 4 or 5; and R ^2a , R ^2b , R ^2c , R ^2d are the same or different and are each independently hydrogen, halogen; oxo; hydroxy, lower alkanoyl, lower Alkoxy or lower alkyl optionally substituted with one or two identical or different substituents selected from hydroxy and lower alkoxy]
It is group represented by these.

X ³ is preferably —O— or —C (R ^2c ) (R ^2d ) —.

  s and t are preferably 1 or 2, and more preferably 2.

  s + t is preferably 2, 3 or 4, more preferably 3 or 4.

[式中、記号は上記の定義と同じである]
で表される基である。 The “optionally substituted aliphatic 3- to 6-membered monocyclic group” represented by R ² is more preferably the following formula [V]:

[Wherein the symbols are as defined above]
It is group represented by these.

  Examples of “optionally substituted amino” represented by Y include unsubstituted amino and substituted amino. Of these, substituted amino is preferable.

Examples of the “substituted amino” represented by Y include those having 1 to 2 substituents which are the same or different. Examples of such a substituent of “substituted amino” include those similar to the groups represented by R ³ and R ² of the aforementioned formula [III].

The “substituted amino” represented by Y is preferably a monosubstituted amino. The substituent in such a case is preferably the same as the group represented by R ^{2 in} the above-mentioned formula [III], more preferably “optionally substituted” represented by R ² . Similar to “aliphatic 3-6 membered monocyclic group” or “optionally substituted lower alkyl”.

Specific examples of the “substituted amino” represented by Y in the formula [I] include
4-tetrahydropyranylamino;
N-methyl-N-tetrahydropyran-4-ylamino;
(2-hydroxy-2-methylpropan-1-yl) amino;
(4-hydroxy-4-methylcyclohexyl) amino;
3-oxetanylamino;
(1-hydroxymethylcyclopropan-1-yl) amino;
Cyclopropylamino;
2-hydroxypropan-1-ylamino;
2-methoxyethane-1-ylamino;
4-hydroxycyclohexylamino;
4-methoxycyclohexylamino;
4-ethoxycyclohexylamino;
2,2-dimethyltetrahydropyran-4-ylamino;
2,6-dimethyltetrahydropyran-4-ylamino;
1,1,1-trifluoro-2-hydroxypropan-3-ylamino;
3-tetrahydropyranylamino;
2-cyanoethane-1-ylamino;
(1-hydroxy-2-methylpropan-2-yl) amino;
1,1-difluoroethane-2-ylamino;
1-hydroxycyclopropan-1-ylmethylamino;
3-tetrahydrofuranylamino;
1-methylpiperidin-4-ylamino;
Di (1-methoxyethane-2-yl) amino;
N-cyclopropyl-N-tetrahydropyran-4-ylamino;
N-ethyl-N-tetrahydropyran-4-ylamino;
2-hydroxypropan-1-ylamino;
3-hydroxy-3-methylbutan-1-ylamino;
2-hydroxycyclohexane-1-ylamino;
1-hydroxy-2,2-dimethylpropan-3-ylamino;
1,1-dioxo-tetrahydrothiophen-3-ylamino;
1-acetylpiperidin-4-ylamino;
1-propylpiperidin-4-ylamino;
1-ethylpiperidin-4-ylamino;
1- (N, N-dimethylamino) ethane-2-ylamino; and 4,4-difluorocyclohexylamino;
In particular, 4-tetrahydropyranylamino, (2-hydroxy-2-methylpropan-1-yl) amino, (4-hydroxy-4-methylcyclohexyl) amino, 2-hydroxypropan-1-ylamino, 1,1 , 1-trifluoro-2-hydroxypropan-3-ylamino and 3-hydroxy-3-methylbutan-1-ylamino.

  Preferred examples of “cyclic amino” represented by Y include 1-pyrrolidinyl, morpholin-4-yl, 1-piperidyl, 1-piperazinyl and the like. Of these, 1-pyrrolidinyl, morpholin-4-yl and the like are preferable.

Examples of the “optionally substituted aliphatic 3-6 membered monocyclic” moiety in the “optionally substituted aliphatic 3-6 membered monocyclyloxy” represented by Y include the above-mentioned formula [ III] and the same as the “optionally substituted aliphatic 3 to 6 membered monocyclic group” represented by R ² .

The “optionally substituted lower alkyl” represented by Y may be unsubstituted, or may have one or more (eg, 1 to 3) substituents that are the same or different. Good. Examples of such substituents include optionally substituted aliphatic 3-6 membered monocyclic groups, hydroxy, halogen, cyano, lower alkoxy, mono- or di-lower alkylamino, cycloalkyl, and the like. It is done. Examples of such “optionally substituted aliphatic 3-6 membered monocyclic group” include “optionally substituted aliphatic 3-6” represented by R ^{2 in} the above-mentioned formula [III]. The same as “6-membered monocyclic group” can be mentioned.

  The “optionally substituted lower alkyl-O—” represented by Y may be unsubstituted or have one or more (eg, 1 to 3) substituents that are the same or different. It may be. Examples of such substituents include halogen; hydroxy, lower alkoxy and the like.

One embodiment of the present invention includes compounds represented by Formula [I], wherein R ¹ is hydrogen.

  Another aspect of the present invention is an optionally substituted monocyclic or bicyclic heteroaryl, wherein ring A contains 1 to 3 nitrogen atoms as heteroatoms, or aliphatic 5 fused thereto Including the above-mentioned compounds which are groups having ˜6-membered rings.

  In one of these embodiments, ring A is an optionally substituted group of formula [II].

  In one of these embodiments, ring A is pyridyl, pyrazinyl, quinolyl, quinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 7,8-dihydro-6H-pyrano [2,3-b. ] Pyrazinyl, pyrido [3,4-b] pyrazinyl, pyrazolo [1,5-a] pyrimidinyl, each optionally substituted.

  In one of these embodiments, ring A is pyridyl, pyrazinyl, quinolyl, quinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 7,8-dihydro-6H-pyrano [2,3-b. ] Pyrazinyl, pyrido [3,4-b] pyrazinyl and pyrazolo [1,5-a] pyrimidinyl, each optionally substituted.

  In one of these embodiments, ring A is pyrazinyl, quinolyl, quinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazinyl. Pyrido [3,4-b] pyrazinyl and pyrazolo [1,5-a] pyrimidinyl.

  In one of these embodiments, ring A is pyrazinyl and quinoxalinyl, each optionally substituted.

  In one of these embodiments, ring A is pyrazin-2-yl, quinolin-2-yl, quinoxalin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7,8- Dihydro-6H-pyrano [2,3-b] pyrazin-2-yl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl, pyrido [3,4-b] pyrazine- 2-yl and pyrido [3,4-b] pyrazin-3-yl, each optionally substituted.

  In one of these embodiments, Ring A is pyrazin-2-yl and quinoxalin-2-yl, each optionally substituted.

  Another embodiment of the present invention is that ring A is selected from lower alkyl; lower cycloalkyl; halogen; halo lower alkyl; hydroxy; lower alkoxy; halo lower alkoxy; optionally substituted amino (eg, lower alkyl, halogen, etc.). Optionally having 1-2 identical or different substituents; and optionally substituted cyclic amino (eg, lower alkyl, halogen etc., identical or different 1-3 1 or more (for example, 1 to 6, preferably 1 to 3) substituents which are the same or different substituents selected from (which may have one substituent). Including the aforementioned compounds.

  In one of these embodiments, the substituent in the “optionally substituted heterocyclic group” represented by ring A is: lower alkyl; halogen; halo lower alkyl; hydroxy; lower alkoxy; halo lower alkoxy; Optionally substituted by one or two identical or different substituents selected from alkyl and halogen; and optionally substituted by one or three identical or different substituents selected from lower alkyl and halogen The same or different 1 to 6 substituents selected from the group consisting of cyclic amino groups.

  In one of these embodiments, the substituent in the “optionally substituted heterocyclic group” represented by ring A is the same or selected from: lower alkyl; halogen; halo lower alkyl; lower alkyl and halogen From the group consisting of amino optionally substituted by 1 to 2 different substituents; and cyclic amino optionally substituted by 1 to 3 identical or different substituents selected from lower alkyl and halogen The same or different 1 to 3 substituents selected.

  In one of these embodiments, the substituents in the “optionally substituted heterocyclic group” represented by ring A are 1 to 3 identical or different groups selected from the group consisting of lower alkyl and halogen. It is a substituent.

  Another embodiment of the present invention includes a compound represented by formula [I], wherein ring A is a group represented by formula [VI] or [VII].

  In one of these embodiments, Ring A is a group represented by Formula [VI].

  In one of these embodiments, Ring A is a group represented by Formula [VII].

  In another embodiment of the present invention, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B is a 4-6 membered monocyclic nitrogen-containing heterocyclic group. Including the aforementioned compounds.

  In one of these embodiments, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B is a 4-6 membered monocyclic nitrogen-containing heterocyclic group or 3 to 6-membered monocyclic hydrocarbon group.

In one of these embodiments, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B is pyrrolidinyl, azetidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, It is selected from the group consisting of morpholinyl, thiomorpholinyl and C _3-6 cycloalkyl, or an unsaturated monocyclic group thereof.

  In one of these embodiments, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B is pyrrolidinyl, azetidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, Selected from the group consisting of morpholinyl, thiomorpholinyl and its unsaturated monocyclic groups that are partially or fully unsaturated.

  In one of these embodiments, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B includes pyrrolidinyl, azetidinyl, pyrazolidinyl and some or all of The unsaturated monocyclic group that is saturated.

  In one of these embodiments, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B is 1-pyrrolidinyl, 1-azetidinyl, 1-pyrazolidinyl and An unsaturated monocyclic group that is partially or fully unsaturated.

  In one of these embodiments, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B is 1-pyrrolidinyl, 1-azetidinyl, 1-pyrazolyl, Cyclopropyl, cyclopentyl or cyclopenten-1-yl.

  In one of these embodiments, the monocyclic moiety in the “optionally substituted 3-6 membered monocyclic group” represented by ring B is 1-pyrrolidinyl.

  Another embodiment of the present invention is the same or different 1 wherein the “optionally substituted 3-6 membered monocyclic group” represented by ring B is selected from halogen; oxo; hydroxy; hydroxy and lower alkoxy Lower alkyl optionally substituted by 2 substituents; lower alkoxy; lower alkylsulfonyloxy; and amino optionally substituted by 1 or 2 identical or different substituents selected from lower alkyl Including the aforementioned compounds, which are 3-6 membered monocyclic groups optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of

  In one of these embodiments, the “optionally substituted 3-6 membered monocyclic group” represented by ring B is halogen; hydroxy; the same or different and is selected from hydroxy and lower alkoxy A 3- to 6-membered monocyclic group optionally substituted with 1 to 3 identical or different substituents selected from lower alkyl optionally substituted with 1 to 2 substituents.

  Another embodiment of the present invention includes the aforementioned compounds, wherein Y is represented by formula [III].

In one of these embodiments, Y is represented by the formula [III], where Z is —N (R ³ ) — or —O—.

In one of these embodiments, Y is represented by formula [III], wherein Z is —N (R ³ ) —.

Another embodiment of the present invention includes the aforementioned compounds, wherein Y is represented by formula [III], wherein R ³ is hydrogen.

Another embodiment of the present invention is that Y is represented by formula [III], wherein the “optionally substituted aliphatic 3-6 membered monocyclic group” represented by R ² is halogen; oxo Hydroxy; lower alkanoyl; lower alkoxy; and the same or different 1 to 1 selected from the group consisting of lower alkyl optionally substituted with 1 to 2 identical or different substituents selected from hydroxy and lower alkoxy Included are the aforementioned compounds that are aliphatic 3-6 membered monocyclic groups optionally substituted with 3 substituents.

  In one of these embodiments, the monocyclic moiety in the “optionally substituted aliphatic 3-6 membered monocyclic group” is represented by formula [IV].

  In one of these embodiments, the monocyclic moiety in the “optionally substituted aliphatic 3-6 membered monocyclic group” is represented by the formula [V].

In one of these embodiments, the monocyclic moiety in the “optionally substituted aliphatic 3-6 membered monocyclic group” represented by R ² is tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, tetrahydrothio Selected from the group consisting of pyranyl, tetrahydrothienyl, thietanyl, piperidyl, cyclohexyl, cyclopentyl and cyclobutyl.

In one of these embodiments, the monocyclic moiety in the “optionally substituted aliphatic 3-6 membered monocyclic group” represented by R ² is 3- or 4-tetrahydropyranyl, 3- Selected from the group consisting of tetrahydrofuranyl, 3-oxetanyl, 3- or 4-tetrahydrothiopyranyl, 3-tetrahydrothienyl, 3-thietanyl, 4-piperidyl and C _3-6 cycloalkyl.

In one of these embodiments, Y is represented by the formula [III], wherein R ² is hydroxy, halogen, cyano, lower alkoxy, lower cycloalkyl, hydroxy substituted lower cycloalkyl, halo lower alkyl and mono -Or lower alkyl optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of di-lower alkylamino.

In one of these embodiments, Y is represented by the formula [III], wherein R ² is an optionally substituted aliphatic 3-6 membered monocyclic group.

In one of these embodiments, Y is represented by formula [III], where
R ² is
(1) optionally by 1-3 identical or different substituents selected from the group consisting of hydroxy, halogen, cyano, lower alkoxy, hydroxy substituted lower cycloalkyl, halo lower alkyl and mono- or di-lower alkylamino Or (2) 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3-tetrahydrothienyl, 4-piperidyl, cyclohexyl or C _3-6 cyclo A group consisting of halogen; oxo; hydroxy; lower alkanoyl; lower alkoxy; and lower alkyl optionally substituted with one or two identical or different substituents selected from hydroxy and lower alkoxy, respectively. Same or different 1 selected from Optionally substituted by three substituents.

In one of these embodiments, Y is represented by formula [III], wherein R ² is 4-tetrahydropyranyl; 4-hydroxy-4-methylcyclohexyl; 2-hydroxypropan-1-yl 2-hydroxy-2-methylpropan-1-yl; 1,1,1-trifluoro-2-hydroxypropan-3-yl; and 3-hydroxy-3-methylbutan-1-yl The

  Another aspect of the present invention includes the aforementioned compounds, wherein Y is an optionally substituted amino.

  Another aspect of the present invention includes the aforementioned compounds, wherein Y is an optionally substituted cyclic amino.

  Another embodiment of the present invention includes the aforementioned compounds wherein Y is an optionally substituted aliphatic 3-6 membered monocyclyloxy.

  Another aspect of the present invention includes the aforementioned compounds, wherein Y is optionally substituted lower alkyl.

  Another aspect of the present invention includes the aforementioned compounds, wherein Y is optionally substituted lower alkyl-O-.

  Preferably, examples of the compound represented by the formula [I] include examples (Examples 1.001 to 1.200, 2.001, 3.001, 4.001 to 4.005, 5.001 and 5.002) or a pharmacologically acceptable salt thereof.

Particularly preferably, examples of the compound include
2- (3-Methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (Examples) 1.001 free form);
N-methyl-2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine-7- An amine (free form of Example 1.002);
5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a ] Pyrimidine-7-amine (free form of Example 1.003);
1-({2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidin-7-yl } Amino) -2-methylpropan-2-ol (free form of Example 1.006);
5- (2,5-dihydro-1H-pyrrol-1-yl) -2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5- a] Pyrimidine-7-amine (Example 1.009);
2-Methyl-3- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-yloxy) pyrazolo [1,5-a] pyrimidin-2-yl] quinoxaline (of Example 1.010 Free form);
5-Cyclopent-1-en-1-yl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine-7- An amine (Example 1.011);
trans-4-({2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidine-7 -Yl} amino) -1-methylcyclohexanol (free form of Example 1.013);
2- (5,7-dipyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-2-yl) -3-methylquinoxaline (free form of Example 1.019);
(2S) -1,1,1-trifluoro-3-{[2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] Amino} propan-2-ol (free form of Example 1.027);
3-{[2- (3-Methylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} propanenitrile (free form of Example 1.031) );
N- (trans-4-methoxycyclohexyl) -2- [3-methyl-7- (trifluoromethyl) quinoxalin-2-yl] -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidine-7- An amine (free form of Example 1.047);
2- (3,7-dimethylquinoxalin-2-yl) -N, N-bis (2-methoxyethyl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-amine (Example 1) .050 free form);
5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) -N-oxetan-3-ylpyrazolo [1,5-a] pyrimidin-7-amine ( Example 1.058);
1-{[5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino}- 2-methylpropan-2-ol (free form of Example 1.059);
N-cyclopropyl-5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-amine (Examples) 1.062 free form);
2- (3-Ethylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] -N- (trans-4-methoxycyclohexyl) pyrazolo [1,5-a] pyrimidine- 7-amine (free form of Example 1.081);
trans-4-({5-[(3R) -3-fluoropyrrolidin-1-yl] -2- [3- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidine-7 -Yl} amino) -1-methylcyclohexanol (free form of Example 1.085);
(1S, 2S) -2-{[2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclo Hexanol (free form of Example 1.097);
2- (3,5-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine ( Free form of Example 1.109);
2- (3,6-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine ( Free form of Example 1.111);
2- (3,7-dimethylquinoxalin-2-yl) -N-[(3R) -1,1-dioxidetetrahydro-3-thienyl] -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidine -7-amine (free form of Example 1.112);
N- (1-acetylpiperidin-4-yl) -2- (3,7-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-amine (Examples) 1.114 free form);
2- (3,7-Dimethylquinoxalin-2-yl) -N- (1-propylpiperidin-4-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-amine (Examples) 1.123 free form);
N ′-[2- (3,7-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] -N, N-dimethylethane-1,2 A diamine (free form of Example 1.126);
N- (4,4-difluorocyclohexyl) -2- (3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] Pyrimidine-7-amine (Example 1.133);
N-methyl-5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) -2- (3,5,6-trimethylpyrazin-2-yl) pyrazolo [1,5-a] Pyrimidine-7-amine (Example 1.158);
((2S) -1- {2- (3-Methylquinoxalin-2-yl) -7-[(3R) -tetrahydro-2H-pyran-3-ylamino] pyrazolo [1,5-a] pyrimidine-5 Yl} pyrrolidin-2-yl) methanol (free form of Example 1.147);
{(2S) -1- [7- [cyclopropyl (tetrahydro-2H-pyran-4-yl) amino] -2- (3,7-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine -5-yl] pyrrolidin-2-yl} methanol (free form of Example 1.152);
1- [2- (3,7-Dimethylquinoxalin-2-yl) -7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidin-5-yl] azetidin-3-ol (Free form of Example 1.154);
2-Methyl-3- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylmethyl) pyrazolo [1,5-a] pyrimidin-2-yl] quinoxaline (Example 2.001) ;
trans-1-methyl-4-{[2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1, 5-a] pyrimidin-7-yl] amino} cyclohexanol (free form of Example 1.173);
cis-4-({2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidine-7 -Yl} amino) -1-methylcyclohexanol (free form of Example 1.175);
N-methyl-2- (3-methyl-6-propylpyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] Pyrimidine-7-amine (free form of Example 1.181);
2-Methyl-1-[(6′-methyl-5-pyrrolidin-1-yl-2,5′-bipyrazolo [1,5-a] pyrimidin-7-yl) amino] propan-2-ol (Examples) 1.184 free form);
1-{[2- (6-Isobutyl-3,5-dimethylpyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} -2-methylpropane -2-ol (Example 1.187);
1-{[2- (6-Cyclopropyl-3,5-dimethylpyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} -2-methyl Propan-2-ol (free form of example 1.189);
2- (6-Cyclopropyl-3,5-dimethylpyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine -7-amine (free form of Example 1.190);
2- (3-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl ) Pyrazolo [1,5-a] pyrimidin-7-amine (free form of Example 1.197);
2-Methyl-1-{[2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5- a] pyrimidin-7-yl] amino} propan-2-ol (free form of Example 1.198);
N- (trans-4-methoxycyclohexyl) -2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1 , 5-a] pyrimidin-7-amine (free form of Example 1.199);
2- (2-Methylpyrido [3,4-b] pyrazin-3-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine -7-amine (Example 5.001); and 2- (3-methylpyrido [3,4-b] pyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran- 4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (Example 5.002)
Or a pharmacologically acceptable salt thereof selected from the group consisting of

  The compound represented by the formula [I] of the present invention may be in a free form (free base or free acid) or a pharmaceutically acceptable salt form thereof. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate or hydrobromide, and acetate, fumarate, oxalate, citrate And organic acid salts such as methanesulfonate, benzenesulfonate, p-toluenesulfonate and maleate. Further, when the compound of the present invention contains a substituent such as a carboxyl group, the pharmacologically acceptable salt thereof may be a base (for example, an alkali metal salt such as sodium salt or potassium salt or an alkaline earth salt such as calcium salt). And the like).

  The compound represented by the formula [I] of the present invention or a salt thereof includes any of its inner salt, adduct, solvate or hydrate.

  The compound represented by the formula [I] of the present invention can be prepared according to the following, but is not limited thereto.

Preparation method 1
R ¹ is hydrogen and Y is optionally substituted amino, optionally substituted cyclic amino, optionally substituted aliphatic 3-6 membered monocyclyloxy or optionally substituted A compound of the formula [I] which is lower alkoxy, i.e.
Formula [Ia ¹ ] [wherein B ¹ is an optionally substituted nitrogen-containing heterocyclic group, and Y ^a is an optionally substituted amino, an optionally substituted cyclic amino, optionally Substituted aliphatic 3-6 membered monocyclyloxy or optionally substituted lower alkoxy, the other symbols have the same meaning as defined above];
Formula [Ia ² ] [wherein B ² is an optionally substituted 3-6 membered monocyclic group where the monocyclic moiety is unsaturated, the other symbols are as defined above. Having the meaning]; and formula [Ia ³ ] [wherein B ³ is an optionally substituted 3-6 membered monocyclic group in which the monocyclic moiety is saturated, the other symbols are: Has the same meaning as defined above]
Can be prepared by the following preparation method.

  A compound represented by the formula [1] [wherein each symbol has the same meaning as defined above] is reacted with acetonitrile, and the formula [2] [wherein each symbol is defined as defined above] Having the same meaning].

  The compound represented by the formula [2] is reacted with hydrazine to obtain a compound represented by the formula [3] [wherein each symbol has the same meaning as defined above].

  The compound represented by the formula [3] is reacted with ethyl malonyl chloride, and then a nucleophile is added thereto, thereby obtaining the formula [4] [wherein each symbol has the same meaning as defined above] To obtain a compound represented by: Alternatively, the compound represented by the formula [3] is reacted with ethyl hydrogen malonate to obtain the compound represented by the formula [4].

  The compound represented by the formula [4] is cyclized to obtain a compound represented by the formula [5] [wherein each symbol has the same meaning as defined above].

  The compound represented by the formula [5] is halogenated to obtain a compound represented by the formula [6] [wherein each symbol has the same meaning as defined above].

  A compound represented by the formula [6] is reacted with a compound represented by the formula [8] [wherein each symbol has the same meaning as defined above] to form the formula [7] [wherein Each symbol has the same meaning as defined above] to obtain a compound represented by

A compound represented by the formula [7] is reacted with a compound represented by the formula [9] [wherein each symbol has the same meaning as defined above], and represented by the formula [Ia ¹ ]. Which is optionally converted into a pharmacologically acceptable salt.

The compound represented by the formula [7] is represented by the formula [10] [wherein L is —B (OR) _2, —B (OH) ₂ or —SnR ₃ , R is lower alkyl, Other symbols have the same meanings as defined above] to give a compound of the formula [Ia ² ], which is optionally a pharmacologically acceptable salt. Convert to

The compound of formula [Ia ² ] is reduced to obtain the compound of formula [Ia ³ ], which is optionally converted to a pharmacologically acceptable salt.

  The reaction of the compound represented by the formula [1] and acetonitrile suitably proceeds in the presence of a base. As such a base, for example, alkali metal alkoxides such as potassium tert-butoxide, alkali metal hydrides such as sodium hydride, and alkali metal hydroxides such as sodium hydroxide can be preferably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, and for example, toluene and the like can be preferably used. The reaction suitably proceeds at −78 ° C. to 100 ° C., particularly 0 ° C. to room temperature.

  The reaction between the compound represented by the formula [2] and hydrazine suitably proceeds in the presence of an acid. As such an acid, for example, an organic acid such as acetic acid and an inorganic acid such as hydrochloric acid can be preferably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, an alcohol solvent such as methanol and ethanol, an organic solvent such as acetic acid, or a combination thereof can be suitably used. The reaction suitably proceeds at 0 ° C. to 150 ° C., particularly 80 ° C. to 120 ° C.

  Regarding the reaction between the compound represented by the formula [3] and ethyl malonyl chloride, preferred examples of the nucleophile include alcohols such as ethanol. The reaction suitably proceeds in the presence of a base. As such a base, for example, organic bases such as triethylamine and pyridine can be preferably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, and for example, methylene chloride, chloroform, pyridine and the like or a combination thereof can be suitably used. The reaction suitably proceeds at −78 ° C. to 100 ° C., particularly 0 ° C. to room temperature.

  Regarding the reaction between the compound represented by the formula [3] and ethyl hydrogen malonate, the reaction suitably proceeds in the presence of a condensing agent. As such a condensing agent, for example, N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride, dicyclohexylcarbodiimide and diisopropylcarbodiimide can be preferably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, methylene chloride, chloroform, pyridine, dimethylformamide, N-methylpyrrolidinone, or a combination thereof can be preferably used. it can. The reaction suitably proceeds at −20 ° C. to 60 ° C., particularly 0 ° C. to room temperature.

  The cyclization reaction of the compound represented by the formula [4] proceeds suitably in the presence of a base. As such a base, for example, an organic base such as dimethylaminopyridine and diisopropylethylamine, a metal base such as sodium hydride, or an aqueous ammonia solution can be suitably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, for example, an alcohol solvent such as methanol and ethanol, water, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or a combination thereof. It can be preferably used. The reaction suitably proceeds at −78 ° C. to 100 ° C., particularly at 0 ° C. to room temperature.

  The halogenation reaction of the compound represented by the formula [5] can be performed by reacting the compound with a halogenating agent. Examples of such halogenating agents include phosphorus oxychloride. The reaction can be carried out in a suitable solvent or without solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, and for example, toluene, xylene and the like can be preferably used. The reaction suitably proceeds at 0 ° C. to 150 ° C., particularly 80 ° C. to 120 ° C.

  The reaction between the compound represented by the formula [6] and the compound represented by the formula [8] suitably proceeds in the presence of a base. When the compound represented by the formula [8] is a compound having an amino group, examples of such a base include organic bases such as dimethylaminopyridine and diisopropylethylamine, metal bases such as sodium bicarbonate and potassium carbonate, and the like. It can be preferably used. When the compound represented by the formula [8] is a compound having an alcoholic hydroxyl group, as such a base, for example, a metal base such as sodium hydride can be preferably used. When the compound represented by the formula [8] is a compound having a phenolic hydroxyl group, for example, a metal base such as sodium hydride and cesium carbonate can be preferably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, and for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc., or a combination thereof can be suitably used. The reaction suitably proceeds at −78 ° C. to 100 ° C., particularly at 0 ° C. to room temperature.

  The reaction between the compound represented by the formula [7] and the compound represented by the formula [9] suitably proceeds in the presence of a base. As such a base, for example, organic bases such as dimethylaminopyridine and diisopropylethylamine, metal bases such as sodium bicarbonate and potassium carbonate, and the like can be preferably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, and for example, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, etc., or a combination thereof can be suitably used. The reaction suitably proceeds at −78 ° C. to 100 ° C., particularly 0 ° C. to 100 ° C.

The reaction of the compound represented by the formula [7] and the compound represented by the formula [10] proceeds suitably in the presence of a palladium catalyst. As such a palladium catalyst, for example, a zero-valent or divalent palladium catalyst such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, palladium (II) acetate is preferably used. Can be used. When L is —B (OR) ₂ or —B (OH) ₂ , the reaction suitably proceeds in the presence of a base. As such a base, for example, metal bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates and alkali metal fluorides, organic bases such as triethylamine, and the like can be preferably used. The reaction can be carried out in a suitable solvent or without solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. Can be used. The reaction suitably proceeds at 60 ° C to 150 ° C, particularly 80 ° C to 120 ° C.

Reduction of the compound represented by the formula [Ia ² ] proceeds satisfactorily by a catalytic hydrogenation reaction in which the reaction is performed in a hydrogen atmosphere and in the presence of a catalyst such as palladium. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, for example, an ester solvent such as ethyl acetate, an alcohol solvent such as ethanol, an ether solvent such as tetrahydrofuran, a halogen solvent such as methylene chloride, or the like. A combination of them can be used. The reaction suitably proceeds in such a solvent at 0 ° C. to room temperature under a hydrogen atmosphere of 1 to 3 atm.

Preparation method 2
A compound of formula [I], wherein R ¹ is hydrogen and Y is optionally substituted alkyl, ie:
Formula [Ia ⁴ ] wherein Y ^b is an optionally substituted alkyl, and other symbols have the same meaning as defined above;
Formula [Ia ⁵ ] [wherein each symbol has the same meaning as defined above]; and Formula [Ia ⁶ ] [wherein each symbol has the same meaning as defined above]
Can be prepared by the following preparation method.

  Reacting a compound represented by formula [3] with a compound represented by formula [11] [wherein each symbol has the same meaning as defined above], and then adding a nucleophile. To obtain a compound represented by the formula [12] [wherein each symbol has the same meaning as defined above].

  The compound represented by the formula [12] is cyclized to obtain a compound represented by the formula [13] [wherein each symbol has the same meaning as defined above].

  The compound represented by the formula [13] is halogenated to obtain a compound represented by the formula [14] [wherein each symbol has the same meaning as defined above].

A compound represented by the formula [14] [wherein each symbol has the same meaning as defined above] is reacted with a compound represented by the formula [9], and represented by the formula [Ia ⁴ ]. Which is optionally converted into a pharmacologically acceptable salt.

The compound represented by the formula [14] is reacted with the compound represented by the formula [10] to obtain a compound represented by the formula [Ia ⁵ ], which is optionally pharmacologically acceptable. Convert to salt.

Reduction of the compound of formula [Ia ⁵ ] yields a compound of formula [Ia ⁶ ], which is optionally converted to a pharmacologically acceptable salt.

  The reaction between the compound represented by the formula [11] and the compound represented by the formula [3] is performed by reacting the compound represented by the formula [11] with a halogenating agent such as oxalyl chloride to form an acid chloride. Then, it can be carried out by carrying out a reaction similar to the reaction of the compound represented by the formula [3] described in Preparation Method 1 with ethylmalonyl chloride. The compound represented by the formula [11] can be prepared by a usual β-ketoester synthesis method.

  The cyclization of the compound represented by the formula [12] proceeds suitably in the presence of a base. As such a base, for example, an organic base such as dimethylaminopyridine and diisopropylethylamine, a metal base such as sodium hydride, or an aqueous ammonia solution can be suitably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, for example, an alcohol solvent such as methanol and ethanol, water, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, or a combination thereof. It can be preferably used. The reaction suitably proceeds at −78 ° C. to 100 ° C., particularly 0 ° C. to room temperature.

  The halogenation of the compound represented by the formula [13] can be carried out in the same manner as the halogenation reaction of the compound represented by the formula [5] described in Preparation Method 1.

  The reaction between the compound represented by the formula [14] and the compound represented by the formula [9] is performed by reacting the compound represented by the formula [7] described in Preparation Method 1 with the compound represented by the formula [9] The reaction can be carried out in the same manner as in the above reaction.

  The reaction between the compound represented by the formula [14] and the compound represented by the formula [10] is carried out by reacting the compound represented by the formula [7] described in Preparation Method 1 with the compound represented by the formula [10] The reaction can be carried out in the same manner as in the above reaction.

Reduction of the compound represented by the formula [Ia ⁵ ] can be carried out in the same manner as the reduction of the compound represented by the formula [Ia ² ] described in Preparation Method 1.

Preparation method 3
The compound represented by the formula [Ia ³ ] can also be prepared by the following method.

  A compound represented by the formula [3] is reacted with a compound represented by the formula [15] [wherein R is lower alkyl, and other symbols have the same meaning as defined above]. And a compound represented by formula [16] [wherein each symbol has the same meaning as defined above].

  The compound represented by the formula [16] is halogenated to obtain a compound represented by the formula [17] [wherein each symbol has the same meaning as defined above].

The compound represented by the formula [17] is reacted with the compound represented by the formula [8] to obtain a compound represented by the formula [Ia ³ ], which is optionally pharmacologically acceptable. Convert to salt.

  The reaction of the compound represented by the formula [3] and the compound represented by the formula [15] suitably proceeds in the presence of a base. As such a base, for example, sodium alkoxide can be preferably used. The reaction can be carried out in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, alcohol solvents such as methanol, ethanol and methoxyethanol, or a combination thereof can be preferably used. The reaction suitably proceeds at 60 ° C to 160 ° C, particularly 80 ° C to 130 ° C.

  The halogenation of the compound represented by the formula [16] can be carried out in the same manner as the halogenation reaction of the compound represented by the formula [5] described in Preparation Method 1.

  The reaction between the compound represented by the formula [17] and the compound represented by the formula [8] is performed by reacting the compound represented by the formula [6] described in Preparation Method 1 with the compound represented by the formula [8] The reaction can be carried out in the same manner as in the above reaction.

Preparation method 4
A compound of formula [I] wherein R ¹ is other than hydrogen, ie:
Formula [Ib ¹ ] [wherein R ^1a is a halogen, and other symbols have the same meaning as defined above]; and Formula [Ib ² ] [wherein R ^1b is a lower alkyl or cyano. And other symbols have the same meaning as defined above]
Can be prepared by the following preparation method.

The compound of formula [Ia] is reacted with a halogenating agent to give a compound of formula [Ib ¹ ], which is optionally converted to a pharmacologically acceptable salt.

The compound represented by the formula [Ib ¹ ] is reacted with an alkylating agent or a cyanating agent to obtain a compound represented by the formula [Ib ² ], which is optionally a pharmacologically acceptable salt. Convert to

Examples of the halogenating agent used in the above process for obtaining a compound represented by the formula [Ib ¹ ] include N-halosuccinimide. The process can be performed in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, halogen solvents such as chloroform and methylene chloride can be preferably used. The process suitably proceeds from 0 ° C. to room temperature.

The above process for obtaining the compound represented by the formula [Ib ² ] proceeds suitably in the presence of a palladium catalyst. Examples of such a palladium catalyst include tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, diphenylphosphino (dppf) palladium (II) chloride, palladium (II) acetate and the like. A zero-valent or divalent palladium catalyst can be preferably used. As such alkylating agents used in the process, boron reagents such as trimethylboroxine and zinc reagents such as dialkylzinc and alkylzinc halides can be suitably used. As such a cyanating agent used in the process, zinc cyanide or the like can be suitably used. When a boron reagent is used as the alkylating agent, the reaction proceeds suitably in the presence of a base. As such a base, for example, metal bases such as alkali metal carbonates, alkali metal hydroxides, alkali metal phosphates and alkali metal fluorides, organic bases such as triethylamine, and the like can be preferably used. The process can be performed in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. Can be used. The process suitably proceeds at 60 ° C. to 150 ° C., particularly 80 ° C. to 120 ° C.

Preparation method 5
A compound represented by the formula [Ia ⁷ ] [wherein each symbol has the same meaning as defined above] can also be prepared by the following method.

  A compound represented by the formula [19] [wherein each symbol has the same meaning as defined above] is replaced by a compound represented by the formula [18] [wherein each compound represented by the formula [3] The symbol has the same meaning as defined above], and can be obtained in the same manner as in Preparation Methods 1 to 4 described above.

  The compound represented by the formula [19] is hydrolyzed to obtain a compound represented by the formula [20] [wherein each symbol has the same meaning as defined above].

  A compound represented by the formula [20] is reacted with N, O-dimethylhydroxylamine hydrochloride, and represented by the formula [21] [wherein each symbol has the same meaning as defined above]. A compound is obtained.

  A compound represented by the formula [21] is reacted with a compound represented by the formula [23] [wherein Hal is a halogen, and each symbol has the same meaning as defined above]. [22] A compound represented by the formula: wherein each symbol has the same meaning as defined above, is obtained.

  The compound represented by the formula [22] is oxidized to obtain a compound represented by the formula [24] [wherein each symbol has the same meaning as defined above].

は、単結合又は二重結合であり、各記号は、上記の定義と同じ意味を有する］で表される化合物と反応させて、式［Ｉａ^７］［式中、各記号は、上記の定義と同じ意味を有する］で表される化合物を得る。 The compound represented by the formula [24] is converted into a compound represented by the formula [25] [wherein

Is a single bond or a double bond, and each symbol has the same meaning as defined above], and a compound represented by the formula [Ia ⁷ ] [wherein each symbol is as defined above Has the same meaning as the above.

  Hydrolysis of the compound represented by the formula [19] proceeds suitably in the presence of a base. Examples of such a base include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide. The process can be performed in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, water; alcohols such as methanol and ethanol; ethers such as tetrahydrofuran and dioxane or mixtures thereof are preferably used. it can. The process suitably proceeds from 0 ° C. to room temperature.

  The reaction of the compound represented by the formula [20] with N, O-dimethylhydroxylamine hydrochloride is carried out by reacting with a carbodiimide reagent (for example, as a carbodiimide reagent, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylamino). Propyl) carbodiimide), phosphoric acid reagent (for example, phosphorus reagent includes diethyl cyanophosphate, etc.) or acid halide reagent (for example, acid halide reagent includes alkyl chlorocarbonate, etc. ) In the presence of a condensing agent. The process can be performed in the presence of a base such as triethylamine. The process can be performed in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, halogen solvents such as chloroform and methylene chloride can be preferably used. The process suitably proceeds from 0 ° C. to room temperature.

  The reaction of the compound represented by the formula [21] and the compound represented by the formula [23] suitably proceeds in an appropriate solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, ethers such as tetrahydrofuran and dioxane can be preferably used. The process suitably proceeds from −78 ° C. to room temperature. The process can be performed in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, and for example, tetrahydrofuran, dioxane and the like can be preferably used. The process suitably proceeds from 0 ° C. to room temperature.

  The oxidation of the compound represented by the formula [22] proceeds suitably in the presence of an oxidizing agent. As such an oxidizing agent, sodium nitrite can be preferably used. The process can be carried out in the presence of an acid such as concentrated hydrochloric acid. The process can be performed in a suitable solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used, and for example, tetrahydrofuran, dioxane and the like can be preferably used. The process suitably proceeds from 0 ° C. to room temperature.

が単結合である場合、式［Ｉａ^７］で表される化合物は、前述の式［２４］で表される化合物と式［２５］で表される化合物を反応させた後、従来の酸化反応により得ることができる。 The reaction of the compound represented by the formula [24] and the compound represented by the formula [25] proceeds suitably in an appropriate solvent. As such a solvent, any solvent that does not adversely influence the reaction can be used. For example, water; alcohols such as methanol and ethanol, or a mixture thereof can be preferably used. The process suitably proceeds from 0 ° C. to room temperature. Formula [25]

Is a single bond, the compound represented by the formula [Ia ⁷ ] is prepared by reacting the compound represented by the formula [24] and the compound represented by the formula [25], followed by the conventional oxidation reaction. Can be obtained.

  The raw material compounds of the above preparation schemes (preparation methods 1 to 4) can be prepared by procedures known in the art and / or procedures described in Reference Examples described below.

  In addition, the compound represented by the formula [I] prepared in the above preparation scheme (preparation methods 1 to 4) is a procedure described in Examples described below and / or a procedure known in the art, Depending on the combination, the structure can be converted into another compound represented by the formula [I].

  When the compound, synthetic intermediate or raw material compound of the present invention has a functional group (hydroxyl group, amino, carboxy), the reaction is usually used in organic synthetic chemistry as described in Greene's Protecting Group in Organic Synthesis. The protective compound can be protected and then the protective group can be removed to obtain the target compound.

  The compound of the present invention or a raw material compound thereof can be isolated and purified as a free form (free base or free acid) or a salt thereof. The salt can be prepared by a commonly used salt forming treatment. For example, the salt formation treatment can be performed by adding an acid or a base or a solution thereof to a solution or suspension of the compound of the present invention. Preferred acids are pharmacologically including hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, acetic acid, fumaric acid, oxalic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and maleic acid. It is an acceptable salt. Preferred bases are pharmaceutically acceptable salts including alkali metal salts such as sodium and potassium salts; and alkaline earth metal salts such as calcium salts. The solvent of the solution or suspension of the compound of the present invention can be any solvent that does not adversely affect the salt formation treatment. Examples include water; alcohols such as methanol, ethanol and propanol; esters such as ethyl acetate; ethers such as diethyl ether, dioxane and tetrahydrofuran; dichloromethane; and chloroform or combinations thereof.

  Isolation and purification can be performed by conventional chemical procedures such as extraction, concentration, crystallization, filtration, recrystallization and various chromatographic methods.

  The compound represented by the formula [I] or the pharmacologically acceptable salt thereof according to the present invention has excellent PDE10 inhibitory activity in mammals, that is, phosphodiesterase 10 (PDE10, more specifically, PDE10A). Has inhibitory activity on enzyme activity. The compound represented by the formula [I] or the pharmacologically acceptable salt thereof according to the present invention is also highly selective for PDE10.

  In the present invention, the compound represented by the formula [I] or a pharmacologically acceptable salt thereof exhibits various pharmacological effects due to its PDE10 inhibitory activity. Therefore, a pharmaceutical composition comprising as an active ingredient a compound represented by the formula [I] or a pharmacologically acceptable salt thereof can be used for inhibiting PDE10 activity. Furthermore, the pharmaceutical composition can be used for the treatment or prevention of diseases or conditions that are expected to be improved by inhibiting PDE10 activity.

Diseases or conditions that are expected to improve by inhibiting PDE10 activity include, for example:
Psychiatric disorders such as schizophrenia:
For example, schizophrenia, schizophrenia-like disorder, paranoid disorder, schizophrenic emotional disorder, substance-induced psychotic disorder, paranoia or schizophrenic personality disorder;
Anxiety disorder:
For example, panic disorder, agoraphobia, specific phobia, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, etc .;
Drug addiction:
For example, addiction to alcohol, amphetamine, cocaine or opium;
Disorders including symptoms of cognitive impairment:
For example, dementia (including Alzheimer's disease, multiple cerebral infarction dementia, etc.), delirium, amnestic disorder, post-traumatic stress disorder, mental retardation, learning disorder, attention deficit hyperactivity disorder (ADHD), age-related Cognitive decline, etc .; and mood disorders:
For example, major depressive disorder, dysthymic disorder, minor depressive disorder, bipolar disorder (including bipolar I disorder, bipolar II disorder), mood circulatory disorder, etc .; or mood episodes:
For example, major depression episodes, mania or mixed episodes, hypomania episodes and the like can be mentioned.

Among these diseases and conditions, using the compounds of the present invention,
schizophrenia:
Anxiety disorder:
For example, panic disorder, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder;
Drug addiction:
Disorders including symptoms of cognitive impairment:
For example, dementia (including Alzheimer's disease, etc.), learning disabilities, attention deficit hyperactivity disorder (ADHD) and age-related cognitive decline; and mood disorders:
For example, it may be noted that treating diseases of major depressive disorder, dysthymic disorder, minor depressive disorder, bipolar disorder.

Among these diseases and conditions, especially using the compounds of the present invention,
schizophrenia:
Anxiety disorder:
For example, panic disorder, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder; and mood disorder:
For example, it may be noted that treating diseases of major depressive disorder, dysthymic disorder, minor depressive disorder, bipolar disorder.

  It can be noted that the compounds of the invention are used more particularly to treat schizophrenia.

Furthermore, the compounds of the invention
Movement disorder or neurodegenerative disorder dyskinesia associated with dopamine agonist treatment;
Huntington's disease;
It can be used to treat diseases or conditions that are expected to improve by inhibition of PDE10 activity, including Parkinson's disease; and restless legs syndrome.

  Furthermore, the compounds of the invention can be used to treat diseases or conditions that are expected to be improved by inhibition of PDE10 activity, including, for example, cancer.

Furthermore, the compounds of the invention
Type 1 or type 2 diabetes (or non-insulin dependent diabetes mellitus (NIDDM));
Impaired glucose tolerance (IGT);
Abnormal fasting blood glucose level (IGF);
It can be used to treat diseases or conditions that are expected to be improved by inhibition of PDE10 activity, including metabolic syndrome; and metabolic-related disorders, including overweight or excess body fat in obese patients.

  Further, the scope of the present invention is to administer an effective amount of a compound represented by the formula [I] or a pharmacologically acceptable salt thereof to a patient (or subject) in need of treatment or prevention of a disease or condition. To treat or prevent a disease or condition.

  In addition, the use of a compound represented by the formula [I] or a pharmaceutically acceptable salt thereof for producing a medicament is also encompassed within the scope of the present invention.

  The PDE10 inhibitory action and pharmacological effect of the compound of the present invention can be confirmed by a known method and its equivalent.

  For example, PDE10 inhibitory activity can be measured by the method described in Experimental Example 1 below or the method disclosed in the literature. For example, Fujishige et al., Eur. J. Biochem., Vol. 266, pp. 1118-1127, 1999, and Mukai et al., Br. J. Pharmacol., Vol. 111, pp. 389-390, 1994 Please refer to.

  Furthermore, the selectivity of the compounds described herein for PDE10 can be assessed using methods disclosed in the literature. For example, Kotera et al., Biochem. Pharmacol., Vol. 60, pp. 1333-1341, 2000; Sasaki et al., Biochem. Biophys. Res. Commun., Vol. 271, pp. 575-583, 2000; See Yuasa et al., Journal of Biological Chemistry, vol. 275, pp. 31469-31479, 2000; Gamanuma et al., Cellular Signaling, vol. 15, pp. 565-574, 2003.

The pharmacological effect on the symptoms of schizophrenia can be detected by the following in vivo test system using mice or rats.
-MK-801-induced spontaneous movement promotion:
[O'Neil and Shaw, Psychopharmacology, 1999, 145: 237-250]
-Promotion of apomorphine-induced spontaneous movement:
[Geyer et al., Pharmacol. Biochem. Behav., 1987, 28: 393-399; Ellenbroek, Pharmacol. Ther., 1993, 57: 1-78]
-Condition avoidance reaction:
[Moor et al., J. Pharmacol. Exp. Ther., 1992, 262: 545-551]

The pharmacological effect for improving cognitive impairment such as schizophrenia can be detected by the following in vivo test system using mice or rats.
-MK-801 induced isolation rearing prepulse inhibition (PPI) disorders:
[Mansbach and Geyer, Neuropsychopharmacology, 1989, 2: 299-308; Bakshi et al., J. Pharmacol. Exp. Ther., 1994, 271: 787-794; Bubenikova et al., Pharmacol. Biochem. Behav., 2005 , 80: 591-596]
-Isolated rearing induced prepulse inhibition (PPI) disorders:
[Cilia et al., Psychopharmacology, 2001, 156: 327-337]
-MK-801-induced disturbances in the novel object recognition task (NOR):
[Karasawa et al., Behav. Brain. Res., 2008, 186: 78-83]

  The compound represented by the formula [I] or a pharmacologically acceptable salt thereof is prepared by mixing the compound with an inert pharmacologically acceptable carrier suitable for each administration route, thereby producing tablets, granules. Can be formulated into conventional pharmaceutical preparations such as capsules, powders, solutions, suspensions, emulsions, inhalents, injections and drops.

  Examples of such carriers include binders (such as gum arabic, gelatin, sorbitol, polyvinylpyrrolidone), excipients (such as lactose, sucrose, corn starch, sorbitol), lubricants (magnesium stearate, talc, polyethylene glycol). And any conventional pharmacologically acceptable materials such as disintegrants (such as potato starch).

  In the case of injections and infusions, the compounds of the present invention can be mixed with distilled water for injections, physiological saline, aqueous glucose solutions and the like.

  The administration route of the compound represented by the formula [I] or a pharmacologically acceptable salt thereof is not limited to a specific route. They can be administered orally or parenterally (eg, via intravenous, intramuscular, subcutaneous, transdermal, nasal, transmucosal or enteral routes).

  Furthermore, when treating diseases of the central nervous system (CNS), the blood brain barrier (BBB) can be avoided and drugs can be introduced directly or indirectly into the brain. Examples of these methods include intracerebroventricular (i.c.v.) administration and administration methods with hypertonic intravenous injection that can temporarily release the BBB (osmotic pressure release).

  When a compound of formula [I] or a pharmaceutically acceptable salt thereof is used in medical applications, the dose of the compound is in a dose range that is sufficiently effective to achieve the desired pharmacological effect. To establish, it can be determined according to the potency or nature of the compound. The dosage can vary depending on the route of administration, the age, weight and condition of the patient. A typical dose range would be, for example, in the range of 0.001 to 300 mg / kg per day, preferably in the range of 0.001 to 30 mg / kg per day.

  The method of treatment or prevention using the compounds of the present invention is applied to humans. However, it can also be applied to mammals other than humans.

  Next, the present invention will be described in more detail with reference to the following examples. This example is provided to illustrate the invention, but not to limit its scope. Reference is made to the claims for determining what is reserved by the inventors.

Experimental Example 1: Measurement of PDE10 Inhibitory Activity (1) Bovine PDE10A (bPDE10A) was obtained according to the method described in the reference Fujishige et al., Eur. J. Biochem., Vol. 266, pp. 1118-1127, 1999. Isolated and prepared from bovine striatum. Human PDE10A (hPDE10A) was transfected with a plasmid encoding human PDE10A2 according to the method described in the reference Kotera et al., Biochem. Biophys. Res. Commun., Vol.261, pp.551-557, 1999. Isolated from COS-7 cells. The resulting enzyme solution was used for the PDE assay.

  The PDE assay was performed by the radiolabeled nucleotide method according to the modified method of the report of Kotera et al. (Kotera et al., Biochem. Pharmacol., Vol. 60, pp. 1333-1341, 2000).

  Specifically, the inhibitory activity was measured by the following method.

(Method)
The test compound was dissolved in dimethyl sulfoxide (DMSO). 2 μL of the compound solution is added to a 96-well plate and 20 μL of PDE enzyme solution in reaction mixture (50 mM Tris-HCl, pH 8.0), assay buffer (50 mM Tris-HCl (pH 8.0), ₂ mM MgCl ₂ , 0.07% 40 μL of 2-mercaptoethanol and 0.825 mg / mL bovine serum albumin) and 20 μL of 1 mg / mL snake venom in 50 mM Tris-HCl (pH 8.0) were added to a 96-well plate. 20 μL of a substrate solution containing about 35 nM ³ H-cAMP in 50 mM Tris-HCl solution (pH 8.0) was added and mixed to start the enzyme reaction. The final concentration of cAMP in the reaction mixture was 7 nM. The reaction mixture was incubated at room temperature for 90 minutes. After incubation, 100 μL of methanol was added to stop the reaction, and the resulting solution was applied to a filter plate containing Dowex (1 × 8 200-400) and centrifuged. The eluate washed with 50 μL of the eluate and 100 μL of additional methanol was collected on a separate plate, and the radioactivity was measured.

  (2) Using the method described above, the compounds of the following examples were tested for PDE inhibition.

These exhibited IC ₅₀ values of 30 nM or less. IC ₅₀ values for some preferred compounds are shown in Tables I and II below.

Example 1.001
(A)
Method A: The preparation was carried out in the same manner as described in Helv. Chim. Acta. 2001, 84, 2379.
Method B: 3-chloroquinoxaline-2-carboxylic acid (86.0 g, 363 mmol), trimethylboroxine (22.8 g, 0.182 mmol), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium ( II) (8.90 g, 11.0 mmol) and potassium carbonate (100 g, 727 mmol) in 1,4-dioxane (726 mL) were heated at 115 ° C. for 4 hours. Next, trimethylboroxine (22.8 g, 0.182 mmol) was added again and heated at the same temperature for 2 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate (700 mL) and filtered through celite with ethyl acetate (1000 mL). The filtrate was collected and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 900 g, hexane: ethyl acetate = 9: 1 to 17: 3), followed by recrystallization with cold hexane to obtain ethyl 3-methylquinoxaline-2-carboxylate. . MS (APCI): m / z 217 (M + H).

(B)
To a suspension of potassium tert-butoxide (72.7 g, 647 mmol) in toluene (810 mL) at 5 ° C., ethyl 3-methylquinoxaline-2-carboxylate (70.0 g, 324 mmol) and acetonitrile (38.3 mL, 809 mmol). ) In toluene (270 mL) was added dropwise over 50 minutes. After stirring at 0 ° C. for 5 minutes, water (585 mL) was added. The organic layer was extracted with water (100 mL), the aqueous layer was collected and acidified to pH 3-4 with 10% aqueous hydrochloric acid. The resulting precipitate was collected and dissolved in tetrahydrofuran. The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude solid was purified by silica gel column chromatography (silica gel 2.2 kg, chloroform to chloroform: ethyl acetate = 19: 1) to give 3- (3-methylquinoxalin-2-yl) -3-oxopropanenitrile. . MS (APCI): m / z 212 (M + H).

(C)
Suspension of 3- (3-methylquinoxalin-2-yl) -3-oxopropanenitrile (45.8 g, 217 mmol) and hydrazine monohydrate (15.8 mL, 325 mmol) in acetic acid (109 mL) and ethanol (1083 mL) The solution was refluxed for 17 hours. After cooling to ambient temperature, the reaction mixture was diluted with water (360 mL) and basified to pH 8 with sodium bicarbonate. The resulting precipitate was collected and washed with diisopropyl ether. The crude material was diluted with methanol (1077 mL) and potassium carbonate (29.9 g) and then heated at 60 ° C. for 2 hours. The precipitate was collected and washed with diisopropyl ether to give 3- (3-methylquinoxalin-2-yl) -1H-pyrazol-5-amine. MS (APCI): m / z 226 (M + H).

(D)
Method A: 3- (3-Methylquinoxalin-2-yl) -1H-pyrazol-5-amine (5.00 g, 22.2 mmol) in N, N-dimethylacetamide (111 mL) at 0 ° C. with ethyl Malonyl chloride (5.68 mL, 44.4 mmol) and pyridine (37.2 mL, 45.9 mmol) were added. After stirring for 3 hours, the reaction mixture was diluted with ethanol (118 mL) and stirred at room temperature for 18 hours. After adding water (260 mL), the resulting precipitate was collected and washed with water to give 3-{[3- (3-methylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino. } Ethyl 3-oxopropanoate was obtained. MS (APCI): m / z 340 (M + H).
Method B: 3- (3-Methylquinoxalin-2-yl) -1H-pyrazol-5-amine (5.00 g, 22.2 mmol) and ethyl hydrogen malonate (2.88 mL, 24.4 mmol) in pyridine (89 mL ) N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (6.38 g, 33.3 mmol) was added to the suspension at 0 ° C. and stirred for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure. The residue was diluted with water (100 mL) and the resulting precipitate was collected and washed with water and then diethyl ether to give 3-{[3- (3-methylquinoxalin-2-yl) -1H. -Pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl ester was obtained. MS (APCI): m / z 340 (M + H).

(E)
Method A (free form): 3-{[3- (3-Methylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl ester (20.0 g, 58.9 mmol) Of 28% aqueous ammonia (295 mL) and methanol (1176 mL) was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was diluted with water (1500 mL) and ethyl acetate (1000 mL). The aqueous layer was concentrated under reduced pressure and water (40 mL) was added. The mixture was acidified with 10% aqueous hydrochloric acid to pH 5-6, then ethanol (360 mL) was added. The resulting precipitate was collected and washed with 95% ethanol water and ethanol to obtain 2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. . MS (ESI): m / z 292 (M-H).
Method B (DMAP salt): 3-{[3- (3-Methylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl (1.00 g, 2.95 mmol) A suspension of 4-dimethylaminopyridine (DMAP) (1.08 g, 8.84 mmol) in water (7 mL), tetrahydrofuran (7 mL) and methanol (7 mL) was heated at 65 ° C. for 4 hours. After cooling to ambient temperature, the reaction mixture was diluted with water and ethyl acetate. The aqueous layer was collected and concentrated under reduced pressure. The residue was triturated with acetic ether to give the DMAP salt of 2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (APCI): m / z 294 (M + H).

(F)
A suspension of 2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (2.98 g, 6.95 mmol) in phosphorus oxychloride (10.7 mL) was added to a suspension of 100. Heated at 0 ° C. for 1 hour. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. After pouring the residue into aqueous potassium carbonate, the precipitate is collected and washed with water to give 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-methylquinoxaline. Got. MS (APCI): m / z 330/332 (M + H).

(G)
3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-methylquinoxaline (991 mg, 3.00 mmol), 4-aminotetrahydropyran (364 mg, 3.60 mmol) and triethylamine A suspension of (1.25 mL, 9.00 mmol) in N, N-dimethylformamide (30 mL) was stirred at room temperature for 2 hours. After cooling to 0 ° C., the reaction mixture was diluted with water. The resulting precipitate was collected and purified by silica gel column chromatography (silica gel 200 g, chloroform to chloroform: ethyl acetate = 1: 1) to give 5-chloro-2- (3-methylquinoxalin-2-yl)- N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained. MS (APCI): m / z 395/397 (M + H).

(H)
5-Chloro-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (620 mg, 1.57 mmol) Of pyrrolidine (12 mL) was heated at 80 ° C. for 3 hours. The reaction mixture was then poured into cold water. The resulting precipitate was collected and washed with water to give 2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo. [1,5-a] pyrimidin-7-amine was obtained. MS (APCI): m / z 430 (M + H).

(I)
2- (3-Methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (655 mg, To a suspension of 1.52 mmol) in ethanol (15 mL) was added 2N aqueous hydrochloric acid (0.915 mL). The mixture was heated at 80 ° C. for 3 hours, then water (3.1 mL) and ethanol (5.0 mL) were added. The mixture is a clear solution, then cooled to ambient temperature and 2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl ) Pyrazolo [1,5-a] pyrimidin-7-amine hydrochloride was obtained (the compound of Example 1.001 is listed in the Examples table below). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 1.86-1.91 (4H, m), 2.04-2.06 (4H, m), 3.08 (3H, s), 3.46-3.53 (2H, m), 3.63 (4H, m), 3.94 (2H, m), 4.09 (1H, m), 5.62 (1H, s), 6.87 (1H, s), 7.83-7.90 (2H, m), 8.08 (1H, dd, J = 8.2, 1.4 Hz), 8.14 (1H, dd, J = 8.0, 1.3 Hz), 8.20 (1H, br).

  The dihydrochloride was prepared in the same manner using an excess amount of aqueous hydrochloric acid.

Example 1.002
(A)
The preparation was made of 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-methylquinoxaline (200 mg, 0.606 mmol) and N-methyl-4-aminotetrahydropyran (84 mg , 0.729 mmol) in the same manner as in Example 1.001 (g) and 5-chloro-N-methyl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran -4-yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained. MS (APCI): m / z 409/411 (M + H).

(B)
Prepared was 5-chloro-N-methyl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (100 mg, 0.245 mmol) as in Example 1.001 (h) and N-methyl-2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (Tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained. MS (APCI): m / z 444 (M + H).

(C)
Preparation was N-methyl-2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine N-methyl-2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-from -7-amine (692 mg, 1.53 mmol) as in Example 1.001 (i). Ile-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine hydrochloride was obtained (the compound of Example 1.002 is listed in the Examples table below. To do). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 1.78-1.81 (2H, m), 1.98-2.07 (6H, m), 3.10 (3H, s), 3.13 (3H, s), 3.63 (4H , br), 3.39-3.44 (2H, m), 3.99 (2H, dd, J = 11.2, 4.5 Hz), 5.24 (1H, m), 5.46 (1H, s), 7.02 (1H, s), 7.85- 7.89 (2H, m), 8.05-8.07 (1H, m), 8.13-8.15 (1H, m).

  The 3/2 hydrochloride was prepared in the same manner using an excess amount of aqueous hydrochloric acid.

Example 1.003
(A)
5-Chloro-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (Example 1.001 ( g)) (4.26 g, 10.8 mmol), (R) -3-fluoropyrrolidine hydrochloride (13.7 g, 108 mmol) and diisopropylethylamine (20.7 g, 160 mmol) in N-methyl-2-pyrrolidinone (108 mL) ) The suspension was heated at 80 ° C. for 3 days. After cooling to ambient temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel 800 g, hexane: ethyl acetate = 1: 1 to ethyl acetate) to give 5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methyl Quinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained. MS (APCI): m / z 448 (M + H).

(B)
The preparation was made of 5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1, 5-a] pyrimidin-7-amine (4.15 g, 9.27 mmol) was carried out in the same manner as Example 1.001 (i) and 5-[(3R) -3-fluoropyrrolidin-1-yl] 2- (3-Methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine hydrochloride was obtained (Example 1. 003 compounds are listed in the Examples table below). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 1.83-1.94 (4H, m), 2.21-2.45 (2H, m), 3.08 (3H, s), 3.47-3.52 (1H, m), 3.66 -3.72 (1H, m), 3.80-4.14 (4H, m), 5.58 (1H, m), 5.66 (1H, s), 6.88 (1H, s), 7.83-7.90 (2H, m), 8.07 (1H , m), 8.14 (1H, m), 8.19 (1H, br).

  The dihydrochloride was prepared in the same manner using an excess amount of aqueous hydrochloric acid.

Example 1.004
(A)
The preparation was performed in the same manner as in Example 1.001 (a). (E)-[(1E) -1-ethyl-3-methoxy-3-oxoprop-1-en-1-yl] diazenecarboxylate tert-butyl (see Synlett. 2003, 8, 1183; 1.50 g, To a solution of 6.19 mmol) in tetrahydrofuran (30 mL) at room temperature was added 1,2-phenylenediamine (683 mg, 6.19 mmol). After stirring for 22 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 6: 1) to obtain ethyl 3-ethylquinoxaline-2-carboxylate. MS (APCI): m / z 217 (M + H).

(B)
Prepared from ethyl 3-ethylquinoxaline-2-carboxylate (2.37 g, 10.3 mmol) in the same manner as in Example 1.001 (b) to give 3- (3-ethylquinoxalin-2-yl) -3-Oxopropanenitrile was obtained. MS (APCI): m / z 226 (M + H).

(C)
Prepared from 3- (3-ethylquinoxalin-2-yl) -3-oxopropanenitrile (1.00 g, 9.01 mmol) in the same manner as in Example 1.001 (c), and 3- (3 -Ethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 240 (M + H).

(D)
Prepared from 3- (3-ethylquinoxalin-2-yl) -1H-pyrazol-5-amine (1.41 g, 5.89 mmol) as in Example 1.001 (d) Method A, Ethyl 3-{[3- (3-ethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate was obtained. MS (APCI): m / z 354 (M + H).

(E)
The preparation was carried out from ethyl 3-{[3- (3-ethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (1.70 g, 4.81 mmol). 1.001 (e) Performed in the same manner as in Method A to obtain 2- (3-ethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (ESI): m / z 306 (M-H).

(F)
Prepared from 2- (3-ethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (1.03 g, 2.41 mmol) from Example 1.001 (f) In the same manner, 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-ethylquinoxaline was obtained. MS (APCI): m / z 344/346 (M + H).

(G)
Prepared from 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-ethylquinoxaline (734 mg, 2.13 mmol) as in Example 1.001 (g). To give 5-chloro-2- (3-ethylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine. . MS (APCI): m / z 409/411 (M + H).

(H)
Prepared was 5-chloro-2- (3-ethylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (204 mg, 0 .500 mmol) in the same manner as in Example 1.001 (h) and 2- (3-ethylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4 -Yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained. MS (APCI): m / z 444 (M + H).

(I)
2- (3-Ethylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (132 mg, To a solution of 2.00 mmol) in chloroform (2.0 mL), 4N hydrogen chloride in 1,4-dioxane (0.5 mL) was added. The resulting precipitate was collected and washed with diethyl ether to give 2- (3-ethylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) Pyrazolo [1,5-a] pyrimidin-7-amine dihydrochloride was obtained (the compound of Example 1.004 is listed in the Examples table below). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.31 (3H, t, J = 7.4 Hz), 1.85-1.91 (4H, m), 2.04-2.06 (4H, m), 3.45 (2H, q , J = 7.4 Hz), 3.65 (4H, m), 3.94 (2H, m), 4.12 (1H, m), 5.64 (1H, s), 6.86 (1H, s), 7.84-7.92 (2H, m) , 8.10-8.15 (2H, m), 8.34 (1H, br-d, J = 8.8 Hz).

Example 1.005
(A)
Prepared from ethyl 3-trifluoromethylquinoxaline (10.4 g, 38.5 mmol) in the same manner as in Example 1.001 (b), and 3- (3-trifluoromethylquinoxalin-2-yl)- 3-Oxopropanenitrile was obtained. MS (ESI): m / z 264 (M-H).

(B)
Prepared from 3- (3-trifluoromethylquinoxalin-2-yl) -3-oxopropanenitrile (8.33 g, 31.4 mmol) as in Example 1.001 (c). (3-Trifluoromethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (ESI): m / z 280 (M + H).

(C)
Prepared from 3- (3-trifluoromethylquinoxalin-2-yl) -1H-pyrazol-5-amine (6.34 g, 22.7 mmol) as in Example 1.001 (d) Method A. And ethyl 3-{[3- (3-trifluoromethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate was obtained. MS (ESI): m / z 394 (M + H).

(D)
Prepared from ethyl 3-{[3- (3-trifluoromethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (6.87 g, 17.5 mmol). Example 1.001 (e) Performed in the same manner as in Method A to obtain 2- (3-trifluoromethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (ESI): m / z 346 (M-H).

(E)
Prepared from 2- (3-trifluoromethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (4.94 g, 14.2 mmol) from Example 1.001 (f ) To give 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-trifluoromethylquinoxaline. MS (APCI): m / z 384/386 (M + H).

(F)
Prepared from 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-trifluoromethylquinoxaline (300 mg, 0.781 mmol) from Example 1.001 (g) 5-chloro-N- (tetrahydro-2H-pyran-4-yl) -2- (3-trifluoromethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-7- An amine was obtained. MS (APCI): m / z 449/451 (M + H).

(G)
Prepared was 5-chloro-N- (tetrahydro-2H-pyran-4-yl) -2- (3-trifluoromethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-amine (172 mg , 0.384 mmol) in the same manner as in Example 1.001 (h), and 5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) -2- [3- (tri Fluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidin-7-amine was obtained. MS (APCI): m / z 484 (M + H).

(H)
Preparation was 5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) -2- [3- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidine 5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) -2 from -7-amine (177 mg, 0.367 mmol) as in Example 1.001 (i) -[3- (Trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidin-7-amine hydrochloride was obtained (the compound of Example 1.005 is listed in the Examples table below. To do). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.78-1.86 (4H, m), 2.03-2.07 (4H, m), 3..45-3.51 (2H, m), 3.63 (4H, m ), 3.91 (2H, m), 4.09 (1H, m), 5.65 (1H, s), 6.69 (1H, s), 8.11-8.19 (2H, m), 8.31-8.39 (2H, m).

Example 1.006
(A)
To a suspension of sodium hydride (60% mineral oil dispersion, 12.0 g, 300 mmol) in toluene (450 mL) at 85 ° C., ethyl 7-fluoro-3-methylquinoxaline-2-carboxylate (35.1 g, 150 mmol). ) And acetonitrile (19.6 mL, 375 mmol) in toluene (40 mL) were added dropwise over 35 minutes. After stirring at the same temperature for 5 minutes, the reaction mixture was cooled to 0 ° C. and then water (175 mL) was added. The aqueous layer was separated and the organic layer was extracted with 1N aqueous sodium hydroxide solution (200 mL). The combined aqueous layers were acidified to pH 2 with concentrated hydrochloric acid (45.0 mL) at 0 ° C., and the resulting precipitate was collected and washed with water (150 mL). The solid was dissolved in chloroform (1000 mL) and water (500 mL). The aqueous layer was extracted with chloroform (300 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with ethanol to give 3- (7-fluoro-3-methylquinoxalin-2-yl) -3-oxopropanenitrile. MS (APCI): m / z 230 (M + H).

(B)
To a suspension of 3- (7-fluoro-3-methylquinoxalin-2-yl) -3-oxopropanenitrile (48.6 g, 212 mmol) in ethanol (530 mL) and acetic acid (53 mL) was added hydrazine hydrate (79 %, 19.6 mL, 318 mmol). The reaction mixture was refluxed for 5 hours and then concentrated under reduced pressure. The residue was triturated sequentially with water and diisopropyl ether to give 3- (7-fluoro-3-methylquinoxalin-2-yl) -1H-pyrazol-5-amine. MS (APCI): m / z 244 (M + H).

(C)
A suspension of 3- (7-fluoro-3-methylquinoxalin-2-yl) -1H-pyrazol-5-amine (45.7 g, 188 mmol) in pyridine (750 mL) at 0 ° C. with ethyl hydrogen malonate ( 5.35 mL, 62.5 mmol) and N-ethyl-N ′-(3-dimethylaminopropyl) carbodiimide hydrochloride (54.0 g, 282 mmol) were added. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated under reduced pressure. The residue was triturated sequentially with water, ethanol and acetone to give 3-{[3- (7-fluoro-3-methylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxo. Ethyl propanoate was obtained. MS (APCI): m / z 358 (M + H).

(D)
3-{[3- (7-Fluoro-3-methylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (30.0 g, 84.0 mmol) in methanol ( To a suspension of 210 mL), tetrahydrofuran (210 mL) and water (210 mL) was added 4-dimethylaminopyridine (51.3 g, 420 mmol) at ambient temperature. After stirring at 85 ° C. for 5 hours, the reaction mixture was diluted with ethyl acetate (750 mL) and water (750 mL) at ambient temperature. The insoluble material was then filtered off. The filtrate was washed with water (450 mL). The combined aqueous layers were washed with ethyl acetate (500 mL × 2), acidified to pH 2 with concentrated hydrochloric acid (17.0 mL) at ambient temperature and then stirred overnight. The resulting precipitate was collected and washed with water to give 2- (7-fluoro-3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (APCI): m / z 312 (M + H).

(E)
2- (7-Fluoro-3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (8.30 g, 26.7 mmol) phosphorus oxychloride (81.1 g, 534 mmol) ) The suspension was heated at 100 ° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into 10% aqueous potassium carbonate (700 mL) at 0 ° C. The resulting precipitate was collected and washed with water to give 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -6-fluoro-2-methylquinoxaline. . MS (APCI): m / z 348/350 (M + H).

(F)
3- (5,7-Dichloropyrazolo [1,5-a] pyrimidin-2-yl) -6-fluoro-2-methylquinoxaline (157 mg, 0.451 mmol) in N, N-dimethylformamide (4.0 mL) ), 1-amino-2-methylpropan-2-ol (48 mg, 0.541 mmol) and potassium carbonate (187 mg, 1.35 mmol) were stirred at room temperature for 2 hours. The reaction mixture was poured into ice-cold water and the resulting precipitate was collected and washed with water to give 1-{[5-chloro-2- (7-fluoro-3-methylquinoxalin-2-yl) pyrazolo [1 , 5-a] pyrimidin-7-yl] amino} -2-methylpropan-2-ol. MS (APCI): m / z 401/403 (M + H).

(G)
1-{[5-chloro-2- (7-fluoro-3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -2-methylpropan-2-ol ( 170 mg, 0.424 mmol), (R) -3-fluoropyrrolidine hydrochloride (268 mg, 2.12 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (387 mg, 2.54 mmol). A suspension of N-methylpyrrolidinone (5.0 mL) was heated at 70 ° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with ice cold water. The resulting precipitate was collected and washed with water to give 1-({2- (7-fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidine-1- Yl] pyrazolo [1,5-a] pyrimidin-7-yl} amino) -2-methylpropan-2-ol. MS (APCI): m / z 454 (M + H).

(H)
1-({2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidin-7-yl } Amino) -2-methylpropan-2-ol (213 mg, 0.470 mmol) in ethanol (3.0 mL) was added 2N aqueous hydrochloric acid (0.282 mL) and the mixture was heated at 80 ° C. , Ethanol (2.0 mL) and water (0.2 mL) were added. After the mixture was slowly cooled to ambient temperature, ethanol (2.0 mL) was added. The resulting precipitate was collected and washed with diethyl ether to give 1-({2- (7-fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidine-1 -Yl] pyrazolo [1,5-a] pyrimidin-7-yl} amino) -2-methylpropan-2-ol hydrochloride was obtained (the compound of Example 1.006 is listed in the Examples table below) To do). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.24 (6H, s), 2.25-2.43 (2H, m), 3.10 (3H, s), 3.62-3.70 (2H, m), 3.80-4.01 (4H, m), 5.52-5.63 (1H, m), 5.71 (1H, s), 6.94 (1H, s), 7.81 (1H, ddd, J = 9.1, 8.8, 2.7 Hz), 7.95 (1H, dd , J = 9.6, 2.9 Hz), 7.99 (1H, br), 8.14 (1H, dd, J = 9.1, 5.9 Hz).

Example 1.007
5-Chloro-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (Example 1.001 ( g)) A suspension of (398 mg, 1.01 mmol) and (S) -3-hydroxypyrrolidine (351 mg, 4.03 mmol) in N-methyl-2-pyrrolidinone (5.0 mL) was heated at 80 ° C. for 6 hours. . The reaction mixture was then poured into cold water. The obtained precipitate was collected and purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 7: 3) to give 1- [2- (3-methylquinoxalin-2-yl) -7- ( Tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidin-5-yl] pyrrolidin-3-ol was obtained (the compound of Example 1.007 is listed in the Examples table below). ). ¹ H-NMR (500 MHz, CDCl ₃ ): δ 1.74-1.81 (2H, m), 2.12-2.22 (4H, m), 3.03 (3H, s), 3.58 (2H, dt, J = 2.3, 11.9 Hz ), 3.65-3.76 (5H, m), 4.08 (2H, dt, J = 11.6, 3.2 Hz), 4.64-4.67 (1H, m), 5.16 (1H, s), 6.16 (1H, d, J = 8.0 Hz), 6.66 (1H, s), 7.70-7.76 (2H, m), 8.03-8.05 (1H, m), 8.17-8.19 (1H, m).

Example 1.008
1- [2- (3-Methylquinoxalin-2-yl) -7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidin-5-yl] pyrrolidin-3-ol (200 mg , 0.449 mmol) and methanesulfonyl chloride (77 mg, 0.673 mmol) in dichloromethane (5.0 mL) at 0 ° C. was added triethylamine (0.125 mL, 0.898 mmol). After stirring for 2 hours, the reaction mixture was poured into water. The mixture was extracted with chloroform and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform to chloroform: methanol = 97: 3) to give (3S) -1- [2- (3-methylquinoxalin-2-yl) -7- (tetrahydro-2H- Pyran-4-ylamino) pyrazolo [1,5-a] pyrimidin-5-yl] pyrrolidin-3-ylmethanesulfonate was obtained (the compound of Example 1.008 is listed in the Examples table below). ). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.73-1.83 (2H, m), 2.12-2.15 (2H, m), 2.30-2.39 (1H, m), 2.47-2.52 (1H, m), 3.04 (3H, s), 3.08 (3H, s), 3.56-3.63 (2H, m), 3.68-3.89 (4H, m), 3.99-4.02 (1H, m), 4.07-4.10 (2H, m), 5.19 (1H, s), 5.44-5.46 (1H, m), 6.20 (1H, d, J = 8.2 Hz), 6.67 (1H, s), 7.70-7.77 (2H, m), 8.03-8.06 (1H, m ), 8.16-8.19 (1H, m).

Example 1.009
(3S) -1- [2- (3-Methylquinoxalin-2-yl) -7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidin-5-yl] pyrrolidine-3 -Ylmethanesulfonate (50 mg, 0.0955 mmol), 4,7,13,16,21,24-hexaoxa-1,10-diazabicyclo [8.8.8] hexacosane (108 mg, 0.286 mmol) and fluoro A solution of potassium halide (17 mg, 0.286 mmol) in acetonitrile (2.0 mL) was refluxed for 15 minutes. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform to chloroform: methanol = 97: 3) to give 5- (2,5-dihydro-1H-pyrrol-1-yl) -2- (3-methylquinoxaline-2 -Yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained (the compound of Example 1.009 is listed in the Examples table below). To do). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.73-1.82 (2H, m), 2.13-2.16 (2H, m), 3.04 (3H, s), 3.59 (2H, dt, J = 11.8, 2.1Hz ), 3.68-3.78 (1H, m), 4.09 (2H, dt, J = 11.8, 3.6 Hz), 4.38 (4H, br), 5.17 (1H, s), 5.98 (2H, s), 6.17 (1H, d, J = 7.9 Hz), 6.67 (1H, s), 7.69-7.77 (2H, m), 8.03-8.06 (1H, m), 8,17-8.19 (1H, m).

Example 1.010
(A)
To a suspension of sodium hydride (60% mineral oil dispersion, 12 mg, 0.303 mmol) in 1,4-dioxane (3.0 mL) at 0 ° C. was added 4-hydroxytetrahydropyran (31 mg, 0.303 mmol). It was. After stirring at room temperature for 10 minutes, 5-chloro-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine-7- Amine (Example 1.001 (g)) (100 mg, 0.303 mmol) was added. The reaction mixture was stirred at the same temperature overnight, then poured into water and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 1: 1) to give 2- [5-chloro-7- (tetrahydro-2H-pyran-4-yloxy) pyrazolo [1, 5-a] pyrimidin-2-yl] -3-methylquinoxaline was obtained. MS (APCI): m / z 396/398 (M + H).

(B)
2- [5-Chloro-7- (tetrahydro-2H-pyran-4-yloxy) pyrazolo [1,5-a] pyrimidin-2-yl] -3-methylquinoxaline (90 mg, 0.227 mmol), pyrrolidine (49 mg 0.682 mmol), sodium tert-butoxide (33 mg, 0.341 mmol), palladium (II) acetate (52 mg, 0.227 mmol) and 2-dicyclohexylphosphino-2 ′-(N, N-dimethylamino) biphenyl ( 179 mg, 0.454 mmol) of 1,4-dioxane (4.0 mL) was heated at 100 ° C. for 40 minutes. After cooling to ambient temperature, the reaction mixture was poured into water and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 9) to give 2-methyl-3- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4). -Iyloxy) pyrazolo [1,5-a] pyrimidin-2-yl] quinoxaline was obtained. MS (APCI): m / z 431 (M + H).

(C)
The preparation was carried out in the same manner as in Example 1.001 (i), and 2-methyl-3- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-yloxy) pyrazolo [1,5 -A] pyrimidin-2-yl] quinoxaline hydrochloride was obtained (the compound of Example 1.010 is listed in the Examples table below). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.82-1.90 (2H, m), 2.04-2.07 (4H, m), 2.14-2.18 (2H, m), 3.09 (3H, s), 3.62 -3.68 (6H, m), 3.90-3.95 (2H, m), 5.35-5.41 (1H, m), 6.12 (1H, s), 6.99 (1H, s), 7.82-7.89 (2H, m), 8.03 -8.08 (1H, m), 8.13-8.15 (1H, m).

  The dihydrochloride was prepared in the same manner using an excess amount of aqueous hydrochloric acid.

Example 1.011
5-Chloro-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (Example 1.001 ( g)) (97 mg, 0.246 mmol), cyclopenten-1-ylboronic acid (55 mg, 0.491 mmol), tetrakis (triphenylphosphine) palladium (0) (57 mg, 0.0493 mmol) and cesium fluoride (112 mg, 0 .737 mmol) of 1,2-dimethoxyethane (2.0 mL) was heated at 80 ° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 2: 3) to give 5-cyclopent-1-en-1-yl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained (the compound of Example 1.011 is listed in the Examples table below). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.73-1.86 (2H, m), 2.03-2.21 (4H, m), 2.60-2.66 (2H, m), 2.86-2.93 (2H, m), 3.05 (3H, s), 3.61 (2H, ddd, J = 11.8, 11.8, 2.4 Hz), 3.77-3.87 (1H, m), 4.10 (2H, ddd, J = 11.8, 3.3, 3.3 Hz), 6.19 (1H , s), 6.33 (1H, d, J = 8.2 Hz), 6.68 (1H, s), 7.08 (1H, s), 7.72-7.79 (2H, m), 8.04-8.08 (1H, m), 8.17- 8.21 (1H, m).

Example 1.012
5-Cyclopent-1-en-1-yl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine-7- A suspension of amine (30 mg, 0.0703 mmol) and palladium on charcoal (5%, 30 mg) in dichloromethane (2.0 mL) and methanol (2.0 mL) was stirred under a hydrogen atmosphere for 3 hours. The reaction mixture was then filtered through chloroform and the filtrate was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 to 1: 1) to give 5-cyclopentyl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H- Pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine was obtained (the compound of Example 1.012 is listed in the Examples table below). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.67-1.95 (8H, m), 2.08-2.20 (4H, m), 3.05 (3H, s), 3.11-3.23 (1H, m), 3.60 (2H , ddd, J = 11.8, 11.8, 2.4 Hz), 3.74-3.85 (1H, m), 4.10 (2H, ddd, J = 11.5, 3.3, 3.3 Hz), 5.94 (1H, s), 6.32 (1H, d , J = 7.9 Hz), 7.02 (1H, s), 7.71-7.79 (2H, m), 8.04-8.08 (1H, m), 8.16-8.20 (1H, m).

Example 1.013
(A)
The preparation consisted of 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -6-fluoro-2-methylquinoxaline (1.90 g, 5.46 mmol) and trans-4-amino. Trans-4-{[5-chloro-2- (7-fluoro-3-methylquinoxaline) was prepared in the same manner as in Example 1.006 (f) from -1-methylcyclohexanol (846 mg, 6.55 mmol). -2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -1-methylcyclohexanol was obtained. MS (APCI): m / z 441/443 (M + H).

(B)
Preparation is trans-4-{[5-chloro-2- (7-fluoro-3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -1-methylcyclo Trans-4-({2- (7-fluoro-3-methylquinoxalin-2-yl) -5 was prepared from hexanol (1.32 g, 3.00 mmol) in the same manner as in Example 1.006 (g). -[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidin-7-yl} amino) -1-methylcyclohexanol). MS (APCI): m / z 494 (M + H).

(C)
Preparation was trans-4-({2- (7-fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a]. Pyrimidin-7-yl} amino) -1-methylcyclohexanol (1.18 g, 2.39 mmol) was prepared in the same manner as in Example 1.006 (h), and trans-4-({2- (7- Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidin-7-yl} amino) -1-methylcyclohexanol The hydrochloride salt was obtained (the compound of Example 1.013 is listed in the Examples table below). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 1.22 (3H, s), 1.55-1.65 (4H, m), 1.70-1.81 (2H, m), 1.83-1.92 (2H, m), 2.19 -2.44 (2H, m), 3.06 (3H, s), 3.63-4.01 (5H, m), 5.55 (1H, m), 5.61 (1H, s), 6.82 (1H, s), 7.79-7.83 (1H , m), 7.91-7.94 (2H, m), 8.14-8.17 (1H, m).

Examples 1.014 to 1.171
The compounds of Examples 1.014 to 1.171 listed in the Examples table below were obtained in the same manner as described in Example 1.001.

Example 1.172
(A)
In order to remove dicyclohexylamine, (S) -2- (tert-butoxycarbonylamino-5-benzyloxypentanoic acid dicyclohexylamine salt (10.0 g, 19.8 mmol) was subjected to silica gel column chromatography (ethyl acetate-ethyl acetate). The resulting oily product, ethyl 2-amino-3-oxobutanoate (3.60 g, 19.8 mmol), ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (5.69 g, 29.7 mmol), 1-hydroxybenzotriazole (4.01 g, 29.7 mmol), triethylamine (6.87 mL, 49.5 mmol) in chloroform (40 mL) was stirred at room temperature for 6 hours, then The organic layer was separated, washed with saturated brine, and washed with sodium sulfate. Dried, filtered and concentrated under reduced pressure The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-3: 2) to give 2-{[5- (benzyloxy)- N- (tert-butoxycarbonyl) -L-norvalyl] amino} -3-oxobutanoic acid ethyl ester was obtained, MS (APCI): m / z 468 (M + NH ₄ ).

(B)
To a solution of ethyl 2-{[5- (benzyloxy) -N- (tert-butoxycarbonyl) -L-norvalyl] amino} -3-oxobutanoate (5.31 g, 11.8 mmol) in ethanol (20 mL) at room temperature. 4N hydrochloric acid in 1,4-dioxane (20 mL) was added. After stirring at the same temperature for 16 hours, the reaction mixture was concentrated under reduced pressure. A solution of the residue in pyridine (40 mL) was heated at 60 ° C. for 23 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was poured into water and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Manganese dioxide (1.03 g) was added to a solution of the residue in dichloromethane (20 mL) at room temperature. After stirring at the same temperature for 1.5 hours, the reaction mixture was filtered through celite with chloroform. The filtrate was collected and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform to chloroform: methanol = 19: 1) to give ethyl 5- [3- (benzyloxy) propyl] -6-hydroxy-3-methylpyrazine-2-carboxylate. Obtained. MS (APCI): m / z 331 (M + H).

(C)
Ethyl 5- [3- (benzyloxy) propyl] -6-hydroxy-3-methylpyrazine-2-carboxylate (2.91 g, 8.80 mmol) and palladium hydroxide (1.06 g) in ethanol (60 mL) The suspension was refluxed for 7 hours. After cooling to ambient temperature, the reaction mixture was filtered through celite with ethanol. The filtrate was collected and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform to chloroform: methanol = 19: 1) to obtain ethyl 6-hydroxy-5- (3-hydroxypropyl) -3-methylpyrazine-2-carboxylate. MS (APCI): m / z 241 (M + H).

(D)
Tetrahydrofuran (86 mL) of ethyl 6-hydroxy-5- (3-hydroxypropyl) -3-methylpyrazine-2-carboxylate (1.03 g, 4.29 mmol) and triphenylphosphine (1.69 g, 6.43 mmol). To the solution was added diethyl azodicarboxylate solution (40% (wt%) toluene, 2.92 mL, 6.43 mmol) at room temperature. After stirring for 50 minutes, the reaction mixture was concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 to 7: 3), triturated with diisopropyl ether, and silica gel column chromatography (chloroform to chloroform: methanol = 19: 1). -Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine-3-carboxylate was obtained. MS (APCI): m / z 223 (M + H).

(E)
Prepared from Example 1.006 (a) Method B from ethyl 2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine-3-carboxylate (725 mg, 3.26 mmol). In the same manner, 3- (2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 218 (M + H).

(F)
Prepared from 3- (2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -3-oxopropanenitrile (505 mg, 2.32 mmol) from Example 1. .001 (c) to give 3- (2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -1H-pyrazol-5-amine It was. MS (APCI): m / z 232 (M + H).

(G)
Preparation was performed from 3- (2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -1H-pyrazol-5-amine (550 mg, 2.38 mmol). Example 1.006 (c) Performed analogously to Method B and yielded 3-{[3- (2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -1H. -Pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl ester was obtained. MS (APCI): m / z 346 (M + H).

(H)
3-{[3- (2-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoic acid A suspension of ethyl (535 mg, 1.55 mmol) and N, N-dimethylaminopyridine (946 mg, 7.75 mmol) in methanol (15 mL), tetrahydrofuran (15 mL) and water (15 mL) was refluxed for 25 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was acidified to pH 2 with 6N aqueous hydrochloric acid solution at 0 ° C. and then concentrated under reduced pressure. The residue was triturated with ethyl acetate. The crude material and phosphorus oxychloride (11.9 g, 77.5 mmol) were treated in a manner similar to Example 1.001 (f) to give 3- (5,7-dichloropyrazolo [1,5-a Pyrimidin-2-yl) -2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine was obtained. MS (APCI): m / z 336/338 (M + H).

(I)
Prepared was 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine (150 mg 0.466 mmol) as in Example 1.001 (g) and trans-4-{[5-chloro-2- (2-methyl-7,8-dihydro-6H-pyrano [2, 3-b] pyrazin-3-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -1-methylcyclohexanol was obtained. MS (APCI): m / z 429/431 (M + H).

(J)
The preparation is trans-4-{[5-chloro-2- (2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) pyrazolo [1,5-a]. Pyrimidin-7-yl] amino} -1-methylcyclohexanol (183 mg, 0.427 mmol) was prepared in the same manner as in Example 1.001 (f) and trans-1-methyl-4-{[2- ( 2-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclo Hexanol was obtained. MS (APCI): m / z 464 (M + H).

(K)
The preparation was trans-1-methyl-4-{[2- (2-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -5-pyrrolidin-1-ylpyrazolo. [1,5-a] pyrimidin-7-yl] amino} cyclohexanol (140 mg, 0.302 mmol) was prepared as in Example 1.004 (i) and trans-1-methyl-4-{[ 2- (2-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] Amino} cyclohexanol hydrochloride was obtained (the compound of Example 1.172 is listed in the Examples table below). MS (APCI): m / z 464 (M + H), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 12.75 (1H, br), 7.92 (1H, br-d), 6.67 (1H, s), 5.55 (1H, s), 4.36 (2H, t, J = 4.8 Hz), 3.88 (1H, br), 3.62 (4H, br), 2.96 (2H, t, J = 6.4 Hz), 2.80 (3H, s) , 2.04 -2.11 (6H, m), 1.82-1.86 (2H, m), 1.72-1.80 (2H, m), 1.58 -1.60 (4H, m), 1.22 (3H, s).

Example 1.173
(A)
N, N of 2-methoxy-6,7-dihydro-8H-pyrano [2,3-b] pyrazine (J. Chem. Soc. Perkin Trans. I 1988, 2585-2593; 3.16 g, 19.0 mmol) -To a dimethylformamide (95 mL) solution was added N-bromosuccinimide (5.08 g, 28.5 mmol) at room temperature and then heated at 60 ° C for 5 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and washed with 2% aqueous sodium sulfite, water and saturated brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-7: 3) to give 3-bromo-2-methoxy-7,8-dihydro-6H-pyrano [2,3-b]. Pyrazine was obtained. MS (APCI): m / z 247 (M + H).

(B)
Prepared from 3-bromo-2-methoxy-7,8-dihydro-6H-pyrano [2,3-b] pyrazine (2.50 mg, 10.2 mmol) from Example 1.001 (a) Method B. In the same manner, 2-methoxy-3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine was obtained. MS (APCI): m / z 181 (M + H).

(C)
A suspension of 2-methoxy-3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine (1.95 g, 10.8 mmol) in sulfolane (25 mL) at 30 ° C. at iodotrimethyl. Silane (15.0 g, 75.0 mmol) was added. The reaction mixture was heated at 40-45 ° C. for 8 hours, then cooled to ambient temperature and stirred for 2 days. The reaction mixture was then diluted with ethyl acetate and washed with 2% aqueous sodium sulfite. The aqueous layer was extracted with ethyl acetate and chloroform. The organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (ethyl acetate to ethyl acetate: methanol = 93: 7) to give 3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-ol. And the recovered starting material was obtained. MS (APCI): m / z 177 (M + H).

(D)
3-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-ol (735 mg, 6.33 mmol) and N, N-diisopropylethylamine (2.45 g, 19.0 mmol) in dichloromethane (37 mL) To the suspension was added trifluoromethanesulfonic anhydride (2.14 g, 7.59 mmol) dropwise at 0 ° C. over 5 minutes. After stirring at the same temperature for 30 minutes, the reaction mixture was poured into a saturated aqueous sodium bicarbonate solution. The mixture was extracted with chloroform and the organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-7: 3) to give 3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine-2- Iltrifluoromethanesulfonate was obtained. MS (APCI): m / z 299 (M + H).

(E)
3-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yltrifluoromethanesulfonate (298 mg, 1.00 mmol), palladium (II) acetate (11 mg, 0.0490 mmol) , Bis (diphenylphosphino) ferrocene (55 mg, 0.0992 mmol) and triethylamine (202 mg, 2.00 mmol) in N, N-dimethylacetamide (3.0 mL) heated at 80 ° C. under carbon monoxide for 24 hours. did. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1-ethyl acetate) to give 3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine-2-carboxylic acid. Ethyl acid was obtained. MS (APCI): m / z 223 (M + H).

(F)
Prepared from Example 1.006 (a) Method B from ethyl 3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine-2-carboxylate (337 mg, 1.52 mmol). In the same manner, 3- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 218 (M + H).

(G)
Prepared from 3- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -3-oxopropanenitrile (236 mg, 1.09 mmol) from Example 1. .001 (c) to give 3- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -1H-pyrazol-5-amine It was. MS (APCI): m / z 232 (M + H).

(H)
The preparation was performed from 3- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -1H-pyrazol-5-amine (253 mg, 1.09 mmol). Example 1.006 (c) Performed analogously to Method A and 3-{[3- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -1H -Pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl ester was obtained. MS (APCI): m / z 346 (M + H).

(I)
3-{[3- (3-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoic acid A suspension of ethyl (293 mg, 0.848 mmol) and N, N-dimethylaminopyridine (518 mg, 4.24 mmol) in methanol (3 mL), tetrahydrofuran (3 mL) and water (3 mL) was heated for 8 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ethyl acetate to give 2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5, 7-diol was obtained. MS (APCI): m / z 300 (M + H).

(J)
Prepared was 2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (376 mg, From 0.843 mmol) as in Example 1.001 (f) and 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3-methyl-7, 8-Dihydro-6H-pyrano [2,3-b] pyrazine was obtained. MS (APCI): m / z 336/338 (M + H).

(K)
Prepared was 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazine (98 mg 0.241 mmol) and trans-4-{[5-chloro-2- (3-methyl-7,8-dihydro-6H-pyrano [2, 3-b] pyrazin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino} -1-methylcyclohexanol was obtained. MS (APCI): m / z 429/431 (M + H).

(L)
The preparation is trans-4-{[5-chloro-2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) pyrazolo [1,5-a]. Pyrimidin-7-yl] amino} -1-methylcyclohexanol (46 mg, 0.107 mmol) was prepared in the same manner as in Example 1.001 (f) and trans-1-methyl-4-{[2- ( 3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclo Hexanol was obtained. MS (APCI): m / z 464 (M + H).

(M)
The preparation is trans-1-methyl-4-{[2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo. [1,5-a] pyrimidin-7-yl] amino} cyclohexanol (44 mg, 0.0949 mmol) was prepared as in Example 1.004 (i) and trans-1-methyl-4-{[ 2- (3-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] Amino} cyclohexanol hydrochloride was obtained (the compound of Example 1.173 is listed in the Examples table below). MS (APCI): m / z 464 (M + H), ¹ H NMR (500 MHz, DMSO-d ₆ ) δ: 7.95 (1H, d, J = 8.7 Hz), 6.65 (1H, s), 5.52 (1H, s ), 4.39 (2H, t, J = 5.1 Hz), 3.80-3.94 (1H, m), 3.57-3.67 (4H, m), 2.96 (2H, dd, J = 6.4, 6.1 Hz), 2.74 (3H, s), 2.09 (2H, ddt, J = 6.4, 6.1, 5.1 Hz), 2.00-2.07 (4H, m), 1.70-1.87 (4H, m), 1.55-1.63 (4H, m), 1.21 (3H, s).

Examples 1.174-1.200
The compounds of Examples 1.174 to 1.200 listed in the Examples table below were obtained in the same manner as described in Example 1.001.

Example 2.001
(A)
Prepared from ethyl hydrogen malonate (2.65 g, 19.3 mmol) and (tetrahydro-2H-pyran-4-yl) acetyl chloride (1.50 g, 8.76 mmol), Chem. Pharm. Bull. 1980, 28 , 2494 to obtain ethyl 3-oxo-4- (tetrahydro-2H-pyran-4-yl) butanoate. MS (APCI): m / z 215 (M + H).

(B)
A suspension of ethyl 3-oxo-4- (tetrahydro-2H-pyran-4-yl) butanoate (960 mg, 4.48 mmol) and 1N aqueous sodium hydroxide solution (9.00 mL, 9.00 mmol) was stirred at room temperature for 48 hours. Stir for hours. The reaction mixture was washed with diethyl ether and then acidified to pH 3 with 0.5N sulfuric acid. The mixture was extracted with ethyl acetate and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-oxo-4- (tetrahydro-2H-pyran-4-yl) butanoic acid. MS (ESI): m / z 185 (M-H).

(C)
To a solution of 3-oxo-4- (tetrahydro-2H-pyran-4-yl) butanoic acid (186 mg, 1.00 mmol) in toluene (2.5 mL) and tetrahydrofuran (2.5 mL) at room temperature, oxalyl chloride (190 mg , 1.50 mmol) was added. After stirring for 1 hour, the reaction mixture was concentrated under reduced pressure to give the crude acid chloride (3-oxo-4- (tetrahydro-2H-pyran-4-yl) butanoyl chloride).
3- (3-Methylquinoxalin-2-yl) -1H-pyrazol-5-amine (Example 1.001 (c)) (68 mg, 0.300 mmol) and diisopropylethylamine (194 mg, 1.50 mmol) in dichloromethane ( 2.0 mL) solution at 0 ° C. was added crude acid chloride in dichloromethane (1.0 mL). After stirring at room temperature for 3 hours, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethanol (6.0 mL) and heated at 60 ° C. for 3 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform to chloroform: methanol = 9: 1) to give N- [3- (3-methylquinoxalin-2-yl) -1H-pyrazol-5-yl] -3-oxo. -4- (Tetrahydro-2H-pyran-4-yl) butanamide was obtained. MS (APCI): m / z 394 (M + H).

(D)
Prepared was N- [3- (3-Methylquinoxalin-2-yl) -1H-pyrazol-5-yl] -3-oxo-4- (tetrahydro-2H-pyran-4-yl) butanamide (41 mg, 0 104 mmol) from Example 1.001 (e) Method A, and 2- (3-methylquinoxalin-2-yl) -7- (tetrahydro-2H-pyran-4-ylmethyl) pyrazolo [1 , 5-a] pyrimidin-5-ol was obtained. MS (ESI): m / z 374 (M-H).

(E)
Prepared from 2- (3-methylquinoxalin-2-yl) -7- (tetrahydro-2H-pyran-4-ylmethyl) pyrazolo [1,5-a] pyrimidin-5-ol (18 mg, 0.047 mmol). In the same manner as in Example 1.001 (f), 2- [5-chloro-7- (tetrahydro-2H-pyran-4-ylmethyl) pyrazolo [1,5-a] pyrimidin-2-yl]- 3-methylquinoxaline was obtained. MS (APCI): m / z 394/396 (M + H).

(F)
Prepared from 2- [5-chloro-7- (tetrahydro-2H-pyran-4-ylmethyl) pyrazolo [1,5-a] pyrimidin-2-yl] -3-methylquinoxaline (16 mg, 0.041 mmol). In the same manner as in Example 1.001 (h), 2-methyl-3- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylmethyl) pyrazolo [1,5-a ] Pyrimidin-2-yl] quinoxaline was obtained (the compounds of Example 2.001 are listed in the Examples table below). ¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.43-1.53 (2H, m), 1.67-1.71 (2H, m), 2.01-2.08 (5H, m), 2.36-2.41 (1H, m), 3.03 (2H, d, J = 7.0 Hz), 3.12 (3H, s), 3.28-3.40 (3H, m), 3.97 (2H, dd, J = 11.3, 3.2 Hz), 6.00 (1H, s), 6.86 ( 1H, s), 7.68-7.75 (2H, m), 8.01-8.06 (1H, m), 8.12-8.16 (1H, m).

Example 3.001
(A)
3- (3-Methylquinoxalin-2-yl) -1H-pyrazol-5-amine (Example 1.001 (c)) (200 mg, 0.888 mmol), ethyl 3-cyclopropyl-3-oxopropanoate ( A mixture of 416 mg, 2.66 mmol) and sodium methoxide (28% methanol solution, 1.03 g, 5.34 mmol) in 2-methoxyethanol (2.0 mL) was refluxed for 10 hours. After cooling to ambient temperature, the reaction mixture was acidified with acetic acid to pH 3-4. The mixture is diluted with water and the resulting precipitate is collected and washed with diisopropyl ether to give 5-cyclopropyl-2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine. -7-ol was obtained. MS (APCI): m / z 318 (M + H).

(B)
Prepared from 5-cyclopropyl-2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-ol (153 mg, 0.481 mmol) from Example 1.001 (f). To give 2- (7-chloro-5-cyclopropylpyrazolo [1,5-a] pyrimidin-2-yl) -3-methylquinoxaline. MS (APCI): m / z 336/338 (M + H).

(C)
Prepared from 2- (7-chloro-5-cyclopropylpyrazolo [1,5-a] pyrimidin-2-yl) -3-methylquinoxaline (140 mg, 0.418 mmol) from Example 1.001 (g And 5-cyclopropyl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine-7- An amine was obtained (the compound of Example 3.001 is listed in the Examples table below). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.31-1.42 (4H, m), 1.80-2.02 (4H, m), 2.26-2.37 (1H, m), 3.08 (3H, s), 3.49 (2H, ddd, J = 11.8, 11.8, 1.8 Hz), 3.96 (2H, dd, J = 10.6, 3.3 Hz), 4.18-4.37 (1H, m), 6.50 (1H, s), 7.09 (1H, s ), 7.83-7.94 (2H, m), 8.09 (1H, dd, J = 7.9, 1.8 Hz), 8.17 (1H, dd, J = 7.9, 1.8 Hz), 9.18-9.36 (1H, m).

Example 4.001
5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) -2- [3- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidine-7- The amine (50 mg, 0.0962 mmol) was neutralized with saturated sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. A solution of the crude material and N-bromosuccinimide (17 mg, 0.0962 mmol) in chloroform (1.0 mL) was stirred at 0 ° C. for 50 minutes. The reaction mixture was then poured into saturated sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to give 3-bromo-5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl). ) -2- [3- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidin-7-amine was obtained (the compound of Example 4.001 is shown in the Examples table below). Enumerate). ¹ H-NMR (500 MHz, DMSO-d ₆ ): δ 1.67-1.75 (2H, m), 1.86-1.89 (2H, m), 1.97 (4H, br), 3.44-3.48 (2H, m), 3.53 (4H, br), 3.87-3.89 (3H, m), 5.56 (1H, s), 7.13 (1H, d, J = 8.7 Hz), 8.14-8.20 (2H, m), 8.33-8.35 (1H, m ), 8.39-8.41 (1H, m).

Example 4.002
The preparation was made of 3-bromo-5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) -2- [3- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5 -A] Pyrimidin-7-amine (30 mg, 0.0533 mmol) was carried out in the same manner as Example 1.001 (a) Method A and 3-methyl-5-pyrrolidin-1-yl-N- (tetrahydro- 2H-pyran-4-yl) -2- [3- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidin-7-amine was obtained (the compound of Example 4.002 was And listed in the Examples table below). ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.62-1.72 (2H, m), 1.89-1.93 (2H, m), 1.94-1.97 (4H, m), 2.05 (3H, s), 3.45 -3.53 (6H, m), 3.86-3.89 (3H, m), 5.49 (1H, s), 6.70 (1H, d, J = 8.8 Hz), 8.07-8.15 (2H, m), 8.28-8.30 (1H , m), 8.34-8.36 (1H, m).

Examples 4.003 to 4.005
The compounds of Examples 4.003 to 4.005 listed in the Examples table below were obtained in the same manner as described in Example 4.001 above.

Examples 5.001 and 5.002
(A)
To a solution of ethyl 5-aminopyrazole-3-carboxylate (5.00 g, 26.1 mmol) and ethyl hydrogen malonate (3.62 g, 27.4 mmol) in pyridine (130 mL) at 0 ° C., N, N′— Diisopropylcarbodiimide (4.28 g, 33.9 mmol) was added. After stirring at the same temperature, the reaction mixture was poured into water. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform to chloroform: methanol = 19: 1), triturated with diisopropyl ether to give 5-[(3-ethoxy-3-oxopropanoyl) amino] -1H-pyrazole- Ethyl 3-carboxylate was obtained. MS (APCI): m / z 270 (M + H).

(B)
To a suspension of ethyl 5-[(3-ethoxy-3-oxopropanoyl) amino] -1H-pyrazole-3-carboxylate (2.60 g, 9.66 mmol) in ethanol (50 mL) and water (50 mL), At room temperature, N, N-dimethylaminopyridine (3.54 g, 29.0 mmol) was added. After stirring for 22 hours, the reaction mixture was concentrated under reduced pressure. The residue was triturated with ethyl acetate / ethanol to give ethyl 5,7-dihydroxypyrazolo [1,5-a] pyrimidine-2-carboxylate. MS (APCI): m / z 224 (M + H), 123 (M + H, DMAP).

(C)
A suspension of ethyl 5,7-dihydroxypyrazolo [1,5-a] pyrimidine-2-carboxylate (9.59 g, 43.0 mmol) and phosphorus oxychloride (20.0 mL, 215 mmol) was refluxed for 1 hour. . After cooling to ambient temperature, the reaction mixture was poured into saturated sodium bicarbonate and chloroform. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined and concentrated under reduced pressure to give ethyl 5,7-dichloropyrazolo [1,5-a] pyrimidine-2-carboxylate. MS (APCI): m / z 260/262 (M + H).

(D)
To a solution of ethyl 5,7-dichloropyrazolo [1,5-a] pyrimidine-2-carboxylate (7.82 g, 30.1 mmol) in N, N-dimethylformamide (100 mL) at 0 ° C., 4-amino Tetrahydropyran (3.65 g, 36.1 mmol) and triethylamine (9.12 g, 90.2 mmol) were added. The reaction mixture was stirred at room temperature for 70 minutes and then poured into water. The resulting precipitate was collected to give ethyl 5-chloro-7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidine-2-carboxylate. MS (APCI): m / z 325 (M + H).

(E)
Ethyl 5-chloro-7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidine-2-carboxylate (5.88 g, 18.1 mmol) in N, N-dimethylacetamide (50 mL ) To the solution was added triethylamine (5.50 g, 54.3 mmol) and pyrrolidine (1.59 mL, 19.0 mmol) at 0 ° C. The mixture was heated at 60 ° C. for 20 hours. Then pyrrolidine (1.59 mL, 19.0 mmol) was added and heated at 60 ° C. for 24 hours. After cooling to ambient temperature, the reaction mixture was poured into water. The resulting precipitate was collected to give ethyl 5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidine-2-carboxylate. MS (APCI): m / z 360 (M + H).

(F)
Ethyl 5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidine-2-carboxylate (1.89 g, 5.26 mmol) in ethanol (25 mL) And 1N aqueous sodium hydroxide solution (10.5 mL, 10.5 mmol) were added to a solution of tetrahydrofuran (25 mL) at room temperature. After stirring at the same temperature for 23 hours, 6N aqueous hydrochloric acid (1.75 mL, 3.50 mmol) was added, and then the reaction mixture was concentrated under reduced pressure. The residue was triturated with diisopropyl ether to give 5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidine-2-carboxylic acid. MS (APCI): m / z 330 (M-H).

(G)
5-Pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidine-2-carboxylic acid (2.15 g, 5.26 mmol) in dichloromethane (60 mL) To the suspension, at 0 ° C., 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.27 g, 13.0 mmol), N, O-dimethylhydroxylamine hydrochloride (2.49 g, 13. 0 mmol) and triethylamine (2.30 g, 22.7 mmol) were added. After stirring at room temperature for 17 hours, the reaction mixture was poured into saturated sodium bicarbonate. The mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform to chloroform: methanol = 19: 1) to give N-methoxy-N-methyl-5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4- (Ilamino) pyrazolo [1,5-a] pyrimidine-2-carboxamide was obtained. MS (APCI): m / z 375 (M + H).

(H)
N-methoxy-N-methyl-5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidine-2-carboxamide (4.34 g, 11.6 mmol ), A suspension of di-tert-butyl dicarbonate (15.2 g, 69.6 mmol) and N, N-dimethylaminopyridine (1.49 g, 12.1 mmol) in tetrahydrofuran (100 mL) is stirred at room temperature for 3 days. Then, it was heated at 50 ° C. for 10 hours. After cooling to ambient temperature, the reaction mixture was poured into water. The mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform: ethyl acetate = 13: 7-ethyl acetate-ethyl acetate: methanol = 4: 1) to give (2-{[methoxy (methyl) amino] carbonyl} -5- Pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl) tetrahydro-2H-pyran-4-ylcarbamate tert-butyl was obtained. MS (APCI): m / z 475 (M + H).

(I)
(2-{[Methoxy (methyl) amino] carbonyl} -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl) tetrahydro-2H-pyran-4-ylcarbamate tert-butyl (2 To a solution of .22 g, 4.68 mmol) in tetrahydrofuran (50 mL) at 0 ° C. was added ethylmagnesium bromide solution (1M tetrahydrofuran solution, 14.0 mL, 14.0 mmol). After stirring at the same temperature for 20 minutes, the reaction mixture was poured into saturated ammonium chloride. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform to chloroform: ethyl acetate = 3: 2) to give (2-propionyl-5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl) tetrahydro Tert-Butyl-2H-pyran-4-ylcarbamate was obtained. MS (APCI): m / z 444 (M + H).

(J)
(2-propionyl-5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl) tetrahydro-2H-pyran-4-ylcarbamate tert-butyl (500 mg, 1.13 mmol) and sodium nitrite To a suspension of (233 mg, 3.38 mmol) in tetrahydrofuran (10 mL) was added concentrated hydrochloric acid solution (36%, 5.0 mL) at 0 ° C. After stirring at room temperature for 20 hours, the reaction mixture was poured into saturated sodium bicarbonate. The mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (chloroform: ethyl acetate = 1: 1 to 1: 9) to give 1- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylamino). -Pyrazolo [1,5-a] pyrimidin-2-yl] propane-1,2-dione was obtained. MS (APCI): m / z 358 (M + H).

(K)
1- [5-Pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylamino) -pyrazolo [1,5-a] pyrimidin-2-yl] propane-1,2-dione (87 mg, 0 .243 mmol) in methanol (3 mL) and water (0.3 mL) at room temperature was added 3,4-diaminopyridine (29 mg, 0.268 mmol). After stirring at the same temperature for 24 hours, the reaction mixture was concentrated under reduced pressure. The crude material was subjected to silica gel column chromatography (chloroform: methanol = 99: 1 to 19: 1) and HPLC (CHIRALPAK IC, 20Φ × 250 mm, hexane: ethanol: diethylamine = 30: 70: 0.1, flow rate 5.0 mL / min). ) To give 2- (3-methylpyrido [3,4-b] pyrazin-3-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1 , 5-a] pyrimidin-7-amine (the compounds of Example 5.001 are listed in the Examples table below) as a more polar compound to give 2- (2-methylpyrido [3,4- b] pyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine (Example 5.0) 2 compounds was obtained listed) in the table of Examples below as less polar compound. 2- (2-Methylpyrido [3,4-b] pyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine The absolute configuration of -7-amine was determined by X-ray analysis.
More polar compound, MS (APCI): m / z 358 (M + H), ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.58 (1H, s), 8.79 (1H, d, J = 5.7 Hz), 7.87 (1H, d, J = 5.7 Hz), 6.70 (1H, s), 6.07 (1H, d, J = 8.2 Hz), 5.21 (1H, s), 4.08 (2H, dt, J = 11.9, 3.4 Hz) , 3.68-3.75 (1H, m), 3.57-3.62 (6H, m), 3.10 (3H, s), 2.13-2.16 (2H, m), 2.03-2.07 (4H, m), 1.72-1.82 (2H, m).
Less polar compound, MS (APCI): m / z 358 (M + H), ¹ H NMR (400 MHz, CDCl ₃ ) δ: 9.48 (1H, s), 8.78 (1H, d, J = 5.7 Hz), 7.99 (1H, d, J = 5.7 Hz), 6.73 (1H, s), 6.07 (1H, d, J = 8.2 Hz), 5.21 (1H, s), 4.08 (2H, dt, J = 11.9, 3.6 Hz) , 3.68-3.75 (1H, m), 3.57-3.62 (6H, m), 3.11 (3H, s), 2.13-2.16 (2H, m), 2.03-2.07 (4H, m), 1.72-1.82 (2H, m).

Reference Example 1.01
(A)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 3,5-dimethylquinoxaline-2-carboxylate (1.03 g, 4.47 mmol), and 3- (3,5-dimethylquinoxaline- 2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 226 (M + H).

(B)
Prepared from 3- (3,5-dimethylquinoxalin-2-yl) -3-oxopropanenitrile (797 mg, 3.54 mmol) in a manner similar to Example 1.001 (c) and 3- (3 , 5-Dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 240 (M + H).

(C)
Prepared from 3- (3,5-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine (783 mg, 3.27 mmol) as in Example 1.001 (d) Method A; Ethyl 3-{[3- (3,5-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate was obtained. MS (APCI): m / z 354 (M + H).

(D)
Prepared from ethyl 3-{[3- (3,5-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (1.17 g, 3.31 mmol), Example 1.001 (e) Performed in the same manner as in Method A to obtain 2- (3,5-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (ESI): m / z 306 (M-H).

(E)
Prepared from 2- (3,5-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (997 mg, 3.24 mmol) from Example 1.001 (f) In the same manner, 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3,5-dimethylquinoxaline was obtained (the compound of Reference Example 1.01 will be described later). Listed in the reference table).

Reference Example 1.02
(A)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 3,6-dimethylquinoxaline-2-carboxylate (555 mg, 2.41 mmol) to give 3- (3,6-dimethylquinoxaline-2- Yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 226 (M + H).

(B)
Prepared from 3- (3,6-dimethylquinoxalin-2-yl) -3-oxopropanenitrile (385 mg, 1.71 mmol) in the same manner as in Example 1.001 (c). , 6-Dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 240 (M + H).

(C)
Prepared from 3- (3,6-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine (347 mg, 1.45 mmol) as in Example 1.001 (d) Method A, Ethyl 3-{[3- (3,6-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate was obtained. MS (APCI): m / z 354 (M + H).

(D)
Prepared from the ethyl 3-{[3- (3,6-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (452 mg, 1.28 mmol). 1.001 (e) Performed in the same manner as in Method A to obtain 2- (3,6-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (ESI): m / z 306 (M-H).

(E)
Prepared from 2- (3,6-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (383 mg, 1.25 mmol) with Example 1.001 (f) In the same manner, 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3,6-dimethylquinoxaline was obtained (the compound of Reference Example 1.02 will be described later). Listed in the reference table). MS (APCI): m / z 344/346 (M + H).

Reference Example 1.03
(A)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 3,7-dimethylquinoxaline-2-carboxylate (10.0 g, 43.4 mmol), and 3- (3,7-dimethylquinoxaline- 2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 226 (M + H).

(B)
Prepared from 3- (3,7-dimethylquinoxalin-2-yl) -3-oxopropanenitrile (8.11 g, 36.0 mmol) as in Example 1.001 (c). (3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 240 (M + H).

(C)
Prepared from 3- (3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine (300 mg, 1.25 mmol) as in Example 1.001 (d) Method A, Ethyl 3-{[3- (3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate was obtained. MS (APCI): m / z 354 (M + H).

(D)
Prepared from ethyl 3-{[3- (3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (700 mg, 1.98 mmol). 1.001 (e) Performed in the same manner as Method A to give 2- (3,7-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (ESI): m / z 306 (M-H).

(E)
Prepared from 2- (3,7-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (1.39 g, 4.52 mmol) from Example 1.001 (f ) To give 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2,6-dimethylquinoxaline (the compound of Reference Example 1.03 is (It is listed in the reference example table below).

Reference Example 1.04
(A)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 3,8-dimethylquinoxaline-2-carboxylate (1.50 g, 6.51 mmol), and 3- (3,8-dimethylquinoxaline- 2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 226 (M + H).

(B)
Prepared from 3- (3,8-dimethylquinoxalin-2-yl) -3-oxopropanenitrile (400 mg, 1.78 mmol) in the same manner as in Example 1.001 (c). , 8-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 240 (M + H).

(C)
Prepared from 3- (3,8-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine (250 mg, 1.04 mmol) as in Example 1.001 (d) Method A; Ethyl 3-{[3- (3,8-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate was obtained. MS (APCI): m / z 354 (M + H).

(D)
Prepared from the ethyl 3-{[3- (3,8-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (158 mg, 0.447 mmol). 1.001 (e) Performed in the same manner as in Method A to give 2- (3,8-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (APCI): m / z 308 (M + H).

(E)
Prepared from 2- (3,8-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (316 mg, 1.01 mmol) from Example 1.001 (f) In the same manner, 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2,5-dimethylquinoxaline was obtained (the compound of Reference Example 1.04 will be described later). Listed in the reference table).

Reference Example 1.05
(A)
Preparation was performed in the same manner as in Example 1.001 (b) from ethyl 3-methyl-7-trifluoromethylquinoxaline-2-carboxylate (15.0 g, 52.8 mmol), and 3-methyl-7- Methyl (trifluoromethyl) quinoxaline-2-carboxylate was obtained. MS (APCI): m / z 280 (M + H).

(B)
Prepared from methyl 3-methyl-7- (trifluoromethyl) quinoxaline-2-carboxylate (2.11 g, 7.56 mmol) in the same manner as in Example 1.001 (c), and 3- [3 -Methyl-7- (trifluoromethyl) quinoxalin-2-yl] -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 294 (M + H).

(C)
Prepared from 3- [3-methyl-7- (trifluoromethyl) quinoxalin-2-yl] -1H-pyrazol-5-amine (2.13 g, 7.25 mmol) from Example 1.001 (d). Performed as in Method A and ethyl 3-({3- [3-methyl-7- (trifluoromethyl) quinoxalin-2-yl] -1H-pyrazol-5-yl} amino) -3-oxopropanoate Got. MS (APCI): m / z 408 (M + H).

(D)
Prepared was ethyl 3-({3- [3-methyl-7- (trifluoromethyl) quinoxalin-2-yl] -1H-pyrazol-5-yl} amino) -3-oxopropanoate (2.29 g, From 5.63 mmol) in the same manner as in Example 1.001 (e) Method A and 2- [3-methyl-7- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] Pyrimidine-5,7-diol was obtained. MS (ESI): m / z 360 (M-H).

(E)
Preparation was performed from 2- [3-methyl-7- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidine-5,7-diol (2.00 g, 5.54 mmol). As in Example 1.001 (f), 3- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -2-methyl-6- (trifluoromethyl) quinoxaline was prepared. (The compounds of Reference Example 1.05 are listed in the Reference Examples table described later).

Reference Example 1.06
(A)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 5-fluoro-3,7-dimethylquinoxaline-2-carboxylate (970 mg, 3.91 mmol), and 3- (5-fluoro-3 , 7-dimethylquinoxalin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 244 (M + H).

(B)
Prepared from 3- (5-fluoro-3,7-dimethylquinoxalin-2-yl) -3-oxopropanenitrile (250 mg, 1.03 mmol) as in Example 1.001 (c) 3- (5-Fluoro-3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 258 (M + H).

(C)
Prepared as in Example 1.001 (d) Method A from 3- (5-fluoro-3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-amine (262 mg, 1.02 mmol). To give ethyl 3-{[3- (5-fluoro-3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate. MS (APCI): m / z 372 (M + H).

(D)
Prepared was ethyl 3-{[3- (5-fluoro-3,7-dimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (224 mg, 0.605 mmol). From Example 1.001 (e) Method A and 2- (5-fluoro-3,7-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7- Diol was obtained. MS (ESI): m / z 324 (M-H).

(E)
Prepared from 2- (5-fluoro-3,7-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (198 mg, 0.605 mmol) from Example 1.001. In the same manner as in (f), 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -5-fluoro-3,7-dimethylquinoxaline was obtained (Reference Example 1). The compound of .06 is listed in the table of reference examples described later).

Reference Example 1.07
(A)
To a solution of D-alanamide hydrochloride (18.5 g, 149 mmol) in methanol (230 mL) and water (23 mL) at −10 ° C. is added 50% aqueous sodium hydroxide solution (13.5 g, 338 mmol), then To the mixture, 1,2-cyclohexanedione (15.1 g, 135 mmol) was added continuously at the same temperature. After stirring overnight, the reaction mixture was neutralized with 2N aqueous hydrochloric acid and saturated aqueous sodium bicarbonate. The resulting precipitate was collected and washed with water and diisopropyl ether to give 2-hydroxy-3-methyl-4,5,6,7-tetrahydroquinoxaline. MS (APCI): m / z 165 (M + H).

(B)
A mixture of 2-hydroxy-3-methyl-4,5,6,7-tetrahydroquinoxaline (1.61 g, 9.78 mmol) and phosphorus (V) oxychloride (7.50 g, 48.9 mmol) was refluxed for 6 hours. . After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was poured into saturated sodium bicarbonate at 0 ° C. and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to hexane: ethyl acetate = 17: 3) to obtain 2-chloro-3-methyl-4,5,6,7-tetrahydroquinoxaline. MS (APCI): m / z 183/185 (M + H).

(C)
2-Chloro-3-methyl-4,5,6,7-tetrahydroquinoxaline (1.16 g, 6.36 mmol), molybdenum hexacarbonyl (2.35 g, 9.35 mmol), palladium (II) acetate (142 mg, 0 .636 mmol), 2,2′-bis (diphenylphosphino) -1,1′-binaphthalene (396 mg, 0.636 mmol), cesium carbonate (2.07 g, 6.36 mmol) and ethanol (0.482 mL, 8. A mixture of 26 mmol) toluene (19 mL) and acetonitrile (12 mL) was heated at 80 ° C. overnight. After cooling to ambient temperature, the reaction mixture was filtered with chloroform. The filtrate was collected and washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 97: 3-3: 2) to give ethyl 3-methyl-4,5,6,7-tetrahydroquinoxaline. MS (APCI): m / z 221 (M + H).

(D)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 3-methyl-4,5,6,7-tetrahydroquinoxaline (2.39 g, 10.9 mmol), and 3- (3-methyl- 5,6,7,8-Tetrahydroquinoxalin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 216 (M + H).

(E)
Prepared from 3- (3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl) -3-oxopropanenitrile (1.82 g, 8.46 mmol) from Example 1.001 (c) To give 3- (3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl) -1H-pyrazol-5-amine. MS (APCI): m / z 230 (M + H).

(F)
Prepared was 3- (3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl) -1H-pyrazol-5-amine (2.08 g, 8.46 mmol) and Example 1.001 (e ) To Example 1.001 (d) in the same manner as Method A and 2- (3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine -5,7-diol was obtained. MS (ESI): m / z 296 (M-H).

(G)
Prepared from 2- (3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (2.16 g, 6.93 mmol). In the same manner as in Example 1.001 (f), 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3-methyl-5,6,7,8 -Tetrahydroquinoxaline was obtained (the compound of Reference Example 1.07 is listed in the table of Reference Examples described later).

Reference Example 1.08
(A)
3,5,6-trimethylpyrazin-2-yl) methanol (see Bioorg. Med. Chem. 2007, 15, 3315; 14.8 g, 97.2 mmol) and manganese (IV) oxide (30.0 g) in dichloromethane. The suspension was stirred at room temperature for 3 days. The reaction mixture was filtered through celite with dichloromethane. The filtrate was collected and concentrated under reduced pressure to give 3,5,6-trimethylpyrazine-2-carbaldehyde. MS (APCI): m / z 151 (M + H).

(B)
3,5,6-trimethyl-2-carbaldehyde (4.51g, 30.0mmol), 2- methyl-2-butene (12.8 mL, 120 mmol) and sodium dihydrogen phosphate dihydrate (4. To a solution of 68 g, 30.0 mmol) tert-butanol (90 mL) and water (30 mL), 80% sodium chlorite (10.2 g, 90.0 mmol) was added dropwise at 0 ° C. After stirring at room temperature for 50 minutes, the reaction mixture was poured into 2N aqueous hydrochloric acid. The mixture was extracted with chloroform and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3,5,6-trimethylpyrazine-2-carboxylic acid. MS (ESI): m / z 165 (M-H).

(C)
To a solution of 3,5,6-trimethylpyrazine-2-carboxylic acid (5.38 g, 30.0 mmol) in methanol (90 mL) at 0 ° C. was added thionyl chloride (3.70 mL, 51.0 mmol). After stirring overnight at room temperature, the reaction mixture was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered, concentrated under reduced pressure, and 3,5,6-trimethylpyrazine-2-carboxylic acid. Methyl was obtained. MS (APCI): m / z 181 (M + H).

(D)
Preparation was carried out in the same manner as in Example 1.001 (b) from methyl 3,5,6-trimethylpyrazine-2-carboxylate (2.91 g, 16.1 mmol), and 3-oxo-3- (3 , 5,6-trimethylpyrazin-2-yl) propanenitrile was obtained. MS (APCI): m / z 190 (M + H).

(E)
Prepared from 3-oxo-3- (3,5,6-trimethylpyrazin-2-yl) propanenitrile (2.58 g, 13.6 mmol) as in Example 1.001 (c), 3- (3,5,6-trimethylpyrazin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 204 (M + H).

(F)
Prepared from 3- (3,5,6-trimethylpyrazin-2-yl) -1H-pyrazol-5-amine (1.00 g, 4.92 mmol) as in Example 1.001 (d) Method B. To give ethyl 3-oxo-3-{[3- (3,5,6-trimethylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} propanoate. MS (APCI): m / z 318 (M + H).

(G)
Preparation was ethyl 3-oxo-3-{[3- (3,5,6-trimethylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} propanoate (1.25 g, 3.94 mmol). From Example 1.001 (e) Method A to give 2- (3,5,6-trimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. Obtained. MS (APCI): m / z 272 (M + H).

(H)
Prepared from 2- (3,5,6-trimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (1.16 g, 4.28 mmol) from Example 1.001. In the same manner as in (f), 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3-methyl-5,6,7,8-tetrahydroquinoxaline was obtained. (The compounds of Reference Example 1.08 are listed in the Reference Example table described later).

Reference Example 1.09
(A)
A mixture of 2-nitrobenzaldehyde (10.0 g, 66.2 mmol) and iron (II) sulfate heptahydrate (129 g, 464 mmol) in ethanol (150 mL) and water (150 mL) was heated at 100 ° C. for 5 minutes, then the same. At temperature, 28% aqueous ammonia (173 mL) was carefully added dropwise. The reaction mixture was filtered through celite with diethyl ether. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 2-aminobenzaldehyde.
A solution of 2-aminobenzaldehyde, 2-oxobutyric acid (13.5 g, 132 mmol) and sodium ethoxide (13.5 g, 198 mmol) in ethanol (331 mL) was refluxed for 20 hours. After cooling to 0 ° C., 96% sulfuric acid (10.6 mL, 97.9 mmol) was added. The reaction mixture was refluxed for 20 hours. After cooling to 0 ° C., the reaction mixture was basified to pH 8-9 with saturated sodium bicarbonate and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 19: 1 to 2: 1) to give ethyl 3-methylquinoline-2-carboxylate. MS (APCI): m / z 218 (M + H).

(B)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 3-methylquinoline-2-carboxylate (500 mg, 2.32 mmol), and 3- (3-methylquinolin-2-yl) -3 -Oxopropanenitrile was obtained. MS (APCI): m / z 211 (M + H).

(C)
Prepared from 3- (3-methylquinolin-2-yl) -3-oxopropanenitrile (243 mg, 1.16 mmol) in the same manner as in Example 1.001 (c) to give 3- (3-methyl Quinolin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 225 (M + H).

(D)
Prepared from 3- (3-methylquinolin-2-yl) -1H-pyrazol-5-amine (250 mg, 1.11 mmol) in a manner similar to Example 1.001 (d) Method A and 3- {[3- (3-Methylquinolin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl ester was obtained. MS (APCI): m / z 339 (M + H).

(E)
The preparation was carried out from ethyl 3-{[3- (3-methylquinolin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (369 mg, 1.09 mmol) from Example 1. 001 (e) Performed in the same manner as in Method A to obtain 2- (3-methylquinolin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (ESI): m / z 293 (M-H).

(F)
Preparation was as in Example 1.001 (f) from 2- (3-methylquinolin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (295 mg, 1.01 mmol). To obtain 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3-methylquinoline (the compound of Reference Example 1.09 is a reference table described later). To list).

Reference Example 1.10.
(A)
Preparation was carried out in the same manner as in Example 1.001 (b) from methyl 4-methylquinoline-2-carboxylate (see Chem. Pharm. Bull. 1981, 29, 2485; 1.00 g, 4.97 mmol). 3- (4-Methylquinolin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 211 (M + H).

(B)
Prepared from 3- (4-methylquinolin-2-yl) -3-oxopropanenitrile (674 mg, 3.35 mmol) in a manner similar to Example 1.001 (c) and prepared 3- (4-methyl Quinolin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 225 (M + H).

(C)
Prepared from 3- (4-methylquinolin-2-yl) -1H-pyrazol-5-amine (985 mg, 3.35 mmol) in the same manner as Example 1.001 (d) Method A. {[3- (4-Methylquinolin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl ester was obtained. MS (APCI): m / z 339 (M + H).

(D)
Prepared from the ethyl 3-{[3- (4-methylquinolin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (1.32 g, 3.35 mmol). 1.001 (e) Performed in the same manner as in Method A to obtain 2- (4-methylquinolin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (ESI): m / z 291 (M-H).

(E)
Prepared from 2- (4-methylquinolin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (1.08 g, 3.32 mmol) from Example 1.001 (f) In the same manner, 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -4-methylquinoline was obtained (the compound of Reference Example 1.10. Listed in the table).

Reference Example 1.11
(A)
N-Butyllithium in a solution of 3,6-dimethyl-2-iodopyrazine (see J. Org. Chem. 1961, 26, 1907; 1.00 g, 4.27 mmol) in diethyl ether (13 mL) at −35 ° C. (2.6 M hexane solution, 1.64 mL, 4.27 mmol) was added dropwise. After stirring at the same temperature for 10 minutes, the reaction mixture was poured into dry ice. The mixture was extracted with 4N aqueous sodium hydroxide solution and then the aqueous layer was acidified with concentrated hydrochloric acid. The mixture was extracted with chloroform and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was triturated with diethyl ether to give 3,6-dimethylpyrazine-2-carboxylic acid. MS (ESI): m / z 151 (M-H).

(B)
Preparation was carried out in the same manner as in Reference Example 1.08 (c) from 3,6-dimethylpyrazine-2-carboxylic acid (161 mg, 1.06 mmol), and 3,5,6-trimethylpyrazine-2-carboxylic acid Methyl was obtained. MS (APCI): m / z 181 (M + H).

(C)
Preparation was carried out in the same manner as in Example 1.001 (b) from methyl 3,6-dimethylpyrazine-2-carboxylate (2.38 g, 14.3 mmol), and 3- (3,6-dimethylpyrazine- 2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 176 (M + H).

(D)
Prepared from 3- (3,6-dimethylpyrazin-2-yl) -3-oxopropanenitrile (2.47 g, 14.1 mmol) as in Example 1.001 (c). (3,6-dimethylpyrazin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 190 (M + H).

(E)
Prepared from 3- (3,6-dimethylpyrazin-2-yl) -1H-pyrazol-5-amine (1.81 g, 9.56 mmol) as in Example 1.001 (d) Method A. And ethyl 3-{[3- (3,6-dimethylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate was obtained. MS (APCI): m / z 304 (M + H).

(F)
Prepared from ethyl 3-{[3- (3,6-dimethylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (1.78 g, 5.87 mmol). Example 1.001 (e) Performed in the same manner as in Method A to obtain 2- (3,6-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (APCI): m / z 258 (M + H).

(G)
Prepared from 2- (3,6-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (750 mg, 2.92 mmol) from Example 1.001 (f) In the same manner, 5,7-dichloro-2- (3,6-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine was obtained (the compound of Reference Example 1.11. Listed in the example table).

Reference Example 1.12
(A)
Preparation was carried out from 3,4-dimethyl-1,2-phenylenediamine (12.0 g, 52.6 mmol) as described in Helv. Chim. Acta. 2001, 84, 2379. Ethyl trimethylquinoxaline-2-carboxylate was obtained. MS (APCI): m / z 231 (M + H).

(B)
Preparation was carried out in the same manner as in Example 1.001 (b) from ethyl 3,6,7-trimethylquinoxaline-2-carboxylate (7.90 g, 34.3 mmol), and 3-oxo-3- (3 , 6,7-Trimethylquinoxalin-2-yl) propanenitrile was obtained. MS (APCI): m / z 240 (M + H).

(C)
Prepared from 3-oxo-3- (3,6,7-trimethylquinoxalin-2-yl) propanenitrile (5.18 g, 21.6 mmol) as in Example 1.001 (c), 3- (3,6,7-trimethylquinoxalin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 254 (M + H).

(D)
Prepared from 3- (3,6,7-trimethylquinoxalin-2-yl) -1H-pyrazol-5-amine (3.90 g, 15.4 mmol) as in Example 1.001 (d) Method A. To give ethyl 3-oxo-3-{[3- (3,6,7-trimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} propanoate. MS (APCI): m / z 368 (M + H).

(E)
Preparation was ethyl 3-oxo-3-{[3- (3,6,7-trimethylquinoxalin-2-yl) -1H-pyrazol-5-yl] amino} propanoate (1.06 g, 2.89 mmol). From Example 1.001 (e) Method A to give 2- (3,6,7-trimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. Obtained. MS (ESI): m / z 320 (M-H).

(F)
Prepared from 2- (3,6,7-trimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (1.44 g, 2.89 mmol) from Example 1.001. In the same manner as in (f), 2- (5,7-dichloropyrazolo [1,5-a] pyrimidin-2-yl) -3,6,7-trimethylquinoxaline was obtained (Reference Example 1.12). Are listed in the table of Reference Examples described later).

Reference Example 1.13
(A)
N- (tert-butoxycarbonyl) glycine (22.4 g, 128 mmol), ethyl 2-amino-3-oxobutanoate (21.1 g, 116 mmol), ethyl-3- (3-dimethylaminopropyl) in chloroform (350 mL) ) Carbodiimide hydrochloride (28.9 g, 151 mmol), 1-hydroxybenzotriazole (23.1 g, 151 mmol), triethylamine (16.2 mL, 116 mmol) are stirred at room temperature for 13 hours, then triethylamine (20.0 mL, 143 mmol) was added. After stirring at the same temperature for 4 hours, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1 to 1: 1) to give ethyl 2-{[N- (tert-butoxycarbonyl) glycyl] amino} -3-oxobutanoate. It was. MS (APCI): m / z 320 (M + NH 4), 303 (M + H).

(B)
Prepared from ethyl 2-{[N- (tert-butoxycarbonyl) glycyl] amino} -3-oxobutanoate (22.1 g, 73.1 mmol) as in Example 1.172 (b). Ethyl 6-hydroxy-3-methylpyrazine-2-carboxylate was obtained. MS (APCI): m / z 183 (M + H).

(C)
Preparation was carried out in the same manner as in Reference Example 1.07 (b) from ethyl 6-hydroxy-3-methylpyrazine-2-carboxylate (6.73 g, 36.9 mmol), and 6-chloro-3-methylpyrazine. Ethyl-2-carboxylate was obtained. MS (APCI): m / z 201/203 (M + H).

(D)
Ethyl 6-chloro-3-methylpyrazine-2-carboxylate (1.94 g, 9.67 mmol), isobutylboronic acid (1.97 g, 19.3 mmol), [1,1′-bis (diphenylphosphino) ferrocene A suspension of dichloropalladium (II) (212 mg, 0.290 mmol) and potassium carbonate (2.67 g, 19.3 mmol) in 1,4-dioxane (30 mL) was heated at 100 ° C. for 4.5 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and filtered through celite with ethyl acetate. The filtrate was collected and concentrated under reduced pressure. The residue was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate and brine, dried over sodium bicarbonate, filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-3: 1) to give ethyl 6-isobutyl-3-methylpyrazine-2-carboxylate. MS (APCI): m / z 223 (M + H).

(E)
Prepared from ethyl 6-isobutyl-3-methylpyrazine-2-carboxylate (1.76 g, 7.92 mmol) in a manner similar to Example 1.006 (a) Method A and 3- (6-isobutyl -3-Methylpyrazin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 218 (M + H).

(F)
Prepared from 3- (6-isobutyl-3-methylpyrazin-2-yl) -3-oxopropanenitrile (1.61 g, 7.41 mmol) as in Example 1.001 (c), 3- (6-Isobutyl-3-methylpyrazin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 232 (M + H).

(G)
Prepared from 3- (6-isobutyl-3-methylpyrazin-2-yl) -1H-pyrazol-5-amine (1.25 g, 5.40 mmol) as in Example 1.006 (c) Method A. To give ethyl 3-{[3- (6-isobutyl-3-methylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate. MS (APCI): m / z 346 (M + H).

(H)
Ethyl 3-{[3- (6-isobutyl-3-methylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (1.13 g, 3.29 mmol) and triethylamine ( A suspension of 1.38 mL, 9.88 mmol) in methanol (9 mL), tetrahydrofuran (9 mL) and water (9 mL) was refluxed for 2 hours. After cooling to ambient temperature, the reaction mixture was acidified to pH 2 with 2N aqueous hydrochloric acid and concentrated under reduced pressure. The residue was triturated with water to give 2- (6-isobutyl-3-methylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol. MS (APCI): m / z 300 (M + H).

(I)
Prepared from 2- (6-isobutyl-3-methylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (663 mg, 2.22 mmol) from Example 1.001 (f ) To give 5,7-dichloro-2- (6-isobutyl-3-methylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine (the compound of Reference Example 1.13 is And listed in the reference example table below).

Reference Example 1.14
(A)
Prepared from N- (tert-butoxycarbonyl) -L-alanine (5.62 g, 29.7 mmol) and L-threonine ethyl ester hydrochloride (4.58 g, 27.0 mmol) from Example 1.001 (d ) Method B was carried out to give N- (tert-butoxycarbonyl) -L-alanyl-L-threonine methyl. MS (APCI): m / z 305 (M + H).

(B)
Dess-Martin periodinane (15.1 g, 35.) in a solution of N- (tert-butoxycarbonyl) -L-alanyl-L-threonine methyl (9.00 g, 29.6 mmol) in dichloromethane (90 mL) at room temperature. 5 mmol) was added. After stirring for 70 minutes, saturated aqueous sodium thiosulfate was added and then the reaction mixture was stirred for 15 minutes. The mixture was poured into saturated aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 1) to give (2S) -2-{[N- (tert-butoxycarbonyl) -L-alanyl] amino} -3. -Methyl oxobutanoate was obtained. MS (APCI): m / z 303 (M + H).

(C)
(2S) -2-{[N- (tert-Butoxycarbonyl) -L-alanyl] amino} -3-oxobutanoic acid methyl ester (3.05 g, 10.1 mmol) and 4N hydrochloric acid 1,4-dioxane (10 mL) The solution was stirred at room temperature. After stirring at the same temperature for 1 hour, the reaction mixture was concentrated under reduced pressure. A solution of the residue in pyridine (50 mL) was heated at 60 ° C. for 4 hours. After cooling to ambient temperature, the mixture was concentrated under reduced pressure. The residue was poured into water and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was triturated with hexane-ethyl acetate (1: 1) to give methyl 6-hydroxy-3,5-dimethylpyrazine-2-carboxylate. MS (APCI): m / z 183 (M + H).

(D)
Preparation was carried out in the same manner as in Reference Example 1.07 (b) from methyl 6-hydroxy-3,5-dimethylpyrazine-2-carboxylate (4.55 g, 25.0 mmol). Methyl 5-dimethylpyrazine-2-carboxylate was obtained. MS (APCI): m / z 201/203 (M + H).

(E)
Preparation was carried out in the same manner as in Reference Example 1.13 (d) from methyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate (960 mg, 4.78 mmol), and 6-isobutyl-3,5- Methyl dimethylpyrazine-2-carboxylate was obtained. MS (APCI): m / z 223 (M + H).

(F)
Prepared from methyl 6-isobutyl-3,5-dimethylpyrazine-2-carboxylate (945 mg, 4.25 mmol) in the same manner as in Example 1.006 (a) Method A to give 3- (6-isobutyl -3,5-dimethylpyrazin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 232 (M + H).

(G)
Prepared from 3- (6-isobutyl-3,5-dimethylpyrazin-2-yl) -3-oxopropanenitrile (972 mg, 4.20 mmol) as in Example 1.001 (c), 3- (6-Isobutyl-3,5-dimethylpyrazin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 246 (M + H).

(H)
Prepared from 3- (6-isobutyl-3,5-dimethylpyrazin-2-yl) -1H-pyrazol-5-amine (950 mg, 3.87 mmol) as in Example 1.006 (c) Method A. To give ethyl 3-{[3- (6-isobutyl-3,5-dimethylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate. MS (APCI): m / z 360 (M + H).

(I)
The preparation was made of ethyl 3-{[3- (6-isobutyl-3,5-dimethylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (1.12 g, 3. 12 mmol) from Example 1.006 (d) and 2- (6-isobutyl-3,5-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7- Diol was obtained. MS (APCI): m / z 314 (M + H).

(J)
Prepared from 2- (6-isobutyl-3,5-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (845 mg, 2.70 mmol) from Example 1.001. In the same manner as in (f), 5,7-dichloro-2- (6-isobutyl-3,5-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine was obtained (Reference Example 1. The 14 compounds are listed in the reference example table below).

Reference Example 1.15
(A)
The preparation consisted of ethyl 6-chloro-3-methylpyrazine-2-carboxylate (Reference Example 1.13 (c)) (1.50 g, 7.48 mmol) and n-propylboronic acid (1.32 g, 15.0 mmol). ) To give ethyl 3-methyl-6-propylpyrazine-2-carboxylate in the same manner as in Reference Example 1.13 (d). MS (APCI): m / z 209 (M + H).

(B)
Prepared from ethyl 3-methyl-6-propylpyrazine-2-carboxylate (1.09 g, 5.23 mmol) in the same manner as Example 1.006 (a) Method A, and 3- (3-methyl -6-propylpyrazin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 204 (M + H).

(C)
Prepared from 3- (3-methyl-6-propylpyrazin-2-yl) -3-oxopropanenitrile (1.07 g, 5.23 mmol) as in Example 1.001 (c), 3- (3-Methyl-6-propylpyrazin-2-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 218 (M + H).

(D)
Prepared from 3- (3-Methyl-6-propylpyrazin-2-yl) -1H-pyrazol-5-amine (1.15 g, 5.29 mmol) as in Example 1.006 (c) Method A. To give ethyl 3-{[3- (3-methyl-6-propylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate. MS (APCI): m / z 332 (M + H).

(E)
Prepared was ethyl 3-{[3- (3-methyl-6-propylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (1.07 g, 3.23 mmol). From the same procedure as in Reference Example 1.13 (h), 2- (3-methyl-6-propylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol was obtained. . MS (APCI): m / z 286 (M + H).

(F)
Prepared from 2- (3-methyl-6-propylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (803 mg, 2.81 mmol) from Example 1.001 (f ) To give 5,7-dichloro-2- (3-methyl-6-propylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine (the compound of Reference Example 1.15 is And listed in the reference example table below).

Reference Example 1.16
(A)
Preparation was methyl 6-chloro-3,5-dimethylpyrazine-2-carboxylate (described in Reference Example 1.14 (d)) (2.30 g, 10.7 mmol) and cyclopropylboronic acid (1.84 g, 21.4 mmol), and in the same manner as in Reference Example 1.13 (d), ethyl 6-cyclopropyl-3,5-dimethylpyrazine-2-carboxylate was obtained. MS (APCI): m / z 221 (M + H).

(B)
Prepared from ethyl 6-cyclopropyl-3,5-dimethylpyrazine-2-carboxylate (2.30 g, 10.4 mmol) as in Example 1.006 (a) Method A, and 3- ( 6-cyclopropyl-3,5-dimethylpyrazin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 216 (M + H).

(C)
First, from 3- (6-cyclopropyl-3,5-dimethylpyrazin-2-yl) -3-oxopropanenitrile (872 mg, 4.05 mmol) in a manner similar to Example 1.001 (c). Prepared to give the crude compound (839 mg, 90%). Next, the crude compound (839 mg) was prepared in the same manner as in Example 1.006 (c) Method A, and 3-{[3- (6-cyclopropyl-3,5-dimethylpyrazine-2- Yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoic acid ethyl ester. MS (APCI): m / z 344 (M + H).

(D)
Prepared was ethyl 3-{[3- (6-cyclopropyl-3,5-dimethylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (990 mg, 2.88 mmol). To 2- (6-cyclopropyl-3,5-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7- Diol was obtained. MS (APCI): m / z 298 (M + H).

(E)
Prepared from 2- (6-cyclopropyl-3,5-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine-5,7-diol (772 mg, 2.60 mmol) from Example 1. In the same manner as in 001 (f), 5,7-dichloro-2- (6-cyclopropyl-3,5-dimethylpyrazin-2-yl) pyrazolo [1,5-a] pyrimidine was obtained (Reference Example). The compounds of 1.16 are listed in the reference example table below).

Reference Example 1.17
(A)
Prepared from N- (tert-butoxycarbonyl) -L-norvaline (13.0 g, 59.8 mmol) and L-threonine ethyl ester hydrochloride (9.23 g, 54.4 mmol) from Example 1.001 (d ) Method B was carried out to obtain N- (tert-butoxycarbonyl) -L-norvalyl-L-threonine methyl. MS (APCI): m / z 333 (M + H).

(B)
Preparation was carried out in the same manner as in Reference Example 1.14 (b) from N- (tert-butoxycarbonyl) -L-norvalyl-L-threonine methyl (15.8 g, 47.5 mmol), and (2S) -2 -{[N- (tert-butoxycarbonyl) -L-norvalyl] amino} -3-oxobutanoic acid methyl ester was obtained. MS (APCI): m / z 348 (M + H).

(C)
Prepared from methyl (2S) -2-{[N- (tert-butoxycarbonyl) -L-norvalyl] amino} -3-oxobutanoate (10.3 g, 31.2 mmol) from Example 1.172 (b ) To obtain methyl 6-hydroxy-3-methyl-5-propylpyrazine-2-carboxylate. MS (APCI): m / z 211 (M + H).

(D)
Preparation was carried out in the same manner as in Reference Example 1.07 (b) from methyl 6-hydroxy-3-methyl-5-propylpyrazine-2-carboxylate (3.49 g, 16.6 mmol). Methyl 3-methyl-5-propylpyrazine-2-carboxylate was obtained. MS (APCI): m / z 229/231 (M + H).

(E)
To a solution of methyl 6-chloro-3-methyl-5-propylpyrazine-2-carboxylate (3.00 g, 13.1 mmol) and triethylamine (1.83 mL, 13.1 mmol) in tetrahydrofuran (40 mL) under argon was added 0. At ° C, palladium on charcoal (5%, M, wet, 300 mg) was added. The reaction mixture was stirred under a hydrogen atmosphere for 8 hours and then filtered through celite with tetrahydrofuran. Manganese dioxide (1.0 g) was added to the filtrate at room temperature. After stirring overnight, the reaction mixture was filtered through celite with tetrahydrofuran. The filtrate was concentrated under reduced pressure and the residue was poured into saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1-13: 7) to give methyl 3-methyl-5-propylpyrazine-2-carboxylate. MS (APCI): m / z 195 (M + H).

(F)
Prepared from methyl 3-methyl-5-propylpyrazine-2-carboxylate (1.77 g, 9.11 mmol) in the same manner as Example 1.006 (a) Method A to give 3- (3-methyl -5-propylpyrazin-2-yl) -3-oxopropanenitrile was obtained. MS (APCI): m / z 204 (M + H).

(G)
First, the preparation was analogous to Example 1.001 (c) from 3- (3-methyl-5-propylpyrazin-2-yl) -3-oxopropanenitrile (2.00 mg, 9.84 mmol). To give 3- (3-methyl-5-propylpyrazin-2-yl) -1H-pyrazol-5-amine. MS (APCI): m / z 218 (M + H).

(H)
First from 3- (3-methyl-5-propylpyrazin-2-yl) -1H-pyrazol-5-amine (1.37 g, 6.31 mmol) from Example 1.006 (c) Method A Preparation was carried out in the same manner to obtain a crude compound (2.19 g). MS (APCI): m / z 344 (M + H). Second, from ethyl 3-{[3- (3-methyl-5-propylpyrazin-2-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (2.19 g) Prepared in a similar manner as in Example 1.13 (h) to give the crude compound (1.04 g). MS (APCI): m / z 286 (M + H). Third, preparation was performed from the crude compound (1.04 g) in the same manner as in Example 1.001 (f), and 5,7-dichloro-2- (3-methyl-5-propylpyrazine-2- Yl) pyrazolo [1,5-a] pyrimidine was obtained (the compound of Reference Example 1.17 is listed in the table of Reference Examples described later).

Reference Example 1.18
(A)
A solution of 3-aminopyrazole (5.00 g, 60.2 mmol) and ethyl oxalpropionate (24.3 g, 120 mmol) in ethanol (602 mL) was refluxed for 24 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was triturated with chloroform and diisopropyl ether to give the crude compound (10.4 g, 78%).
A solution of the crude compound (7.38 g, 33.4 mmol) and phosphorus oxychloride (62.3 g, 668 mmol) in toluene (67 mL) was refluxed for 3 hours. After cooling to ambient temperature, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform and poured into a 10% aqueous potassium carbonate solution. The organic layer was separated and the aqueous layer was extracted with chloroform. The organic layers were combined, washed with water and saturated brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1-7: 3) to obtain a crude compound (7.07 g, 88%).
A suspension of crude compound (4.49 g, 18.7 mmol), palladium on charcoal (5%, M, wet, 2.25 g) and triethylamine (2.61 mL, 18.7 mmol) in tetrahydrofuran (190 mL) was added to a hydrogen atmosphere. Under stirring at room temperature for 40 minutes. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 to 2: 3) to obtain ethyl 6-methylpyrazolo [1,5-a] pyrimidine-5-carboxylate. MS (APCI): m / z 206 (M + H).

(B)
Prepared from ethyl 6-methylpyrazolo [1,5-a] pyrimidine-5-carboxylate (3.42 g, 16.7 mmol) as in Example 1.006 (a) Method A, and 3- ( 6-methylpyrazolo [1,5-a] pyrimidin-5-yl) -3-oxopropionitrile was obtained. MS (APCI): m / z 201 (M + H).

(C)
First, from 3- (6-methylpyrazolo [1,5-a] pyrimidin-5-yl) -3-oxopropionitrile (2.45 g, 12.2 mmol) as in Example 1.001 (c). In this manner, 3- (6-methylpyrazolo [1.5-a] pyrimidin-5-yl) -1H-pyrazol-5-amine was obtained. MS (APCI): m / z 215 (M + H).

(D)
Prepared from 3- (6-Methylpyrazolo [1.5-a] pyrimidin-5-yl) -1H-pyrazol-5-amine (2.30 g, 10.7 mmol) from Example 1.006 (c). As in A, ethyl 3-{[3- (6-methylpyrazolo [1,5-a] pyrimidin-5-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate is obtained. It was. MS (APCI): m / z 329 (M + H).

(E)
The preparation was made of ethyl 3-{[3- (6-methylpyrazolo [1,5-a] pyrimidin-5-yl) -1H-pyrazol-5-yl] amino} -3-oxopropanoate (3.20 g, 9 .75 mmol), 6′-methyl-2,5′-bipyrazolo [1,5-a] pyrimidine-5,7-diol was obtained in the same manner as in Example 1.006 (d). MS (APCI): m / z 283 (M + H).

(F)
Prepared from 6′-methyl-2,5′-bipyrazolo [1,5-a] pyrimidine-5,7-diol (2.86 g, 9.75 mmol) as in Example 1.001 (f). Thus, 5,7-dichloro-6′-methyl-2,5′-bipyrazolo [1,5-a] pyrimidine was obtained (the compounds of Reference Example 1.18 are listed in the Reference Examples table described later). ).

The following abbreviations are used herein:
“MS (APCI)” means mass spectrometry (atmospheric pressure chemical ionization mass spectrometry),
“MS (ESI)” means mass spectrometry (electrospray ionization mass spectrometry)
“Me” means methyl group;
“Et” means ethyl group;
“Pr” means a propyl group;
“Bu” means a butyl group; and
“Boc” means a tert-butoxycarbonyl group.

  The structural formulas and physical properties of the compounds of Examples and Reference Examples are shown in the Tables of Examples and Reference Examples below.

Claims (11)

Formula [I]:

[Where
R ¹ is hydrogen, halogen, C _1-6 alkyl or cyano;
Ring A, I 1-3 monocyclic or bicyclic heteroaryl containing a nitrogen atom, or condensed with groups der having an aliphatic 5- or 6-membered ring as the hetero atom,
C _1-6 alkyl; C _3-6 cycloalkyl; halogen; halo C _1-6 alkyl; hydroxy; C _1-6 alkoxy; halo C _1-6 alkoxy; identical or selected from C _1-6 alkyl and halogen From amino optionally substituted by 1 to 2 different substituents; and from cyclic amino optionally substituted by 1 to 3 identical or different substituents selected from C _1-6 alkyl and halogen Optionally substituted by the same or different 1 to 6 substituents selected from the group consisting of ;
Ring B is a 4-6 membered monocyclic nitrogen-containing heterocyclic group or a 3-6 membered monocyclic hydrocarbon group,
Halogen; oxo; hydroxy; hydroxy and _{C 1-6 C} are optionally substituted by identical or different 1 to 2 substituents selected from alkoxy _{1-6 alkyl; C 1-6 alkoxy; C 1-6} Alkylsulfonyloxy; and the same or different 1-3 substituents selected from the group consisting of amino optionally substituted with 1-2 identical or different substituents selected from C _1-6 alkyl Optionally substituted by : and Y is of the formula [III]:
-ZR ² [III]
Wherein Z is —N (R ³ ) —, —O— or C _1-2 alkylene;
R ³ is hydrogen; be or _{C 3-6} cycloalkyl; optionally _{C 1-6} alkyl substituted by the same or different 1 to 2 substituents selected from hydroxy and _{C 1-6} alkoxy;
R ² is
(1) From hydroxy, halogen, cyano, C _1-6 alkoxy, C _3-6 cycloalkyl, hydroxy substituted C _3-6 cycloalkyl, haloC _1-6 alkyl and mono- or di-C _1-6 alkylamino Or C _1-6 alkyl optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of ; or
(2) a 4-6 membered aliphatic monocyclic heterocyclic group containing 1 to 2 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom; or C _3-6 cycloalkyl,
C _1-6 alkanoyl; C _1-6 alkoxy; and C ₁ optionally substituted by one or two identical or different substituents selected from hydroxy and C _1-6 alkoxy Optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of _-6 alkyl)
It is group shown by these. ]
Or a pharmacologically acceptable salt thereof as an active ingredient. Represented by ring A “ a monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as a heteroatom, or a group having an aliphatic 5 to 6 membered ring fused thereto” is pyridyl, Pyrazinyl, quinolyl, quinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazinyl, pyrido [3,4-b] pyrazinyl and pyrazolo [ Selected from the group consisting of 1,5-a] pyrimidinyl;
And
" 4-6 membered monocyclic nitrogen-containing heterocyclic group or 3-6 membered monocyclic hydrocarbon group" represented by ring B is pyrrolidinyl, azetidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and C Selected from the group consisting of _3-6 cycloalkyl, or an unsaturated monocyclic group thereof;
And
" 4- to 6-membered aliphatic monocyclic heterocyclic group containing 1 to 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom " represented by R ² is tetrahydropyranyl, tetrahydrofuranyl , oxetanyl, tetrahydrothiopyranyl, tetrahydrothienyl, thietanyl, is selected from the group consisting of piperidyl and C _3-6 cycloalkyl, pharmaceutical composition according to claim 1. "A monocyclic or bicyclic heteroaryl containing 1 to 3 nitrogen atoms as a heteroatom, or a group having an aliphatic 5 to 6 membered ring fused thereto " represented by ring A is pyridine- 2-yl, pyrazin-2-yl, quinolin-2-yl, quinoxalin-2-yl, 5,6,7,8-tetrahydroquinoxalin-2-yl, 7,8-dihydro-6H-pyrano [2,3 -B] pyrazin-2-yl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazin-3-yl, pyrido [3,4-b] pyrazin-2-yl and pyrido [3,4 -B] selected from the group consisting of pyrazin-3-yl,
And
“ 4- to 6-membered monocyclic nitrogen-containing heterocyclic group or 3- to 6-membered monocyclic hydrocarbon group” represented by ring B is from 1-pyrrolidinyl, 1-azetidinyl, 1-pyrazolidinyl, cyclopentyl and cyclopentenyl. Selected from the group consisting of
And
“4- to 6-membered aliphatic monocyclic heterocyclic group containing 1 to 2 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom ” represented by R ² is 3- or 4-tetrahydro Selected from the group consisting of pyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3- or 4-tetrahydrothiopyranyl, 3-tetrahydrothienyl, 3-thietanyl, 4-piperidyl and C _3-6 cycloalkyl, Item 10. A pharmaceutical composition according to Item 1 . Ring A is pyrazinyl, quinolyl, quinoxalinyl, 5,6,7,8-tetrahydroquinoxalinyl, 7,8-dihydro-6H-pyrano [2,3-b] pyrazinyl, pyrido [3,4-b] pyrazinyl and pyrazolo [1,5-a] pyrimidinyl, each, _{C 1-6} alkyl; _{C 3-6} cycloalkyl; halogen; halo C _1-6 alkyl; and is selected from _{C 1-6} alkyl and halogen Optionally substituted with 1 to 3 identical or different substituents selected from the group consisting of cyclic amino optionally substituted with 1 to 3 identical or different substituents,
And
Ring B is 1-pyrrolidinyl, 1-azetidinyl, 1-pyrazolyl, cyclopropyl, cyclopentyl or cyclopenten-1-yl, each being the same or different 1 selected from halogen; hydroxy; hydroxy, C _1-6 alkoxy Optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of C _1-6 alkyl optionally substituted by ~ 2 substituents;
And
R ² is
Same selected from the group consisting of _{C 1-6} alkylamino - (1) hydroxy, halogen, cyano, _{C 1-6} alkoxy, hydroxy substituted C _1-6 cycloalkyl, halo C _1-6 alkyl and mono- - or di Or is C _1-6 alkyl optionally substituted with 1 to 3 different substituents; or (2) 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3-oxetanyl, 3-tetrahydro Thienyl, 4-piperidyl or C _3-6 cycloalkyl, each being halogen; oxo; hydroxy; C _1-6 alkanoyl; C _1-6 alkoxy; and the same or selected from hydroxy and C _1-6 alkoxy the group consisting of C _1-6 alkyl which is optionally substituted by a different one to two substituents Are optionally substituted by identical or different one to three substituents selected,
And
R ³ is hydrogen, a pharmaceutical composition according to claim 1. Ring A is pyrazin-2-yl or quinoxalin-2-yl, each optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of C _1-6 alkyl and halogen. And
Ring B is the same or selected from the group consisting of C _1-6 alkyl optionally substituted with 1-2 identical or different substituents selected from halogen; hydroxy; hydroxy, C _1-6 alkoxy 5. A pharmaceutical composition according to claim 4 which is 1-pyrrolidinyl optionally substituted by 1 to 3 different substituents. The pharmaceutical composition according to any one of claims 1 to 5 , wherein R ¹ is hydrogen. The pharmaceutical composition according to any one of claims 1 to 6 , wherein R ¹ is hydrogen and Z is -N (R ³ )-. The compound is
2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine;
N-methyl-2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine-7- Amines;
5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a ] Pyrimidine-7-amine;
1-({2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidin-7-yl } Amino) -2-methylpropan-2-ol;
5- (2,5-dihydro-1H-pyrrol-1-yl) -2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5- a] pyrimidine-7-amine;
2-methyl-3- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-yloxy) pyrazolo [1,5-a] pyrimidin-2-yl] quinoxaline;
5-Cyclopent-1-en-1-yl-2- (3-methylquinoxalin-2-yl) -N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine-7- Amines;
trans-4-({2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidine-7 -Yl} amino) -1-methylcyclohexanol;
2- (5,7-dipyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-2-yl) -3-methylquinoxaline;
(2S) -1,1,1-trifluoro-3-{[2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] Amino} propan-2-ol;
3-{[2- (3-methylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} propanenitrile;
N- (trans-4-methoxycyclohexyl) -2- [3-methyl-7- (trifluoromethyl) quinoxalin-2-yl] -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidine-7- Amines;
2- (3,7-dimethylquinoxalin-2-yl) -N, N-bis (2-methoxyethyl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-amine;
5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) -N-oxetan-3-ylpyrazolo [1,5-a] pyrimidin-7-amine;
1-{[5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-yl] amino}- 2-methylpropan-2-ol;
N-cyclopropyl-5-[(3R) -3-fluoropyrrolidin-1-yl] -2- (3-methylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidin-7-amine;
2- (3-Ethylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] -N- (trans-4-methoxycyclohexyl) pyrazolo [1,5-a] pyrimidine- 7-amine;
trans-4-({5-[(3R) -3-fluoropyrrolidin-1-yl] -2- [3- (trifluoromethyl) quinoxalin-2-yl] pyrazolo [1,5-a] pyrimidine-7 -Yl} amino) -1-methylcyclohexanol;
(1S, 2S) -2-{[2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} cyclo Hexanol;
2- (3,5-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine;
2- (3,6-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidin-7-amine;
2- (3,7-dimethylquinoxalin-2-yl) -N-[(3R) -1,1-dioxidetetrahydro-3-thienyl] -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidine -7-amine;
N- (1-acetylpiperidin-4-yl) -2- (3,7-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-amine;
2- (3,7-dimethylquinoxalin-2-yl) -N- (1-propylpiperidin-4-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-amine;
N ′-[2- (3,7-dimethylquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] -N, N-dimethylethane-1,2 A diamine;
N- (4,4-difluorocyclohexyl) -2- (3-methyl-5,6,7,8-tetrahydroquinoxalin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] Pyrimidine-7-amine;
N-methyl-5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) -2- (3,5,6-trimethylpyrazin-2-yl) pyrazolo [1,5-a] Pyrimidine-7-amine;
((2S) -1- {2- (3-Methylquinoxalin-2-yl) -7-[(3R) -tetrahydro-2H-pyran-3-ylamino] pyrazolo [1,5-a] pyrimidine-5 Yl} pyrrolidin-2-yl) methanol;
{(2S) -1- [7- [cyclopropyl (tetrahydro-2H-pyran-4-yl) amino] -2- (3,7-dimethylquinoxalin-2-yl) pyrazolo [1,5-a] pyrimidine -5-yl] pyrrolidin-2-yl} methanol;
1- [2- (3,7-Dimethylquinoxalin-2-yl) -7- (tetrahydro-2H-pyran-4-ylamino) pyrazolo [1,5-a] pyrimidin-5-yl] azetidin-3-ol ;
2-methyl-3- [5-pyrrolidin-1-yl-7- (tetrahydro-2H-pyran-4-ylmethyl) pyrazolo [1,5-a] pyrimidin-2-yl] quinoxaline;
trans-1-methyl-4-{[2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1, 5-a] pyrimidin-7-yl] amino} cyclohexanol;
cis-4-({2- (7-Fluoro-3-methylquinoxalin-2-yl) -5-[(3R) -3-fluoropyrrolidin-1-yl] pyrazolo [1,5-a] pyrimidine-7 -Yl} amino) -1-methylcyclohexanol;
N-methyl-2- (3-methyl-6-propylpyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] Pyrimidine-7-amine;
2-methyl-1-[(6′-methyl-5-pyrrolidin-1-yl-2,5′-bipyrazolo [1,5-a] pyrimidin-7-yl) amino] propan-2-ol;
1-{[2- (6-Isobutyl-3,5-dimethylpyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} -2-methylpropane -2-ol;
1-{[2- (6-Cyclopropyl-3,5-dimethylpyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5-a] pyrimidin-7-yl] amino} -2-methylpropane -2-ol;
2- (6-Cyclopropyl-3,5-dimethylpyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine -7-amine;
2- (3-Methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl ) Pyrazolo [1,5-a] pyrimidin-7-amine;
2-Methyl-1-{[2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1,5- a] pyrimidin-7-yl] amino} propan-2-ol;
N- (trans-4-methoxycyclohexyl) -2- (3-methyl-7,8-dihydro-6H-pyrano [2,3-b] pyrazin-2-yl) -5-pyrrolidin-1-ylpyrazolo [1 , 5-a] pyrimidin-7-amine;
2- (2-Methylpyrido [3,4-b] pyrazin-3-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1,5-a] pyrimidine -7-amine; and 2- (3-methylpyrido [3,4-b] pyrazin-2-yl) -5-pyrrolidin-1-yl-N- (tetrahydro-2H-pyran-4-yl) pyrazolo [1 , 5-a] A pharmaceutical composition according to claim 1, which is a compound selected from the group consisting of pyrimidine-7-amine or a pharmacologically acceptable salt thereof. It is a phosphodiesterase 10 inhibitor, The pharmaceutical composition as described in any one of Claims 1-8 . The pharmaceutical composition according to any one of claims 1 to 8 , which is a therapeutic or prophylactic agent for a disease or condition expected to be improved by inhibiting phosphodiesterase 10 activity. The pharmaceutical composition according to any one of claims 1 to 8 , which is a therapeutic or prophylactic agent for schizophrenia, anxiety disorder, drug addiction, disease with symptoms of cognitive impairment, mood disorder or mood episode.