JP2016108326A - Pharmaceutical consisting of cyclic aminomethyl pyrimidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a cyclic aminomethyl pyrimidine derivative and a pharmaceutically acceptable salt thereof exhibiting effects on dopamine Dreceptor with high selectivity and useful as a treatment agent of central nervous system diseases such as attention deficit hyperkinesis disorder.SOLUTION: There is provide a compound represented by the formula (1) and a pharmaceutically acceptable salt thereof. (1), where n and m are each independently 1 or 2, Ris a Calkyl group, a Ccycloalkyl group or an amino group, Ris H, a Calkyl group or an alkyl group-substituted/unsubstituted amino group, Ris H when Ris the amino group, Rand Rare each independently H or a Calkyl group, Rand Rare each independently H, F or a Calkyl group, a ring Q is substituted/unsubstituted 5- to 10-membered nitrogen-containing heteroaryl group and bond containing break lines is a single bond or a double bond.SELECTED DRAWING: None

Description

The present invention relates to a pharmaceutical comprising a cyclic aminomethylpyrimidine derivative having a selective dopamine D ₄ receptor agonistic action or a salt thereof. More specifically, the present invention relates to a therapeutic agent for attention deficit / hyperactivity disorder and the like comprising a cyclic aminomethylpyrimidine derivative having a pyridyl group or an isoquinolinyl group on the ring of the cyclic aminomethyl group or a salt thereof as an active ingredient.

Dopamine D ₄ receptors, G-protein coupled receptors (G protein-coupled receptors: GPCRs ) is one of, since it is highly expressed in prefrontal cortex associated with attention behavior and cognitive function, dopamine D ₄ Receptor agonists are expected as therapeutic agents for central nervous system diseases related to higher-order functions such as attention deficit hyperactivity disorder (ADHD). ADHD is one of the developmental disorders that develop in childhood with inattention, hyperactivity, and impulsivity as core symptoms. Core symptoms persist even in adulthood. It is known to do. The central nervous system stimulant methylphenidate is used as a first-line drug in ADHD drug therapy. The therapeutic effect of methylphenidate is thought to be based on the functional regulation of the dopamine transporter involved in the release of the neurotransmitter dopamine, and exhibits immediate effect. However, methylphenidate has the risk of drug dependence and abuse, and the risk of side effects on the cardiovascular system such as palpitation, tachycardia, and blood pressure fluctuations. The selective noradrenaline reuptake inhibitor atomoxetine, which is a non-central nervous stimulant, is selected as an ADHD therapeutic agent with small drug dependence formation. However, atomoxetine requires a sufficient administration period before the therapeutic effect is exhibited. For these reasons, it is desired to develop an ADHD therapeutic agent that can reduce the risk of drug dependence and cardiovascular side effects and exhibits rapid onset of efficacy.
The ADHD patient, the mutation of the dopamine transporter gene and the dopamine D ₄ receptor gene is observed has been reported (e.g., see Non-Patent Document 1). Also, the child with a genetic polymorphism of seven repeat sequence of 48bp in the third exon of the dopamine D ₄ receptor gene, developmental delay of the cerebral cortex has been observed (for example, see Non-Patent Document 3). Then, dopamine D ₄ receptors are highly expressed in prefrontal cortex associated with attention behavior and cognitive function (e.g., see Non-Patent Document 2). From these facts, dopamine D ₄ receptor is considered to be related to attention / cognitive function. In addition, dopamine D ₄ receptors are known to be not expressed in the nucleus accumbens involved in drug dependence.
Based on the above, a drug that selectively exhibits an agonistic action on the dopamine D ₄ receptor is a therapeutic agent for central nervous system diseases related to dopaminergic nerves, particularly ADHD and has a drug dependence. It is expected as a therapeutic agent for ADHD with reduced side effects.

Patent Document 1, useful in the control or prevention of disease (e.g., psychoses such as schizophrenia) dopamine D ₄ receptor ligands represented by the following formula I, where and the compound is caused by disorders of the dopamine system It is disclosed that there is.

［式中、Ｒ^１とＲ^２は、個々に低級アルキル又はアミノを表し；
Ａは、

[Wherein R ¹ and R ² individually represent lower alkyl or amino;
A is

を表し；
Ｂは、Ａ^４、Ａ^５及びＡ^６では水素を表し；
Ａ^１〜Ａ^６では：

Represents;
B represents hydrogen in A ⁴ , A ⁵ and A ⁶ ;
In A ¹ ~A ^6:

を表し；
Ａ^４〜Ａ^６では低級アルコキシを表し；そしてＡ^１及びＡ^２では低級アルキル、スチリル、フェニルエチニル又はベンゾイルオキシ−低級アルキルを表し；
ｎは、０〜２を表し；
ｍ、ｐは、０、１を表し；そしてＲ^３、Ｒ^４、Ｒ^５及びＲ^６は、各々独立して水素、ハロゲン、低級アルキル、トリフルオロメチル、低級アルコキシ又はニトロを表す。］

Represents;
A ^{4 to} A ⁶ represent lower alkoxy; and A ¹ and A ² represent lower alkyl, styryl, phenylethynyl or benzoyloxy-lower alkyl;
n represents 0-2;
m and p represent 0 and 1; and R ³ , R ⁴ , R ⁵ and R ⁶ each independently represent hydrogen, halogen, lower alkyl, trifluoromethyl, lower alkoxy or nitro. ]

  The said compound does not contain the substituent which has a heteroaryl ring in the definition of B, and a chemical structure differs from this invention compound.

Japanese National Patent Publication No. 11-500745

Biological Psychiatry 2005, 57, 1313. Archives of General Psychiatry, 2007, 64, 921. The Journal of Pharmacology Experimental Therapeutics, 1997, 282, 1020.

An object of the present invention is to provide a novel selective dopamine D ₄ receptor agonist useful as a therapeutic agent for central nervous system diseases.

As a result of intensive studies to achieve the above-mentioned problems, the present inventors have found that the compound represented by the following formula (1) and a pharmaceutically acceptable salt thereof (hereinafter abbreviated as “the compound of the present invention” as necessary). Has been found to have an excellent selective dopamine D ₄ receptor agonist activity, and the present invention has been completed.

  That is, the present invention is as follows.

[1] Formula (1):

（式中、
ｎおよびｍは、それぞれ独立して、１または２を表し；
Ｒ^ａは、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、またはアミノ基を表し；
Ｒ^ｂは、水素原子、Ｃ_１−６アルキル基、または１〜２個の同一又は異なるＣ_１−６アルキル基で置換されていてもよいアミノ基を表し（ただし、Ｒ^ａがアミノ基のときは、Ｒ^ｂは水素原子である。）；
Ｒ^ｃ１およびＲ^ｃ２は、それぞれ独立して、水素原子、またはＣ_１−６アルキル基を表し；
Ｒ^ｄ１およびＲ^ｄ２は、それぞれ独立して、水素原子、フッ素原子、もしくはＣ_１−６アルキル基であるか、またはそれらが結合する炭素原子と一緒になって、３員〜８員のシクロアルカン環または３員〜８員のシクロアルケン環を形成してもよく（ここにおいて、当該シクロアルカン環またはシクロアルケン環は、ハロゲン原子、Ｃ_１−６アルキル、およびＣ_１−６アルコキシからなる群から独立して選択される１〜２個の基で置換されていてもよい。）；
環Ｑは、置換されていてもよい５員〜１０員の含窒素ヘテロアリール基を表し；
破線を含む結合は単結合または二重結合を表す。）
で表される化合物またはその薬学上許容される塩からなる医薬。

(Where
n and m each independently represent 1 or 2;
R ^a represents a C _1-6 alkyl group, a C _3-6 cycloalkyl group, or an amino group;
R ^b represents a hydrogen atom, a C _1-6 alkyl group, or an amino group which may be substituted with 1 to 2 identical or different C _1-6 alkyl groups (provided that when R ^a is an amino group) In which R ^b is a hydrogen atom);
R ^c1 and R ^c2 each independently represent a hydrogen atom or a C _1-6 alkyl group;
R ^d1 and R ^d2 are each independently a hydrogen atom, a fluorine atom, or a C _1-6 alkyl group, or together with the carbon atom to which they are attached, a 3- to 8-membered cycloalkane. A ring or a 3- to 8-membered cycloalkene ring may be formed (wherein the cycloalkane ring or cycloalkene ring is selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkoxy). Optionally substituted with 1-2 groups independently selected);
Ring Q represents an optionally substituted 5- to 10-membered nitrogen-containing heteroaryl group;
A bond including a broken line represents a single bond or a double bond. )
Or a pharmaceutically acceptable salt thereof.

[2] Formula (1):

（式中、
ｎおよびｍは、それぞれ独立して、１または２を表し；
Ｒ^ａは、Ｃ_１−６アルキル基、Ｃ_３−６シクロアルキル基、またはアミノ基を表し；
Ｒ^ｂは、水素原子、Ｃ_１−６アルキル基、または１〜２個のＣ_１−６アルキル基で置換されていてもよいアミノ基を表し（ただし、Ｒ^ａがアミノ基のときは、Ｒ^ｂは水素原子である。）；
Ｒ^ｃ１およびＲ^ｃ２は、それぞれ独立して、水素原子、またはＣ_１−６アルキル基を表し；
Ｒ^ｄ１およびＲ^ｄ２は、それぞれ独立して、水素原子、フッ素原子、もしくはＣ_１−６アルキル基であるか、またはそれらが結合する炭素原子と一緒になって、３員〜８員のシクロアルカン環または３員〜８員のシクロアルケン環を形成してもよく（ここにおいて、当該シクロアルカン環またはシクロアルケン環は、ハロゲン原子、Ｃ_１−６アルキル、およびＣ_１−６アルコキシからなる群から選択される１〜２個の基で置換されていてもよい。）；
環Ｑは、置換されていてもよいピリジル基、または置換されていてもよいイソキノリニル基を表し；
破線を含む結合は単結合または二重結合を表す。）
で表される化合物またはその薬学上許容される塩からなる医薬。

(Where
n and m each independently represent 1 or 2;
R ^a represents a C _1-6 alkyl group, a C _3-6 cycloalkyl group, or an amino group;
R ^b represents a hydrogen atom, a C _1-6 alkyl group, or an amino group which may be substituted with 1 to 2 C _1-6 alkyl groups (provided that when R ^a is an amino group, ^b is a hydrogen atom));
R ^c1 and R ^c2 each independently represent a hydrogen atom or a C _1-6 alkyl group;
R ^d1 and R ^d2 are each independently a hydrogen atom, a fluorine atom, or a C _1-6 alkyl group, or together with the carbon atom to which they are attached, a 3- to 8-membered cycloalkane. A ring or a 3- to 8-membered cycloalkene ring may be formed (wherein the cycloalkane ring or cycloalkene ring is selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkoxy). Optionally substituted with 1 to 2 groups selected);
Ring Q represents an optionally substituted pyridyl group or an optionally substituted isoquinolinyl group;
A bond including a broken line represents a single bond or a double bond. )
Or a pharmaceutically acceptable salt thereof.

[3] The ring Q is represented by the following formula (2a), (2b), (2c), (2d) or (2e):

（式中、Ｒ^ｅ１およびＲ^ｅ２は、それぞれ独立して、水素原子、ハロゲン原子、または１〜３個の同一又は異なるハロゲン原子で置換されていてもよいＣ_１−６アルキル基を表す。）で表される基である、〔１〕または〔２〕に記載の化合物またはその薬学上許容される塩からなる医薬。

(In the formula, R ^e1 and R ^e2 each independently represent a hydrogen atom, a halogen atom, or a C _1-6 alkyl group which may be substituted with 1 to 3 identical or different halogen atoms.) A pharmaceutical comprising the compound of [1] or [2] or a pharmaceutically acceptable salt thereof, which is a group represented by:

[4] A medicament comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein R ^a is a C _1-4 alkyl group.

[5] A medicament comprising the compound according to any one of [1] to [3] or a pharmaceutically acceptable salt thereof, wherein R ^a is an amino group and R ^b is a hydrogen atom.

[6] A medicament comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein R ^b is a C _1-6 alkyl group or an amino group.

[7] A pharmaceutical comprising the compound according to any one of [1] to [4] or [6] or a pharmaceutically acceptable salt thereof, wherein R ^b is an amino group.

[8] A medicament comprising the compound according to any one of [1] to [7] or a pharmaceutically acceptable salt thereof, wherein both R ^c1 and R ^c2 are hydrogen atoms.

[9] The compound according to any one of [1] to [8] or a pharmaceutically acceptable salt thereof, wherein R ^d1 and R ^d2 are each independently a hydrogen atom or a C _1-6 alkyl group. A pharmaceutical comprising a salt.

[10] A pharmaceutical comprising the compound according to any one of [1] to [9] or a pharmaceutically acceptable salt thereof, wherein both R ^d1 and R ^d2 are hydrogen atoms.

[11] A pharmaceutical comprising the compound or a pharmaceutically acceptable salt thereof according to any one of [3] to [10], wherein ring Q is a group represented by formula (2a) or (2b) .

[12] A medicament comprising the compound of [11] or a pharmaceutically acceptable salt thereof, wherein ring Q is a group represented by formula (2a).

[13] A medicament comprising the compound according to [11] or a pharmaceutically acceptable salt thereof, wherein ring Q is a group represented by formula (2b).

[14] The compound according to any one of [3] to [13] or a pharmaceutically acceptable salt thereof, wherein R ^e1 and R ^e2 are each independently a hydrogen atom or a fluorine atom. Medicine.

[15] A medicament comprising the compound according to any one of [1] to [14] or a pharmaceutically acceptable salt thereof, wherein the bond including a broken line is a single bond.

[16] A medicament comprising a compound represented by any of the following formulas or a pharmaceutically acceptable salt thereof:

[17] A pharmaceutical composition comprising the pharmaceutical according to any one of [1] to [16] and a pharmaceutically acceptable excipient.

[18] Attention deficit / hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive dysfunction comprising the medicine according to any one of [1] to [16] as an active ingredient A therapeutic agent for central nervous system disease selected from the group consisting of:

[19] A therapeutic agent for attention deficit / hyperactivity disorder comprising the pharmaceutical according to any one of [1] to [16] as an active ingredient.

[20] The therapeutic agent according to [19], wherein the attention deficit / hyperactivity disorder is a disorder mainly having attention deficit (Inattention).

[21] The therapeutic agent according to [19], wherein the attention deficit / hyperactivity disorder is a disorder whose main symptom is hyperactivity.

[22] The therapeutic agent according to [19], wherein the attention deficit / hyperactivity disorder is a disorder whose main symptom is impulsivity.

[23] A therapeutic agent for autism spectrum disorder, comprising the medicine according to any one of [1] to [16] as an active ingredient.

[24] The therapeutic agent according to [23], wherein the autism spectrum disorder is a disorder whose main symptom is a persistent defect in social communication and social interaction.

[25] The therapeutic agent according to [23], wherein the autism spectrum disorder is a disorder whose main symptom is a repetitive behavior, interest, or activity pattern.

The compound of the present invention exhibits a strong selective action on the dopamine D ₄ receptor, and has a weak effect on other GPCRs such as adrenaline α _1A receptor and α _2A receptor. In addition, the compound of the present invention has high bioavailability (bioavailability) at the time of oral administration, excellent brain transferability, and low liver toxicity risk. Therefore, the compound of the present invention has excellent drug safety (for example, attention deficit), which has no drug dependence, has reduced side effects of the cardiovascular system, and exhibits rapid efficacy at a low dose. It is useful as a therapeutic agent for hyperactivity disorder.

It is a graph which shows the alternation action rate improvement effect | action of the compound administration group of Example 2 of Test Example 7. It is a graph which shows the alternation action rate improvement effect | action of the compound administration group of Example 5 of Experiment 7. 4 is a chart showing a powder X-ray diffraction pattern of the compound of Example 58. 2 is a graph showing a characteristic DSC curve of the compound of Example 58. FIG. 4 is a chart showing a powder X-ray diffraction pattern of the compound of Example 59. FIG. 10 is a graph showing a characteristic DSC curve of the compound of Example 59. 2 is a chart showing a powder X-ray diffraction pattern of the compound of Example 61. FIG. 2 is a diagram illustrating a characteristic DSC curve of the compound of Example 61. FIG. 2 is a chart showing a powder X-ray diffraction pattern of the compound of Example 62. FIG. 2 is a diagram illustrating a characteristic DSC curve of the compound of Example 62. FIG. 2 is a graph showing a characteristic DSC curve of the compound of Example 63. FIG.

The present invention is described in detail below. In the present specification, the number of carbons in the definition of “substituent” may be expressed as “C _1-6 ”, for example. Specifically, the notation “C _1-6 alkyl” is synonymous with an alkyl group having 1 to 6 carbon atoms.

  Specific examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

“C _1-6 alkyl group” means a linear or branched saturated hydrocarbon group having 1 to 6 carbon atoms. Preferably, it is a “C _1-4 alkyl group”. Specific examples of “C _1-6 alkyl group” include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl and isohexyl. 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl and the like.

“C _3-6 cycloalkyl group” means a 3- to 6-membered monocyclic saturated hydrocarbon group. Preferably, it is “C _3-5 cycloalkyl group”. Specific examples of “C _3-6 cycloalkyl group” include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The “C _1-6 alkyl” part of the “C _1-6 alkoxy group” has the same _{meaning as} the above “C _1-6 alkyl”. Preferably, it is a “C _1-4 alkoxy group”. Specific examples of “C _1-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.

  Examples of the “5-membered to 10-membered nitrogen-containing heteroaryl group” include 5-membered to 10-membered monocyclic or bicyclic aromatic groups containing 1 to 3 nitrogen atoms. The group may further contain one or more heteroatoms selected from the group consisting of a sulfur atom and an oxygen atom. Preferably, a pyridyl group and an isoquinolinyl group are mentioned, More preferably, a pyridyl group is mentioned.

  Specific examples of the “5-membered to 10-membered nitrogen-containing heteroaryl group” include, for example, groups represented by the following formulae.

  A bond across the ring means that the “group” is attached at a substitutable position in the ring. For example, the following formula

のヘテロアリール基の場合には、２−ピリジル基、３−ピリジル基、または４−ピリジル基であることを意味する。

In the case of the heteroaryl group, it means a 2-pyridyl group, a 3-pyridyl group, or a 4-pyridyl group.

  Further, when the “heteroaryl group” is a polycyclic group, for example, the following formula

で表される場合には、１−ベンゾイミダゾリル、または２−ベンゾイミダゾリルの他に、４−、５−、６−または７−ベンゾイミダゾリルであってもよい。

In addition to 1-benzimidazolyl or 2-benzimidazolyl, 4-, 5-, 6-, or 7-benzimidazolyl may be used.

“R ^d1 and R ^d2 may combine with the carbon atoms to which they are bonded to form a 3- to 8-membered cycloalkane ring or a 3- to 8-membered cycloalkene ring” (1) R ^{when d1} and R ^d2 are bonded to the same carbon atom in the cyclic amino group to form a spiro ring with the cyclic amino group, and (2) R ^d1 and R ^d2 are different carbon atoms in the cyclic amino group To form a condensed ring or a bicyclo ring with a cyclic amino group. Specific examples include the groups shown below.

Examples of the substituent in the “optionally substituted 5- to 10-membered nitrogen-containing heteroaryl group”, “optionally substituted pyridyl group”, and “optionally substituted isoquinolinyl group” include (1 ) Halogen atom,
(2) a C _1-6 alkyl group (this group may be substituted with 1 to 3 identical or different halogen atoms),
(3) C _1-6 alkoxy group (this group may be substituted with 1 to 3 identical or different halogen atoms),
(4) a cyano group,
(5) an amino group (the group may be substituted with one or two groups of the same or different types selected from the group consisting of C _1-6 alkyl and C _3-7 cycloalkyl);
(6) a hydroxy group,
(7) C _1-6 alkylcarbonyl group (this group may be substituted with 1 to 3 identical or different halogen atoms)
(8) C _1-6 alkoxycarbonyl group (this group may be substituted with 1 to 3 identical or different halogen atoms),
(9) Aminocarbonyl group (the amino may be substituted with 1 or 2 groups of the same or different types selected from the group consisting of C _1-6 alkyl and C _3-7 cycloalkyl)
(10) a C _1-6 alkylsulfonyl group (the group may be substituted with 1 to 3 identical or different halogen atoms), and (11) an aminosulfonyl group (the amino is a C _1-6 alkyl) And may be substituted with the same or different 1-2 groups selected from the group consisting of C _3-7 cycloalkyl).
Preferably, a halogen atom or a C _1-6 alkyl group (this group may be substituted with 1 to 3 identical or different halogen atoms) is mentioned, and a fluorine atom is more preferred.

“N and m” are each independently 1 or 2; preferably, n is 1 and m is 1.
A “bond including a broken line” is a single bond or a double bond; preferably a single bond.

  Since the compounds of the present invention may exist in the form of hydrates and / or solvates, solvates such as these hydrates or ethanol solvates are also included in the compounds of the present invention. Further, the compounds of the present invention include all forms of crystal forms.

  Examples of the pharmaceutically acceptable salt of the compound represented by the formula (1) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; and formate and acetate , Trifluoroacetate, propionate, oxalate, succinate, lactate, malate, tartrate, citrate, maleate, malonate, fumarate, methanesulfonate, p Specific examples include organic acid salts such as toluene sulfonate, benzene sulfonate, and ascorbate.

  The compound represented by Formula (1) may exist as a tautomer. Therefore, this invention compound also includes the tautomer of the compound represented by Formula (1).

The compound represented by formula (1) may have at least one asymmetric carbon atom. Accordingly, the compound of the present invention includes not only the racemic form of the compound represented by the formula (1) but also optically active forms of these compounds. The compound represented by formula (1) may give rise to various stereoisomerisms. Therefore, this invention compound also includes the stereoisomer of these compounds, and its mixture.
In addition, a deuterium converter obtained by converting any one or two or more ¹ H of the compound represented by the formula (1) into ² H (D) is also included in the compound represented by the formula (1). .

Hereinafter, the production method of the compound of the present invention will be described with reference to examples, but the present invention is not limited to these examples. In this specification, the following abbreviations may be used for the sake of simplicity.
Boc group: tert-butoxycarbonyl group Cbz group: benzyloxycarbonyl group Alloc group: allyloxycarbonyl group Fmoc group: 9-fluorenylmethyloxycarbonyl group THF: tetrahydrofuran DMF: N, N-dimethylformamide

Production Method The compound of the present invention can be produced, for example, by the methods shown in the following production methods 1 to 3. These production methods can be improved as appropriate based on the knowledge of those skilled in organic synthesis. The compounds used as raw materials may be used as salts as necessary.

  In the following production method, even when the use of a protecting group is not specifically stated, when any functional group other than the reactive site changes under the reaction conditions described, or inappropriate for carrying out the described method In such a case, the desired product can be obtained by protecting the points other than the reaction point as necessary and deprotecting after completion of the reaction or after a series of reactions. As protecting groups, ordinary protecting groups described in literature (TWGreene and PGMWuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New York (1999)) are used. More specifically, specific examples of protecting groups for amino groups include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, benzyl and the like, and specific examples of hydroxy group protection include For example, trialkylsilyl, acetyl, benzyl and the like can be mentioned.

  The introduction and removal of protecting groups are commonly used in organic synthetic chemistry (eg, TWGreene and PGMWuts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999). Etc.)) or a method analogous thereto.

Manufacturing method 1
The compound represented by the formula (1) (hereinafter also referred to as “compound (1)”) is produced, for example, by the method shown below.

〔式中、ｍ、ｎ、Ｒ^ａ、Ｒ^ｂ、Ｒ^ｃ１、Ｒ^ｃ２、Ｒ^ｄ１、Ｒ^ｄ２、環Ｑ、破線を含む結合は、前記〔１〕と同義であり、ＬＧは、脱離基（ヨウ素原子、臭素原子、塩素原子、置換スルホニル基（例えば、メタンスルホニル基、ｐ-トルエンスルホニル基など））等を表す。〕

[Wherein, the bond including m, n, R ^a , R ^b , R ^c1 , R ^c2 , R ^d1 , R ^d2 , the ring Q and the broken line has the same meaning as the above [1], and LG is a leaving group (Iodine atom, bromine atom, chlorine atom, substituted sulfonyl group (for example, methanesulfonyl group, p-toluenesulfonyl group, etc.)) and the like. ]

  Compound (1) can be produced by reacting compound (3) with compound (4) in a suitable inert solvent. The reaction may be performed in the presence of a base, if necessary, in the presence of a phase transfer catalyst. The reaction temperature is usually in the range of about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw material, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, metal alkoxides such as sodium methoxide, potassium tert-butoxide, etc. It is done.
Specific examples of the phase transfer catalyst include, for example, tetrabutylammonium hydrogen sulfate.
Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.

  Among the compounds (1), the compound represented by the formula (1b) is reductive in a suitable inert solvent using the compound (3), the aldehyde or ketone represented by the formula (5), and a reducing agent. It is also produced by amination reaction. The reaction may be performed in the presence of a base or an acid as necessary. The reaction temperature is usually in the range from about -20 ° C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the reducing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.

Specific examples of the reducing agent include complex hydrogen compounds such as sodium triacetoxyborohydride, lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, diborane and borane complexes (borane-dimethylsulfide complex or borane). -Tetrahydrofuran complex).
Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride, metal alkoxides such as sodium methoxide, potassium tert-butoxide, etc. It is done.
Specific examples of the acid include organic acids such as acetic acid, trifluoroacetic acid and methanesulfonic acid, and inorganic acids such as hydrochloric acid and sulfuric acid.
Specific examples of the solvent include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane and the like. Examples include ether solvents, alcohol solvents such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone, and mixed solvents thereof.

  Among the compounds (1), the compound represented by the formula (1c) can also be produced by reacting the compound (7) with a reducing agent in an inert solvent. The reaction temperature is usually in the range of about −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours. Specific examples of the reducing agent include lithium aluminum hydride, borane complex (borane-dimethyl sulfide complex, borane-tetrahydrofuran complex, etc.), and the like. Specific examples of the inert solvent include ether solvents such as tetrahydrofuran and 1,4-dioxane, and mixed solvents thereof.

Compound (7) is produced by reacting compound (3) with a carboxylic acid represented by formula (6) in the presence of a condensing agent in an inert solvent. The reaction may be further performed in the presence of a base. The reaction temperature is usually in the range from about -20 ° C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.
Compound (7) can also be produced by reacting compound (3) with an acid halide or acid anhydride derived from compound (6) in the presence of a base in an inert solvent. The reaction temperature is usually in the range from about -20 ° C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the condensing agent used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.

  Specific examples of the condensing agent include, for example, dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide (WSC), benzotriazol-1-yl- Tris (dimethylamino) phosphonium hexafluorophosphide salt (BOP), diphenylphosphonyl diamide (DPPA), N, N-carbonyldimimidazole (CDI), benzotriazol-1-yl-N, N, N ′, N '-Tetramethyluronium hexafluorophosphide salt (HBTU) and the like. If necessary, for example, N-hydroxysuccinimide (HOSu), 1-hydroxybenzotriazole (HOBt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOOBt), etc. The additive can be added to carry out the reaction.

  Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal alkoxides such as sodium methoxide and potassium tert-butoxide It is done.

  Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; Examples include aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; basic solvents such as pyridine; or a mixed solvent thereof.

Manufacturing method 2
Among the compounds (3), the compounds represented by the formula (3a) and the formula (3b) are produced, for example, by the method shown below.

（式中、ｍ、ｎ、Ｒ^ｄ１、Ｒ^ｄ２、Ｒ^ｅ１およびＲ^ｅ２は前記〔１〕と同義である。）

(In the formula, m, n, R ^d1 , R ^d2 , R ^e1 and R ^e2 have the same ^{meanings as} the above [1].)

  Compound (3a) is produced by treating compound (8a) with an acid (for example, an inorganic acid such as hydrochloric acid or sulfuric acid or an organic acid such as trifluoroacetic acid) in a suitable inert solvent. The treatment temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the acid used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours. Specific examples of the inert solvent include, for example, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; diethyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, and the like. Ether solvents; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.

  Compound (3b) is produced from compound (8b) by treating in the same manner as in the production method of compound (3a).

Compound (8b) is produced by catalytic reduction of compound (8a) in a suitable inert solvent under normal pressure or pressurized hydrogen atmosphere. Specific examples of the catalyst used in this reduction reaction include palladium-based catalysts such as palladium carbon, rhodium-based catalysts such as rhodium carbon, platinum-based catalysts such as platinum carbon, and ruthenium-based catalysts such as ruthenium carbon. . The reaction temperature is usually in the range of 0 ° C to 50 ° C. The reaction time varies depending on conditions such as reaction temperature, catalyst used, raw material, and solvent, but is usually 10 minutes to 48 hours. Specific examples of the inert solvent include, for example, ester solvents such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane Solvents; Alcohol solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.
The other compounds represented by the formula (3) are commercially available, or can be produced using a known production method or a production method based thereon.

Production method 3
Compound (8a) is produced, for example, by the method shown below.

〔式中、ｍ、ｎ、Ｒ^ｄ１、Ｒ^ｄ２、Ｒ^ｅ１およびＲ^ｅ２は前記〔１〕と同義である。Ｗは、脱離基（例えば、トリフルオロメタンスルホニルオキシなどのスルホニルオキシ基など）を表し、Ｘは、ボロン酸基（−Ｂ（ＯＨ）_２）またはボロン酸エステル基（例えば、ピナコールボロン酸エステル基など）を表し、Ｙは、脱離基（例えば、塩素原子、臭素原子またはヨウ素原子などのハロゲン原子、トリフルオロメタンスルホニルオキシなどのスルホニルオキシ基など）を表し、Ｚは、ボロン酸基（−Ｂ（ＯＨ）_２）、ボロン酸エステル基（例えば、ピナコールボロン酸エステル基など）、有機スズ基（例えば、−Ｓｎ（ｎ−Ｂｕ）_４など）、または有機金属ピリジン化合物を形成するアルカリ土類金属（例えば、マグネシウム、亜鉛など）を表す。〕

[Wherein, m, n, R ^d1 , R ^d2 , R ^e1 and R ^e2 have the same ^{meanings as} the above [1]. W represents a leaving group (for example, a sulfonyloxy group such as trifluoromethanesulfonyloxy), and X represents a boronic acid group (—B (OH) ₂ ) or a boronic acid ester group (for example, pinacol boronic acid ester group). Y represents a leaving group (for example, a halogen atom such as a chlorine atom, a bromine atom or an iodine atom, a sulfonyloxy group such as trifluoromethanesulfonyloxy, etc.), and Z represents a boronic acid group (—B (OH) ₂ ), boronic acid ester groups (such as pinacol boronic acid ester groups), organotin groups (such as —Sn (n—Bu) ₄ ), or alkaline earth metals that form organometallic pyridine compounds (For example, magnesium, zinc, etc.). ]

  Compound (8a) is produced by subjecting compound (9c) and compound (9d) to a coupling reaction in a suitable inert solvent in the presence of a transition metal catalyst. The reaction can be performed in the presence of a ligand, a base, an additive, or the like as necessary. The reaction temperature is usually in the range from −10 ° C. to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the transition metal catalyst used, the raw materials, the solvent and the like, but is usually 10 minutes to 48 hours.

  Specific examples of the transition metal include, for example, palladium (II) acetate, palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0), tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine). Palladium chloride (II), dichlorobis (tri-O-tolylphosphine) palladium (II), bis (tri-tert-butylphosphine) palladium (0), or [1,1′-bis (diphenylphosphino) ferrocene] Examples include dichloropalladium (II).

  Specific examples of the ligand include, for example, triphenylphosphine, tri-O-tolylphosphine, tri-tert-butylphosphine, tri-2-furylphosphine, tricyclohexylphosphine, triphenylarsine, 1,1′-bis. (Diphenylphosphino) ferrocene, 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl and the like.

Specific examples of the base include organic bases such as triethylamine and diisopropylethylamine; inorganic bases such as sodium carbonate, sodium hydrogen carbonate, potassium carbonate, cesium carbonate, and potassium phosphate.
Specific examples of the additive include inorganic salts such as lithium chloride, cesium fluoride, copper (I) iodide, and copper (I) bromide.

  Specific examples of the inert solvent include water, acetonitrile, halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; 1,2-dimethoxyethane, tetrahydrofuran and 1,4-dioxane. And ether solvents such as methanol, ethanol and 2-propanol; aprotic polar solvents such as dimethylformamide and N-methyl-2-pyrrolidinone; and mixed solvents thereof.

  Compound (9c) is produced by coupling reaction of compound (9b) and alkoxodiboron (for example, bis (pinacolato) diboron) in an appropriate inert solvent in the presence of a transition metal catalyst. . The reaction conditions are the same as in the coupling reaction of compound (9c) and compound (9d) in the previous period.

  Compound (8a) can also be produced by subjecting compound (9b) and compound (9e) to a coupling reaction. The reaction conditions are the same as the coupling reaction of the compound (9c) and the compound (9d).

  Compound (9b) is obtained by reacting compound (9a) with a sulfonic acid anhydride (eg, trifluoromethanesulfonic acid anhydride) or a sulfonic acid imide [eg, N-phenyl] in a suitable inert solvent in the presence of a base. Bis (trifluoromethanesulfonimide) and the like]. The reaction temperature is usually in the range from −20 ° C. to the boiling point of the solvent used. The reaction time varies depending on conditions such as reaction temperature, base used, raw materials, and solvent, but is usually 10 minutes to 48 hours.

Specific examples of the base include, for example, organic bases such as triethylamine, diisopropylethylamine, pyridine; potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, phosphorus Inorganic bases such as potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, sodium hydride; metal amides such as lithium diisopropylamide and lithium hexamethylene disilazane It is done. Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane; or a mixed solvent thereof. Can be mentioned.
The compounds represented by the formulas (4), (5), (6), (9a), (9d) and (9e) in the above production methods are either commercially available, known production methods or modifications thereof. It can be manufactured using a manufacturing method.

  The intermediates and target compounds in each of the above production methods are isolated by purification methods commonly used in synthetic organic chemistry, such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. Can be purified. In addition, each intermediate can be subjected to the next reaction without any particular purification.

  The optically active form of the compound of the present invention can be produced by using optically active starting materials and intermediates, or by optical resolution of the final racemate. Examples of the optical resolution method include a physical separation method using an optically active column and a chemical separation method such as a fractional crystallization method. The diastereomer of the compound of the present invention is produced, for example, by a fractional crystallization method.

  The pharmaceutically acceptable salt of compound (1) is a solid formed by adding a corresponding pharmaceutically acceptable acid directly or a solution containing a pharmaceutically acceptable acid to a solution containing compound (1). It is manufactured by filtering.

  Examples of the solvent of the compound (1) or a pharmaceutically acceptable acid solution include water; alcohol solvents such as methanol, ethanol and 2-propanol; ether solvents such as tetrahydrofuran, dioxane and 1,2-dimethoxyethane; And aprotic solvents such as acetone and acetonitrile; or a mixed solvent thereof.

Examples of the pharmaceutically acceptable acid charging temperature include the melting point of the solvent used to the reflux temperature of the solvent used. Preferably, the temperature at which the compound is dissolved to the reflux temperature of the solvent used is used.
After adding a pharmaceutically acceptable acid, the mixture may be stirred for about 1 minute to 5 hours at a charging temperature to a boiling point of a solvent to be used, preferably at a charging temperature to 80 ° C.
The production and filtration of the solid can be performed, for example, by the following procedure.
(1) A method of filtering a solid precipitated from a solution containing the compound (1) and a pharmaceutically acceptable acid;
(2) A method of adding a poor solvent to a solution containing the compound (1) and a pharmaceutically acceptable acid, and collecting the precipitated solid by filtration;
(3) A method of drying a solution containing the compound (1) and a pharmaceutically acceptable acid, adding a poor solvent, and collecting the precipitated solid by filtration;
(4) A method in which a poor solvent is added after partially evaporating the solvent of the solution containing the compound (1) and a pharmaceutically acceptable acid, and the precipitated solid is filtered.
Here, the poor solvent means a solvent in which the solubility of the compound (1) is lower than the solvent of the solution containing the compound (1) and a pharmaceutically acceptable acid.
Examples of the poor solvent include ester solvents such as ethyl acetate, isopropyl acetate, and isobutyl acetate; ether solvents such as tetrahydrofuran, diethyl ether, methyl tertbutyl ether, diisopropyl ether, cyclopentylmethyl ether (CPME), and 1,4-dioxane. Examples thereof include hydrocarbon solvents such as hexane, heptane, cyclohexane, toluene, xylene and chlorobenzene.
In the case of using a poor solvent, 1 to 10,000% (W / W) of the poor solvent may be added to the solvent of the solution containing compound (1) and a pharmaceutically acceptable acid.
Fixed precipitation may be performed by stirring the solution at 0 ° C. to the reflux temperature of the solvent used for about 1 minute to 10 hours.
The temperature at which the solid is collected by filtration is not particularly limited, and preferably 0 ° C. to the reflux temperature of the solvent to be used.
Although the usage-amount of a pharmacologically acceptable acid is not specifically limited, The range of 0-5 mol (however, except the case of 0) is preferable with respect to 1 mol of compounds (1), 0.5-2 mol The range is more preferable, and the range of 0.5 to 1 mol is more preferable.

  Crystals of 2-methyl-5- [4- (pyridin-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine (hereinafter also referred to as “compound X”) are compound X (form A, B, non- Crystallized, and mixtures thereof). Examples of the method of “crystallization from solution” include a concentration method, a slow cooling method, a stirring method, a reaction method (diffusion method, electrolysis method) and the like, and a slow cooling method and a stirring method are preferable. The crystal of compound X can also be produced by suspending compound X in a solvent and then collecting the solid substance by filtration.

  Examples of the solvent include water; alcohol solvents such as methanol, ethanol, 2-propanol, and 2-butanol; tetrahydrofuran, diethyl ether, methyl tert butyl ether, diisopropyl ether, cyclopentyl methyl ether (CPME), 1,4-dioxane, 1 Ether solvents such as 1,2-dimethoxyethane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, diisobutyl ketone and cyclohexanone; aprotic solvents such as acetonitrile; ester solvents such as ethyl acetate, isopropyl acetate and isobutyl acetate Hydrocarbon solvents such as hexane, heptane, cyclohexane, toluene, xylene, chlorobenzene; or a mixed solvent thereof.

The concentration of Compound X in the solvent can be appropriately selected from the range of 0.5 to 50% (g / mL).
The melting temperature can be selected from the range of 10 to 90 ° C. The solution is usually 0-30 ° C., preferably slowly cooled / ripened to room temperature (about 20-30 ° C.) over 1-24 hours.

When a mixed solvent is used, the mixing ratio of a good solvent (a solvent having a relatively high solubility with respect to Compound X) and a poor solvent (a solvent having a relatively low solubility with respect to Compound X) is 1: 0.1. It can be suitably selected from the range of ˜100 (v / v). In this case, the poor solvent is preferably added dropwise to a solution obtained by dissolving the compound X in the good solvent.
The crystal of the present invention can be obtained by washing and drying the obtained crystal with the solvent used for filtration and crystallization.

  The crystal of Form A of Compound X is, for example, the crystal of Form A of Compound X, the above alcohol solvent, ether solvent, ketone solvent, aprotic solvent, ester solvent, hydrocarbon solvent, or these It is produced by dissolving or suspending in a mixed solvent of (2) and filtering the solid. Preferably, it is produced by a slow cooling method from a solution of ethanol, 2-propanol, acetone, isopropyl acetate, or a mixed solvent of these solvents and toluene or heptane, more preferably a mixed solvent of 2-propanol and heptane. Manufactured by a slow cooling method from

  The crystal of Form B of Compound X is produced, for example, by dissolving or suspending the crystal of Form A of Compound X in a water-acetone mixed solvent, and then filtering the solid.

  As a method for analyzing the compound (1) of the present invention thus obtained, a measurement method for analyzing a solid can be generally applied without limitation, but preferably, a diffraction angle in a powder X-ray diffraction spectrum ( 2θ, °) or lattice spacing (d, Å) and relative intensity (%). Although the measurement conditions of a powder X-ray diffraction spectrum are not specifically limited, It is preferable to measure on the measurement conditions described in this specification. Powder X-ray diffraction is important because of the nature of the data, the diffraction angle, crystal lattice spacing, and overall pattern are important in identifying the identity of the crystal, and the relative intensity is the crystal growth direction, particle size, and measurement. It should not be interpreted strictly as it can vary somewhat depending on conditions.

  Further, as a solid analysis method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), or the like may be used in combination. Although these measurement conditions are not specifically limited, It is preferable to measure on the measurement conditions as described in this specification.

Each spectrum obtained by these analysis methods has a certain measurement error due to its nature. A crystal having a peak whose spectral error is within the error range is also included in the scope of the present invention. For example, in the case of powder X-ray diffraction measurement, a crystal having a peak within an error range of ± 0.2 mm at a lattice plane distance represented by d, or a diffraction angle peak represented by 2θ is ± 0. Crystals having a peak within an error range of 2 ° are included in the present invention.
Further, ± 5 ° C. is allowed in the extrapolation start temperature (Tim), endothermic peak temperature (Tpm), etc. of the differential scanning calorimetry (DSC). Differential scanning calorimetry (DSC) extrapolation start temperature (Tim) refers to the temperature at which the extrapolated line of the rising portion of the endothermic peak curve and the baseline intersect, and the endothermic peak temperature (Tpm). Says the temperature at the peak top of the endothermic peak.

In a preferred embodiment of the compound of the present invention, those shown below are obtained as crystals and have the following physical property values.
(1) Crystal of Form A of Compound X In the powder X-ray diffraction spectrum, diffraction angles represented by 2θ are 11.9 °, 15.8 °, 16.1 °, 17.8 °, 20.3 °, Peaks at 20.5 °, 21.3 °, 21.4 °, 21.9 ° and 26.3 ° (each ± 0.2 °), preferably
It shows peaks at 11.9 °, 16.1 °, 17.8 °, 20.5 °, 21.4 °, 21.9 ° and 26.3 ° (each ± 0.2 °), more preferably , 11.9 °, 16.1 °, 17.8 ° and 20.5 ° (each ± 0.2 °).
In differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolation start temperature (Tim) at 134 ° C. (± 5 ° C.) is shown.

(2) Crystal of Form B of Compound X In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 5.9 °, 13.5 °, 16.1 °, 17.9 °, 18.2 °, 19.0 °, 19.7 °, 20.4 °, 21.6 °, 23.2 °, 23.6 °, 27.6 °, 28.0 °, 28.1 ° and 38.3 ° ( Each shows a peak at ± 0.2 °, preferably
5.9 °, 13.5 °, 16.1 °, 17.9 °, 18.2 °, 19.0 °, 20.4 °, 21.6 °, 28.0 ° and 28.1 ° ( Each shows a peak at ± 0.2 °, and more preferably 5.9 °, 17.9 °, 19.0 °, 20.4 °, 21.6 °, and 28.0 ° (each ± 0. 0). (2 °) shows a characteristic peak.
In differential scanning calorimetry (DSC), an endothermic exothermic peak accompanying a transition having an extrapolation start temperature (Tim) at 114 ° C. (± 5 ° C.) is shown, and an extrapolation start temperature (Tim) at 134 ° C. (± 5 ° C.) Shows an endothermic peak associated with melting of the transitioned crystal form.

(3) Crystal of 1.5 Succinate of Compound X In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 4.9 °, 14.8 °, 16.9 °, 17.4 °, 18 .6 °, 19.2 °, 19.8 °, 21.8 °, 22.1 °, 24.8 °, 26.6 °, 27.1 °, 29.8 ° and 31.2 ° (respectively Shows a peak at ± 0.2 °), preferably
Peaks at 4.9 °, 14.8 °, 17.4 °, 18.6 °, 19.2 °, 19.8 ° and 27.1 (each ± 0.2 °), more preferably Characteristic peaks are shown at 4.9 °, 14.8 °, 18.6 ° and 19.8 (each ± 0.2 °).
In the differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolation start temperature (Tim) at 167 ° C. (± 5 ° C.) is shown.

(4) Crystal of 1.5 fumarate salt of Compound X In the powder X-ray diffraction spectrum, the diffraction angles represented by 2θ are 4.9 °, 14.6 °, 17.3 °, 18.6 °, 19 Peaks at .2 °, 19.5 °, 21.7 °, 22.1 °, 26.4 °, 27.4 °, 27.9 ° and 30.9 ° (each ± 0.2 °) ,Preferably,
Peaks at 4.9 °, 14.6 °, 17.3 °, 19.2 °, 19.5 °, 22.1 °, 27.9 ° and 30.9 ° (each ± 0.2 °) More preferably, characteristic peaks are exhibited at 4.9 °, 14.6 °, 17.3 ° and 19.5 ° (each ± 0.2 °).
In differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolation onset temperature (Tim) at 196 ° C. (± 5 ° C.) is shown.

Since the compound of the present invention is a dopamine D ₄ receptor agonist, it is a central nervous disease exhibiting symptoms similar to ADHD, for example, autism spectrum disorder (diagnosis and statistical guide 5th edition of mental disorders (DSM- 5) Autism spectrum disorder that was classified as autism, Asperger's syndrome, atypical pervasive developmental disorder, and childhood disintegrative disorder in conventional DSM-5), ADHD-like It can be a therapeutic agent for schizophrenia showing symptoms, mood disorder, cognitive dysfunction, etc. The compound of the present invention can be used in combination with a central stimulant such as methylphenidate, a selective noradrenaline reuptake inhibitor such as atomoxetine, various schizophrenia therapeutic agents and the like. ADHD (attention deficit hyperactivity disorder) is sometimes translated as “attention deficit hyperactivity disorder” or “attention deficit hyperactivity disorder” or “attention deficit hyperactivity disorder” (DSM-5 disease name / term) See translation guidelines).

One of the etiology hypotheses of autism spectrum disorder is the lack of synchrony of neural networks associated with the excitability-inhibitory neurotransmitter imbalance in the cerebral cortex. It has been observed that amplification improves this imbalance. Dopamine D ₄ receptor agonists can be amplified γ waves in the cerebral cortex it has been reported.
On the other hand, oxytocin, a hormone produced in the hypothalamus, has been reported to be involved in social cognition, suggesting an association with autism. Since dopamine D ₄ receptors are highly expressed in oxytocin-producing neurons expressed in the hypothalamic paraventricular nucleus, dopamine D ₄ receptor agonists activate oxytocin-producing neurons and promote oxytocin release in the brain. It is expected.
From the above, a dopamine D ₄ receptor agonist can be a therapeutic agent for autism spectrum disorder through the γ-wave amplification effect in the cerebral cortex and the oxytocin release promoting effect in the hypothalamus.

The compound of the present invention is suitably used for the treatment of ADHD and autism spectrum disorder.
As a treatment for ADHD, it is particularly preferably used for ADHD whose main symptoms are attention deficit (Inattention), hyperactivity (Hyperactivity), and impulsivity (Impulsivity).
The treatment of autism spectrum disorders includes, among other things, persistent deficits in social communication and social interaction, and autism spectrum disorders whose main symptoms are limited repetitive behaviors, interests and activities. Is preferably used.

Adrenergic α _1A receptors are known to be distributed in the sympathetic post-synaptic region, and the agonists are known to increase blood pressure by vasoconstriction.
The present invention compounds exhibit a selective strong effect on dopamine D ₄ receptor, since the action of the adrenergic alpha _1A receptor which is another GPCR is weak, it is reduced side effects cardiovascular safety High can be expected.

After the pharmaceutical compound is taken into the living body, it undergoes metabolism to change its chemical structure, producing highly reactive intermediates, ie reactive metabolites, and toxicity (liver toxicity, allergy, tissue necrosis, mutagen) Sex, carcinogenicity, etc.). One of the tests for easily evaluating the toxicity risk due to this reactive metabolite is a glutathione (GSH) trapping test using dansylated glutathione (dGSH). The higher the dGSH covalent bond value, the higher the toxicity risk when exposed to whole body.
Since the compound of the present invention has an extremely low dGSH covalent bond amount (Test Example 5), it is expected that the compound has a low risk such as liver toxicity and can be safely administered over a long period of time.

  The compound of the present invention can be administered orally or parenterally. When administered orally, it can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal preparation, nasal preparation and the like. Examples of the oral agent or rectal administration agent include capsules, tablets, pills, powders, cachets, suppositories, and liquids. Examples of injections include sterile solutions or suspensions. Examples of the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.

The above-mentioned dosage form is formulated by a usual method together with pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.
Examples of the pharmaceutically acceptable carrier include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting point wax, cocoa butter Etc. Capsules can be formulated by placing the compound of the present invention in a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachets can be produced in the same manner.

  Examples of the liquid for injection include solutions, suspensions, emulsions and the like. Examples thereof include an aqueous solution and a water-propylene glycol solution. The solution can also be prepared in the form of a solution of polyethylene glycol and / or propylene glycol, which may contain water. A solution suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. A solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water to make it viscous. Examples of the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.

  The dose varies depending on the individual compound and the disease, age, weight, sex, symptom, route of administration, etc. of the patient, but usually 0.1 to 1000 mg of the compound of the present invention for an adult (50 kg body weight). / Day, preferably 0.1 to 300 mg / day, once a day or divided into 2 to 3 times. It can also be administered once every few days to several weeks.

  The purity of the crystal of the present invention can be determined by a known method such as powder X-ray diffraction measurement or thermal analysis. The purity of the crystal of the present invention is not necessarily 100%, and is usually 70% or more, preferably 80% or more, more preferably 90% or more, further preferably 95% or more, and most preferably 98% or more. It is. It is preferable that the purity is within this range in order to guarantee the quality as a pharmaceutical product.

  Crystal purity means the ratio (purity) of a compound in a specific crystal form to the total amount of crystals.

Hereinafter, the present invention will be described more specifically with reference to reference examples, examples and test examples, but the present invention is not limited thereto. In addition, the compound names shown in the following Reference Examples and Examples do not necessarily follow the IUPAC nomenclature. In addition, although abbreviations may be used for simplification of description, these abbreviations have the same meanings as described above.
The compound was identified using proton nuclear magnetic resonance absorption spectrum ( ¹ H-NMR), LC-MS, and the like. In the reference examples and examples, amino columns manufactured by Yamazen Co., Ltd. were used. LC-MS was measured using various conditions shown in Table 1 below. Retention time (RT) represents the time when a mass spectrum peak appeared in LC-MS measurement.

The powder X-ray diffraction measurement was performed under the following conditions.
・ Apparatus: X'pert-MPD (Spectris)
· _{X-ray: Cu Kα 1/45 kV /} 40 mA
-Incident slit: 15 mm (automatic) / divergence prevention slit: 15 mm (automatic)
・ Step size: 0.017 °
Scanning range: 4-40 ° (2θ)
-Integration time: 100 seconds / step

Differential scanning calorimetry (DSC) was performed under the following conditions.
・ Device: DSCQ1000 (manufactured by TA Instruments)
・ Measurement temperature range: 10 ~ 300 ℃
・ Temperature increase rate: 10 ° C./min ・ Container: Aluminum hermetic pan (Pin hole)
・ Atmospheric gas flow rate: Dry nitrogen, about 50mL / min

Thermogravimetry (TGA) can be measured under the following conditions.
・ Device: TGAQ500 (TA Instruments)
・ Measurement temperature range: Room temperature to 300 ℃
・ Temperature increase rate: 10 ° C./min ・ Vessel: Platinum pan ・ Atmospheric gas flow rate: Dry nitrogen, sample flow rate about 60 mL / min, balance flow rate about 40 mL / min

In the present specification, the following abbreviations may be used. The following abbreviations are used in the NMR data of Reference Examples and Examples.
Me group: methyl group Et group: ethyl group Boc group: tert-butoxycarbonyl group tert-: tertiary s: singlet
brs: Broad singlet
d: Doublet
t: triplet
m: multiplet
br: broad
J: coupling constant
Hz: Hertz
CDCl ₃ : deuterated chloroform DMSO-d ₆ : deuterated dimethyl sulfoxide MeOH: methanol EtOH: ethanol IPA: isopropyl alcohol (2-propanol)
THF: Tetrahydrofuran CPME: Cyclopentyl methyl ether

Example 1
5- (3 ', 6'-dihydro-2,4'-bipyridin-1' (2'H) -ylmethyl) -2-methylpyrimidin-4-amine

参考例１の化合物（１８０ｍｇ，０．７７３ｍｍｏｌ）のジメチルホルムアミド溶液（３．０ｍＬ）に炭酸カリウム（５３４ｍｇ，３．８７ｍｍｏｌ）と５−（クロロメチル）−２−メチルピリミジン−４−アミン塩酸塩（１５０ｍｇ，０．７７３ｍｍｏｌ）を加えた。室温で１５時間撹拌後、水（３０ｍＬ）を加え、酢酸エチル（２０ｍＬ）で６回抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０から５０：５０まで）で精製した後、アミノカラムクロマトグラフィー（ｎ−ヘキサン：酢酸エチル＝５７：４３から１２：８８まで）で精製した。得られた精製物に酢酸エチル（０．５ｍＬ）を加え、室温で３０分間撹拌後、ｎ−ヘキサン（１．５ｍＬ）を加え、さらに、室温で３０分間撹拌し、析出物をろ取し、表題化合物（１０７ｍｇ，４９％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 2.50 (3H, s), 2.76-2.62 (4H, m), 3.22-3.14 (2H, m), 3.57 (2H, s), 6.63 (1H, brs), 7.18-7.13 (1H, m), 7.37 (1H, brd, J = 7.9 Hz), 7.65 (1H, ddd, J = 7.9, 1.8, 1.8 Hz), 7.97 (1H, s), 8.56 (1H, brd, J = 5.0 Hz).

To a solution of the compound of Reference Example 1 (180 mg, 0.773 mmol) in dimethylformamide (3.0 mL) was added potassium carbonate (534 mg, 3.87 mmol) and 5- (chloromethyl) -2-methylpyrimidin-4-amine hydrochloride ( 150 mg, 0.773 mmol) was added. After stirring at room temperature for 15 hours, water (30 mL) was added, and the mixture was extracted 6 times with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 50:50) and then amino column chromatography (n-hexane: ethyl acetate = 57: 43 to 12:88). Purified. Ethyl acetate (0.5 mL) was added to the purified product obtained, and after stirring at room temperature for 30 minutes, n-hexane (1.5 mL) was added, and further stirred at room temperature for 30 minutes, and the precipitate was collected by filtration. The title compound (107 mg, 49%) was obtained.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 2.50 (3H, s), 2.76-2.62 (4H, m), 3.22-3.14 (2H, m), 3.57 (2H, s), 6.63 (1H, brs) , 7.18-7.13 (1H, m), 7.37 (1H, brd, J = 7.9 Hz), 7.65 (1H, ddd, J = 7.9, 1.8, 1.8 Hz), 7.97 (1H, s), 8.56 (1H, brd , J = 5.0 Hz).

Example 2
5- (3 ', 6'-dihydro-3,4'-bipyridin-1' (2'H) -ylmethyl) -2-methylpyrimidin-4-amine

参考例２の化合物（２０ｇ，８５．８ｍｍｏｌ）のジクロロメタン溶液（４２０ｍＬ）に氷冷下トリエチルアミン（２７．５ｍＬ，１９７ｍｍｏｌ）を加え、室温で２０分間撹拌後、氷冷下、参考例２１の化合物（１２．９ｇ，９４．４ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（２７．３ｇ，１２９ｍｍｏｌ）を加えた。室温で１．５時間撹拌後、氷冷下、水素化トリアセトキシホウ素ナトリウム（１８．２ｇ，８５．８ｍｍｏｌ）を加え、室温でさらに２０時間撹拌した。その後、反応混合物に氷冷下、１０％炭酸カリウム水溶液（４２０ｍＬ）を加え、有機層を分抽し、さらにクロロホルム（１００ｍＬ）で２回抽出した。有機層を合わせて、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０から９７：３まで）で精製し、表題化合物（１９．７ｇ，８２％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 2.51 (3H, s), 2.61-2.52 (2H, m), 2.72 (2H, t, J = 5.7 Hz), 3.16 (2H, dd, J = 2.9, 2.9 Hz), 3.56 (2H, s), 6.16-6.10 (1H, m), 7.28-7.22 (1H, m), 7.65 (1H, ddd, J = 8.1, 2.0, 2.0 Hz), 7.98 (1H, s), 8.49 (1H, dd, J = 4.8, 1.7 Hz), 8.66 (1H, brd, J = 2.0 Hz).

Triethylamine (27.5 mL, 197 mmol) was added to a dichloromethane solution (420 mL) of the compound of Reference Example 2 (20 g, 85.8 mmol) under ice cooling, and the mixture was stirred at room temperature for 20 minutes. 12.9 g, 94.4 mmol) and sodium triacetoxyborohydride (27.3 g, 129 mmol) were added. After stirring at room temperature for 1.5 hours, sodium triacetoxyborohydride (18.2 g, 85.8 mmol) was added under ice cooling, and the mixture was further stirred at room temperature for 20 hours. Thereafter, 10% aqueous potassium carbonate solution (420 mL) was added to the reaction mixture under ice-cooling, the organic layer was extracted, and further extracted twice with chloroform (100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 97: 3) to obtain the title compound (19.7 g, 82%).
¹ H-NMR (300MHz, CDCl ₃ ) δ: 2.51 (3H, s), 2.61-2.52 (2H, m), 2.72 (2H, t, J = 5.7 Hz), 3.16 (2H, dd, J = 2.9, 2.9 Hz), 3.56 (2H, s), 6.16-6.10 (1H, m), 7.28-7.22 (1H, m), 7.65 (1H, ddd, J = 8.1, 2.0, 2.0 Hz), 7.98 (1H, s ), 8.49 (1H, dd, J = 4.8, 1.7 Hz), 8.66 (1H, brd, J = 2.0 Hz).

Example 3
5- (3-Fluoro-3 ', 6'-dihydro-2,4'-bipyridin-1' (2'H) -ylmethyl) -2-methylpyrimidin-4-amine

参考例７の化合物（５０ｍｇ，０．１９９ｍｍｏｌ）のジクロロメタン溶液（１．５ｍＬ）にトリエチルアミン（０．０５５４ｍＬ，０．３９８ｍｍｏｌ）を加え、室温で１０分間撹拌後、参考例２１の化合物（３０ｍｇ，０．２１９ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（６３．３ｍｇ，０．２９９ｍｍｏｌ）を加えた。室温で１時間撹拌後、水素化トリアセトキシホウ素ナトリウム（４２．２ｍｇ，０．１９９ｍｍｏｌ）を加え、室温でさらに３時間撹拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液（２０ｍＬ）を加え、クロロホルム（２０ｍＬ）で２回抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０から９７：３まで）で精製し、表題化合物（４５．０ｍｇ，７６％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 2.50 (3H, s), 2.77-2.67 (4H, m), 3.23-3.16 (2H, m), 3.57 (2H, s), 6.57-6.52 (1H, m), 7.20-7.13 (1H, m), 7.38 (1H, ddd, J = 11.6, 8.3, 1.5 Hz), 7.97 (1H, s), 8.38 (1H, ddd, J = 3.1, 1.5, 1.5 Hz).

Triethylamine (0.0554 mL, 0.398 mmol) was added to a dichloromethane solution (1.5 mL) of the compound of Reference Example 7 (50 mg, 0.199 mmol), stirred for 10 minutes at room temperature, and then the compound of Reference Example 21 (30 mg, 0 .219 mmol) and sodium triacetoxyborohydride (63.3 mg, 0.299 mmol) were added. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (42.2 mg, 0.199 mmol) was added, and the mixture was further stirred at room temperature for 3 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted twice with chloroform (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 97: 3) to obtain the title compound (45.0 mg, 76%).
¹ H-NMR (300MHz, CDCl ₃ ) δ: 2.50 (3H, s), 2.77-2.67 (4H, m), 3.23-3.16 (2H, m), 3.57 (2H, s), 6.57-6.52 (1H, m), 7.20-7.13 (1H, m), 7.38 (1H, ddd, J = 11.6, 8.3, 1.5 Hz), 7.97 (1H, s), 8.38 (1H, ddd, J = 3.1, 1.5, 1.5 Hz) .

Example 4
5- (5-Fluoro-3 ', 6'-dihydro-3,4'-bipyridin-1' (2'H) -ylmethyl) -2-methylpyrimidin-4-amine

参考例１３の化合物から、実施例３と同様の手法により、表題化合物（５９％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 2.50 (3H, s), 2.52-2.58 (2H, m), 2.72 (2H, t, J = 5.7 Hz), 3.13-3.19 (2H, m), 3.56 (2H, s), 6.15-6.21 (1H, m), 7.33-7.39 (1H, m), 7.98 (1H, s), 8.36 (1H, brd, J = 2.6 Hz), 8.48 (1H, brs).

The title compound (59%) was obtained from the compound of Reference Example 13 by the same method as in Example 3.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 2.50 (3H, s), 2.52-2.58 (2H, m), 2.72 (2H, t, J = 5.7 Hz), 3.13-3.19 (2H, m), 3.56 (2H, s), 6.15-6.21 (1H, m), 7.33-7.39 (1H, m), 7.98 (1H, s), 8.36 (1H, brd, J = 2.6 Hz), 8.48 (1H, brs).

Example 5
2-Methyl-5- [4- (pyridin-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例３の化合物から、実施例１と同様の手法により、表題化合物（８０％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 1.77-2.00 (4H, m), 2.11 (2H, td, J = 11.6, 2.5 Hz), 2.49 (3H, s), 2.66-2.78 (1H, m), 2.93-3.04 (2H, m), 3.46 (2H, s), 7.10-7.19 (2H, m), 7.62 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 7.93 (1H, s), 8.53-8.57 (1H, m).

補外開始温度：１３４℃〜１３５℃

The title compound (80%) was obtained from the compound of Reference Example 3 by the same method as in Example 1.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.77-2.00 (4H, m), 2.11 (2H, td, J = 11.6, 2.5 Hz), 2.49 (3H, s), 2.66-2.78 (1H, m) , 2.93-3.04 (2H, m), 3.46 (2H, s), 7.10-7.19 (2H, m), 7.62 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 7.93 (1H, s), 8.53 -8.57 (1H, m).

Extrapolation start temperature: 134 ° C to 135 ° C

Example 6
2-Methyl-5- [4- (pyridin-3-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例１１の化合物から、実施例１と同様の手法により、表題化合物（８０％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 1.77-2.00 (4H, m), 2.11 (2H, td, J = 11.6, 2.5 Hz), 2.49 (3H, s), 2.66-2.78 (1H, m), 2.93-3.04 (2H, m), 3.46 (2H, s), 7.10-7.19 (2H, m), 7.62 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 7.93 (1H, s), 8.53-8.57 (1H, m).

The title compound (80%) was obtained from the compound of Reference Example 11 by the same method as in Example 1.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.77-2.00 (4H, m), 2.11 (2H, td, J = 11.6, 2.5 Hz), 2.49 (3H, s), 2.66-2.78 (1H, m) , 2.93-3.04 (2H, m), 3.46 (2H, s), 7.10-7.19 (2H, m), 7.62 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 7.93 (1H, s), 8.53 -8.57 (1H, m).

Example 7
5- [4- (5-Fluoropyridin-3-yl) piperidin-1-ylmethyl] -2-methylpyrimidin-4-amine

参考例１３の化合物（６０ｍｇ，０．２４ｍｍｏｌ）のメタノール溶液（２ｍＬ）に１０％パラジウム／炭素（２５ｍｇ）を加え、水素雰囲気下、室温で１時間撹拌した。その後、セライトろ過し濃縮した。得られた濃縮残渣をジクロロメタン（３ｍＬ）に溶解し、これにトリエチルアミン（０．０６７ｍＬ，０．４８ｍｍｏｌ）を加え、室温で１０分間撹拌後、参考例２１の化合物（３３ｍｇ，０．２４ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（７６ｍｇ，０．３６ｍｍｏｌ）を加え、室温で３時間撹拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液（２０ｍＬ）を加え、クロロホルム（２０ｍＬ）で２回抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過し濃縮した。得られた残渣をアミノカラムクロマトグラフィー（酢酸エチル：ヘキサン＝５０：５０）で精製し、表題化合物（２５ｍｇ，３４％）を得た。
¹H-NMR (400MHz, CDCl₃) δ：1.65-1.76 (m, 2H), 1.89-1.93 (m, 2H), 2.08-2.15 (m, 2H), 2.50 (s, 3H), 2.60-2.68 (m, 1H), 3.00 (d, J = 11.7 Hz, 2H), 3.46 (s, 2H), 7.24-7.28 (m, 1H), 7.95 (s, 1H), 8.32-8.33 (m, 2H).

To a methanol solution (2 mL) of the compound of Reference Example 13 (60 mg, 0.24 mmol) was added 10% palladium / carbon (25 mg), and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. Thereafter, the mixture was filtered through celite and concentrated. The obtained concentrated residue was dissolved in dichloromethane (3 mL), triethylamine (0.067 mL, 0.48 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Then, the compound of Reference Example 21 (33 mg, 0.24 mmol) and hydrogen were added. Sodium triacetoxyborohydride (76 mg, 0.36 mmol) was added and stirred at room temperature for 3 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted twice with chloroform (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by amino column chromatography (ethyl acetate: hexane = 50: 50) to obtain the title compound (25 mg, 34%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.65-1.76 (m, 2H), 1.89-1.93 (m, 2H), 2.08-2.15 (m, 2H), 2.50 (s, 3H), 2.60-2.68 ( m, 1H), 3.00 (d, J = 11.7 Hz, 2H), 3.46 (s, 2H), 7.24-7.28 (m, 1H), 7.95 (s, 1H), 8.32-8.33 (m, 2H).

Example 8
5- [4- (Isoquinolin-1-yl) piperidin-1-yl] methyl] -2-methylpyrimidin-4-amine

参考例１５の化合物（２８５ｍｇ，１．０ｍｍｏｌ）のアセトニトリル溶液（５．０ｍＬ）に炭酸カリウム（４１５ｍｇ，３．０ｍｍｏｌ）とヨウ化カリウム（１９９ｍｇ，１．２ｍｍｏｌ）と５−（クロロメチル）−２−メチルピリミジン−４−アミン塩酸塩（２３３ｍｇ，１．２ｍｍｏｌ）を加えた。６０℃で１８時間撹拌後、反応混合物をろ過し、濃縮した。得られた残渣を分取高速液体クロマトグラフィーで精製し、表題化合物（３０．０ｍｇ，９％）を得た。
¹H-NMR (400MHz, CD₃OD) δ: 1.85-1.95 (2H, m), 2.05-2.17 (2H, m), 2.23-2.34 (2H, m), 2.42 (3H, s), 2.96-3.06 (2H, m), 3.53 (2H, s), 3.65-3.75 (1H, m), 7.64 (1H, d, J = 6.0 Hz), 7.65-7.71 (1H, m), 7.72-7.78 (1H, m), 7.87-7.94 (2H, m), 8.30-8.38 (2H, m).

To an acetonitrile solution (5.0 mL) of the compound of Reference Example 15 (285 mg, 1.0 mmol), potassium carbonate (415 mg, 3.0 mmol), potassium iodide (199 mg, 1.2 mmol) and 5- (chloromethyl) -2 -Methylpyrimidin-4-amine hydrochloride (233 mg, 1.2 mmol) was added. After stirring at 60 ° C. for 18 hours, the reaction mixture was filtered and concentrated. The obtained residue was purified by preparative high performance liquid chromatography to give the title compound (30.0 mg, 9%).
¹ H-NMR (400MHz, CD ₃ OD) δ: 1.85-1.95 (2H, m), 2.05-2.17 (2H, m), 2.23-2.34 (2H, m), 2.42 (3H, s), 2.96-3.06 (2H, m), 3.53 (2H, s), 3.65-3.75 (1H, m), 7.64 (1H, d, J = 6.0 Hz), 7.65-7.71 (1H, m), 7.72-7.78 (1H, m ), 7.87-7.94 (2H, m), 8.30-8.38 (2H, m).

Example 9
5- [4- (Isoquinolin-3-yl) piperidin-1-ylmethyl] -2-methylpyrimidin-4-amine

参考例１８の化合物から、実施例８と同様の手法により、表題化合物（７．５％）を得た。
¹H-NMR (400MHz, CD₃OD) δ: 1.91-2.12 (2H, m), 2.32-2.43 (2H, m), 2.48 (3H, s), 2.86-3.00 (1H, m), 3.08-3.17 (2H, m), 3.65 (2H, s), 7.65 (1H, dd, J = 7.2, 7.2 Hz), 7.68 (1H, s), 7.76 (1H, dd, J = 7.4, 7.4 Hz), 7.90 (1H, d, J = 8.4 Hz), 8.00 (1H, s), 8.06 (1H, d, J = 8.0 Hz), 9.18 (1H, s).

The title compound (7.5%) was obtained from the compound of Reference Example 18 by the same method as in Example 8.
¹ H-NMR (400MHz, CD ₃ OD) δ: 1.91-2.12 (2H, m), 2.32-2.43 (2H, m), 2.48 (3H, s), 2.86-3.00 (1H, m), 3.08-3.17 (2H, m), 3.65 (2H, s), 7.65 (1H, dd, J = 7.2, 7.2 Hz), 7.68 (1H, s), 7.76 (1H, dd, J = 7.4, 7.4 Hz), 7.90 ( 1H, d, J = 8.4 Hz), 8.00 (1H, s), 8.06 (1H, d, J = 8.0 Hz), 9.18 (1H, s).

Example 10
5- (3 ', 6'-dihydro-2,4'-bipyridin-1' (2'H) -ylmethyl) -2-ethylpyrimidin-4-amine

参考例１の化合物（２３３ｍｇ，１．０ｍｍｏｌ）のメタノール溶液（３．０ｍＬ）に参考例２３の化合物（１５１ｍｇ，１．０ｍｍｏｌ）と水素化シアノホウ素ナトリウム（１２６ｍｇ，２．０ｍｍｏｌ）を加えた。４５℃で１６時間撹拌後、反応混合物を分取高速液体カラムクロマトグラフィーにて精製し、表題化合物（５３．２ｍｇ，１８％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.32 (3H, t, J = 7.6 Hz), 2.64-2.81 (6H, m), 3.16-3.24 (2H, m), 3.57 (2H, s), 6.60-6.66 (1H, m), 7.15 (1H, dd, J = 6.8, 5.2 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.65 (1H, dd, J = 7.6, 6.0 Hz), 8.01 (1H, s), 8.56 (1H, d, J = 3.6 Hz).

To a methanol solution (3.0 mL) of the compound of Reference Example 1 (233 mg, 1.0 mmol), the compound of Reference Example 23 (151 mg, 1.0 mmol) and sodium cyanoborohydride (126 mg, 2.0 mmol) were added. After stirring at 45 ° C. for 16 hours, the reaction mixture was purified by preparative high performance liquid column chromatography to obtain the title compound (53.2 mg, 18%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.32 (3H, t, J = 7.6 Hz), 2.64-2.81 (6H, m), 3.16-3.24 (2H, m), 3.57 (2H, s), 6.60 -6.66 (1H, m), 7.15 (1H, dd, J = 6.8, 5.2 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.65 (1H, dd, J = 7.6, 6.0 Hz), 8.01 ( 1H, s), 8.56 (1H, d, J = 3.6 Hz).

Examples 11-28
The compounds of Examples 11 to 28 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 10.

Example 29
1 '-[(2-methylpyrimidin-5-yl) methyl] -1', 2 ', 3', 6'-tetrahydro-2,4'-bipyridine

参考例１の化合物（３０ｍｇ，０．１２９ｍｍｏｌ）のジメチルホルムアミド溶液（１．５ｍＬ）に炭酸カリウム（８９．１ｍｇ，０．６４５ｍｍｏｌ）と５−（クロロメチル）−２−メチルピリミジン（１８．３ｍｇ，０．１２９ｍｍｏｌ）を加えた。室温で１５時間撹拌後、反応混合物をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０から９５：５まで）で精製し、表題化合物（８．６ｍｇ，２５％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 2.64-2.72 (2H, m), 2.72-2.75 (2H, m), 2.75 (3H, s), 3.22-3.28 (2H, m), 3.63 (2H, s), 6.59-6.64 (1H, m), 7.14 (1H, ddd, J = 7.5, 4.8, 1.1 Hz), 7.35-7.39 (1H, m), 7.64 (1H, ddd, J = 7.8, 7.8, 1.8 Hz), 8.54-8.58 (1H, m), 8.65 (2H, s).

To a solution of the compound of Reference Example 1 (30 mg, 0.129 mmol) in dimethylformamide (1.5 mL) was added potassium carbonate (89.1 mg, 0.645 mmol) and 5- (chloromethyl) -2-methylpyrimidine (18.3 mg, 0.129 mmol) was added. After stirring at room temperature for 15 hours, the reaction mixture was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 95: 5) to obtain the title compound (8.6 mg, 25%).
¹ H-NMR (300MHz, CDCl ₃ ) δ: 2.64-2.72 (2H, m), 2.72-2.75 (2H, m), 2.75 (3H, s), 3.22-3.28 (2H, m), 3.63 (2H, s), 6.59-6.64 (1H, m), 7.14 (1H, ddd, J = 7.5, 4.8, 1.1 Hz), 7.35-7.39 (1H, m), 7.64 (1H, ddd, J = 7.8, 7.8, 1.8 Hz), 8.54-8.58 (1H, m), 8.65 (2H, s).

Examples 30-32
The compounds of Examples 30 to 32 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 29.

Example 33
5- [4- (5-Fluoropyridin-3-yl) piperidin-1-ylmethyl] -2-methylpyrimidine

参考例１３の化合物から、実施例７と同様の手法により、表題化合物（３４％）を得た。
¹H−NMR (400MHz, CDCl₃) δ：1.72-1.90 (m, 4H), 2.15 (t, J = 11.7 Hz, 2H), 2.58-2.66 (m, 1H), 2.74 (s, 3H), 3.00 (d, J = 11.2 Hz, 2H), 3.53 (s, 2H), 7.25-7.30 (m, 1H), 8.32 (s, 2H), 8.61 (s, 2H).

The title compound (34%) was obtained from the compound of Reference Example 13 by the same method as in Example 7.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.72-1.90 (m, 4H), 2.15 (t, J = 11.7 Hz, 2H), 2.58-2.66 (m, 1H), 2.74 (s, 3H), 3.00 (d, J = 11.2 Hz, 2H), 3.53 (s, 2H), 7.25-7.30 (m, 1H), 8.32 (s, 2H), 8.61 (s, 2H).

Example 34
5- (3 ', 6'-dihydro-2,4'-bipyridin-1' (2'H) -ylmethyl) pyrimidin-2-amine

参考例１の化合物（３０ｍｇ，０．１２９ｍｍｏｌ）のジクロロメタン溶液（１．５ｍＬ）にトリエチルアミン（０．０３６ｍＬ，０．２５８ｍｍｏｌ）を加え、室温で１０分間撹拌後、２−アミノピリミジン−５−カルボキシアルデヒド（１５．９ｍｇ，０．１２９ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（４１．０ｍｇ，０．１９４ｍｍｏｌ）を加えた。室温で１．５時間撹拌後、水素化トリアセトキシホウ素ナトリウム（４１．０ｍｇ，０．１９４ｍｍｏｌ）を加え、室温でさらに２４時間撹拌した。その後、反応混合物に飽和炭酸水素ナトリウム水溶液（２０ｍＬ）を加え、クロロホルム（２０ｍＬ）で２回抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１００：０から９０：１０まで）で精製し、表題化合物（２０．１ｍｇ，５８％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 2.65-2.70 (2H, m), 2.71-2.75 (2H, m), 3.20-3.24 (2H, m), 3.50 (2H, s), 4.99 (2H, brs), 6.60-6.64 (1H, m), 7.13 (1H, ddd, J = 7.4, 4.8, 1.0 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.63 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 8.30 (2H, s), 8.54-8.57 (1H, m).

Triethylamine (0.036 mL, 0.258 mmol) was added to a dichloromethane solution (1.5 mL) of the compound of Reference Example 1 (30 mg, 0.129 mmol), stirred at room temperature for 10 minutes, and then 2-aminopyrimidine-5-carboxaldehyde. (15.9 mg, 0.129 mmol) and sodium triacetoxyborohydride (41.0 mg, 0.194 mmol) were added. After stirring at room temperature for 1.5 hours, sodium triacetoxyborohydride (41.0 mg, 0.194 mmol) was added, and the mixture was further stirred at room temperature for 24 hours. Thereafter, a saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture, and the mixture was extracted twice with chloroform (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 100: 0 to 90:10) to obtain the title compound (20.1 mg, 58%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.65-2.70 (2H, m), 2.71-2.75 (2H, m), 3.20-3.24 (2H, m), 3.50 (2H, s), 4.99 (2H, brs), 6.60-6.64 (1H, m), 7.13 (1H, ddd, J = 7.4, 4.8, 1.0 Hz), 7.37 (1H, d, J = 8.0 Hz), 7.63 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 8.30 (2H, s), 8.54-8.57 (1H, m).

Examples 35-37
The compounds of Examples 35 to 37 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 34.

Example 38
2-Methyl-5- [2-methyl-4- (pyridin-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例３５の化合物（１５０ｍｇ，０．６０ｍｍｏｌ）のジクロロメタン溶液（３ｍＬ）にトリエチルアミン（０．１９２ｍＬ，１．３８ｍｍｏｌ）を加え、室温で５分間撹拌後、参考例２１の化合物（９１．０ｍｇ，０．６６ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（１９０ｍｇ，０．９０ｍｍｏｌ）を加えた。室温で７時間撹拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄後、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をアミノカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製した。その後、精製物のメタノール溶液（３ｍＬ）に１０％パラジウム/炭素（３０ｍｇ）を加え、水素雰囲気下、室温で攪拌した。４時間後、セライトろ過し、濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、表題化合物（５７％）を得た。
¹H-NMR (400MHz, CDCl₃) δ： 1.12, 1.28 (d, J = 6.0 Hz, 3H, diastereo ratio = 1 : 4), 1.64-2.38 (m, 5H), 2.49 (s, 3H), 2.63-2.93 (m, 3H), 3.57 (s, 2H), 7.11-7.17 (m, 2H), 7.59-7.64 (m, 1H), 7.93, 7.94 (s, 1H, diastereo ratio = 4 : 1), 8.54-8.55 (m, 1H).
LC‐MS：条件Ａ Ｒ.Ｔ.= 0.6 min ObsMS = 298.1 [M+1]

Triethylamine (0.192 mL, 1.38 mmol) was added to a dichloromethane solution (3 mL) of the compound of Reference Example 35 (150 mg, 0.60 mmol), stirred for 5 minutes at room temperature, and then the compound of Reference Example 21 (91.0 mg, 0 .66 mmol) and sodium triacetoxyborohydride (190 mg, 0.90 mmol) were added. After stirring at room temperature for 7 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by amino column chromatography (hexane: ethyl acetate = 1: 1). Thereafter, 10% palladium / carbon (30 mg) was added to a methanol solution (3 mL) of the purified product, and the mixture was stirred at room temperature in a hydrogen atmosphere. After 4 hours, the mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (57%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.12, 1.28 (d, J = 6.0 Hz, 3H, diastereo ratio = 1: 4), 1.64-2.38 (m, 5H), 2.49 (s, 3H), 2.63 -2.93 (m, 3H), 3.57 (s, 2H), 7.11-7.17 (m, 2H), 7.59-7.64 (m, 1H), 7.93, 7.94 (s, 1H, diastereo ratio = 4: 1), 8.54 -8.55 (m, 1H).
LC-MS: Condition A RT = 0.6 min ObsMS = 298.1 [M + 1]

Example 39
2-Methyl-5- [2-methyl-4- (pyridin-3-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例３９の化合物（５２．０ｍｇ，０．２１ｍｍｏｌ）のジクロロメタン溶液（２ｍＬ）にトリエチルアミン（０．０６４ｍＬ，０．４６ｍｍｏｌ）を加え、室温で５分間撹拌後、参考例２１の化合物（３２．０ｍｇ，０．２３ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（６７．０ｍｇ，０．３２ｍｍｏｌ）を加えた。室温で６時間撹拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、表題化合物（１０％）を得た。
¹H-NMR (400MHz, CDCl₃) δ： 1.12, 1.29 (d, J = 6.3 Hz, 3H, diastereo ratio = 3 : 1), 1.60-2.00 (m, 5H), 3.42 (s, 3H), 2.63-2.66 (m, 1H), 2.85-3.17 (m, 2H), 3.57 (s, 2H), 7.24 (dd, J = 7.6, 5.1 Hz, 1H), 7.52-7.54 (m, 1H), 7.94, 7.95 (s, 1H, diastereo ratio = 1 : 3), 8.45-8.50 (m, 2H).
LC‐MS：条件Ａ Ｒ.Ｔ.= 1.1 min ObsMS = 298.1 [M+1]

Triethylamine (0.064 mL, 0.46 mmol) was added to a dichloromethane solution (2 mL) of the compound of Reference Example 39 (52.0 mg, 0.21 mmol), stirred for 5 minutes at room temperature, and then the compound of Reference Example 21 (32.0 mg). 0.23 mmol) and sodium triacetoxyborohydride (67.0 mg, 0.32 mmol) were added. After stirring at room temperature for 6 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (10%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.12, 1.29 (d, J = 6.3 Hz, 3H, diastereo ratio = 3: 1), 1.60-2.00 (m, 5H), 3.42 (s, 3H), 2.63 -2.66 (m, 1H), 2.85-3.17 (m, 2H), 3.57 (s, 2H), 7.24 (dd, J = 7.6, 5.1 Hz, 1H), 7.52-7.54 (m, 1H), 7.94, 7.95 (s, 1H, diastereo ratio = 1: 3), 8.45-8.50 (m, 2H).
LC-MS: Condition A RT = 1.1 min ObsMS = 298.1 [M + 1]

Example 40
2-Methyl-5- [3-methyl-4- (pyridin-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例４２の化合物（１７２ｍｇ，０．６９ｍｍｏｌ）のジクロロメタン溶液（３ｍＬ）にトリエチルアミン（０．２２１ｍＬ，１．６ｍｍｏｌ）を加え、室温で５分間攪拌後、参考例２１の化合物（１０５ｍｇ，０．７６ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（２１９ｍｇ，１．０４ｍｍｏｌ）を加えた。室温で６時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をアミノカラムクロマトグラフィー（ヘキサン：酢酸エチル=１：１）で精製した。その後、精製物（１４３ｍｇ，０．４８ｍｍｏｌ）のメタノール（５ｍＬ）溶液に、１０％パラジウム/炭素（８０ｍｇ）を加え、水素雰囲気下、室温で攪拌した。４時間後、セライトろ過し、濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、表題化合物（７０％）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 1.2 min ObsMS = 298.2 [M+1]

Triethylamine (0.221 mL, 1.6 mmol) was added to a dichloromethane solution (3 mL) of the compound of Reference Example 42 (172 mg, 0.69 mmol), stirred for 5 minutes at room temperature, and then the compound of Reference Example 21 (105 mg, 0.76 mmol). ) And sodium triacetoxyborohydride (219 mg, 1.04 mmol). After stirring at room temperature for 6 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by amino column chromatography (hexane: ethyl acetate = 1: 1). Then, 10% palladium / carbon (80 mg) was added to a methanol (5 mL) solution of the purified product (143 mg, 0.48 mmol), and the mixture was stirred at room temperature in a hydrogen atmosphere. After 4 hours, the mixture was filtered through celite and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (70%).
LC-MS: Condition A RT = 1.2 min ObsMS = 298.2 [M + 1]

Example 41
2-Methyl-5- [3-methyl-4- (pyridin-3-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例４６の化合物（１１０ｍｇ，０．４４ｍｍｏｌ）のジクロロメタン溶液（３ｍＬ）にトリエチルアミン（０．１２３ｍＬ，１．８８ｍｍｏｌ）を加え、室温で５分間攪拌後、参考例２１の化合物（６０．０ｍｇ，０．４４ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（１４０ｍｇ，０．６６ｍｍｏｌ）を加えた。室温で６時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をアミノカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：１）で精製し、表題化合物（２０％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 0.79 (d, J = 7.1 Hz, 3H), 2.05-2.35 (m, 5H), 2.49 (s, 3H), 2.78-3.04 (m, 3H), 3.36-3.46 (m, 2H), 7.24 (dd, J = 7.3, 4.9 Hz, 1H), 7.45-7.50 (m, 1H), 7.94 (s, 1H), 8.45-8.50 (m, 2H).
LC‐MS：条件Ａ Ｒ.Ｔ.= 1.2 min ObsMS = 298.1 [M+1]

Triethylamine (0.123 mL, 1.88 mmol) was added to a dichloromethane solution (3 mL) of the compound of Reference Example 46 (110 mg, 0.44 mmol), stirred for 5 minutes at room temperature, and then the compound of Reference Example 21 (60.0 mg, 0 .44 mmol) and sodium triacetoxyborohydride (140 mg, 0.66 mmol) were added. After stirring at room temperature for 6 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by amino column chromatography (hexane: ethyl acetate = 1: 1) to obtain the title compound (20%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 0.79 (d, J = 7.1 Hz, 3H), 2.05-2.35 (m, 5H), 2.49 (s, 3H), 2.78-3.04 (m, 3H), 3.36 -3.46 (m, 2H), 7.24 (dd, J = 7.3, 4.9 Hz, 1H), 7.45-7.50 (m, 1H), 7.94 (s, 1H), 8.45-8.50 (m, 2H).
LC-MS: Condition A RT = 1.2 min ObsMS = 298.1 [M + 1]

Example 42
2-Methyl-5- [4- (pyridin-2-yl) azepan-1-ylmethyl] pyrimidin-4-amine

参考例４９の化合物（８．０ｍｇ，０．０３ｍｍｏｌ）のジクロロメタン溶液（２ｍＬ）にトリエチルアミン（０．０１０ｍＬ，０．０７ｍｍｏｌ）を加え、室温で５分間攪拌後、参考例２１の化合物（４．０ｍｇ，０．０３ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（１０ｍｇ，０．０５ｍｍｏｌ）を加えた。室温で４時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をアミノカラムクロマトグラフィー（クロロホルム：メタノール=１：１）で精製した。その後、精製物（３．０ｍｇ，０．０３ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、１０％パラジウム/炭素（３．０ｍｇ）を加え、水素雰囲気下、室温で攪拌した。３時間後、セライトろ過し、濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、表題化合物（６６％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.78-2.02 (m, 6H), 2.49 (s, 3H), 2.64-2.82 (m, 4H), 2.93-3.01 (m, 1H), 3.70-3.76 (m, 2H), 7.09-7.13 (m, 2H), 7.56-7.62 (m, 2H), 8.14 (s, 1H), 8.52 (d, J = 4.9 Hz, 1H).
LC‐MS：条件Ａ Ｒ.Ｔ.= 1.1 min ObsMS = 298.1 [M+1]

Triethylamine (0.010 mL, 0.07 mmol) was added to a dichloromethane solution (2 mL) of the compound of Reference Example 49 (8.0 mg, 0.03 mmol), stirred at room temperature for 5 minutes, and then the compound of Reference Example 21 (4.0 mg). , 0.03 mmol) and sodium triacetoxyborohydride (10 mg, 0.05 mmol) were added. After stirring at room temperature for 4 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by amino column chromatography (chloroform: methanol = 1: 1). Then, 10% palladium / carbon (3.0 mg) was added to a methanol (2 mL) solution of the purified product (3.0 mg, 0.03 mmol), and the mixture was stirred at room temperature in a hydrogen atmosphere. After 3 hours, the mixture was filtered through Celite and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (66%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.78-2.02 (m, 6H), 2.49 (s, 3H), 2.64-2.82 (m, 4H), 2.93-3.01 (m, 1H), 3.70-3.76 ( m, 2H), 7.09-7.13 (m, 2H), 7.56-7.62 (m, 2H), 8.14 (s, 1H), 8.52 (d, J = 4.9 Hz, 1H).
LC-MS: Condition A RT = 1.1 min ObsMS = 298.1 [M + 1]

Example 43
2-Methyl-5- [4- (pyridin-3-yl) azepan-1-ylmethyl] pyrimidin-4-amine

参考例５３の化合物（４７ｍｇ，０．１９ｍｍｏｌ）のジクロロメタン溶液（２ｍＬ）にトリエチルアミン（０．０６１ｍＬ，０．４４ｍｍｏｌ）を加え、室温で５分間攪拌後、参考例２１の化合物（２９ｍｇ，０．２１ｍｍｏｌ）と水素化トリアセトキシホウ素ナトリウム（６０ｍｇ，０．２９ｍｍｏｌ）を加えた。室温で６時間攪拌後、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール=１：１）で精製した。その後、精製物（８．０ｍｇ，０．０３ｍｍｏｌ）のメタノール（２ｍＬ）溶液に、１０％パラジウム/炭素（２０ｍｇ）を加え、水素雰囲気下、室温で攪拌した。４時間後、セライトろ過し、濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール＝１０：１）で精製し、表題化合物（１４％）を得た。
LC‐MS：条件Ｂ Ｒ.Ｔ.= 1.8 min ObsMS = 298 [M+1]

Triethylamine (0.061 mL, 0.44 mmol) was added to a dichloromethane solution (2 mL) of the compound of Reference Example 53 (47 mg, 0.19 mmol), stirred for 5 minutes at room temperature, and then the compound of Reference Example 21 (29 mg, 0.21 mmol). ) And sodium triacetoxyborohydride (60 mg, 0.29 mmol) were added. After stirring at room temperature for 6 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 1: 1). Thereafter, 10% palladium / carbon (20 mg) was added to a methanol (2 mL) solution of the purified product (8.0 mg, 0.03 mmol), and the mixture was stirred at room temperature in a hydrogen atmosphere. After 4 hours, the mixture was filtered through celite and concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain the title compound (14%).
LC-MS: Condition B RT = 1.8 min ObsMS = 298 [M + 1]

Example 44
2,4-Dimethyl-5- [4- (pyridin-2-yl) piperidin-1-ylmethyl] pyrimidine

（２，４−ジメチルピリミジン−５−イル）メタノール（１．７１ｇ，１２．４ｍｍｏｌ）のテトラヒドロフラン溶液（４０ｍＬ）に、トリエチルアミン（１．７４ｍＬ，１２．５ｍｍｏｌ）とメタンスルホニルクロリド（０．９６９ｍＬ，１２．５ｍｍｏｌ）を０℃で加えた。０℃で１時間撹拌後、不溶物をろ過した。得られたろ液を、参考例３の化合物（２．９４ｇ，１２．５ｍｍｏｌ）、ジメチルホルムアミド（６０ｍＬ）および炭酸カリウム（７．７１ｇ，５５．８ｍｍｏｌ）の混合物へ加えた。室温で終夜撹拌後、水（４００ｍＬ）を加え、酢酸エチル（３００ｍＬ）とクロロホルム（３００ｍＬ×２回）で抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム：メタノール）で精製し、さらに、アミノカラムクロマトグラフィー（ヘキサン：酢酸エチル）で精製し、表題化合物（２．２５ｇ，６４％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 1.74-1.97 (4H, m), 2.16 (2H, td, J = 11.5, 2.8 Hz), 2.56 (3H, s), 2.65-2.78 (1H, m), 2.69 (3H, s), 2.90-2.99 (2H, m), 3.46 (2H, s), 7.11 (1H, ddd, J = 7.5, 5.0, 1.1 Hz), 7.14-7.18 (1H, m), 7.61 (1H, td, J = 7.7, 1.8 Hz), 8.40 (1H, s), 8.52-8.55 (1H, m).

To a tetrahydrofuran solution (40 mL) of (2,4-dimethylpyrimidin-5-yl) methanol (1.71 g, 12.4 mmol), triethylamine (1.74 mL, 12.5 mmol) and methanesulfonyl chloride (0.969 mL, 12 0.5 mmol) was added at 0 ° C. After stirring at 0 ° C. for 1 hour, the insoluble material was filtered off. The obtained filtrate was added to a mixture of the compound of Reference Example 3 (2.94 g, 12.5 mmol), dimethylformamide (60 mL) and potassium carbonate (7.71 g, 55.8 mmol). After stirring overnight at room temperature, water (400 mL) was added, and the mixture was extracted with ethyl acetate (300 mL) and chloroform (300 mL × twice). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform: methanol), and further purified by amino column chromatography (hexane: ethyl acetate) to give the title compound (2.25 g, 64%).
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.74-1.97 (4H, m), 2.16 (2H, td, J = 11.5, 2.8 Hz), 2.56 (3H, s), 2.65-2.78 (1H, m) , 2.69 (3H, s), 2.90-2.99 (2H, m), 3.46 (2H, s), 7.11 (1H, ddd, J = 7.5, 5.0, 1.1 Hz), 7.14-7.18 (1H, m), 7.61 (1H, td, J = 7.7, 1.8 Hz), 8.40 (1H, s), 8.52-8.55 (1H, m).

Example 45
2,4-Dimethyl-5- [4- (pyridin-3-yl) piperidin-1-ylmethyl] pyrimidine

参考例１１の化合物から、実施例４４と同様の手法により、表題化合物（８６％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 1.64-1.88 (4H, m), 2.16 (2H, td, J = 11.4, 2.8 Hz), 2.49-2.62 (1H, m), 2.57 (3H, s), 2.69 (3H, s), 2.90-3.00 (2H, m), 3.47 (2H, s), 7.23 (1H, ddd, J = 7.8, 4.8, 0.7 Hz), 7.53 (1H, ddd, J = 7.9, 2.0, 2.0 Hz), 8.41 (1H, s), 8.45 (1H, dd, J = 4.8, 1.7 Hz), 8.49 (1H, brd, J = 2.2 Hz).

The title compound (86%) was obtained from the compound of Reference Example 11 by the same method as in Example 44.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.64-1.88 (4H, m), 2.16 (2H, td, J = 11.4, 2.8 Hz), 2.49-2.62 (1H, m), 2.57 (3H, s) , 2.69 (3H, s), 2.90-3.00 (2H, m), 3.47 (2H, s), 7.23 (1H, ddd, J = 7.8, 4.8, 0.7 Hz), 7.53 (1H, ddd, J = 7.9, 2.0, 2.0 Hz), 8.41 (1H, s), 8.45 (1H, dd, J = 4.8, 1.7 Hz), 8.49 (1H, brd, J = 2.2 Hz).

Example 46
5- [4- (5-Fluoropyridin-3-yl) piperidin-1-ylmethyl] pyrimidin-2-amine

参考例１３の化合物から、実施例７と同様の手法により、表題化合物（３４％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 1.73-1.93 (4H, m), 2.11 (2H, td, J = 11.6, 2.7 Hz), 2.55-2.67 (1H, m), 2.98-3.07 (2H, m), 3.42 (2H, s), 5.06 (2H, s), 7.24-7.31 (1H, m), 8.28 (2H, s), 8.34 (2H, brd, J = 2.4 Hz).

The title compound (34%) was obtained from the compound of Reference Example 13 by the same method as in Example 7.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.73-1.93 (4H, m), 2.11 (2H, td, J = 11.6, 2.7 Hz), 2.55-2.67 (1H, m), 2.98-3.07 (2H, m), 3.42 (2H, s), 5.06 (2H, s), 7.24-7.31 (1H, m), 8.28 (2H, s), 8.34 (2H, brd, J = 2.4 Hz).

Example 47
2-Methyl-5- [4- (1,3-thiazol-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例５５の化合物から、実施例１と同様の手法により、表題化合物（１３％）を得た。
¹H-NMR (400MHz, CD₃OD) δ: 1.78-1.93 (2H, m), 2.06-2.23 (4H, m), 2.42 (3H, s), 2.90-3.00 (2H, m), 3.03-3.14 (1H, m), 3.47 (2H, s), 7.47 (1H, d, J = 3.2 Hz), 7.71 (1H, d, J = 3.2 Hz), 7.89 (1H, s).

The title compound (13%) was obtained from the compound of Reference Example 55 by the same method as in Example 1.
¹ H-NMR (400MHz, CD ₃ OD) δ: 1.78-1.93 (2H, m), 2.06-2.23 (4H, m), 2.42 (3H, s), 2.90-3.00 (2H, m), 3.03-3.14 (1H, m), 3.47 (2H, s), 7.47 (1H, d, J = 3.2 Hz), 7.71 (1H, d, J = 3.2 Hz), 7.89 (1H, s).

Example 48
5- [4- (5-Fluoropyridin-3-yl) piperidin-1-ylmethyl] -2,4-dimethylpyrimidine

参考例５６の化合物（２５３ｍｇ，１．００ｍｍｏｌ）と２，４−ジメチルピリミジン−５−カルボン酸（１５２ｍｇ，１．００ｍｍｏｌ）と１−ヒドロキシベンゾトリアゾール（１３５ｍｇ，１．００ｍｍｏｌ）と１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド塩酸塩（２３０ｍｇ，１．２０ｍｍｏｌ）とトリエチルアミン（４１８μＬ，３．００ｍｍｏｌ）とＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）の混合物を室温で１６時間攪拌した。その後、反応混合物をそのまま分取高速液体カラムクロマトグラフィーにより精製した。続いて得られた生成物（１５７ｍｇ，０．５０ｍｍｏｌ）のテトラヒドロフラン溶液（５．０ｍＬ）に水素化リチウムアルミニウム（５６．９ｍｇ，１．５０ｍｍｏｌ）を１０℃で加えた。１０℃で１６時間攪拌後、水と１０％水酸化ナトリウム水溶液を加え、析出物をセライトろ過により除き、ろ液を濃縮した。得られた濃縮残渣を分取高速液体カラムクロマトグラフィーにより精製し、表題化合物（４％）を得た。
¹H-NMR (400MHz,CＤＣｌ_３) δ: 1.63-1.82 (2H, m), 1.82-1.93 (2H, m), 2.17 (2H, brt, J = 10.8 Hz), 2.53-2.70 (1H, m), 2.58 (3H, s), 2.71 (3H, s), 2.97 (2H, brd, J = 11.2 Hz), 3.48 (2H, s), 7.23-7.34 (1H, m), 8.33 (2H, s), 8.42 (1H, s).

The compound of Reference Example 56 (253 mg, 1.00 mmol), 2,4-dimethylpyrimidine-5-carboxylic acid (152 mg, 1.00 mmol), 1-hydroxybenzotriazole (135 mg, 1.00 mmol) and 1- (3- A mixture of dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (230 mg, 1.20 mmol), triethylamine (418 μL, 3.00 mmol) and N, N-dimethylformamide (2 mL) was stirred at room temperature for 16 hours. Thereafter, the reaction mixture was directly purified by preparative high performance liquid column chromatography. Subsequently, lithium aluminum hydride (56.9 mg, 1.50 mmol) was added at 10 ° C. to a tetrahydrofuran solution (5.0 mL) of the obtained product (157 mg, 0.50 mmol). After stirring at 10 ° C. for 16 hours, water and a 10% aqueous sodium hydroxide solution were added, the precipitate was removed by celite filtration, and the filtrate was concentrated. The resulting concentrated residue was purified by preparative high performance liquid column chromatography to obtain the title compound (4%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.63-1.82 (2H, m), 1.82-1.93 (2H, m), 2.17 (2H, brt, J = 10.8 Hz), 2.53-2.70 (1H, m) , 2.58 (3H, s), 2.71 (3H, s), 2.97 (2H, brd, J = 11.2 Hz), 3.48 (2H, s), 7.23-7.34 (1H, m), 8.33 (2H, s), 8.42 (1H, s).

Examples 49-50
The compounds of Examples 49 to 50 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 48.

Examples 51-56
The compounds of Examples 51 to 56 were synthesized from the corresponding compounds of Reference Examples according to the method described in Example 10.

Example 57
2-Methyl-5- [4- (4-methylpyridin-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine

参考例５７の化合物（２７６ｍｇ，１．００ｍｍｏｌ）の１，４−ジオキサン溶液（１．５ｍＬ）に４ｍｏｌ／Ｌ−塩酸１，４−ジオキサン溶液（３．０ｍＬ）を加え、室温で１６時間攪拌した。その後、反応混合物を濃縮し、得られた残渣を酢酸エチルで洗浄した。続いて、得られた生成物から、実施例１０と同様の手法により、表題化合物（１３％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.62-1.92 (4H, m), 2.02 (2H, brt, J = 8.8 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.54-2.65 (1H, m), 2.90 (2H, brd, J = 11.6 Hz), 3.38 (2H, s), 6.88 (1H, d, J = 5.2 Hz), 6.90 (1H, s), 7.86 (1H, s), 8.32 (1H, d, J = 4.8 Hz).

To a 1,4-dioxane solution (1.5 mL) of the compound of Reference Example 57 (276 mg, 1.00 mmol) was added 4 mol / L-hydrochloric acid 1,4-dioxane solution (3.0 mL), and the mixture was stirred at room temperature for 16 hours. . Thereafter, the reaction mixture was concentrated, and the resulting residue was washed with ethyl acetate. Subsequently, the title compound (13%) was obtained from the obtained product by the same method as in Example 10.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.62-1.92 (4H, m), 2.02 (2H, brt, J = 8.8 Hz), 2.26 (3H, s), 2.42 (3H, s), 2.54-2.65 (1H, m), 2.90 (2H, brd, J = 11.6 Hz), 3.38 (2H, s), 6.88 (1H, d, J = 5.2 Hz), 6.90 (1H, s), 7.86 (1H, s) , 8.32 (1H, d, J = 4.8 Hz).

Reference example 1
1 ', 2', 3 ', 6'-tetrahydro-2,4'-bipyridine dihydrochloride

参考例４の化合物（３２７ｍｇ，１．２６ｍｍｏｌ）の１，４−ジオキサン溶液（３．２ｍＬ）に４ｍｏｌ／Ｌ−塩酸１，４−ジオキサン溶液（６．５ｍＬ）を加えた。室温で１時間撹拌後、溶媒を留去し、表題化合物（２９３ｍｇ，９９％）を得た。
¹H-NMR (300MHz, DMSO-D₆) δ: 2.76-2.86 (2H, m), 3.24-3.35 (2H, m), 3.76-3.87 (2H, m), 6.82 (1H, m), 7.52 (1H, t, J = 6.2 Hz), 7.79 (1H, d, J = 8.1 Hz), 8.06 (1H, t, J = 7.2 Hz), 8.64 (1H, d, J = 5.0 Hz), 9.47 (2H, brs).

To a 1,4-dioxane solution (3.2 mL) of the compound of Reference Example 4 (327 mg, 1.26 mmol), a 4 mol / L-hydrochloric acid 1,4-dioxane solution (6.5 mL) was added. After stirring at room temperature for 1 hour, the solvent was distilled off to obtain the title compound (293 mg, 99%).
¹ H-NMR (300MHz, DMSO-D ₆ ) δ: 2.76-2.86 (2H, m), 3.24-3.35 (2H, m), 3.76-3.87 (2H, m), 6.82 (1H, m), 7.52 ( 1H, t, J = 6.2 Hz), 7.79 (1H, d, J = 8.1 Hz), 8.06 (1H, t, J = 7.2 Hz), 8.64 (1H, d, J = 5.0 Hz), 9.47 (2H, brs).

Reference example 2
1 ', 2', 3 ', 6'-tetrahydro-3,4'-bipyridine dihydrochloride

参考例５の化合物（１．１７ｇ，４．４９ｍｍｏｌ）の１，４−ジオキサン溶液（７．０ｍＬ）に４ｍｏｌ／Ｌ−塩酸１，４−ジオキサン溶液（１４ｍＬ）を加えた。室温で２時間撹拌後、濃縮した。得られた濃縮残渣にジエチルエーテル（７．０ｍＬ）を加え、室温で３０分間撹拌後、析出物をろ取した。ろ上物をジエチルエーテル（２．３ｍＬ）で洗浄し、減圧乾燥することで、表題化合物（９４２ｍｇ，９０％）を得た。
¹H-NMR (300MHz, DMSO-D₆) δ: 2.69-2.81 (2H, m), 3.25-3.37 (2H, m), 3.75-3.83 (2H, m), 6.51-6.56 (1H, m), 7.86 (1H, dd, J = 8.3, 5.3 Hz), 8.40-8.46 (1H, m), 8.74 (1H, dd, J = 5.3, 1.3 Hz), 8.92 (1H, d, J = 2.2 Hz), 9.46 (2H, brs).

To a 1,4-dioxane solution (7.0 mL) of the compound of Reference Example 5 (1.17 g, 4.49 mmol), a 4 mol / L-hydrochloric acid 1,4-dioxane solution (14 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated. Diethyl ether (7.0 mL) was added to the obtained concentrated residue, and the mixture was stirred at room temperature for 30 minutes, and the precipitate was collected by filtration. The filtered product was washed with diethyl ether (2.3 mL) and dried under reduced pressure to obtain the title compound (942 mg, 90%).
¹ H-NMR (300MHz, DMSO-D ₆ ) δ: 2.69-2.81 (2H, m), 3.25-3.37 (2H, m), 3.75-3.83 (2H, m), 6.51-6.56 (1H, m), 7.86 (1H, dd, J = 8.3, 5.3 Hz), 8.40-8.46 (1H, m), 8.74 (1H, dd, J = 5.3, 1.3 Hz), 8.92 (1H, d, J = 2.2 Hz), 9.46 (2H, brs).

Reference example 3
2- (Piperidin-4-yl) pyridine dihydrochloride

参考例６の化合物から、参考例１と同様の手法により、表題化合物（９９％）を得た。
¹H-NMR (400MHz, DMSO-D₆) δ: 1.93-2.08 (2H, m), 2.08-2.17 (2H, m), 2.93-3.07 (2H, m), 3.28-3.43 (3H, m), 7.67-7.78 (2H, m), 8.26-8.36 (1H, m), 8.70-8.75 (1H, m), 9.03-9.32 (2H, m).

The title compound (99%) was obtained from the compound of Reference Example 6 by the same method as in Reference Example 1.
¹ H-NMR (400MHz, DMSO-D ₆ ) δ: 1.93-2.08 (2H, m), 2.08-2.17 (2H, m), 2.93-3.07 (2H, m), 3.28-3.43 (3H, m), 7.67-7.78 (2H, m), 8.26-8.36 (1H, m), 8.70-8.75 (1H, m), 9.03-9.32 (2H, m).

Reference example 4
tert-butyl 3 ', 6'-dihydro-2,4'-bipyridine-1' (2'H) -carboxylate

２−ブロモピリジン（５．１１ｇ，３２．３ｍｍｏｌ）のジメトキシエタン溶液（１００ｍＬ）に、水（５０ｍＬ）と１−Ｎ−Ｂｏｃ−４−（４，４，５，５−テトラメチル−［１，３，２］−ジオキサボロラン−２−イル）−３，６−ジヒドロ−２Ｈ−ピリジン（１０ｇ，３２．３ｍｍｏｌ）と炭酸ナトリウム（１７．１ｇ，１６２ｍｍｏｌ）とテトラキス（トリフェニルホスフィン）パラジウム（０）（０．３７３ｇ，０．３２３ｍｍｏｌ）を加えた。６時間加熱還流後、水（１５０ｍＬ）を加え、酢酸エチル（２００ｍＬ）で２回抽出した。有機層を無水硫酸マグネシウムで乾燥後、ろ過し、濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝８１：９から６０：４０まで）で精製し、表題化合物（４．９９ｇ，５９％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 1.49 (9H, s), 2.60-2.70 (2H, m), 3.59-3.72 (2H, m), 4.09-4.19 (2H, m), 6.56-6.64 (1H, m), 7.15 (1H, ddd, J = 7.5, 4.8, 1.0 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.66 (1H, ddd, J = 7.8, 7.8, 1.8 Hz), 8.54-8.59 (1H, m).

To a solution of 2-bromopyridine (5.11 g, 32.3 mmol) in dimethoxyethane (100 mL), water (50 mL) and 1-N-Boc-4- (4,4,5,5-tetramethyl- [1, 3,2] -Dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine (10 g, 32.3 mmol), sodium carbonate (17.1 g, 162 mmol) and tetrakis (triphenylphosphine) palladium (0) ( 0.373 g, 0.323 mmol) was added. After heating at reflux for 6 hours, water (150 mL) was added, and the mixture was extracted twice with ethyl acetate (200 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The obtained concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 81: 9 to 60:40) to obtain the title compound (4.99 g, 59%).
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.49 (9H, s), 2.60-2.70 (2H, m), 3.59-3.72 (2H, m), 4.09-4.19 (2H, m), 6.56-6.64 ( 1H, m), 7.15 (1H, ddd, J = 7.5, 4.8, 1.0 Hz), 7.37 (1H, d, J = 8.1 Hz), 7.66 (1H, ddd, J = 7.8, 7.8, 1.8 Hz), 8.54 -8.59 (1H, m).

Reference Example 5
tert-Butyl 3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate

３−ブロモピリジン（１０２ｍｇ，０．６４７ｍｍｏｌ）のジメトキシエタン溶液（４．０ｍＬ）に、水（２．０ｍＬ）と１−Ｎ−Ｂｏｃ−４−（４，４，５，５−テトラメチル−［１，３，２］−ジオキサボロラン−２−イル）−３，６−ジヒドロ−２Ｈ−ピリジン（２００ｍｇ，０．６４７ｍｍｏｌ）と炭酸ナトリウム（３４３ｍｇ，３．２４ｍｍｏｌ）とテトラキス（トリフェニルホスフィン）パラジウム（０）（７．５ｍｇ，０．００６４７ｍｍｏｌ）を加えた。４時間加熱還流後、水（２０ｍＬ）を加え、酢酸エチル（２０ｍＬ）で２回抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過し、濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５７：４３から３６：６４まで）で精製し、表題化合物（１５６ｍｇ，９３％）を得た。
¹H-NMR (300MHz, CDCl₃) δ: 1.50 (9H, s), 2.49-2.57 (2H, m), 3.66 (2H, t, J = 5.7 Hz), 4.07-4.12 (2H, m), 6.05-6.14 (1H, m), 7.26 (1H, ddd, J = 7.8, 4.9, 0.9 Hz), 7.64 (1H, ddd, J = 8.0, 2.3, 1.6 Hz), 8.50 (1H, dd, J = 4.9, 1.6 Hz), 8.65 (1H, d, J = 1.8 Hz).

To a solution of 3-bromopyridine (102 mg, 0.647 mmol) in dimethoxyethane (4.0 mL), water (2.0 mL) and 1-N-Boc-4- (4,4,5,5-tetramethyl- [ 1,3,2] -Dioxaborolan-2-yl) -3,6-dihydro-2H-pyridine (200 mg, 0.647 mmol), sodium carbonate (343 mg, 3.24 mmol) and tetrakis (triphenylphosphine) palladium (0 ) (7.5 mg, 0.00647 mmol) was added. After heating at reflux for 4 hours, water (20 mL) was added, and the mixture was extracted twice with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 57: 43 to 36:64) to obtain the title compound (156 mg, 93%).
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.50 (9H, s), 2.49-2.57 (2H, m), 3.66 (2H, t, J = 5.7 Hz), 4.07-4.12 (2H, m), 6.05 -6.14 (1H, m), 7.26 (1H, ddd, J = 7.8, 4.9, 0.9 Hz), 7.64 (1H, ddd, J = 8.0, 2.3, 1.6 Hz), 8.50 (1H, dd, J = 4.9, 1.6 Hz), 8.65 (1H, d, J = 1.8 Hz).

Reference Example 6
tert-Butyl 4- (pyridin-2-yl) piperidine-1-carboxylate

参考例４の化合物（４．９９ｇ，１９．２ｍｍｏｌ）のメタノール溶液（１００ｍＬ）に１０％パラジウム／炭素（２．０ｇ）を加え、水素雰囲気下、室温で６時間撹拌した。その後、セライトろ過し、濃縮し、得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝７６：２４から５５：４５まで）で精製し、表題化合物（４．１６ｇ，８３％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.48 (9H, s), 1.66-1.79 (2H, m), 1.86-1.96 (2H, m), 2.75-2.93 (3H, m), 4.15-4.40 (2H, m), 7.10-7.17 (2H, m), 7.63 (1H, ddd, J = 7.7, 7.7, 1.9 Hz), 8.52-8.56 (1H, m).

To a methanol solution (100 mL) of the compound of Reference Example 4 (4.99 g, 19.2 mmol) was added 10% palladium / carbon (2.0 g), and the mixture was stirred at room temperature for 6 hours in a hydrogen atmosphere. Thereafter, the mixture was filtered through celite and concentrated. The resulting concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 76: 24 to 55:45) to give the title compound (4.16 g, 83%). It was.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48 (9H, s), 1.66-1.79 (2H, m), 1.86-1.96 (2H, m), 2.75-2.93 (3H, m), 4.15-4.40 ( 2H, m), 7.10-7.17 (2H, m), 7.63 (1H, ddd, J = 7.7, 7.7, 1.9 Hz), 8.52-8.56 (1H, m).

Reference Examples 7-20
In accordance with the method described in Reference Examples 1-6 above, 1-N-Boc-4- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl) -3, The compounds of Reference Examples 7 to 20 were synthesized from 6-dihydro-2H-pyridine.

Reference Example 21
4-Amino-2-methylpyrimidine-5-carbaldehyde

参考例２２の化合物（５０．０ｇ，３７３ｍｍｏｌ）のギ酸溶液（１５０ｍＬ）に水（６５ｍＬ）とラネーニッケル（５０ｇ）を加えた。１５分間加熱還流後、室温に冷却し、セライトろ過し、氷冷下２８％アンモニア水（２２０ｍＬ）を加え、氷冷下１時間撹拌後、析出物をろ取した。ろ上物を水（３０ｍＬ）とクロロホルム（３０ｍＬ×２回）で洗浄し、減圧乾燥を行った。さらに、ろ液をクロロホルム（２００ｍＬ）で９回抽出後、有機層を濃縮した。この濃縮残渣と先に得たろ上物を合わせ、クロロホルム（７０ｍＬ）を加え、室温で３０分間撹拌後、ヘキサン（２１０ｍＬ）を１０分間で滴下し、さらに、室温で１時間撹拌した。その後、析出物をろ取し、ヘキサン／クロロホルム（３／１，２８ｍＬ）で洗浄し、減圧乾燥して表題化合物（４２．６ｇ，８３％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 2.57 (3H, s), 5.98 (1H, brs), 8.15 (1H, brs), 8.57 (1H, s), 9.86 (1H, s).

Water (65 mL) and Raney nickel (50 g) were added to a formic acid solution (150 mL) of the compound of Reference Example 22 (50.0 g, 373 mmol). The mixture was heated to reflux for 15 minutes, cooled to room temperature, filtered through celite, 28% aqueous ammonia (220 mL) was added under ice cooling, and the mixture was stirred for 1 hour under ice cooling, and the precipitate was collected by filtration. The filtered product was washed with water (30 mL) and chloroform (30 mL × twice), and dried under reduced pressure. Furthermore, the filtrate was extracted 9 times with chloroform (200 mL), and then the organic layer was concentrated. The concentrated residue was combined with the filtrate obtained above, chloroform (70 mL) was added, and after stirring at room temperature for 30 minutes, hexane (210 mL) was added dropwise over 10 minutes, and the mixture was further stirred at room temperature for 1 hour. Thereafter, the precipitate was collected by filtration, washed with hexane / chloroform (3/1, 28 mL), and dried under reduced pressure to obtain the title compound (42.6 g, 83%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.57 (3H, s), 5.98 (1H, brs), 8.15 (1H, brs), 8.57 (1H, s), 9.86 (1H, s).

Reference Example 22
4-Amino-2-methylpyrimidine-5-carbonitrile

ジメチルホルムアミド（７４．５ｍＬ，９６２ｍｍｏｌ）とジメチル硫酸（９０．８ｍＬ，９６２ｍｍｏｌ）の混合物を７０℃で３．５時間撹拌した後、ナトリウムメトキシド（５２．０ｇ，９６２ｍｍｏｌ）のメタノール溶液（４４０ｍＬ）を−２０℃から−１０℃の温度範囲内で４０分間かけて滴下し、続いて、マロノニトリル（６３．６ｇ，９６２ｍｍｏｌ）のメタノール溶液（１２０ｍＬ）を−２０℃から−１０℃の温度範囲内で４０分間かけて滴下した。−１５℃で１時間撹拌した。別途、ナトリウムメトキシド（５７．２ｇ，１０６０ｍｍｏｌ）のメタノール溶液（３２０ｍＬ）に氷冷下アセトアミジン塩酸塩（１００ｇ，１０６０ｍｍｏｌ）を加え１５分間撹拌後、ろ過してアセトアミジンのメタノール溶液を調製した。このアセトアミジンのメタノール溶液を先の反応混合物に−２０℃から−１０℃の温度範囲内で１５分間かけ滴下し、−１５℃で３０分間撹拌後、室温で１５時間撹拌した。その後、析出物をろ取し、水（２００ｍＬ×２回）で洗浄後、減圧乾燥して表題化合物（８８．５ｇ，６９％）を得た。
¹H-NMR (300MHz, DMSO-D₆) δ: 2.37 (3H, s), 7.76 (2H, brs), 8.49 (1H, s).

A mixture of dimethylformamide (74.5 mL, 962 mmol) and dimethyl sulfate (90.8 mL, 962 mmol) was stirred at 70 ° C. for 3.5 hours, and then a methanol solution (440 mL) of sodium methoxide (52.0 g, 962 mmol) was added. It was added dropwise over 40 minutes within a temperature range of −20 ° C. to −10 ° C., and then a solution of malononitrile (63.6 g, 962 mmol) in methanol (120 mL) was added within a temperature range of −20 ° C. to −10 ° C. for 40 minutes. Added dropwise over a period of minutes. Stir at -15 ° C for 1 hour. Separately, acetamidine hydrochloride (100 g, 1060 mmol) was added to a methanol solution (320 mL) of sodium methoxide (57.2 g, 1060 mmol) under ice-cooling, stirred for 15 minutes, and then filtered to prepare a methanol solution of acetamidine. This methanol solution of acetamidine was added dropwise to the previous reaction mixture over a period of 15 minutes within a temperature range of −20 ° C. to −10 ° C., stirred at −15 ° C. for 30 minutes, and then stirred at room temperature for 15 hours. Thereafter, the precipitate was collected by filtration, washed with water (200 mL × 2 times), and dried under reduced pressure to obtain the title compound (88.5 g, 69%).
¹ H-NMR (300 MHz, DMSO-D ₆ ) δ: 2.37 (3H, s), 7.76 (2H, brs), 8.49 (1H, s).

Reference Example 23
4-Amino-2-ethylpyrimidine-5-carbaldehyde

参考例２４の化合物（１４８ｍｇ，１．００ｍｍｏｌ）の７０％酢酸溶液（５．０ｍＬ）にラネーニッケル（１．０ｇ）を加え、水素雰囲気下、室温で３２時間撹拌した。その後、反応混合物をセライトろ過し、濃縮した。濃縮残渣に飽和炭酸水素ナトリウム水溶液をｐＨ９になるまで加え、酢酸エチル（２０ｍＬ）で抽出した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して、濃縮し、表題化合物（１０７ｍｇ，７１％）を得た。
¹H-NMR (400MHz, DMSO-D₆) δ: 1.20 (3H, t, J = 7.6 Hz), 2.66 (2H, q, J = 7.6 Hz), 7.89 (1H, brs), 8.15 (1H, brs), 8.66 (1H, s), 9.81 (1H, s).

Raney nickel (1.0 g) was added to a 70% acetic acid solution (5.0 mL) of the compound of Reference Example 24 (148 mg, 1.00 mmol), and the mixture was stirred at room temperature for 32 hours in a hydrogen atmosphere. Thereafter, the reaction mixture was filtered through Celite and concentrated. Saturated aqueous sodium hydrogen carbonate solution was added to the concentrated residue until pH 9 and extracted with ethyl acetate (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (107 mg, 71%).
¹ H-NMR (400MHz, DMSO-D ₆ ) δ: 1.20 (3H, t, J = 7.6 Hz), 2.66 (2H, q, J = 7.6 Hz), 7.89 (1H, brs), 8.15 (1H, brs ), 8.66 (1H, s), 9.81 (1H, s).

Reference Example 24
4-Amino-2-ethylpyrimidine-5-carbonitrile

２．２７ｍｏｌ／Ｌ−ナトリウムエトキシド／エタノール溶液（２．５０ｍＬ，１．１０ｍｍｏｌ）にプロピオンアミジン塩酸塩（１０９ｍｇ，１．００ｍｍｏｌ）を加え、室温で１０分間撹拌した。その後、反応混合物をセライトろ過し、ろ液にエトキシメチレンマロノニトリル（１１０ｍｇ，０．９００ｍｍｏｌ）を加えた。室温で３０分間撹拌後、反応混合物を濃縮した。得られた濃縮残渣にｔｅｒｔ−ブチルメチルエーテル（１．０ｍＬ）を加え、１時間撹拌後、析出物をろ取し、表題化合物（１０５ｍｇ，７３％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.26 (3H, t, J = 7.6 Hz), 2.76 (2H, q, J = 7.6 Hz), 5.99 (2H, brs), 8.43 (1H, s).

Propionamidine hydrochloride (109 mg, 1.00 mmol) was added to a 2.27 mol / L-sodium ethoxide / ethanol solution (2.50 mL, 1.10 mmol), and the mixture was stirred at room temperature for 10 minutes. Thereafter, the reaction mixture was filtered through Celite, and ethoxymethylenemalononitrile (110 mg, 0.900 mmol) was added to the filtrate. After stirring at room temperature for 30 minutes, the reaction mixture was concentrated. To the resulting concentrated residue was added tert-butyl methyl ether (1.0 mL), and the mixture was stirred for 1 hour. The precipitate was collected by filtration to give the title compound (105 mg, 73%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.26 (3H, t, J = 7.6 Hz), 2.76 (2H, q, J = 7.6 Hz), 5.99 (2H, brs), 8.43 (1H, s).

Reference Examples 25-30
The compounds of Reference Examples 25 to 30 were synthesized from ethoxymethylenemalononitrile according to the method described in Reference Examples 23 to 24 above.

Reference Example 31
2-Methyl-4- (methylamino) pyrimidine-5-carbaldehyde

参考例３２の化合物（１５３ｍｇ，１．００ｍｍｏｌ）のジクロロメタン溶液（５．０ｍＬ）に二酸化マンガン（８６９ｍｇ，１０．０ｍｍｏｌ）を加えた。室温で１６時間撹拌後、反応混合物をろ過し、濃縮して表題化合物（１０１ｍｇ，６７％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 2.61 (3H, s), 3.13 (3H, d, J = 4.8 Hz), 8.45 (1H, s), 9.79 (1H, s).

Manganese dioxide (869 mg, 10.0 mmol) was added to a dichloromethane solution (5.0 mL) of the compound of Reference Example 32 (153 mg, 1.00 mmol). After stirring at room temperature for 16 hours, the reaction mixture was filtered and concentrated to give the title compound (101 mg, 67%).
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.61 (3H, s), 3.13 (3H, d, J = 4.8 Hz), 8.45 (1H, s), 9.79 (1H, s).

Reference Example 32
[2-Methyl-4- (methylamino) pyrimidin-5-yl] methanol

水素化リチウムアルミニウム（１．０ｇ，２６．４ｍｍｏｌ）のテトラヒドロフラン懸濁液（１００ｍＬ）に参考例３３の化合物（５．１５ｇ，２６．４ｍｍｏｌ）のテトラヒドロフラン溶液（３０ｍＬ）を−５℃で滴下した。滴下後、−５℃で２時間撹拌後、水（１．０ｍＬ）と１０％水酸化ナトリウム水溶液（１．０ｍＬ）をゆっくりと順に加えた。反応混合物をろ過し、無水硫酸ナトリウムで乾燥後、ろ過して、濃縮し、表題化合物（３．８８ｇ，９６％）を得た。
¹H-NMR (400MHz, DMSO-D₆) δ: 2.35 (3H, s), 2.86 (3H, d, J = 4.8 Hz), 4.32 (2H, brs), 6.59 (1H, brs), 7.86 (1H, s).

To a tetrahydrofuran suspension (100 mL) of lithium aluminum hydride (1.0 g, 26.4 mmol), a tetrahydrofuran solution (30 mL) of the compound of Reference Example 33 (5.15 g, 26.4 mmol) was added dropwise at −5 ° C. After dropping, the mixture was stirred at −5 ° C. for 2 hours, and then water (1.0 mL) and a 10% aqueous sodium hydroxide solution (1.0 mL) were slowly added in order. The reaction mixture was filtered, dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (3.88 g, 96%).
¹ H-NMR (400MHz, DMSO-D ₆ ) δ: 2.35 (3H, s), 2.86 (3H, d, J = 4.8 Hz), 4.32 (2H, brs), 6.59 (1H, brs), 7.86 (1H , s).

Reference Example 33
Ethyl 2-methyl-4- (methylamino) pyrimidine-5-carboxylate

参考例３４の化合物（７．２８ｇ，４０．０ｍｍｏｌ）とオキシ塩化リン（８０ｍＬ）の混合物にトリエチルアミン（５．０ｍＬ，３６．０ｍｍｏｌ）を３０℃で加えた。４０℃で５０分間撹拌後、濃縮した。得られた濃縮残渣にクロロホルム（４００ｍＬ）を加え、混合物を氷水（４００ｍＬ）に注ぎ、有機層を分抽した。有機層を５％炭酸水素ナトリウム水溶液（２００ｍＬ）と飽和食塩水（２００ｍＬ）で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過して、濃縮した。得られた濃縮残渣をテトラヒドロフラン溶液（６０ｍＬ）に溶解し、これにメチルアミン（６．２１ｇ，２００ｍｍｏｌ）を加え、室温で１０分間撹拌した。その後、反応混合物にクロロホルム（４００ｍＬ）を加え、飽和食塩水（２００ｍＬ）で洗浄した。有機層を無水硫酸ナトリウムで乾燥後、ろ過して、濃縮した。得られた濃縮残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル）で精製し、表題化合物（３．９８ｇ，５１％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.39 (3H, t, J = 7.2 Hz), 2.56 (3H, s), 3.08 (3H, d, J = 5.2 Hz), 4.34 (2H, q, J = 7.2 Hz), 8.10 (1H, brs), 8.73 (1H, s).

To a mixture of the compound of Reference Example 34 (7.28 g, 40.0 mmol) and phosphorus oxychloride (80 mL) was added triethylamine (5.0 mL, 36.0 mmol) at 30 ° C. The mixture was stirred at 40 ° C. for 50 minutes and concentrated. Chloroform (400 mL) was added to the obtained concentrated residue, the mixture was poured into ice water (400 mL), and the organic layer was extracted. The organic layer was washed with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The obtained concentrated residue was dissolved in a tetrahydrofuran solution (60 mL), methylamine (6.21 g, 200 mmol) was added thereto, and the mixture was stirred at room temperature for 10 minutes. Thereafter, chloroform (400 mL) was added to the reaction mixture, and the mixture was washed with saturated brine (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate) to obtain the title compound (3.98 g, 51%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.39 (3H, t, J = 7.2 Hz), 2.56 (3H, s), 3.08 (3H, d, J = 5.2 Hz), 4.34 (2H, q, J = 7.2 Hz), 8.10 (1H, brs), 8.73 (1H, s).

Reference Example 34
Ethyl 2-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylate

ナトリウム（２．９０ｇ，１２６ｍｍｏｌ）のエタノール溶液（１５０ｍＬ）にアセトアミジン塩酸塩（１１．９ｇ，１２６ｍｍｏｌ）を０℃で加えた。０℃で２０分間撹拌後、エトキシメチレンマロン酸ジエチル（２８．６ｇ，１３２ｍｍｏｌ）を滴下し、０℃で３０分間撹拌し、トリエチルアミン（２０ｍＬ，１４５ｍｍｏｌ）を加えた。２時間加熱還流後、反応混合物を濃縮し、水（４００ｍＬ）を加えた後、クエン酸を加えｐＨ４〜５に調整し、ジクロロメタン（２００ｍＬ）で３回抽出した。有機層を合わせて無水硫酸ナトリウムで乾燥し、ろ過して、濃縮した。得られた濃縮残渣にｔｅｒｔ−ブチルメチルエーテル（２００ｍＬ）を加え、析出物をろ取することで、表題化合物（１４．０ｇ，６１％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.40 (3H, t, J = 7.2 Hz), 2.61 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 8.73 (1H, s).

Acetamidine hydrochloride (11.9 g, 126 mmol) was added to an ethanol solution (150 mL) of sodium (2.90 g, 126 mmol) at 0 ° C. After stirring at 0 ° C. for 20 minutes, diethyl ethoxymethylenemalonate (28.6 g, 132 mmol) was added dropwise, stirred at 0 ° C. for 30 minutes, and triethylamine (20 mL, 145 mmol) was added. After heating under reflux for 2 hours, the reaction mixture was concentrated, water (400 mL) was added, citric acid was added to adjust to pH 4-5, and the mixture was extracted 3 times with dichloromethane (200 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. To the obtained concentrated residue, tert-butyl methyl ether (200 mL) was added, and the precipitate was collected by filtration to obtain the title compound (14.0 g, 61%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.40 (3H, t, J = 7.2 Hz), 2.61 (3H, s), 4.39 (2H, q, J = 7.2 Hz), 8.73 (1H, s).

Reference Example 35
6'-methyl-1 ', 2', 3 ', 6'-tetrahydro-2,4'-bipyridine dihydrochloride

参考例３６の化合物（５２１ｍｇ，１．９ｍｍｏｌ）の１，４−ジオキサン溶液（２ｍＬ）に、４ｍｏｌ／Ｌの塩酸１，４−ジオキサン溶液（２ｍＬ）を加えた。室温で６時間攪拌後、濃縮し、得られた固体をヘキサンで洗浄した後、乾燥し、表題化合物（３８２ｍｇ，７３％）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 1.0 min ObsMS = 177.1 [M+1]

To a 1,4-dioxane solution (2 mL) of the compound of Reference Example 36 (521 mg, 1.9 mmol), a 4 mol / L hydrochloric acid 1,4-dioxane solution (2 mL) was added. After stirring at room temperature for 6 hours, the mixture was concentrated, and the resulting solid was washed with hexane and dried to give the title compound (382 mg, 73%).
LC-MS: Condition A RT = 1.0 min ObsMS = 177.1 [M + 1]

Reference Example 36
tert-Butyl 6'-methyl-3 ', 6'-dihydro-2,4'-bipyridine-1' (2'H) -carboxylate

参考例３７の化合物（１．４ｇ，４．３ｍｍｏｌ）の１，４−ジオキサン溶液（１０ｍＬ）に、２-ブロモピリジン（６８６ｍｇ，４．３ｍｍｏｌ）とテトラキス（トリフェニルホスフィン）パラジウム（０）（９９３ｍｇ，０．８６ｍｍｏｌ）とリン酸三カリウム（２．７ｇ，１２．９ｍｍｏｌ）を加えた。８０℃で６時間攪拌後、室温に冷却し、セライトろ過により沈殿物を取り除いた。ろ液を濃縮後、残渣を酢酸エチルに溶かし、有機層を水、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝１：５）で精製し、表題化合物（５２１ｍｇ，４４％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.16, 1.29 (d, J = 6.8 Hz, 3H, diastereo ratio = 4 : 3), 1.49 (s, 9H), 2.54-2.67 (m, 2H), 2.73-2.80 (m, 0.5H), 2.90-3.05 (m, 0.5H), 3.75-3.80 (m, 0.5H), 4.41-4.46 (m, 0.5H), 4.69 (brs, 1H), 6.55-6.61 (m, 1H), 7.31-7.39 (m, 2H), 7.14-7.17 (m, 1H), 7.31-7.39 (m, 2H), 7.63-7.67 (m, 1H), 8.56-8.58 (m, 1H).
LC‐MS：条件Ａ Ｒ.Ｔ.= 6.6 min ObsMS = 275.1 [M+1]

To a 1,4-dioxane solution (10 mL) of the compound of Reference Example 37 (1.4 g, 4.3 mmol), 2-bromopyridine (686 mg, 4.3 mmol) and tetrakis (triphenylphosphine) palladium (0) (993 mg) , 0.86 mmol) and tripotassium phosphate (2.7 g, 12.9 mmol) were added. After stirring at 80 ° C. for 6 hours, the mixture was cooled to room temperature, and the precipitate was removed by celite filtration. After the filtrate was concentrated, the residue was dissolved in ethyl acetate, and the organic layer was washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 5) to give the title compound (521 mg, 44%).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.16, 1.29 (d, J = 6.8 Hz, 3H, diastereo ratio = 4: 3), 1.49 (s, 9H), 2.54-2.67 (m, 2H), 2.73 -2.80 (m, 0.5H), 2.90-3.05 (m, 0.5H), 3.75-3.80 (m, 0.5H), 4.41-4.46 (m, 0.5H), 4.69 (brs, 1H), 6.55-6.61 ( m, 1H), 7.31-7.39 (m, 2H), 7.14-7.17 (m, 1H), 7.31-7.39 (m, 2H), 7.63-7.67 (m, 1H), 8.56-8.58 (m, 1H).
LC-MS: Condition A RT = 6.6 min ObsMS = 275.1 [M + 1]

Reference Example 37
tert-Butyl 6-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate

参考例３８の化合物（１．８ｇ，５．２ｍｍｏｌ）の１，４−ジオキサン溶液（３０ｍＬ）に、ビス（ピナコレイト）ジボラン（１．４ｇ，５．７ｍｍｏｌ）と１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（II）ジクロリド（７６１ｍｇ，１．０４ｍｍｏｌ）と酢酸カリウム（１．５０ｇ，１５．６ｍｍｏｌ）を加えた。８０℃で６時間攪拌後、室温に冷却し、セライトろ過により沈殿物を取り除いた。ろ液を濃縮後、残渣を酢酸エチルに溶かし、有機層を水、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後ろ過して、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）で精製し、表題化合物（１．４０ｇ，８４%）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 9.2 min ObsMS = 346.1 [M+23]

To a 1,4-dioxane solution (30 mL) of the compound of Reference Example 38 (1.8 g, 5.2 mmol), bis (pinacolate) diborane (1.4 g, 5.7 mmol) and 1,1′-bis (diphenylphosphine) were added. Fino) ferrocene-palladium (II) dichloride (761 mg, 1.04 mmol) and potassium acetate (1.50 g, 15.6 mmol) were added. After stirring at 80 ° C. for 6 hours, the mixture was cooled to room temperature, and the precipitate was removed by celite filtration. After the filtrate was concentrated, the residue was dissolved in ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain the title compound (1.40 g, 84%).
LC-MS: Condition A RT = 9.2 min ObsMS = 346.1 [M + 23]

Reference Example 38
tert-Butyl 6-methyl-4-{[(trifluoromethyl) sulfonyl] oxa} -3,6-dihydropyridine-1 (2H) -carboxylate

１−（ｔｅｒｔ−ブトキシカルボニル）−２−メチルピペリジン−４−オン（１．００ｇ,４．７ｍｍｏｌ）のテトラヒドロフラン溶液（１０ｍＬ）に−７８℃で１．５mol/L リチウムジイソプロピルアミドのテトラヒドロフラン溶液（３．７ｍＬ，５．６ｍｍｏｌ）を滴下した。１０分攪拌後、Ｎ−フェニルビス（トリフルオロメタンスルホンイミド）（１．９ｇ，５．６ｍｍｏｌ）のテトラヒドロフラン溶液（５ｍＬ）を滴下した後、徐々に室温に昇温した。６時間攪拌後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：クロロホルム＝５：１） で精製し、表題化合物（１．６ｇ，定量的）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.18, 1.24 (d, J = 6.8 Hz, 3H, diastereo ratio = 3 : 2), 1.47 (s, 9H), 2.05-2.23 (m, 1H), 2.59-2.99 (m, 1H), 3.62-3.76 (m, 1H), 4.20-4.67 (m, 2H), 5.71, 5.75 (s, 1H, diastereo ratio = 3 : 2).
LC‐MS：条件Ａ Ｒ.Ｔ.= 8.4 min ObsMS = 368.0 [M+23]

To a tetrahydrofuran solution (10 mL) of 1- (tert-butoxycarbonyl) -2-methylpiperidin-4-one (1.00 g, 4.7 mmol) at −78 ° C. in a tetrahydrofuran solution of 1.5 mol / L lithium diisopropylamide (3 0.7 mL, 5.6 mmol) was added dropwise. After stirring for 10 minutes, a tetrahydrofuran solution (5 mL) of N-phenylbis (trifluoromethanesulfonimide) (1.9 g, 5.6 mmol) was added dropwise, and the temperature was gradually raised to room temperature. After stirring for 6 hours, a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: chloroform = 5: 1) to obtain the title compound (1.6 g, quantitative).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.18, 1.24 (d, J = 6.8 Hz, 3H, diastereo ratio = 3: 2), 1.47 (s, 9H), 2.05-2.23 (m, 1H), 2.59 -2.99 (m, 1H), 3.62-3.76 (m, 1H), 4.20-4.67 (m, 2H), 5.71, 5.75 (s, 1H, diastereo ratio = 3: 2).
LC-MS: Condition A RT = 8.4 min ObsMS = 368.0 [M + 23]

Reference Example 39
3- (2-Methylpiperidin-4-yl) pyridine dihydrochloride

参考例４０の化合物から、参考例３５と同様の手法により、表題化合物（定量的）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 2.0 min ObsMS = 177.0 [M+1]

The title compound (quantitative) was obtained from the compound of Reference Example 40 by the same method as in Reference Example 35.
LC-MS: Condition A RT = 2.0 min ObsMS = 177.0 [M + 1]

Reference Example 40
tert-Butyl 2-methyl-4- (pyridin-3-yl) piperidine-1-carboxylate

参考例４１の化合物（５８ｍｇ，０．２１ｍｍｏｌ）のメタノール溶液（３ｍＬ）に、１０％パラジウム／炭素（５０mg）を加えた。水素雰囲気下、室温で４時間攪拌後、セライトろ過し、濃縮して、表題化合物（５８ｍｇ，定量的）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.17, 1.28 (d, J = 6.8 Hz, 3H, diastereo ratio = 1 : 1), 1.50 (s, 9H), 2.21-2.40 (m, 1H), 2.50-2.62 (m, 0.5H), 2.80-2.84 (m, 0.5H), 2.95-3.04 (m, 0.5H), 3.71-3.76 (m, 0.5H), 4.20-4.42 (m, 2H), 4.69 (brs, 1H), 6.03-6.08 (m, 1H), 7.24-7.29 (m, 1H), 7.63-7.66 (m, 1H), 8.49-8.50 (m, 1H), 8.64-8.65 (m, 1H).
LC‐MS：条件Ａ Ｒ.Ｔ.= 6.1 min ObsMS = 277.1 [M+1]

To a methanol solution (3 mL) of the compound of Reference Example 41 (58 mg, 0.21 mmol), 10% palladium / carbon (50 mg) was added. The mixture was stirred at room temperature for 4 hours under a hydrogen atmosphere, filtered through celite, and concentrated to obtain the title compound (58 mg, quantitative).
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.17, 1.28 (d, J = 6.8 Hz, 3H, diastereo ratio = 1: 1), 1.50 (s, 9H), 2.21-2.40 (m, 1H), 2.50 -2.62 (m, 0.5H), 2.80-2.84 (m, 0.5H), 2.95-3.04 (m, 0.5H), 3.71-3.76 (m, 0.5H), 4.20-4.42 (m, 2H), 4.69 ( brs, 1H), 6.03-6.08 (m, 1H), 7.24-7.29 (m, 1H), 7.63-7.66 (m, 1H), 8.49-8.50 (m, 1H), 8.64-8.65 (m, 1H).
LC-MS: Condition A RT = 6.1 min ObsMS = 277.1 [M + 1]

Reference Example 41
tert-Butyl 6'-methyl-3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate

参考例３８の化合物（１５０ｍｇ，０．４３ｍｍｏｌ）の１，４−ジオキサン溶液（１．５mＬ）に、水（０．５ｍＬ）と３−ピリジルボロニックアシッド（６４ｍｇ，０．５２ｍｍｏｌ）と１，１’−ビス（ジフェニルホスフィノ）フェロセン−パラジウム（ＩＩ）ジクロリド（６３ｍｇ，０．１０ｍｍｏｌ）と炭酸ナトリウム（２２８ｍｇ，２．２ｍｍｏｌ）を加えマイクロウェーブ照射下、１００℃で１０分攪拌した。その後、セライトろ過し、濃縮した。得られた残渣を酢酸エチルに溶かし、有機層を水、飽和塩化ナトリウム水溶液で洗浄し、無水硫酸ナトリウムで乾燥後、ろ過して、濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝５：１）で精製し、表題化合物（５８ｍｇ，４９％）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 6.6 min ObsMS = 275.1 [M+1]

To a 1,4-dioxane solution (1.5 mL) of the compound of Reference Example 38 (150 mg, 0.43 mmol), water (0.5 mL), 3-pyridylboronic acid (64 mg, 0.52 mmol) and 1,1 '-Bis (diphenylphosphino) ferrocene-palladium (II) dichloride (63 mg, 0.10 mmol) and sodium carbonate (228 mg, 2.2 mmol) were added, and the mixture was stirred at 100 ° C. for 10 minutes under microwave irradiation. Thereafter, the mixture was filtered through Celite and concentrated. The obtained residue was dissolved in ethyl acetate, and the organic layer was washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give the title compound (58 mg, 49%).
LC-MS: Condition A RT = 6.6 min ObsMS = 275.1 [M + 1]

Reference Examples 42-45
The compounds of Reference Examples 42 to 45 were synthesized from 1- (tert-butoxycarbonyl) -3-methylpiperidin-4-one according to the method described in Reference Examples 35 to 38 above.

Reference Example 46
3- (3-Methylpiperidin-4-yl) pyridine dihydrochloride

参考例４７の化合物から、参考例３５と同様の手法により、表題化合物（７３％）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 1.0 min ObsMS = 177.1 [M+1]

The title compound (73%) was obtained from the compound of Reference Example 47 by a method similar to that of Reference Example 35.
LC-MS: Condition A RT = 1.0 min ObsMS = 177.1 [M + 1]

Reference Example 47
tert-Butyl 3-methyl-4- (pyridin-3-yl) piperidine-1-carboxylate

参考例４８の化合物から、参考例４０と同様の手法により、表題化合物（定量的）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 2.0 min ObsMS = 277.0 [M+1]

The title compound (quantitative) was obtained from the compound of Reference Example 48 by the same method as in Reference Example 40.
LC-MS: Condition A RT = 2.0 min ObsMS = 277.0 [M + 1]

Reference Example 48
tert-Butyl 3'-methyl-3 ', 6'-dihydro-3,4'-bipyridine-1' (2'H) -carboxylate

参考例４５の化合物から、参考例４１と同様の手法により、表題化合物（３８％）を得た。
¹H-NMR (400MHz, CDCl₃) δ: 1.02 (d, J = 6.8 Hz, 3H), 1.50 (s, 9H), 2.84 (brs, 1H), 3.33 (d, J = 13.2, 3.4 Hz, 1H), 3.81-3.95 (m, 2H), 4.18-4.45 (m, 1H), 5.93 (brs, 1H), 7.20-7.30 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 8.51-8.61 (m, 1H).
LC‐MS：条件Ａ Ｒ.Ｔ.= 7.1 min ObsMS = 275.1 [M+1]

The title compound (38%) was obtained from the compound of Reference Example 45 by the same method as in Reference Example 41.
¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.02 (d, J = 6.8 Hz, 3H), 1.50 (s, 9H), 2.84 (brs, 1H), 3.33 (d, J = 13.2, 3.4 Hz, 1H ), 3.81-3.95 (m, 2H), 4.18-4.45 (m, 1H), 5.93 (brs, 1H), 7.20-7.30 (m, 1H), 7.62 (d, J = 7.8 Hz, 1H), 8.51- 8.61 (m, 1H).
LC-MS: Condition A RT = 7.1 min ObsMS = 275.1 [M + 1]

Reference Examples 49-52
The compounds of Reference Examples 49 to 52 were synthesized from 1- (tert-butoxycarbonyl) -homopiperazin-4-one according to the method described in Reference Examples 35 to 38.

Reference Example 53
4- (Pyridin-3-yl) -2,3,6,7-tetrahydro-1H-azepine dihydrochloride

参考例５４の化合物から、参考例３５と同様の手法により、表題化合物（３７％）を得た。
LC‐MS：条件Ｂ Ｒ.Ｔ.= 0.3 min ObsMS = 175 [M+1]

The title compound (37%) was obtained from the compound of Reference Example 54 by a method similar to that of Reference Example 35.
LC-MS: Condition B RT = 0.3 min ObsMS = 175 [M + 1]

Reference Example 54
tert-Butyl 4- (pyridin-3-yl) -2,3,6,7-tetrahydro-1H-azepine-1-carboxylate

参考例５２の化合物から、参考例４１と同様の手法により、表題化合物（５１％）を得た。
LC‐MS：条件Ａ Ｒ.Ｔ.= 7.1 min ObsMS = 275.0 [M+1]

The title compound (51%) was obtained from the compound of Reference Example 52 by a method similar to that of Reference Example 41.
LC-MS: Condition A RT = 7.1 min ObsMS = 275.0 [M + 1]

Reference Examples 55-63
In accordance with the method described in Reference Examples 1-6 above, 1-N-Boc-4- (4,4,5,5-tetramethyl- [1,3,2] -dioxaborolan-2-yl) -3, The compounds of Reference Examples 55 to 63 were synthesized from 6-dihydro-2H-pyridine.

Reference Example 64
To a mixture of aqueous sodium hydroxide solution prepared from 2- (piperidin-4-yl) pyridine water (400 mL) and sodium hydroxide (107 g, 2.69 mol) and toluene (2000 mL), the mixture of Reference Example 3 was stirred under ice-cooling. Compound (300 g, 1.28 mol) was added and then stirred at room temperature for 30 minutes. The layers were separated, and the aqueous layer was extracted with toluene (2000 mL). The combined toluene layers were concentrated under reduced pressure to obtain the title compound (196 g, 95%).

Example 58
Crystal of Form A of 2-methyl-5- [4- (pyridin-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine (Compound X) Sodium triacetoxyborohydride (2.06 kg, 9.74 mol) ) In a tetrahydrofuran (6.65 parts by weight) suspension of the compound of Reference Example 64 (1.05 parts by weight), the compound of Reference Example 21 (0.89 parts by weight) and tetrahydrofuran (2.85 parts by weight). The mixture was added at 20 ° C. and stirred at 35 ° C. for 7 hours and then at room temperature for 17 hours. Toluene (9.50 parts by weight) was added to the reaction mixture, 15% aqueous sodium hydroxide solution (13.0 parts by weight) was added dropwise, and the mixture was stirred at 25 ° C. for 30 minutes. The layers were separated, and the aqueous layer was extracted with toluene (2.85 parts by weight). The combined organic layers were washed with 15% brine (5.59 parts by weight) and concentrated. Toluene (3.30 parts by weight) was added to the residue, and the mixture was stirred at 80 ° C. and then filtered. The material on the filter was washed with toluene (500 g). To the obtained filtrate, heptane (1.90 parts by weight) was added dropwise with stirring at 80 ° C., and then cooled to 20 ° C. over 4 hours. The precipitated crystals were collected by filtration, and the crystals were washed with a toluene-heptane (1: 1) mixture (5.70 parts by weight) and dried to obtain crude title compound crystals (1.47 parts by weight, 80%). It was. Crude crystals (1.46 parts by weight) were dissolved in a mixture of 2-propanol (1.10 parts by weight) and heptane (6.62 parts by weight) at 80 ° C., cooled to 70 ° C. and then heptane (4.41 parts by weight). ) Was added dropwise, and then cooled to 20 ° C. in 4 hours. The precipitated crystals were collected by filtration, washed with a mixture of 2-propanol-heptane (1:10) (4.41 parts by weight) and dried to give the title compound (1.26 parts by weight) as Form A crystals. Obtained. A chart of the powder X-ray diffraction pattern of Form A is shown in FIG. 3, and a DSC chart is shown in FIG.
¹ H-NMR (300MHz, CDCl ₃ ) δ: 1.77-2.00 (4H, m), 2.11 (2H, td, J = 11.6, 2.5 Hz), 2.49 (3H, s), 2.66-2.78 (1H, m) , 2.93-3.04 (2H, m), 3.46 (2H, s), 7.10-7.19 (2H, m), 7.62 (1H, ddd, J = 7.7, 7.7, 1.8 Hz), 7.93 (1H, s), 8.53 -8.57 (1H, m).
Form A showed an endothermic peak accompanying melting having an extrapolation onset temperature (Tim) at 131 ° C. (± 5 ° C.) in differential scanning calorimetry (DSC).

Example 59
2-Methyl-5- [4- (pyridin-2-yl) piperidin-1-ylmethyl] pyrimidin-4-amine (Compound X) Form B Crystals Compound X Form A (5 mg) was mixed with water-acetone (1 : 50) of the mixed solution of 10) was added and dissolved by heating at 90 ° C. Then, after standing to cool to room temperature, the solvent was dried by natural evaporation to obtain Form B crystals.
A powder X-ray diffraction pattern chart of Compound X Form B is shown in FIG. 5, and a DSC chart is shown in FIG. Form B shows an endothermic peak associated with a transition having an extrapolation start temperature (Tim) at 114 ° C. (± 5 ° C.) in differential scanning calorimetry (DSC), and starts extrapolation at 134 ° C. (± 5 ° C.). An endothermic peak with melting of the transitioned crystal form with temperature (Tim) was shown.

Example 60: Recrystallization examination When recrystallization of Form A of Compound X was attempted, crystals of Form A of Compound X were obtained from the following solvents.
EtOH, IPA, 2-butanol, chloroform, acetonitrile, 1,2-dimethoxyethane, THF, 1,4-dioxane, t-butyl methyl ether, CPME, ethyl acetate, isopropyl acetate, acetone, methyl ethyl ketone, chlorobenzene, toluene, acetic acid Isobutyl,
MeOH-water, EtOH-water, THF-water, isopropyl acetate-heptane.
On the other hand, crystals of Form B of Compound X were obtained from the following solvents.
IPA-water.

Example 61 Production of 1.5 Succinate of Compound X Ethanol (10 mL) was added to Compound X (1.00 g, 3.53 mmol), and the temperature was raised to 70 ° C. Succinic acid (0.834 mg, 7.06 mmol) was added, and the mixture was stirred at 70 ° C. for 1 hour, and then gradually cooled to room temperature. After stirring for 1 hour under ice cooling, the title compound was obtained by filtering the precipitated solid. A chart of the powder X-ray diffraction pattern of the compound of Example 61 is shown in FIG. 7, and a DSC chart is shown in FIG.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.66-1.85 (4H, m), 1.99-2.09 (2H, m), 2.29 (3H, s), 2.40 (6H, s), 2.62-2.71 ( 1H, m), 2.84-2.93 (2H, m), 3.37 (2H, s), 6.86 (2H, s), 7.18 (1H, ddd, J = 7.6, 4.8, 1.1 Hz), 7.26 (1H, d, J = 7.8 Hz), 7.69 (1H, ddd, J = 7.7, 7.7, 2.0 Hz), 7.86 (1H, s), 8.46-8.48 (1H, m).
^From the results of ¹ H-NMR and ion chromatography, it was confirmed that 1.5 molecules of succinic acid existed per molecule of compound X. In differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolation start temperature (Tim) at 167 ° C. (± 5 ° C.) was shown.

Example 62: Production of 1.5 fumarate salt of Compound X Ethanol (40 mL) was added to Compound X (1.00 g, 3.53 mmol), and the temperature was raised to 70 ° C. Fumaric acid (0.819 g, 7.06 mmol) was added, and the mixture was stirred at 70 ° C. for 1 hr, and then gradually cooled to room temperature. After stirring for 1 hour under ice cooling, the title compound was obtained by filtering the precipitated solid. A chart of the powder X-ray diffraction pattern of the compound of Example 61 is shown in FIG. 9, and a DSC chart is shown in FIG.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.67-1.86 (4H, m), 2.04-2.15 (2H, m), 2.30 (3H, s), 2.63-2.72 (1H, m), 2.87- 2.95 (2H, m), 3.41 (2H, s), 6.60 (3H, s), 6.93 (2H, s), 7.19 (1H, ddd, J = 7.5, 4.9, 1.0 Hz), 7.26 (1H, d, J = 7.8 Hz), 7.69 (1H, ddd, J = 7.8, 7.8, 1.8 Hz), 7.89 (1H, s), 8.46-8.49 (1H, m).
^From the result of ¹ H-NMR, it was confirmed that 1.5 molecules of fumaric acid existed for one molecule of compound X. Further, in differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolation start temperature (Tim) at 196 ° C. (± 5 ° C.) was shown.

Example 63 Preparation of Citrate of Compound X
The title compound was obtained from compound X and citric acid according to the method described in Example 61. A DSC chart is shown in FIG. In differential scanning calorimetry (DSC), an endothermic peak accompanying melting having an extrapolation start temperature (Tim) at 165 ° C. (± 5 ° C.) was shown.

Example 64 Preparation of Trihydrochloride of Compound X Concentrated hydrochloric acid (33.1 g, 327 mmol) was added to a methanol solution (148 mL) of compound X (18.5 g, 65.3 mmol), stirred at room temperature for 10 minutes and concentrated. . Ethanol (380 mL) and water (38 mL) were added to the concentrated residue, the temperature was raised to reflux temperature, and after dissolution was confirmed, the mixture was gradually cooled. Since solid precipitation was confirmed at 45 ° C., the mixture was stirred at the same temperature for 30 minutes, hexane (126 mL) was added dropwise, and the mixture was gradually cooled to room temperature again. After stirring for 2 hours under ice cooling, the precipitated solid was collected by filtration to give the title compound.
¹ H-NMR (300 MHz, DMSO-d ₆ ) δ: 2.10-2.23 (4H, m), 2.51 (3H, s), 3.19-3.37 (3H, m), 3.54-3.64 (2H, m), 4.46 ( 2H, s), 7.60-7.69 (2H, m), 8.14-8.30 (1H, m), 8.59 (1H, s), 8.70 (1H, d, J = 4.6 Hz), 9.24-9.38 (2H, m) , 11.28 (1H, brs).
Elemental analysis Measured value; C: 46.24%, H: 6.35%, N: 16.73%, Cl: 25.24%
Theoretical value (1.25 hydrate); C: 46.28%, H: 6.43%, N: 16.86%, Cl: 25.61%
From the above results, it was judged as trihydrochloride 1.25 hydrate.

Reference Example 65: Preparation of Compound X Phosphate, L-Tartrate, L-Malate, p-Toluenesulfonate, and Benzenesulfonate According to the method described in Example 61 and corresponding to Compound X The title compound was obtained from the acid.

Test Examples Hereinafter, pharmacological test results of representative compounds of the present invention will be shown and the pharmacological action of the compounds will be described. However, the present invention is not limited to these test examples.

Action G protein-dependent pathway of the present invention compounds on G-protein-dependent pathway of dopamine D ₄ receptor, G protein guanosine triphosphate (Guanosine triphosphate: GTP) that binds, G protein is activated, It is a pathway that transmits signals into cells via second messengers. When GPCRs are activated by a ligand, G protein binds to GPCRs, GTP binds to Gα which is one of G protein subunits, and Gγβ subunits dissociate. The activated Gα transmits a signal into the cell by adjusting intracellular cAMP concentration through activation and inhibition of adenylate cyclase and adjusting intracellular calcium concentration through activation of phospholipase C. Therefore, G protein-dependent pathway activity can be measured by measuring the amount of intracellular cAMP and the concentration of intracellular calcium.
In this study, the effect of the compounds of the present invention on the G protein-dependent pathway, together with the dopamine D ₄ receptor, was measured by measuring the effect on dopamine D ₂ , adrenaline α ₁ , α ₂ receptor and evaluating the receptor selectivity. did.

Production of expression cell lines Human dopamine D ₂ and D ₄ receptors, human adrenergic α ₁ and α ₂ receptors, calcium-binding photoprotein aequorin and Gα16 cDNA were obtained by PCR. Plasmids expressing each receptor, aequorin and Gα16 were prepared, and these were introduced into CHO cells (chinese hamster ovary cells) or HEK293 cells (human embryonic kidney 293 cells) to prepare expression cell lines.

G protein-dependent pathway activity measurement
Test Example 1 (Evaluation of agonist activity and selectivity for receptors)
G protein-dependent agonist activity and antagonist activity were measured as follows using intracellular calcium concentration as an index. CHO-K1 or HEK293 cell line introduced with D ₂ , D ₄ , α _1A , α _2A gene was seeded on a 384-well plate, cultured at 37 ° C. for 24 hours in a CO ₂ incubator, and then coelenterazine was taken up in advance. The compound of the present invention dissolved in DMSO was added to the cells, and the change in the amount of luminescence was measured with FDSS (manufactured by Hamamatsu Photonics). For agonist activity, the luminescence level of wells to which the compound of the present invention was not added was set to 0%, and the luminescence level of wells to which 10 μM endogenous ligand (dopamine or adrenaline) was added instead of the compound of the present invention was set to 100%. The maximum activity (Emax) of the inventive compound was calculated. On the other hand, for the antagonist activity, the inhibitory activity of the compound of the present invention against the endogenous ligand when the amount of luminescence in the well to which only 10 μM endogenous ligand was added was taken as 100% was calculated. The EC ₅₀ value is calculated as the reaction concentration corresponding to 50% of the compound Emax of the present invention, and the IC ₅₀ value is calculated as the concentration of the compound of the present invention that inhibits 50% of Emax of the endogenous ligand.

  The results obtained using the test method of Test Example 1 are shown in Table 19, Table 20, and Table 21. A comparative example is the result of having similarly tested about the compound as described in Example 14 of patent document 1. FIG.

Effect G-protein-independent pathway of the compound of the present invention G-protein-independent pathway of dopamine D ₄ receptor, an intracellular signal transduction pathways G protein is not involved. When GPCRs are activated by a ligand, GRKs (G protein coupled receptor kinase) phosphorylate GPCR, and βarrestin binds to the phosphorylated GPCR. When βarrestin binds to GPCRs, MAPKs (mitogen-actiated protein kinases), protein kinase B (PKB), PI3 kinase (Phosphoinositide 3-kinase), NFκB (nuclear factor-kappa B) pathway, etc. are activated. Transmits independent signals into cells. In addition, it is known that βarrestin binds to GPCR to cause internalization of GPCR, and is thus involved in GPCR desensitization. Therefore, G protein-independent pathway activity can be measured by examining the ability of β-arrestin to recruit GPCRs.
In this test, the effect on G-protein-independent pathways for dopamine D ₄ receptor of the present invention compounds, the evaluation by examining the recruitment ability of intracellular calcium concentration and β-arrestin was performed.

Plasmid expressing a fusion protein of the fusion protein, and β-arrestin and β-galactosidase large fragment of the expression cell lines producing human dopamine D ₄ receptor and DiscoveRx Corporation than the β-galactosidase of the small fragments purchase (ProLinkTM) (Enzyme Acceptor) These were introduced into CHO cells or HEK293 cells to produce transient or stable expression cell lines.

G protein-independent pathway activity measurement
Test Example 2 (Evaluation of effects on G protein-independent pathway for D ₄ receptors)
The activity of the G protein-independent pathway was measured as follows using β-arrestin's recruitment ability as an index. The cell line into which the gene had been introduced was seeded in a 384-well plate and cultured in a CO ₂ incubator at 37 ° C. for 24 hours, and then the compound of the present invention dissolved in DMSO was added and left at 37 ° C. for 90 minutes. A buffer containing a β-galactosidase reaction substrate (PathHunter Cell Assay Buffer, manufactured by DiscoverRx) was added, and the amount of luminescence was measured using FDSS (manufactured by Hamamatsu Photonics). The maximum activity (Emax) of the compound of the present invention is defined by setting the luminescence amount of the well to which the compound of the present invention is not added to 0% and the luminescence amount of the well to which 10 μM endogenous ligand (dopamine) is added instead of the compound of the present invention as 100%. ) Was calculated. The EC ₅₀ value is calculated as a reaction concentration corresponding to 50% of the compound Emax of the present invention.

The results obtained using the test method of Test Example 2 are shown in Table 22. Combined with the results in Table 20 to 22, the compounds of the present invention, with respect to D ₄ receptor, but agonism holds for G-protein-dependent pathway, effects on G protein-independent pathway intrinsic It was found to be a biasing ligand having a characteristic that it is weaker than the sex ligand dopamine.

Test Example 3 Evaluation of bioavailability
Rat PK Test In this test, the pharmacokinetics of the compound of the present invention can be evaluated. For SD or WKY 7-week-old rats, the compound of the present invention is administered intravenously in physiological saline solution or orally in carboxymethylcellulose suspension solution or methylcellulose suspension solution, and blood is collected at the following times, respectively. did.
Intravenous administration: 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours and 24 hours after administration Oral administration: 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours after administration And plasma was obtained from the blood collected for 24 hours, the drug concentration in plasma was measured by LC-MS, and the pharmacokinetic parameters were calculated from this concentration transition.

Test Example 4 Evaluation of migration into the brain
Rat Brain Translocation Test This test can evaluate the brain translocation of the compounds of the present invention. The compound of the present invention is subcutaneously administered in a physiological saline solution or orally in a methylcellulose suspension solution to an SD-type or WKY-type 7-week-old rat, 0.5 hours, 1 hour or 2 hours after administration. Plasma and brain were collected, and plasma and brain drug concentrations were measured by LC-MS.
Serum and brain protein binding rates of the compounds of the present invention were measured using equilibrium dialysis.
By fitting the plasma and brain compound concentrations and plasma and brain protein binding rates obtained by the above test to the following formula, Kp, uu, brain (brain / plasma non-binding drug concentration ratio) Can be calculated.
Kp, uu, brain = (Brain compound concentration × (100−protein binding rate in brain (%)) / 100) / (plasma compound concentration × (100−plasma protein binding rate (%)) / 100)

  The results of Test Example 3 and Test Example 4 are shown in Table 23. A comparative example is the result of having similarly tested about the compound as described in Example 14 of patent document 1. FIG.

Test Example 5 Assessment of hepatotoxicity risk
Dansylated glutathione (dGSH) trapping assay The compound of the present invention was metabolized in liver microsomes, and reactive metabolites reacting with dansylated glutathione (dGSH) were detected and quantified. The metabolic reaction was measured using a screening robot (Tecan), and the metabolite-dGSH conjugate concentration was measured using a fluorescence detection UPLC system (Waters).

(Solution preparation)
The compound of the present invention was dissolved in DMSO to prepare a 10 mmol / L test substance solution. A microsome solution was prepared by mixing 7.6 mL of potassium phosphate buffer (500 mmol / L, pH 7.4), 1.9 mL of human liver microsome (Xenotech, 20 mg protein / mL), and 1.27 mL of pure water. . A microsome (dGSH (−)) solution was prepared by adding 0.67 mL of pure water to 3.78 mL of the microsome solution. 1.14 mL of dGSH solution (20 mmol / L) was added to 6.48 mL of microsome solution to prepare a microsome (dGSH (+)) solution. A cofactor solution was prepared by dissolving 80.9 mg of NADPH in 30 mL of pure water. A reaction stop solution was prepared by dissolving 33 mg of Tris (2-carboxyethyl) phosphine (TECP) in 115 mL of methanol.

(reaction)
12 μL of the test substance solution was mixed with 388 μL of pure water, and 50 μL each was dispensed into 6 wells in a 96-well plate. The 6 wells were divided into 3 groups of 2 wells, which were designated as “reaction group”, “unreacted group” and “dGSH non-added group”, respectively. The microsome (dGSH (+)) solution was added to the “reaction group” and “unreacted group”, and 50 μL of the microsome (dGSH (−)) was added to the “dGSH non-added group”. Cofactor solution was added to the “reaction group” and “dGSH non-added group”, and 50 μL of pure water was added to the “non-reacted group”. After incubation at 37 ° C. for 60 minutes, 450 μL of reaction stop solution was added to stop the reaction. Purified water was added to the “reaction group” and “dGSH non-added group”, and 50 μL of cofactor solution was added to the “unreacted group”. The plate was cooled at −20 ° C. for 1 hour, and then centrifuged (4000 rpm, 10 minutes). went. The supernatant was collected on a separate plate and subjected to analysis.

(analysis)
Using a fluorescence detection UPLC system (manufactured by Waters), the metabolite-dGSH conjugate concentration was measured under the following conditions.
Column: Waters ACQUITY UPLC BEHC18 1.7 μm 2.1 × 10 mm
Elution solvent: A, 0.2% formic acid / 40% methanol; B, 0.2% formic acid / methanol gradient: B, 0% (0 min) → 83.3% (9.33 min) → 83.3% (10.63 min) → 0% (10.64 min) → 0% (13 min)
Since the fluorescence intensity varies depending on the organic solvent composition, correction was performed with the organic solvent composition at the time of elution.

  The results of Test Example 5 are shown in Table 24. A comparative example is the result of having similarly tested about the compound as described in Example 14 of patent document 1. FIG. The compound of the comparative example showed a dGSH covalent bond amount of 0.777 μM. On the other hand, the dGSH covalent bond amounts of the compounds of Examples 2, 5, 33, 36, 37, 44, 45, and 46 were all below the detection limit.

Test Example 6 Evaluation of Pharmacological Action for Hyperactivity in SHR Rats SHR rats in early childhood are widely recognized as highly relevant ADHD models. The inhibitory action when the compound of the present invention was administered to the hyperactive behavior in the open field environment in the rat was evaluated. The compounds of the present invention were orally administered to 7-week-old SHR rats, and the amount of exercise for 90 minutes was measured after 30 minutes. SuperMex (Muromachi Kikai Co., Ltd.) was used for the measurement. The total exercise amount for 90 minutes was statistically processed by expressing the inhibition rate (%) as a numerical value of 0 to 100 based on the exercise amount of the vehicle administration group. As shown in Table 25, the compounds of Example 2 and Example 5 suppressed the hyperactivity behavior exhibited by SHR rats.

Test Example 7 Evaluation of pharmacological action against carelessness in SHR rats In this rat, a low spontaneous alternation behavior rate was observed in the Y-shaped maze test as compared to the background animals WKY rats. Therefore, the compound of the present invention was pretreated and the effect on attention function was evaluated. The compounds of the present invention were orally administered to 4-week-old SHR rats, and the spontaneous alternation behavior rate was measured for 8 minutes from 30 minutes later. The improvement rate (%) was shown as a numerical value based on the spontaneous alternation behavior rate of the vehicle administration group. A Y-shaped maze device (made of black acrylic: 450 mm × 100 mm × 350 mm, Horikawa Seisakusho) was used for the experiment. The compounds of Example 2 (administered at 10 mg / kg) and Example 5 (administered at 1 mg / kg) showed a significant improvement in alternation behavior rate (see FIGS. 1 and 2).

Test Example 8 Evaluation of Pharmacological Action for Social Disorders in Embryonic Valproic Acid Administered Rats Rats exposed to valproic acid at 12.5 days of fetal life are widely recognized as highly valid autism models. In this rat, social cognitive impairment is observed in the three-chamber test, which is a social evaluation test. Therefore, the compound of the present invention was pretreated, and the improvement effect on social cognition was evaluated. For the experiment, a social cage (600 mm × 400 mm × 220 mm, Muromachi Kikai Co., Ltd.) was used. The compound of the present invention was orally administered to a 3-week-old gestational valproic acid-treated rat, and after 30 minutes, the approach time to the rat or a new object was measured for 10 minutes. The ratio of the approach time to the rat when the approach time to the new object was 100% was calculated, and the improvement rate (%) was evaluated based on the result of the vehicle administration group. The oral administration (1 mg / kg) of the compound of Example 5 was 27.6%, and a significant increase in the approach time to the rat was observed.

Since the compound of the present invention exhibits a highly selective action on the dopamine D ₄ receptor, it is useful as a therapeutic agent for central test system diseases such as attention deficit hyperactivity disorder.

Claims (25)

Formula (1):

(Where
n and m each independently represent 1 or 2;
R ^a represents a C _1-6 alkyl group, a C _3-6 cycloalkyl group, or an amino group;
R ^b represents a hydrogen atom, a C _1-6 alkyl group, or an amino group which may be substituted with 1 to 2 identical or different C _1-6 alkyl groups (provided that when R ^a is an amino group) In which R ^b is a hydrogen atom);
R ^c1 and R ^c2 each independently represent a hydrogen atom or a C _1-6 alkyl group;
R ^d1 and R ^d2 are each independently a hydrogen atom, a fluorine atom, or a C _1-6 alkyl group, or together with the carbon atom to which they are attached, a 3- to 8-membered cycloalkane. A ring or a 3- to 8-membered cycloalkene ring may be formed (wherein the cycloalkane ring or cycloalkene ring is selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkoxy). Optionally substituted with 1-2 groups independently selected);
Ring Q represents an optionally substituted 5- to 10-membered nitrogen-containing heteroaryl group;
A bond including a broken line represents a single bond or a double bond. )
Or a pharmaceutically acceptable salt thereof. Formula (1):

(Where
n and m each independently represent 1 or 2;
R ^a represents a C _1-6 alkyl group, a C _3-6 cycloalkyl group, or an amino group;
R ^b represents a hydrogen atom, a C _1-6 alkyl group, or an amino group which may be substituted with 1 to 2 C _1-6 alkyl groups (provided that when R ^a is an amino group, ^b is a hydrogen atom));
R ^c1 and R ^c2 each independently represent a hydrogen atom or a C _1-6 alkyl group;
R ^d1 and R ^d2 are each independently a hydrogen atom, a fluorine atom, or a C _1-6 alkyl group, or together with the carbon atom to which they are attached, a 3- to 8-membered cycloalkane. A ring or a 3- to 8-membered cycloalkene ring may be formed (wherein the cycloalkane ring or cycloalkene ring is selected from the group consisting of a halogen atom, C _1-6 alkyl, and C _1-6 alkoxy). Optionally substituted with 1 to 2 groups selected);
Ring Q represents an optionally substituted pyridyl group or an optionally substituted isoquinolinyl group;
A bond including a broken line represents a single bond or a double bond. )
Or a pharmaceutically acceptable salt thereof. Ring Q is represented by the following formula (2a), (2b), (2c), (2d) or (2e):

(In the formula, R ^e1 and R ^e2 each independently represent a hydrogen atom, a halogen atom, or a C _1-6 alkyl group which may be substituted with 1 to 3 identical or different halogen atoms.) The pharmaceutical which consists of the compound of Claim 1 or 2 which is group represented by these, or its pharmaceutically acceptable salt. The pharmaceutical which consists of a compound as described in any one of Claims 1-3 whose R ^<a> is a _C1-4 alkyl group, or its pharmaceutically acceptable salt. The pharmaceutical which consists of a compound as described in any one of Claims 1-3 whose R ^<a> is an amino group, and R ^<b> is a hydrogen atom, or its pharmaceutically acceptable salt. R ^b is, C _1-6 alkyl group or an amino group, a pharmaceutical comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4,. A pharmaceutical comprising the compound according to any one of claims 1 to 4 or 6 or a pharmaceutically acceptable salt thereof, wherein R ^b is an amino group. The pharmaceutical consisting of the compound as described in any one of Claims 1-7 whose R ^{< c1>} and R ^<c2> are both hydrogen atoms, or its pharmaceutically acceptable salt. The pharmaceutical consisting of the compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein R ^d1 and R ^d2 each independently represent a hydrogen atom or a C _1-6 alkyl group. . The pharmaceutical consisting of the compound as described in any one of Claims 1-9 whose R ^{< d1>} and R ^<d2> are both hydrogen atoms, or its pharmaceutically acceptable salt.   The pharmaceutical which consists of the compound or its pharmaceutically acceptable salt as described in any one of Claims 3-10 whose ring Q is group represented by Formula (2a) or (2b).   The pharmaceutical consisting of the compound of Claim 11 whose ring Q is group represented by Formula (2a), or its pharmaceutically acceptable salt.   The pharmaceutical which consists of the compound of Claim 11 whose ring Q is group represented by Formula (2b), or its pharmaceutically acceptable salt. The pharmaceutical consisting of the compound or pharmaceutically acceptable salt thereof according to any one of claims 3 to 13, wherein R ^e1 and R ^e2 are each independently a hydrogen atom or a fluorine atom.   The pharmaceutical which consists of a compound as described in any one of Claims 1-14 whose bond containing a broken line is a single bond, or its pharmaceutically acceptable salt. A medicament comprising a compound represented by any of the following formulas or a pharmaceutically acceptable salt thereof:

  A pharmaceutical composition comprising the pharmaceutical according to any one of claims 1 to 16 and a pharmaceutically acceptable excipient.   17. A drug selected from the group consisting of attention deficit / hyperactivity disorder, autism spectrum disorder, schizophrenia, mood disorder, and cognitive dysfunction, comprising the medicine according to any one of claims 1 to 16 as an active ingredient. A therapeutic agent for central nervous system diseases.   A therapeutic agent for attention deficit / hyperactivity disorder, comprising the pharmaceutical according to any one of claims 1 to 16 as an active ingredient.   The therapeutic agent according to claim 19, wherein the attention deficit / hyperactivity disorder is a disorder mainly having attention deficit (Inattention).   The therapeutic agent according to claim 19, wherein the attention deficit hyperactivity disorder is a disorder mainly having hyperactivity.   The therapeutic agent according to claim 19, wherein the attention deficit / hyperactivity disorder is a disorder whose main symptom is impulsivity.   The therapeutic agent of autism spectrum disorder | damage | failure containing the pharmaceutical as described in any one of Claims 1-16 as an active ingredient.   The therapeutic agent according to claim 23, wherein the autism spectrum disorder is a disorder whose main symptom is a persistent defect in social communication and social interaction.   The therapeutic agent according to claim 23, wherein the autism spectrum disorder is a disorder whose main symptom is a repetitive behavior, interest, or activity pattern with limited autism spectrum disorder.

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