JP2009073743A - Novel fused cyclic pyrimidine compound or salt thereof and pharmaceutical composition thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new compound which has anti-tumor activity based on the inhibition of PLK1 and can orally be administered. <P>SOLUTION: Provided is this new cyclic pyrimidine compound of general formula (I) (wherein, -X<SP>1</SP>-X<SP>2</SP>- is -N-N- bond or -C=C- bond; X<SP>3</SP>is C or N; R<SP>1</SP>to R<SP>6</SP>are each H, a lower alkyl group which may have a substituent, a saturated or unsaturated heterocyclic group which may have a substituent, an aryl group which may have a substituent, or the like). <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a novel condensed cyclic pyrimidine compound or a salt thereof, and a pharmaceutical composition thereof useful in the field of medicine and useful as an antitumor agent based on inhibiting PLK1.

  Cell division is one of the most important life phenomena that produces two genetically identical cells from one cell. In particular, the even distribution of chromosomes in the mitotic phase (M phase) is strictly controlled by a spindle having two poles, and is essential for cell growth and survival. If the M-phase regulatory mechanism fails, the cells die or become cancerous. M phase kinase Polo-Like Kinase 1 (PLK1) is a centrosome maturation and spindle by phosphorylating various substrates at each step such as entering M phase, centrosome control, chromosome segregation, cytokinesis, etc. It has been shown to play an important role in control (Non-Patent Document 1). PLK1 is overexpressed in various cancer tissues such as colorectal cancer (Non-patent document 2), stomach cancer (Non-patent document 3), head and neck cancer (Non-patent document 4), and ovarian cancer (Non-patent document 5). , PLK1 overexpression has been reported to correlate with the prognosis of these patients.

  In addition, in studies using siRNA technology, when PLK1 is specifically deleted in cancer cells, cell cycle arrest with tetraploid DNA is caused, cell proliferation is inhibited, and the viable cell rate is decreased by apoptosis. (For example, Non-Patent Document 6). There is also a report that induction of cell death by PLK1 inhibition is selective for cancer cells (Non-patent Document 7). It has been reported that a mouse bladder cancer model also exhibits an antitumor effect (Non-patent Document 8). These experimental results indicate that inhibition of PLK1 activity leads to cancer cell growth inhibition and cell death induction, and strongly suggests that PLK1 inhibitors are effective as antitumor agents.

So far, condensed cyclic pyrimidine compounds having a skeleton similar to the compound of the present invention and having a PLK inhibitory action useful as an antitumor agent have been reported (for example, Patent Document 1 and Patent Document 2). However, since these compounds do not exhibit oral absorbability (Test Example 2), the development of orally administrable drugs is desired from the economical viewpoint of cancer patients' QOL or medical costs.
That is, the compound group represented by the above general formula (I) that has an excellent PLK1 inhibitory action and can be administered orally has not been reported so far.

Oncogene 2005 24: 2844-2859 Cancer Sci. 2003 94: 148-152 Int J Oncol. 2006 29 (3): 589-594 Cancer Res. 1999 59: 2794-2797 Br. J. Cancer 2004 90: 815-812 J Natl Cancer Inst. 2002 94: 1863-1877 Cell Growth & Diff. 2000 22: 615-623 J. Clin. Invest. 2005 115: 978-985 Special table 2005-501904 pamphlet International Publication No. 2006/018185 Pamphlet

  An object of the present invention is to provide a novel compound having antitumor activity based on inhibiting PLK1 and capable of being administered orally.

  In order to solve the above-mentioned problems, the present inventors have synthesized a novel condensed cyclic pyrimidine compound widely, and the compound represented by the general formula (I) exhibits excellent PLK1 inhibitory action and cell growth inhibitory action based thereon. Furthermore, the present invention was completed by finding that these compounds show excellent oral absorbability.

（ 式中、−Ｘ¹−Ｘ²−は−Ｎ−Ｎ−結合又は−Ｃ＝Ｃ−結合を示し、
Ｘ³は、炭素原子又は硫黄原子を示し、
Ｒ¹は、水素原子、又は置換基を有していてもよい低級アルキル基を示し、
Ｒ²、Ｒ³は、Ｘ³が炭素原子を示すとき、同一又は相異なって、置換基を有していてもよい低級アルキル基を示すか、もしくは一緒になって酸素原子又は硫黄原子を示すか、あるいはＸ³が硫黄原子を示すとき、互いにオキソ基を示すか、もしくは一緒になって酸素原子を示し、
Ｒ⁴は、置換基を有していてもよい炭素数１〜１０アルキル基を示し、
Ｒ⁵は、置換基を有していてもよい低級アルキル基、炭素数３〜１０環状アルキル基、又はアリール基を示し、
Ｒ⁶は、ハロゲン原子、置換基を有していてもよいアリール基、−ＮＲ⁷Ｒ⁸又は−ＯＲ⁹を示し、
Ｒ⁷、Ｒ⁸は、同一又は相異なって、水素原子、置換基を有していてもよい低級アルキル基、置換基を有していてもよい飽和又は不飽和ヘテロ環式基、置換基を有していてもよいアリール基を示し、
Ｒ⁹は、置換基を有していてもよいアリール基を示す）
で表される縮合環式ピリミジン化合物又はその塩を提供するものである。 That is, the present invention relates to the general formula (I)

(In the formula, —X ¹ —X ² — represents an —N—N— bond or —C═C— bond,
X ³ represents a carbon atom or a sulfur atom,
R ¹ represents a hydrogen atom or an optionally substituted lower alkyl group,
R ² and R ³ , when X ³ represents a carbon atom, are the same or different and represent a lower alkyl group which may have a substituent, or together represent an oxygen atom or a sulfur atom. Or when X ³ represents a sulfur atom, each represents an oxo group or together represents an oxygen atom,
R ⁴ represents a C 1-10 alkyl group which may have a substituent,
R ⁵ represents an optionally substituted lower alkyl group, a C 3-10 cyclic alkyl group, or an aryl group,
R ⁶ represents a halogen atom, an aryl group which may have a substituent, —NR ⁷ R ⁸ or —OR ⁹ ;
R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group which may have a substituent, a saturated or unsaturated heterocyclic group which may have a substituent, or a substituent. An aryl group which may have,
R ⁹ represents an aryl group which may have a substituent)
The condensed cyclic pyrimidine compound represented by these, or its salt is provided.

Moreover, this invention provides the pharmaceutical composition which uses the compound or its salt represented with the said general formula (I) as an active ingredient.
Moreover, this invention provides the antitumor agent which uses the compound or its salt represented with the said general formula (I) as an active ingredient.

  The fused cyclic pyrimidine compound or salt thereof of the present invention has been found to exhibit excellent PLK1 inhibitory action and cell growth inhibitory action based thereon, and is useful as an antitumor agent that can be administered orally.

The fused cyclic pyrimidine compound or a salt thereof of the present invention is a compound represented by the above general formula (I) and is a novel compound not disclosed in Patent Document 1 and Patent Document 2.
For example, Patent Documents 1 and 2 disclose dihydropteridinone compounds having PLK inhibitory activity and useful as antitumor agents. However, the compound of the present invention is different from the compounds disclosed in the above-mentioned patent documents in that -X ¹ -X ² -is a compound showing -N-N- bond or -C = C- bond.

In the above and following descriptions of the present specification, “lower” means 1 to 6 carbon atoms unless otherwise specified.
In the above and the following description of the present specification, “heteroaryl” is a monocyclic or polycyclic aromatic heterocyclic group containing at least one N, O or S atom, for example, a thienyl group or a furyl group. , Pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, imidazolyl group, triazolyl group, tetrazolyl group, pyridyl group, pyrazyl group, pyrimidinyl group, pyridazyl group, indolyl group, isoindolyl group, indazolyl group, benzofuranyl Group, dihydrobenzofuranyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, purinyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalyl group and the like.

  In the above and following descriptions of the present specification, the “amino group optionally having substituent (s)” may be an amino group, mono- or dialkylamino group, alkanesulfonylamino group, or lower alkyl group substituted. Examples include a good arylsulfonylamino group, a C-substituted carbonylamino group and the like, wherein the alkyls of the “dialkylamino group” may be the same or different.

In the above and the following description of the present specification, the “C-substituted carbonyl” in the “C-substituted carbonylamino group” means a carbonyl in which the carbon atom of the carbonyl group has a suitable substituent, As, for example, “an alkyl group which may have a substituent” defined by R ¹ below, “an aryl group which may have a substituent” defined by R ⁶ below, And “saturated or unsaturated heterocyclic group optionally having substituent (s)” defined by R ⁷ and R ⁸ .

  In the above and the following description of the present specification, the “N-substituted carbamoyl group” means a carbamoyl group in which the nitrogen atom of the carbamoyl group has an appropriate substituent, and the nitrogen atom represents an appropriate substituent 1 or 2 In the case of having two appropriate substituents, the substituents may be the same or different.

Examples of the “suitable substituent” of the nitrogen atom of the carbamoyl group include “an alkyl group which may have a substituent” defined by R ¹ below, and “defined by R ⁶ ” below. An aryl group optionally having substituent (s) ”and a“ saturated or unsaturated heterocyclic group optionally having substituent (s) ”defined by R ⁷ and R ⁸ below.

  In the above and the following description of the present specification, the “substituent” of the “aryl group optionally having substituent (s)” and the “heteroaryl group optionally having substituent (s)” are as follows unless otherwise specified. A halogen atom, a hydroxy group, a cyano group, a nitro group, a formyl group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an amino which may have a substituent Group, N-substituted or unsubstituted carbamoyl group and the like.

  In the above and the following description of the present invention, as the “substituent” of the “alkyl group optionally having substituent (s)”, unless otherwise specified, a halogen atom, a hydroxy group, a cyano group, a nitro group, a formyl group, It has an alkoxy group which may have a substituent, an amino group which may have a substituent, an N-substituted or unsubstituted carbamoyl group, an aryl group which may have a substituent, and a substituent. And a heteroaryl group which may be used.

  In the above and the following description of the present invention, the “substituent” of the “optionally substituted alkoxy group” is, unless otherwise specified, a halogen atom, a hydroxy group, a cyano group, a nitro group, a formyl group, It has an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an amino group which may have a substituent, an N-substituted or unsubstituted carbamoyl group, and a substituent. An aryl group which may be substituted, a heteroaryl group which may have a substituent, and the like.

In general formula (I), —X ¹ —X ² — represents a —N—N— bond or a —C═C— bond.
In general formula (I), X ³ is a carbon atom or a sulfur atom, and when —X ¹ —X ² — is an —N—N— bond, preferably is a carbon atom or a sulfur atom, and —X ¹ — When X ² — is a —C═C— bond, it is preferably a carbon atom.
In the general formula (I), the “lower alkyl group” of the “lower alkyl group which may have a substituent” represented by R ¹ is a linear or branched alkyl group having 1 to 6 carbon atoms. And a methyl group, an ethyl group, an n-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-hexyl group and the like are exemplified, and a methyl group and an ethyl group are preferable.

In the general formula (I), the “substituent” of the “lower alkyl group optionally having substituent (s)” represented by R ¹ is a halogen atom (preferably a fluorine atom), a hydroxy group, a cyano group, nitro Group, formyl group, alkoxy group, optionally substituted amino group, N-substituted or unsubstituted carbamoyl group, optionally substituted aryl group, optionally substituted hetero An aryl group etc. are illustrated, Preferably it is a heteroaryl group, More preferably, it is a pyridyl group, More preferably, it is a 4-pyridyl group. The “lower alkyl group optionally having substituent (s)” may have the same or different substituents as described above.

In the general formula (I), examples of the “lower alkyl group” of the “lower alkyl group which may have a substituent” represented by R ² and R ³ include the above alkyl groups, preferably a methyl group It is.
In the general formula (I), the “substituent” of the “lower alkyl group optionally having substituent (s)” represented by R ² and R ³ is a halogen atom (preferably a fluorine atom), a hydroxy group, cyano Group, nitro group, formyl group, alkoxy group, optionally substituted amino group, N-substituted or unsubstituted carbamoyl group, optionally substituted aryl group, substituted Examples of the heteroaryl group may be exemplified. The “lower alkyl group optionally having substituent (s)” may have the same or different substituents as described above.

In the general formula (I), R ² and R ³ are together an oxygen atom or a sulfur atom when X ³ represents a carbon atom, or when X ³ represents a sulfur atom, Or together, an oxygen atom, and when —X ¹ —X ² — is an —N—N— bond is preferably an oxo group to each other, or together, an oxygen atom or a sulfur atom And when —X ¹ —X ² — is a —C═C— bond, it is preferably an oxygen atom together.
In the general formula (I), the “C 1-10 alkyl group” of the “optionally substituted C 1-10 alkyl group” represented by R ⁴ is a straight chain having 1-10 carbon atoms. A chain or branched or cyclic alkyl group, methyl, ethyl, n-propyl, isopropylmethyl, n-butyl, sec-butyl, tert-butyl, cyclobutylmethyl, n -Hexyl group, n-octyl group and the like are exemplified, and preferred are methyl group, ethyl group, isopropylmethyl group, cyclobutylmethyl group and n-octyl group.

In the general formula (I), examples of the “substituent” of the “optionally substituted C 1-10 alkyl group” represented by R ⁴ include a halogen atom, a hydroxy group, a cyano group, a nitro group, Formyl group, alkoxy group, amino group optionally having substituent, N-substituted or unsubstituted carbamoyl group, aryl group optionally having substituent, heteroaryl group optionally having substituent Etc., preferably halogen atoms, cyano groups, alkoxy groups, mono- or dialkylamino groups, N-substituted or unsubstituted carbamoyl groups, aryl groups optionally having substituents, heteroaryl groups, more preferably Is a fluorine atom, cyano group, methoxy group, diethylamino group, unsubstituted carbamoyl group, methoxy group, trifluoromethyl group, unsubstituted carbamoyl group and amino as substituents A phenyl group which may have a substituent group selected from a pyridyl group. The “optionally substituted alkyl group having 1 to 10 carbon atoms” may have the same or different above-described substituents.

In the general formula (I), examples of the “lower alkyl group” of the “lower alkyl group optionally having substituent (s)” represented by R ⁵ include the above alkyl groups having 1 to 6 carbon atoms, preferably A methyl group and an isopropyl group.
In the general formula (I), as the “substituent” of the “lower alkyl group optionally having substituent (s)” represented by R ⁵ , a halogen atom (preferably a fluorine atom), a hydroxy group, a cyano group, nitro Group, formyl group, alkoxy group, optionally substituted amino group, N-substituted or unsubstituted carbamoyl group, optionally substituted aryl group, optionally substituted hetero An aryl group etc. are illustrated, Preferably it is the aryl group which may have a substituent, More preferably, it is a dimethoxyphenyl group, Especially preferably, it is a 3, 4- dimethoxyphenyl group. The “lower alkyl group optionally having substituent (s)” may have the same or different substituents as described above.

In the general formula (I), examples of the “C3-C10 cyclic alkyl group” represented by R ⁵ include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, an adamantyl group and the like, preferably a cyclopentyl group, An adamantyl group;
In the general formula (I), the “aryl group” represented by R ⁵ is an aryl group having 6 to 14 carbon atoms, such as a phenyl group and a naphthyl group, preferably a phenyl group.

In the general formula (I), examples of the “halogen atom” represented by R ⁶ include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a chlorine atom.
In the general formula (I), the “aryl group” of the “aryl group optionally having substituent (s)” represented by R ⁶ is exemplified by the above aryl group, preferably a phenyl group.

In the general formula (I), the “substituent” of the “aryl group optionally having substituent (s)” represented by R ⁶ includes a halogen atom, hydroxy group, cyano group, nitro group, formyl group, trifluoro Methyl group, alkyl group, alkoxy group, optionally substituted amino group, N-substituted or unsubstituted carbamoyl group, optionally substituted aryl group, optionally substituted Heteroaryl group etc. are illustrated, Preferably it is N substituted carbamoyl group, More preferably, it is (1-methylpiperidin-4-yl) carbamoyl group. The “aryl group optionally having substituent (s)” may be the same as or different from the above substituent (s).

In the general formula (I), examples of the “lower alkyl group” of the “lower alkyl group optionally having substituent (s)” represented by R ⁷ and R ⁸ include the above alkyl groups, preferably a methyl group It is.
In the general formula (I), the “substituent” of the “lower alkyl group optionally having substituent (s)” represented by R ⁷ and R ⁸ is a halogen atom (preferably a fluorine atom), a hydroxy group, cyano Group, nitro group, formyl group, alkoxy group, optionally substituted amino group, N-substituted or unsubstituted carbamoyl group, optionally substituted aryl group, substituted And a heteroaryl group, etc. may be exemplified, and an aryl group is preferable, and a phenyl group is preferable. The “lower alkyl group optionally having substituent (s)” may have the same or different substituents as described above.

In the general formula (I), the “saturated or unsaturated heterocyclic group” of the “saturated or unsaturated heterocyclic group optionally having substituents” represented by R ⁷ and R ⁸ includes N, A monocyclic or polycyclic saturated heterocyclic group or an unsaturated heterocyclic group containing at least one O or S atom is preferable, and a monocyclic saturated heterocyclic group (for example, pyrrolidyl group, piperidyl group) is preferable. , Piperazyl group, morpholyl group, thiomorpholyl group, homopiperidinyl group, etc.), monocyclic unsaturated heterocyclic group (for example, thienyl group, furyl group, pyrrolyl group, pyrrolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, pyrazolyl group, Imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrazyl, pyrimidinyl, pyridazyl, etc.) and bicyclic unsaturated heterocyclic groups (eg Endolinyl group, indolyl group, isoindolyl group, indazolyl group, methylenedioxyphenyl group, ethylenedioxyphenyl group, benzofuranyl group, dihydrobenzofuranyl group, benzoimidazolyl group, benzoxazolyl group, benzothiazolyl group, purinyl group, quinolyl group , Isoquinolyl group, quinazolinyl group, quinoxalyl group, and the like. The monocyclic saturated heterocyclic group is preferably a piperidinyl group, and the monocyclic unsaturated heterocyclic group is preferably a thienyl group, a thiazolyl group, or a pyridyl group, and a bicyclic unsaturated heterocyclic ring As the formula group, an indolinyl group is preferable.

In the general formula (I), the “substituent” of the “saturated or unsaturated heterocyclic group which may have a substituent” represented by R ⁷ and R ⁸ includes a halogen atom, a hydroxy group, and a cyano group. , An oxo group, a nitro group, a formyl group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an amino group which may have a substituent, N-substituted or non-substituted Examples include a substituted carbamoyl group, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, etc., preferably an oxo group, an alkyl group which may have a substituent, An N-substituted carbamoyl group, more preferably an oxo group, a methyl group optionally having a carboxy group, and a (1-methylpiperidin-4-yl) carbamoyl group.
In the general formula (I), the “aryl group” of the “aryl group optionally having substituent (s)” represented by R ⁷ and R ⁸ is exemplified by the above aryl group, preferably a phenyl group. .

In the general formula (I), the “substituent” of the “aryl group optionally having substituent (s)” represented by R ⁷ and R ⁸ is a halogen atom, hydroxy group, cyano group, nitro group, formyl Group, an alkyl group which may have a substituent, an alkoxy group which may have a substituent, an amino group which may have a substituent, an N-substituted or unsubstituted carbamoyl group, and a substituent. An aryl group which may have a substituent, a heteroaryl group which may have a substituent, and the like are exemplified, and preferably a hydroxy group, an alkyl group which may have a substituent, and a substituent. Preferred alkoxy group, amino group optionally having methanesulfonyl group, C-substituted carbonylamino group, N-substituted carbamoyl group, more preferably hydroxy group, trifluoromethyl group, methyl group, (1-methylpiperidine 4-yl) carbamoylmethyl group, methoxy group, 1-methylpiperidin-4-ylmethoxy group, thiophen-2-ylmethoxy group, amino group, (1-methylpiperidin-4-yl) carbamoyl group, (N-methylazetidine) -3-yl) carbamoyl group, 2- (diethylamino) ethylcarbamoyl group, 3-pyridylcarbamoyl group, 4-pyridylcarbamoyl group, thiophene-2-methylcarbamoyl group, 3-pyridylmethylcarbamoyl group, 2- (pyridine-2) -Yl) ethylcarbamoyl group, 2- (1-piperidinylmethyl) phenylmethylcarbamoyl group, (1,2,2,6,6-pentamethylpiperidin-4-yl) carbamoyl group, 4-pyridylcarbonylamino group , A methanesulfonylamino group. The “aryl group optionally having substituent (s)” may be the same as or different from the above substituent (s).

In the general formula (I), the “aryl group” of the “aryl group optionally having substituent (s)” represented by R ⁹ is exemplified by the above aryl group, preferably a phenyl group.
In the general formula (I), as the “substituent” of the “aryl group optionally having substituent (s)” represented by R ⁹ , a halogen atom, hydroxy group, cyano group, nitro group, formyl group, substituent An alkyl group that may have a substituent, an alkoxy group that may have a substituent, an amino group that may have a substituent, an N-substituted or unsubstituted carbamoyl group, and a substituent. Examples include a good aryl group, a heteroaryl group which may have a substituent, and the like, preferably an N-substituted carbamoyl group and a C-substituted carbonylamino group, more preferably (1-methylpiperidin-4-yl) carbamoyl. It is a group.

Reaction process formula 1

In Reaction Scheme 1, R ^4a represents R ⁴ or an amine protecting group. The amine protecting group is not particularly limited as long as it is usually used as a protecting group, but benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 3,4,5-trimethoxybenzyl group. Etc., and 4-methoxybenzyl group is preferred. X ³ , R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ are as defined above.

[Step 1]
A compound represented by the general formula (3) can be synthesized by reacting a readily available compound (1) with a hydrazide compound represented by the general formula (2) in the presence of a base.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include acetone, tetrahydrofuran, diethyl ether, dioxane and the like, preferably tetrahydrofuran. Examples of the base used include organic amines such as trimethylamine, triethylamine, tripropylamine, diisopropylethylamine, N-methylmorpholine, pyridine, lutidine, collidine, and inorganic bases such as sodium bicarbonate, sodium carbonate, and potassium carbonate. Is triethylamine, and the number of equivalents thereof is 0.5 to 2 equivalents, preferably 0.8 to 1.5 equivalents. Reaction temperature is 0-30 degreeC, Preferably it is 20-30 degreeC. The reaction time is 0.5 to 24 hours, preferably 1 hour.

[Step 2]
The compound represented by the general formula (4) can be synthesized by reacting the hydrazide compound represented by the general formula (3) with the compound represented by R ^4a X ^a in the presence of a base. X ^a represents a halogen atom.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction. Examples thereof include dimethylformamide and dimethylacetamide, and dimethylacetamide is preferable. Examples of the base to be used include lithium hydride, sodium hydride, and potassium hydride, preferably sodium hydride, and the number of equivalents is 0.5 to 5 equivalents, preferably 1 to 3 equivalents. . The reaction temperature is −10 to 10 ° C., preferably −5 to 5 ° C. The reaction time is 5 minutes to 24 hours, preferably 10 minutes.

[Step 3]
A compound represented by the general formula (5) can be synthesized from the compound represented by the general formula (4) by a generally known reductive cyclization reaction.
For example, the nitro compound represented by the general formula (4) is reacted with a reducing agent such as zinc, tin or iron, preferably iron, under acidic conditions to obtain the compound represented by the general formula (5). I can do it. The reaction solvent is not particularly limited as long as it does not affect the reaction, but an acid such as glacial acetic acid, formic acid or hydrochloric acid can be used as the reaction solvent, and glacial acetic acid is preferred. The reaction temperature is 50 to 150 ° C, preferably 60 to 100 ° C. The reaction time is 10 minutes to 2 hours, preferably 30 minutes to 1 hour.

[Step 4]
By reacting the compound represented by the general formula (5) with the compound represented by R ¹ X ^a by the same method as in Step 2, the compound represented by the general formula (6) can be synthesized. I can do it. X ^a has the same meaning as above.
When R ^4a is an amine protecting group, the desired compound represented by the general formula (6) can be synthesized by the same method as in Step 2 after deprotection by an ordinary method. For example, the deprotection when the protecting group of the amine is a 4-methoxybenzyl group includes a method of treating with trifluoroacetic acid in an organic solvent.

[Step 5]
The compound represented by the general formula (7) can be synthesized by reacting the compound represented by the general formula (6) in the presence of a base.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane and the like are exemplified, and ethanol is preferable. Examples of the base to be used include lithium hydroxide, sodium hydroxide, and potassium hydroxide, preferably sodium hydroxide, and the number of equivalents is 0.8 to 10 equivalents, preferably 1 to 2 equivalents. . The reaction temperature is 20 to 100 ° C, preferably 60 to 80 ° C. The reaction time is 5 minutes to 1 hour, preferably 10 minutes to 30 minutes.

[Step 6]
The compound represented by the general formula (7) is converted into a corresponding ketone compound (for example, acetone, methyl ethyl ketone, phenylmethyl ketone, etc.), an aldehyde compound (for example, acetaldehyde, benzaldehyde, etc.) under basic or acidic conditions by a generally known method. , Thionyl chloride, thiophosgene and the like can be reacted to synthesize the compound represented by the general formula (8).

[Step 7]
A compound represented by the general formula (9) can be synthesized by reacting the compound represented by the general formula (8) as follows.
(A) When R ⁶ is —NR ⁷ R ⁸ Group By reacting an amino compound corresponding to —NR ⁷ R ⁸ group with a compound represented by formula (8) by a generally known method, A compound represented by the formula (9) can be synthesized.

For example, when the —NR ⁷ R ⁸ group is an alkylamino group, by reacting a compound represented by the general formula (8) with an amino compound corresponding to the —NR ⁷ R ⁸ group in a reaction solvent, The target compound represented by the general formula (9) can be obtained. The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, and dimethyl sulfoxide is preferable. The reaction temperature is 0 to 200 ° C, preferably 130 to 150 ° C. The reaction time is 10 minutes to 24 hours, preferably 1 to 3 hours. The number of equivalents of the amino compound as the substrate is 1 to 10 equivalents, preferably 1 to 3 equivalents.

For example, when the —NR ⁷ R ⁸ group is an arylamino group, a compound represented by the general formula (8) and an amino compound corresponding to the —NR ⁷ R ⁸ group are reacted under acidic conditions in a reaction solvent. By reacting, the target compound represented by the general formula (9) can be obtained. The reaction solvent is not particularly limited as long as it does not affect the reaction, but methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane and the like are exemplified, and tert-butanol is preferable. Examples of the acid to be used include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, tosylic acid, etc., preferably tosylic acid, and the number of equivalents is 0.5 to 2 equivalents, preferably 0.8 to 1.8 equivalents. It is. The reaction temperature is 0 to 200 ° C, preferably 10 to 100 ° C. The reaction time is 30 minutes to 72 hours, preferably 12 to 24 hours. The number of equivalents of the amino compound as the substrate is 1 to 10 equivalents, preferably 1 to 3 equivalents.

When the —NR ⁷ R ⁸ group is an arylamino group or a heteroarylamino group, Org. Lett. According to the method (Pd ₂ dba) described in 2002, 4 (20): 3481-3484, for example, Pd ₂ dba ₃ , xanthophos, K ₃ PO ₄ can also be used for synthesis.

(B) When R ⁶ is —OR ⁹ group By reacting a hydroxy compound corresponding to —OR ⁹ group with a compound represented by formula (8) in the presence of a base by a generally known method, A compound represented by the formula (9) can be synthesized.

For example, when the —OR ⁹ group is a hydroxy compound, the compound represented by the general formula (8) is reacted with the hydroxy compound corresponding to the —OR ⁹ group under acidic conditions in a reaction solvent. A compound represented by the general formula (9) can be obtained. The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include dimethylformamide, dimethylacetamide, dimethyl sulfoxide and the like, and dimethyl sulfoxide is preferable. Examples of the base to be used include sodium hydrogen carbonate, potassium carbonate, potassium phosphate, sodium carbonate and the like, preferably potassium carbonate, and the number of equivalents thereof is 1 to 5 equivalents, preferably 3 equivalents. The reaction temperature is 0 to 200 ° C, preferably 10 to 100 ° C. The reaction time is 30 minutes to 72 hours, preferably 1 to 24 hours. The number of equivalents of the amino compound as the substrate is 1 to 10 equivalents, preferably 1 to 3 equivalents.

(C) When R ⁶ is an aryl group which may have a substituent In the presence of a base, the compound represented by formula (8) may have a substituent by a generally known method. A compound represented by the general formula (9) can be synthesized by reacting an aryl compound corresponding to a good aryl group.
For example, it can be synthesized according to the Suzuki coupling method described in Chemical Review (Miyaura N .; Suzuki A. 1995, 95, 2457-2483).
The aryl compound corresponding to the aryl group which may have a substituent is usually synthesized by a known method or is easily available.

Reaction process formula 2

In Reaction Scheme 2, R ^4a represents R ⁴ or an amine protecting group. The amine protecting group is not particularly limited as long as it is usually used as a protecting group, but benzyl group, 4-methoxybenzyl group, 3,4-dimethoxybenzyl group, 3,4,5-trimethoxybenzyl group. Etc., and 4-methoxybenzyl group is preferred. R ¹ , R ⁴ , R ⁵ and R ⁶ are as defined above.

[Step 8]
By reacting 5-bromo-2-methoxypyrimidine (10) with an alkyl or aryl aldehyde represented by R ⁵ —CHO under acidic conditions, a divalent iron compound and a peroxide, the general formula ( 11) can be synthesized.

  As the acid to be used, acetic acid, sulfuric acid, nitric acid, hydrochloric acid, or a mixture thereof, for example, a mixture of acetic acid and sulfuric acid can be used. The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, and the above acid can be used as the reaction solvent. Examples of the divalent iron compound used include iron (II) sulfate heptahydrate, iron (II) acetate, iron (II) bromide tetrahydrate, and iron (II) chloride tetrahydrate. Is iron (II) sulfate heptahydrate. The number of equivalents is 1 to 3 equivalents, preferably 1.6 equivalents. Examples of the peroxide to be used include hydrogen peroxide solution, tert-butylhydroxyperoxide, metachloroperbenzoic acid (mCPBA), cumene hydroxyperoxide, etc., preferably tert-butylhydroxyperoxide, the equivalent number of which Is 1 to 5 equivalents, preferably 3.5 equivalents. The reaction temperature is 10 to 100 ° C, preferably 15 to 30 ° C. The reaction time is 30 minutes to 24 hours, preferably 1 to 2 hours.

[Step 9]
A compound represented by the general formula (12) can be synthesized from the compound represented by the general formula (11) by a generally known method.
For example, the methoxy group of the compound represented by the general formula (11) is replaced with an acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or tosylic acid in a solvent such as methanol, ethanol, propanol, isopropanol, tert-butanol or dioxane. The compound represented by the general formula (12) can be synthesized by treating it with a hydroxyl group and reacting with phosphorus oxychloride.

[Step 10]
By reacting the compound represented by the general formula (12) in the same manner as in Step 7, the compound represented by the general formula (13) can be synthesized.

[Step 11]
By reacting the compound represented by the general formula (13) with an amine compound represented by R ¹ —NH ₂ which can be easily obtained in the presence of a divalent copper compound, the compound represented by the general formula (14) is represented. Can be synthesized.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but water, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane and the like are exemplified, and water is preferable. Examples of the divalent copper compound to be used include copper (II) sulfate, copper (II) acetate, copper (II) bromide, and copper (II) chloride dihydrate, preferably copper (II) sulfate. . The equivalent number is 0.05 to 1 equivalent, preferably 0.1 to 0.2 equivalent. The number of equivalents of the amine compound represented by R ¹ —NH ₂ is 1 to 100 equivalents, preferably 2 to 50 equivalents. The reaction temperature is 0 to 200 ° C, preferably 60 to 100 ° C. The reaction time is 30 minutes to 24 hours, preferably 6 to 10 hours, and may be sealed if necessary.

[Step 12]
Synthesis of a compound represented by the general formula (15) by reacting a readily represented acid chloride represented by R ^4a —CH ₂ —COX with the compound represented by the general formula (14). I can do it. X represents a halogen atom.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but nitromethane, dioxane and the like are exemplified, and nitromethane is preferable. The number of equivalents of acid chloride represented by R ^4a —CH ₂ —COX is 1 to 10 equivalents, preferably 2 to 5 equivalents. The reaction temperature is 0 to 200 ° C, preferably 80 to 150 ° C. The reaction time is 30 minutes to 6 hours, preferably 1 to 2 hours.

[Step 13]
The compound represented by the general formula (1) can be synthesized by heating and stirring the compound represented by the general formula (15) in a reaction solvent.
The reaction solvent to be used is not particularly limited as long as it does not affect the reaction, but methanol, ethanol, propanol, isopropanol, tert-butanol and the like are exemplified, and ethanol is preferable. Sodium alkoxide or potassium alkoxide may be used as necessary, and the number of equivalents is 0.1 to 40 equivalents, preferably 10 to 25 equivalents. The reaction temperature is 0 to 100 ° C, preferably 60 to 90 ° C. The reaction time is 30 minutes to 24 hours, preferably 1 to 2 hours.

The intermediate product thus obtained and the compound of the present invention can be purified by conventional separation means in terms of synthetic chemistry such as extraction, precipitation, suspension washing, recrystallization, distillation, column chromatography and the like.
The compound of the present invention and the other compounds obtained as described above can form a salt, particularly a pharmaceutically acceptable salt, by a generally known method.
The compound of the present invention or a salt thereof, or another compound or a salt thereof can be isolated and purified by using a generally known separation and purification means such as concentration, solvent extraction, filtration, recrystallization, various chromatography and the like.

The compound represented by formula (I) may have one or more optical isomers based on asymmetric carbon atoms, and these isomers and mixtures thereof are also included in the scope of the present invention.
Further, it includes hydrates and solvates of the compound represented by the general formula (I) or a salt thereof, and these crystals and crystal polymorphs are also included in the scope of the present invention.

  When the compound of the present invention is used as a medicine, it can be combined with a pharmaceutical carrier as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment. Examples of such forms include oral preparations and injections. Any of suppositories, suppositories, ointments, patches and the like may be used, and oral preparations are preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.

  As the pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, solubilizers, suspensions It is blended as an agent, isotonic agent, buffer, soothing agent and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.

  When preparing an oral solid preparation, after adding an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. to the compound of the present invention, if necessary, a tablet by a conventional method, Coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid As binders, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone and the like; Disintegrants include dry starch, sodium alginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, lactose, etc .; lubricants include purified talc, stearic acid , Borax, polyethylene glycol and the like; As the colorant, titanium oxide, iron oxide and the like; white as the flavoring agent sugar, orange peel, citric acid, can be exemplified tartaric acid.

  When preparing an oral liquid preparation, a liquid preparation, a syrup, an elixir and the like can be produced by a conventional method by adding a flavoring agent, a buffer, a stabilizer, a flavoring agent and the like to the compound of the present invention. In this case, the flavoring and flavoring agents may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH adjuster, buffer, stabilizer, tonicity agent, local anesthetic, etc. are added to the compound of the present invention, and subcutaneous, intramuscular and intravenous injections are prepared by conventional methods. Can be manufactured. In this case, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a formulation carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and an interface such as Tween (registered trademark) as necessary are added to the compound of the present invention. After adding an activator etc., it can manufacture by a conventional method.

  When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used for the compound of the present invention are blended as necessary, and mixed and formulated by a conventional method. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.

  When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane film or foam sheet made of cotton, suf, chemical fiber is suitable.

  The amount of the compound of the present invention to be formulated in each of the above dosage unit forms is not constant depending on the symptom of the patient to which this compound is to be applied, or its dosage form, but generally it is about an oral dosage form per dosage unit form. 0.05 to 1000 mg, about 0.01 to 500 mg for injections, and about 1 to 1000 mg for suppositories are desirable.

  In addition, the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but is usually about 0.05 to 5000 mg per day for an adult, preferably It may be 0.1-1000 mg, and it is preferable to administer this once a day or divided into 2-4 times.

  Diseases that can be treated by administering a drug containing the compound of the present invention include, for example, malignant tumors, head and neck cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, liver cancer, gallbladder / bile duct cancer, pancreatic cancer, Examples include lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, renal cancer, bladder cancer, prostate cancer, testicular tumor, bone / soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, etc. .

  Reference Examples, Examples, Test Examples and Formulation Examples are shown below to explain the present invention in more detail. However, the present invention is not limited to these examples.

Reference example 1
Synthesis of 2-cyclopentyl-1-methoxycarbonylhydrazine 9.73 ml of cyclopentanone and 9.9 g of methyl carbamate were dissolved in 300 ml of methanol and stirred at room temperature for 2 hours. Subsequently, methanol was distilled off under reduced pressure, and the residue was dissolved in a mixed solution of 130 ml of acetic acid and 130 ml of water. To the reaction solution, 6.9 g of cyanoborohydride hydride was added in three portions, and the mixture was stirred at room temperature for 2 hours. A sodium hydroxide aqueous solution was added to the reaction solution to make it basic, and the mixture was stirred at room temperature for 30 minutes. The reaction suspension was extracted with chloroform, dried over sodium sulfate, and concentrated to obtain 16.8 g of the title compound as a colorless oily product.

Reference example 2
Synthesis of 2- (2-adamantyl) -1-methoxycarbonylhydrazine According to the method of Reference Example 1, 3.02 g of the title compound was obtained from 2.07 g of 2-adamantanone.

Reference example 3
Synthesis of 2-isopropyl-1-methoxycarbonylhydrazine According to the method of Reference Example 1, 1.59 g of the title compound was obtained from 12 ml of acetone.

Reference example 4
Synthesis of 2- (3,4-dimethoxybenzyl) -1-methoxycarbonylhydrazine According to the method of Reference Example 1, 2.33 g of the title compound was obtained from 1.66 g of 3,4-dimethoxybenzaldehyde.

Reference Example 5
Synthesis of 2- (2-chloro-5-nitropyrimidin-4-yl) -2-cyclopentyl-1-methoxycarbonylhydrazine 9.49 g of 2-cyclopentyl-1-methoxycarbonylhydrazine obtained in Reference Example 1 was added to tetrahydrofuran ( Hereinafter, dissolved in 60 ml of THF), 11.6 g of 2,4-dichloropyrimidine was added to a solution of 60 ml of THF, and 8.4 ml of triethylamine (hereinafter, TEA) was added dropwise, followed by stirring at room temperature for 2 hours. The reaction suspension is filtered under reduced pressure to remove the precipitate, and the resulting solution is concentrated, purified by silica gel column chromatography, crystallized from a mixed solvent of ether-hexane, and collected by filtration under reduced pressure. 9 g was obtained.

Reference Example 6
Synthesis of 2- (2-adamantyl) -2- (2-chloro-5-nitropyrimidin-4-yl) -1-methoxycarbonylhydrazine 2- (2-adamantyl) -1-methoxy obtained in Reference Example 2 According to the method of Reference Example 5, 2.94 g of the title compound was obtained from 3.02 g of carbonylhydrazine.

Reference Example 7
Synthesis of 2- (2-chloro-5-nitropyrimidin-4-yl) -2-isopropyl-1-methoxycarbonylhydrazine From 1.59 g of 2-isopropyl-1-methoxycarbonylhydrazine obtained in Reference Example 3, According to the method of Example 5, 2.28 g of the title compound was obtained.

Reference Example 8
Synthesis of 2- (2-chloro-5-nitropyrimidin-4-yl) -2- (3,4-dimethoxybenzyl) -1-methoxycarbonylhydrazine 2- (3,4-dimethoxy obtained in Reference Example 4 According to the method of Reference Example 5, 1.79 g of the title compound was obtained from 1.89 g of benzyl) -1-methoxycarbonylhydrazine.

Reference Example 9
Synthesis of 2- (2-chloro-5-tropyrimidin-4-yl) -2-cyclopentyl-1-ethyl-1-methoxycarbonylhydrazine 2- (2-chloro-5-nitropyrimidine obtained in Reference Example 5 -4-yl) -2-cyclopentyl-1-methoxycarbonylhydrazine (2.84 g) was dissolved in 30 ml of dimethylacetamide (hereinafter referred to as DMA), 10.8 ml of iodoethane was added, and the mixture was cooled in an ice bath. Under ice-cooling, 785 mg of 55% sodium hydride (mineral oil dispersion) was added in three portions, stirred for 10 minutes under ice-cooling, and ice was immediately added to stop the reaction. The reaction solution was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.58 g of the title compound.

Reference Example 10
Synthesis of 2- (2-chloro-5-nitropyrimidin-4-yl) -2-cyclopentyl-1- (4-methoxybenzyl) -1-methoxycarbonylhydrazine 2- (2-chloro obtained in Reference Example 5 Reference from 16.3 g of 5-nitropyrimidin-4-yl) -2-cyclopentyl-1-methoxycarbonylhydrazine, 15.6 g of 4-methoxybenzyl bromide and 3.37 g of 55% sodium hydride (mineral oil dispersion) According to the method of Example 9, 19.2 g of the title compound was obtained.

Reference Example 11
Synthesis of 2- (2-adamantyl) -2- (2-chloro-5-nitropyrimidin-4-l) -1-ethyl-1-methoxycarbonylhydrazine 2- (2- According to the method of Reference Example 10, 1.16 g of the title compound was obtained from 2.00 g of adamantyl) -2- (2-chloro-5-nitropyrimidin-4-yl) -1-methoxycarbonylhydrazine.

Reference Example 12
Synthesis of 2- (2-chloro-5-nitropyrimidin-4-yl) -1-ethyl-2-isopropyl-1-methoxycarbonylhydrazine 2- (2-chloro-5- 5) obtained by Reference Example 7 above According to the method of Reference Example 10, 869.9 mg of the title compound was obtained from 1.01 g of nitropyrimidin-4-yl) -2-isopropyl-1-methoxycarbonylhydrazine.

Reference Example 13
Synthesis of 2- (2-chloro-5-nitropyrimidin-4-yl) -2- (3,4-dimethoxybenzyl) -1-ethyl-1-methoxycarbonylhydrazine 2- (2 obtained by Reference Example 8 According to the method of Reference Example 10, 448 mg of the title compound was obtained from 796 mg of -chloro-5-nitropyrimidin-4-yl) -2- (3,4-dimethoxybenzyl) -1-methoxycarbonylhydrazine.

Reference Example 14
Synthesis of 7-chloro-1-cyclopentyl-2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 2- (2) obtained by Reference Example 9 2-Chloro-5-nitropyrimidin-4-yl) -2-cyclopentyl-1-ethyl-1-methoxycarbonylhydrazine (2.92 g) was dissolved in acetic acid (30 ml), iron powder (2.3 g) was added, and the mixture was heated at 70 ° C. for 1 hour. Stir and then stir at 100 ° C. for 1 hour. Ethyl acetate was added to the reaction suspension, and the mixture was filtered through Celite under reduced pressure to remove the precipitate. The resulting solution was washed with water, basified with sodium carbonate, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, crystallized from ether-hexane, and collected by filtration under reduced pressure to obtain 1.82 g of the title compound.

Reference Example 15
Synthesis of 7-chloro-1-cyclopentyl-2- (4-methoxybenzyl) -1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one Above, Reference Example 10 In accordance with the method of Reference Example 14, from 336 mg of 2- (2-chloro-5-nitropyrimidin-4-yl) -2-cyclopentyl-1- (4-methoxybenzyl) -1-methoxycarbonylhydrazine obtained by To obtain 233 mg of the title compound.

Reference Example 16
Synthesis of 1- (2-adamantyl) -7-chloro-2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one According to Reference Example 11 above According to the method of Reference Example 14, from 1.16 g of the obtained 2- (2-adamantyl) -2- (2-chloro-5-nitropyrimidin-4-yl) -1-ethyl-1-methoxycarbonylhydrazine The title compound 617.6 mg was obtained.

Reference Example 17
Synthesis of 7-chloro-2-ethyl-1-isopropyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 2- (2) obtained by Reference Example 12 According to the method of Reference Example 14, 563.6 mg of the title compound was obtained from 870 mg of 2-chloro-5-nitropyrimidin-4-yl) -1-ethyl-2-isopropyl-1-methoxycarbonylhydrazine.

Reference Example 18
Synthesis of 7-chloro-1- (3,4-dimethoxybenzyl) -2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one Reference Example 13 To 445 mg of 2- (2-chloro-5-nitropyrimidin-4-yl) -2- (3,4-dimethoxybenzyl) -1-ethyl-1-methoxycarbonylhydrazine obtained by Accordingly, 168 mg of the title compound was obtained.

Reference Example 19
Synthesis of 7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one Obtained by Reference Example 14. 7-chloro-1-cyclopentyl-2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one (1.82 g) was dissolved in 22 ml of DMA, and iodomethane 1 .2 ml was added and cooled in an ice bath. Under ice-cooling, 785 mg of 55% sodium hydride (mineral oil dispersion) was added in three portions, stirred for 10 minutes under ice-cooling, and ice was immediately added to stop the reaction. The reaction solution was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, crystallized from ether-hexane, and filtered under reduced pressure to obtain 1.80 g of the title compound.

Reference Example 20
Synthesis of 7-chloro-1-cyclopentyl-2- (4-methoxybenzyl) -4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 7-chloro-1-cyclopentyl-2- (4-methoxybenzyl) -1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3- obtained in Reference Example 15 According to the method of Reference Example 19, 13.2 g of the title compound was obtained from 12.6 g of ON.

Reference Example 21
Synthesis of 1- (2-adamantyl) -7-chloro-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 1- (2-adamantyl) -7-chloro-2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 618 mg obtained according to Reference Example 16 Thus, 629 mg of the title compound was obtained according to the method of Reference Example 19.

Reference Example 22
Synthesis of 7-chloro-2-ethyl-1-isopropyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one Obtained by Reference Example 17 7-chloro-2-ethyl-1-isopropyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3-one from 564 mg according to the method of Reference Example 19 457 mg of the title compound were obtained.

Reference Example 23
Of 7-chloro-1- (3,4-dimethoxybenzyl) -2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one Synthesis 7-Chloro-1- (3,4-dimethoxybenzyl) -2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-obtained in Reference Example 18 According to the method of Reference Example 19, 159 mg of the title compound was obtained from 160 mg of 3-one.

Reference Example 24
Synthesis of 7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one trifluoroacetate obtained by Reference Example 20 7. 7-chloro-1-cyclopentyl-2- (4-methoxybenzyl) -4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 31 g was dissolved in 16 ml of trifluoroacetic acid (hereinafter TFA) and stirred for 2 hours. Water and ether were added to the reaction mixture, and the mixture was collected by filtration under reduced pressure, washed successively with ethanol and ether and dried to obtain 5.42 g of the title compound.

Reference Example 25
Synthesis of 7- (4-carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 7-Chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 1 obtained according to Reference Example 19 To 50 g and 754 mg of 4-aminobenzoic acid were added 50 ml of a tert-butanol solution of tosylic acid adjusted to 0.08 M, and the mixture was stirred at 95 ° C. for 24 hours. The reaction mixture was cooled to room temperature, water was added, and the precipitate was collected by filtration under reduced pressure, washed successively with water, ethanol and ether and dried (title compound: tosylic acid = 2.1: 1). .54 g was obtained. This mixture was used in the subsequent reaction without purification.

Reference Example 26
7- (4-Carboxy-2-methoxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3 Synthesis of -one 7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- obtained by Reference Example 19 According to the method of Reference Example 25, 89.2 mg of the title compound was obtained from 104 mg of 3-one and 73 mg of 4-amino-3-methoxybenzoic acid.

Reference Example 27
7- (4-Carboxy-3-trifluoromethylphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine Synthesis of 3-one 7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained according to Reference Example 19 According to the method of Reference Example 25, 44 mg of the title compound was obtained from 100 mg of triazin-3-one and 76.7 mg of 4-amino-2-trifluoromethylbenzoic acid.

Reference Example 28
7- (4-Carboxy-2-methylphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3 Synthesis of -one 7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- obtained by Reference Example 19 According to the method of Reference Example 25, 37 mg of the title compound was obtained from 100 mg of 3-one and 67 mg of 4-amino-3-methylbenzoic acid.

Reference Example 29
Synthesis of 1- (2-chloro-5-methylaminopyrimidin-4-yl) -1-cyclopentyl-2-ethylhydrazine 7-chloro-1-clopentyl-2-ethyl-4-methyl obtained according to Reference Example 19 -1,2-Dihydropyrimido [5,4-e] [1,2,4] Triazin-3-one 500 mg was added with 6 ml of ethanol, 6 ml of 4N aqueous sodium hydroxide solution was further added, and the mixture was stirred at room temperature for 1 hour. . The reaction solution was adjusted to pH 5 with 2N hydrochloric acid, then basified with aqueous sodium carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue for crystallization, and 355 mg of the title compound was obtained by filtration under reduced pressure.

Reference Example 30
Synthesis of 2-amino-5-ethoxycarbonylpyridine 1.1 g of 2-amino-5-carboxypyridine was dissolved in 40 ml of ethanol, 1.0 ml of sulfuric acid was added, and the mixture was heated to reflux for 24 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure to about 1/5 volume. Basified with aqueous sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Ether was added to the residue for crystallization, and the residue was filtered under reduced pressure to obtain 1.01 mg of the title compound.

Reference Example 31
Synthesis of 5-amino-2-ethoxycarbonylthiophene 30 ml of methylene chloride was added to 1.04 g of 2-carboxy-5-nitrothiophene, and 567 μl of oxalyl chloride was added. One drop of dimethylformamide (hereinafter referred to as DMF) was added to this suspension and stirred at room temperature for 1.5 hours. The reaction solution was concentrated, dissolved in 30 ml of ethanol, and heated to reflux for 1 hour. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, crystallized from hexane, and filtered under reduced pressure to obtain 927 mg of intermediate 2-ethoxycarbonyl-5-nitrothiophene. 400 mg of this intermediate was dissolved in 7.2 ml of acetic acid, 556 mg of iron powder was added, and the mixture was stirred at 60 ° C. for 1 hour. Ethyl acetate was added to the reaction suspension, and the mixture was filtered through Celite under reduced pressure to remove the precipitate. The resulting solution was washed with water, basified with sodium carbonate, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, crystallized from ether-hexane, and collected by filtration under reduced pressure to obtain 355.7 mg of the title compound.

Reference Example 32
1-cyclopentyl-7- (5-ethoxycarbonylpyridin-2-yl) amino-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- Synthesis of 3-one In a Schlenk tube, 68 mg of 2-amino-5-ethoxycarbonylpyridine obtained in Reference Example 30 and 7-chloro-1-cyclopentyl-2-ethyl-4-methyl obtained in Reference Example 19 -1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 100 mg, xantphos 12 mg, Pd ₂ dba ₃ 6 mg, K ₃ PO ₄ 108 mg were substituted with argon, Dioxane 1.4 ml was added. This suspension was stirred at 100 ° C. for 24 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 68.6 mg.

Reference Example 33
1-cyclopentyl-7- (5-ethoxycarbonylthiophen-2-yl) amino-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- Synthesis of 3-one From 150 mg of 5-amino-2-ethoxycarbonylthiophene obtained in Reference Example 31, 150 mg of the title compound was obtained according to the method of Reference Example 32.

Reference Example 34
7- (5-carboxypyridin-2-yl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3 Synthesis of -one 1-cyclopentyl-7- (5-ethoxycarbonylpyridin-2-yl) amino-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4- e] To 200 mg of [1,2,4] triazin-3-one, 10 ml of methanol, 5 ml of THF, and 1 ml of 4N sodium hydroxide aqueous solution were added and stirred at room temperature for 20 hours. 2N hydrochloric acid was added to the reaction solution to adjust to pH 5. The precipitate was collected by filtration under reduced pressure and dried to obtain 162.2 mg of the title compound.

Reference Example 35
7- (5-Carboxythiophen-2-yl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- Synthesis of 3-one 1-cyclopentyl-7- (5-ethoxycarbonylthiophen-2-yl) amino-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4] obtained according to Reference Example 32 -E] 3 ml of methanol and 3 ml of 4N aqueous sodium hydroxide solution were added to 150 mg of [1,2,4] triazin-3-one, and the mixture was stirred at 50 ° C. for 7 hours. The reaction solution was cooled to room temperature, adjusted to pH 5 with 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was added to the residue, and the precipitate was collected by filtration under reduced pressure to obtain 45 mg of the title compound.

Reference Example 36
Synthesis of 6-chloro-4-cyclopentyl-3-ethyl-1-methyl-3,4-dihydropyrimido [4,5-d] [1,2,3,6] thiatriazin-2-one Reference Example 29 6 ml of methylene chloride and 335 μl of TEA were added to 163 mg of 1- (2-chloro-5-methylaminopyrimidin-4-yl) -1-clopentyl-2-ethylhydrazine obtained by 1 above, and 70 ml of thionyl chloride in 6 ml of methylene chloride. The solution was added and stirred at room temperature for 1 hour. Chloroform was added to the reaction solution, and an aqueous sodium carbonate solution was added to make the solution basic. The organic layer was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, crystallized from ether-hexane, and collected by filtration under reduced pressure to obtain 151 mg of the title compound.

Reference Example 37
Synthesis of 7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3-thione Obtained by Reference Example 29 According to the method of Reference Example 32, 205 mg of the title compound was obtained from 188 mg of 1- (2-chloro-5-methylaminopyrimidin-4-yl) -1-cyclopentyl-2-ethylhydrazine and 80 μl of thiophosgene.

Reference Example 38
Synthesis of 4-benzoyl-5-bromo-2-methoxypyrimidine To 9.42 g of 5-bromo-2-chloropyrimidine was added 75 ml of 1N sodium methoxide-methanol solution, and the mixture was stirred at room temperature for 1 hour. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was crystallized from ether-hexane, yielding 8.44 g of intermediate 5-bromo-2-methoxypyrimidine. Dissolve 2.08 g of this intermediate and 1.67 ml of benzaldehyde in 11 ml of acetic acid and 7 ml of 6N sulfuric acid, add 4.9 g of iron (II) sulfate heptahydrate in 11 ml of water under ice cooling, and then add 70% tert- 2.4 ml of butyl hydroperoxide aqueous solution was added dropwise over 10 minutes. The reaction solution was stirred for 30 minutes under ice-cooling and then stirred at room temperature for 3.5 hours. Ethyl acetate was added to the reaction mixture, and the mixture was basified with sodium carbonate. The mixture was extracted 3 times with ethyl acetate, washed with water and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.29 g of the title compound.

Example 1
1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (2,2,2-trifluoroethyl-1,2-dihydro Synthesis of pyrimido [5,4-e] [1,2,4] triazin-3-one

  7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 300 mg and 2,2 obtained according to Reference Example 24 , 2-trifluoroiodoethane (770 μl) was dissolved in DMA (5 ml), then lithium hydride (17 mg) was added, and the mixture was stirred at 95 ° C. for 5 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and the intermediate 7-chloro-1-cyclopentyl-4-methyl-2- (2,2,2-trifluoroethyl-1,2-dihydropyrimido [5,4 -E] 96.2 mg of [1,2,4] triazin-3-one was obtained, to 61.4 mg of this intermediate and 51 mg of 4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyaniline. 1.8 ml of a tert-butanol solution of tosylic acid adjusted to 0.18 M was added and stirred for 24 hours at 95 ° C. The reaction solution was cooled to room temperature, added with water, extracted with ethyl acetate, washed with water, The residue was purified by silica gel column chromatography to give 40 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.25 (14H, m), 2.34 (3H, s), 2.80-2.95 (2H, m), 3.29 (3H, s), 3.80-4.10 (5H, m), 4.10-4.25 (2H, m), 5.95-6.05 (1H, m), 7.26-7.30 (1H, m), 7.45 (1H, d, J = 2.0 Hz), 7.88 (1H, s), 7.98 (1H, s), 8.55 (1H, d, (J = 8.3 Hz)

Example 2
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 104 mg obtained according to Reference Example 19 To 115 mg of 4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyaniline, 3.5 ml of a tert-butanol solution of tosylic acid adjusted to 0.18 M was added and stirred at 95 ° C. for 24 hours. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 143.3 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.25 (14H, m), 2.33 (3H, s), 2.75-2.90 (2H, m), 3.22 (3H, s), 3.61 (2H, q, J = 7.1 Hz), 3.90-4.15 (5H, m), 5.95 (1H, d, J = 7.8 Hz), 7.25-7.27 (1H, m), 7.44 (1H, d, J = 2.0 Hz), 7.79 ( 1H, s), 7.81 (1H, s), 8.55 (1H, d, J = 8.3 Hz)

Example 3
1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (octane-1-yl) -1,2-dihydropyrimido [ 5,4-e] Synthesis of [1,2,4] triazin-3-one

  145 mg of 7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one obtained according to Reference Example 24 and 685 μl of iodooctane Was dissolved in 2 ml of DMA, then 8 mg of lithium hydride was added, and the mixture was stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and the intermediate 7-chloro-1-cyclopentyl-4-methyl-2- (octane-1-yl) -1,2-dihydropyrimido [5,4-e] 107 mg of [1,2,4] triazin-3-one was obtained. 1.6 ml of a tert-butanol solution of tosylic acid adjusted to 0.18 M was added to 60.2 mg of this intermediate and 46 mg of 4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyaniline at 95 ° C. Stir for 24 hours. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 20 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
0.82 (3H, t, J = 7.1 Hz), 1.00-2.30 (28H, m), 3.22 (3H, s), 2.75-2.90 (2H, m), 3.22 (3H, s), 3.54 (2H, t, J = 7.3 Hz), 3.90-4.15 (5H, m), 5.99 (1H, d, J = 8.1 Hz), 7.25-7.30 (1H, m), 7.44 (1H, d, J = 1.7 Hz), 7.80 ( 1H, s), 7.82 (1H, s), 8.56 (1H, d, J = 8.5 Hz)

Example 4
1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (2-methylpropan-1-yl) -1,2-dihydro Synthesis of pyrimido [5,4-e] [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 100 mg and 2-methyl obtained according to Reference Example 24 300 μl of iodopropane was dissolved in 2 ml of DMA, then 6 mg of lithium hydride was added and stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and the intermediate 7-chloro-1-cyclopentyl-4-methyl-2- (2-methylpropan-1-yl) -1,2-dihydropyrimido [5,4 -E] 48.5 mg of [1,2,4] triazin-3-one was obtained. To 46 mg of this intermediate and 41.1 mg of 4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyaniline, 1.4 ml of a tert-butanol solution of tosylic acid adjusted to 0.18 M was added, and the mixture was heated at 95 ° C. Stir for 24 hours. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 30.8 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
0.79 (6H, d, J = 6.8 Hz), 1.50-2.30 (15H, m), 2.36 (3H, s), 2.80-3.00 (2H, m), 3.23 (3H, s), 3.41 (2H, d, J = 7.1 Hz), 3.80-4.10 (5H, m), 6.00-6.10 (1H, m), 7.25-7.27 (1H, m), 7.45 (1H, d, J = 1.7 Hz), 7.82 (1H, s ), 7.87 (1H, s), 8.56 (1H, d, J = 8.5 Hz)

Example 5
1-cyclopentyl-2-cyclobutylmethyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4- e] Synthesis of [1,2,4] triazin-3-one

  145 mg of 7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one obtained according to Reference Example 24 and bromomethylcyclobutane 427 μl was dissolved in 2 ml of DMA, then 8.4 ml of lithium hydride was added and stirred at room temperature for 26 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography and the intermediate 7-chloro-1-cyclopentyl-2-cyclobutylmethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2- , 4] 63.2 mg of triazin-3-one was obtained. To 63.6 mg of this intermediate and 54.9 mg of 4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyaniline was added 1.9 ml of a tert-butanol solution of tosylic acid adjusted to 0.18 M, and 95 ° C. For 24 hours. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 47.4 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.50 (20H, m), 2.63 (1H, quint, J = 7.6 Hz), 2.80-3.00 (2H, m), 3.21 (3H, s), 3.58 (2H, d, J = 7.6 Hz), 3.90 -4.10 (5H, m), 6.05-6.15 (1H, m), 7.29 (1H, dd, J = 8.5 Hz, 1.7 Hz),
7.45 (1H, d, J = 1.7 Hz), 7.80 (1H, s), 7.81 (1H, s), 8.57 (1H, d, J = 8.5 Hz)

Example 6
1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (2-fluoroethane-1-yl) -1,2-dihydro Synthesis of pyrimido [5,4-e] [1,2,4] triazin-3-one

  7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 145 mg obtained according to Reference Example 24 and 2-fluoro From 660 μl of iodoethane, according to the method of Example 4, the intermediate 7-chloro-1-cyclopentyl-4-methyl-2- (2-fluoroethane-1-yl) -1,2-dihydropyrimido [ 5,4-e] [1,2,4] Triazin-3-one (91.4 mg) was obtained, and the intermediate compound (56 mg) was used to obtain the title compound (27 mg).

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.80 (17H, m), 2.80-3.00 (2H, m), 3.24 (3H, s), 3.70-4.10 (9H, m), 4.50 (1H, t, J = 4.9 Hz), 4.62 (1H, t, J = 4.9 Hz), 6.00-6.10 (1H, m), 7.26-7.30 (1H, m), 7.44 (1H, d, J = 1.7 Hz), 7.81 (1H, s), 7.89 (1H, s ), 8.54 (1H, d, J = 8.5 Hz)

Example 7
2-carbamoylmethyl-1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4-e Synthesis of [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 250 mg obtained by Reference Example 24 and iodoacetic acid 304 mg Then, 29 mg of lithium hydride was added and stirred at room temperature for 24 hours. The reaction mixture was acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the intermediate 2-carboxymethyl-7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,2 4] 53.2 mg of triazin-3-one was obtained. To this intermediate 53.2 mg, ammonium chloride 57 mg, 1-hydroxybenzotriazole monohydrate (hereinafter HOBt) 160 mg and N-ethyl-N- (3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter WSC) 228 mg 2 ml of DMF was added, and 208 μl of diisopropylethylamine (hereinafter DIPEA) was further added. The reaction mixture was stirred at room temperature overnight, water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain intermediate 2-carbamoylmethyl-7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4]. 24.1 mg of triazin-3-one was obtained. According to the method of Example 2, 7.8 mg of the title compound was obtained from 21.9 mg of this intermediate.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.30 (14H, m), 2.32 (3H, s), 2.80-3.00 (2H, m), 3.27 (3H, s), 3.90-4.20 (5H, m), 4.20 (2H, s), 5.33 ( 1H, brs), 5.94 (1H, d, J = 8.1 Hz), 6.20 (1H, brs), 7.25-7.27 (1H, m), 7.44 (1H, d, J = 1.7 Hz), 7.80 (1H, s ), 7.89 (1H, s), 8.52 (1H, d, J = 8.3 Hz)

Example 8
1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (2-methoxyethane-1-yl) -1,2-dihydro Synthesis of pyrimido [5,4-e] [1,2,4] triazin-3-one

  145 mg of 7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one obtained according to Reference Example 24 and 2-methoxy From 360 μl of bromoethane, according to the method of Example 5, the intermediate 7-chloro-1-cyclopentyl-4-methyl-2- (2-methoxyethane-1-yl) -1,2-dihydropyrimido [ 5,4-e] [1,2,4] Triazin-3-one (28.6 mg) was obtained, and 25.5 mg of this intermediate was used to obtain 2.5 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.35 (14H, m), 2.39 (3H, s), 2.80-3.00 (2H, m), 3.06 (3H, s), 3.49 (2H, t, J = 5.1 Hz), 3.72 (1H, t, J = 5.1 Hz), 3.95-4.20 (5H, m), 5.95-6.10 (1H, m), 7.25-7.27 (1H, m), 7.44 (1H, d, J = 2.0 Hz), 7.79 (1H, s ), 7.82 (1H, s), 8.57 (1H, d, J = 8.3 Hz)

Example 9
2-Cyanomethyl-1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7-chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 145 mg obtained from Reference Example 24 and 265 μl of bromoacetonitrile To 7-chloro-2-cyanomethyl-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] as an intermediate according to the method of Example 4. ] 40.2 mg of triazin-3-one was obtained, and 12.1 mg of the title compound was obtained by using 37.8 mg of this intermediate (melting point: 128.5-133.3 ° C.).

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.40 (14H, m), 2.43 (3H, s), 2.90-3.10 (2H, m), 3.28 (3H, s), 3.90-4.20 (5H, m), 4.43 (2H, s), 6.05 ( 1H, brs), 7.25-7.27 (1H, m), 7.44 (1H, d, J = 1.7 Hz), 7.85 (1H, s), 7.94 (1H, s), 8.53 (1H, d, J = 8.5 Hz )

Example 10
1-cyclopentyl-2- (4-methoxybenzyl) -4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5 , 4-e] Synthesis of [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-2- (4-methoxybenzyl) -4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine obtained by Reference Example 20 According to the method of Example 2, 27.7 mg of the title compound was obtained from 69.8 mg of 3-one.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.35 (14H, m), 2.37 (3H, s), 2.80-3.00 (2H, m), 3.18 (3H, s), 3.70 (3H, s), 3.97 (3H, s), 4.00-4.15 ( 2H, m), 4.58 (2H, s), 5.95-6.10 (1H, m), 6.72 (2H, d, J = 8.5 Hz), 7.17 (2H, d, J = 8.5 Hz), 7.25-7.27 (1H , m), 7.43 (1H, d, J = 1.7 Hz), 7.65 (1H, s), 7.72 (1H, s), 8.51 (1H, d, J = 8.3 Hz)

Example 11
1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (3-trifluoromethylbenzyl) -1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 145 mg and 3 obtained in Reference Example 24 -From 86 μl of trifluoromethylbenzyl bromide, according to the method of Example 5, the intermediate 7-chloro-1-cyclopentyl-4-methyl-2- (3-trifluoromethylbenzyl) -1,2-dihydropyrim 162 mg of [1,4-4] mido [5,4-e] [1,2,4] triazin-3-one was obtained, and 22 mg of the title compound was obtained by using 45.4 mg of this intermediate.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.30 (14H, m), 2.36 (3H, s), 2.80-3.00 (2H, m), 3.21 (3H, s), 3.95-4.10 (5H, m), 4.73 (2H, s), 5.95- 6.05 (1H, m), 7.25-7.50 (5H, m), 7.53 (1H, s), 7.70-7.80 (1H, m), 8.48 (1H, d, J = 8.3 Hz)

Example 12
1-cyclopentyl-2- (4-carbamoylbenzyl) -4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5 , 4-e] Synthesis of [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 200 mg obtained according to Reference Example 24 and 4-methoxy From 86 μl of carbonylbenzyl bromide, the intermediate 7-chloro-1-cyclopentyl-2- (4-methoxycarbonylbenzyl) -4-methyl-1,2-dihydropyrimido [5, according to the method of Example 5 4-e] 264.7 mg of [1,2,4] triazin-3-one were obtained and without further purification, 110.4 mg of this intermediate was used to give intermediate 1-cyclopentyl-2- (4-methoxy Carbonylbenzyl) -4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2 , 4] Triazin-3-one 6 It was obtained .1mg. To 57.4 mg of this intermediate, 2 ml of 7N ammonia-methanol solution was added, sealed, and stirred at 80 ° C. for 2 days. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain 18.8 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.30 (14H, m), 2.31 (3H, s), 2.75-3.00 (2H, m), 3.21 (3H, s), 3.90-4.10 (5H, m), 4.73 (2H, s), 5.55 ( 1H, brs), 5.80-6.20 (2H, m), 7.25-7.26 (1H, m), 7.34 (2H, d, J = 8.1 Hz), 7.44 (1H, d, J = 1.7 Hz), 7.66 (1H , d, J = 8.1 Hz), 7.75 (1H, s), 7.76 (1H, s), 8.47 (1H, d, J = 8.5 Hz)

Example 13
2- (4-aminobenzyl) -1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5 , 4-e] Synthesis of [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 200 mg and 4-nitro obtained according to Reference Example 24 From 280 mg of benzyl bromide, the intermediate 7-chloro-1-cyclopentyl-4-methyl-2- (4-nitrobenzyl) -1,2-dihydropyrimido [5,4- e] Obtained 238.5 mg of [1,2,4] triazin-3-one and used the intermediate 125 mg without purification to give the intermediate 1-cyclopentyl-4-methyl-7- [4- (N -Methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (4-nitrobenzyl) -1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3 -ON To give a 4.1mg. 0.5 ml of water, methanol, and THF were added to 32.7 mg of this intermediate, 14 mg of ammonium chloride and 14.5 mg of iron powder were added, and the mixture was stirred at 70 ° C. for 4 hours. Ethyl acetate was added to the reaction suspension, and the mixture was filtered through Celite under reduced pressure to remove the precipitate. The resulting solution was washed with water, basified with sodium carbonate, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 7.6 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.30 (14H, m), 2.36 (3H, s), 2.90-3.00 (2H, m), 3.17 (3H, s), 3.54 (2H, brs), 3.95-4.15 (5H, m), 4.51 ( 2H, s), 5.95-6.00 (1H, m), 6.49 (2H, d, J = 8.3 Hz), 7.03 (2H, d, J = 8.3 Hz), 7.25-7.26 (1H, m), 7.43 (1H , d, J = 1.5 Hz), 7.61 (1H, d, J = 8.1 Hz), 7.70 (1H, s), 8.54 (1H, d, J = 8.5 Hz)

Example 14
1-cyclopentyl-2,4-diethyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4-e] [1 , 2,4] Triazin-3-one

  From 100 mg of 7-chloro-1-cyclopentyl-2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one obtained according to Reference Example 14 and 43 μl of iodoethane In accordance with the method of Reference Example 19, intermediate 7-chloro-1-cyclopentyl-2,4-diethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3- 112 mg of on was obtained. According to the method of Example 2, 62 mg of the title compound was obtained from 104 mg of this intermediate.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J = 7.1 Hz), 1.50-2.20 (14H, m), 2.30 (3H, s), 2.75-3.00 (2H, m), 3.59 (2H, q, J = 7.1 Hz), 3.81 (2H, q, J = 7.1 Hz), 3.90-4.20 (5H, m), 6.09 (1H, d, J = 7.8 Hz), 7.25-7.27 (1H, m), 7.45 (1H, d, J = 2.0 Hz), 7.77 (1H, s), 7.86 (1H, s), 8.54 (1H, d, J = 8.5 Hz)

Example 15
Synthesis of 7-chloro-1-cyclopentyl-2-ethyl-4- (4-pyridylmethyl) -1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-2-ethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 100 mg obtained according to Reference Example 14 and 4-bromo According to the method of Reference Example 19, 82 mg of the title compound was obtained from 135 mg of methylpyridine hydrobromide and 16 mg of lithium hydride as the base.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.20 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 3.68 (2H, q, J = 7.1 Hz), 4.15-4.30 (1H, m), 4.94 (2H, s), 7.14 (2H, dd, J = 4.4 Hz, 1.5 Hz), 7.48 (1H, s), 8.60 (2H, dd, J = 4.4 Hz, 1.5Hz)

Example 16
Synthesis of 7-chloro-1-cyclopentyl-2,4-dimethyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one

7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 145 mg obtained in Reference Example 24 and 71 μl of iodomethane were added. After dissolving in 1.3 ml of DMA, 41 mg of 55% sodium hydride (mineral oil dispersion) was added and stirred at room temperature for 10 minutes. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 91.7 mg of the title compound (melting point: 84.4-85.3 ° C.).
¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.00 (8H, m), 3.20 (3H, s), 3.24 (3H, s), 4.05-4.20 (1H, m), 7.76 (1H, s)

Example 17
Synthesis of 7-chloro-1-cyclopentyl-4-methyl-2- (4-pyridylmethyl) -1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 50 mg obtained according to Reference Example 24 and 4-bromo 82 mg of methylpyridine hydrobromide was dissolved in 1 ml of DMA, then 6 mg of lithium hydride was added, and the mixture was stirred at room temperature for 26 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 20.2 mg of the title compound (melting point: 149.2-151.5 ° C.).

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.50-2.00 (8H, m), 3.21 (3H, s), 4.11 (1H, quin, J = 7.1 Hz), 4.67 (2H, s), 7.16 (2H, d, J = 5.6 Hz), 7.75 (1H , s), 8.50 (2H, d, J = 5.6 Hz),

Example 18
Synthesis of 7-chloro-1-cyclopentyl-2- (2-diethylaminoethyl) -4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one

  7-Chloro-1-cyclopentyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 50 mg obtained according to Reference Example 24 and 2-diethylamino According to the method of Example 17, 18.8 mg of the title compound was obtained from 170 mg of bromoethane hydrobromide.

¹ H-NMR (CDCl ₃ ) δ (ppm):
0.71 (6H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 2.24 (4H, q, J = 7.1 Hz), 2.51 (2H, t, J = 5.6 Hz), 3.16 (3H, s ), 3.62 (2H, t, J = 5.6 Hz), 4.10-4.25 (1H, m), 7.64 (1H, s)

Example 19
7- [4- (3-Pyridylcarbamoyl) phenyl] amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- Synthesis of 3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained by Reference Example 25 40 mg of triazin-3-one, 10 mg of 3-aminopyridine and 34 mg of N, N, N ′, N′-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate (hereinafter referred to as TBTU), 1 ml of DMA and 37 μl of DIPEA was added and stirred at 60 ° C. for 24 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 16.1 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.12 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 3.22 (3H, s), 3.61 (2H, q, J = 7.1 Hz), 4.00-4.10 (1H, m), 7.22 (1H, s), 7.33 (1H, dd, J = 8.3 Hz, 4.6 Hz), 7.74 (2H, d, J = 8.5 Hz), 7.78 (1H, s), 7.88 (2H, d, J = 8.5 Hz) ), 8.02 (1H, brs), 8.33 (1H, dd, J = 8.3 Hz, 1.7 Hz), 8.38 (1H, d, J = 4.6 Hz), 8.69 (1H, d, J = 1.7 Hz)

Example 20
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) phenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2, 4] Synthesis of triazin-3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained by Reference Example 25 To 300 mg of triazin-3-one and 190 mg of TBTU, 2 ml of DMA, 280 μl of DIPEA and 100 μl of 4-amino-1-methylpiperidine were added and stirred at room temperature for 3 hours. Water was added to the reaction solution, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 236 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.25 (14H, m), 2.31 (3H, s), 2.75-2.90 (2H, m), 3.22 (3H, s), 3.60 (2H, q, J = 7.1 Hz), 3.90-4.10 (2H, m), 5.89 (1H, d, j = 7.8 Hz), 7.66 (2H, d, J = 8.8 Hz), 7.73 (2H, d, J = 8.8 Hz) , 7.77 (1H, s)

Example 21
1-cyclopentyl-7- [4- (2-diethylaminoethylcarbamoyl) phenyl] amino-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine Synthesis of -3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained by Reference Example 25 According to the method of Example 20, 177 mg of the title compound was obtained from 300 mg of triazin-3-one and 112 μl of N, N-diethylethylenediamine.

¹ H-NMR (CDCl ₃ ) δ (ppm):
0.95-1.25 (9H, m), 1.50-2.00 (8H, m), 2.61 (4H, q, J = 7.1 Hz), 2.60-2.80 (2H, m), 3.22 (3H, s), 3.45-3.60 ( 2H, m), 3.61 (2H, q, J = 7.1 Hz), 4.05 (1H, quin, J = 8.1 Hz), 6.97 (1H, brs), 7.09 (1H, s), 7.66 (2H, d, J = 8.5 Hz) 7.77 (2H, d, J = 8.5 Hz), 7.77 (1H, s)

Example 22
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (N-methylazetidin-3-yl) carbamoyl] phenyl] amino-1,2-dihydropyrimido [[5,4-e] [ Synthesis of 1,2,4] triazin-3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained by Reference Example 25 According to the method of Example 20, 249.3 mg of the title compound was obtained from 300 mg of triazin-3-one and 153 mg of 3-amino-1-methylazetidine dihydrochloride.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.11 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 2.43 (3H, s), 3.10-3.40 (5H, m), 3.61 (2H, q, J = 7.1 Hz), 3.70 -3.80 (2H, m), 4.00-4.10 (1H, m), 4.70-4.80 (1H, m), 6.60-6.75 (1H, m), 7.08 (1H, s), 7.67 (2H, d, J = 8.5 Hz), 7.78 (1H, s), 7.78 (2H, d, J = 8.5 Hz)

Example 23
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (4-pyridylcarbamoyl) phenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- Synthesis of 3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained by Reference Example 25 188.7 mg of the title compound was obtained from 400 mg of triazin-3-one and 99 mg of 4-aminopyridine according to the method of Example 19 (melting point: 242.9-244.5 ° C.).

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.12 (3H, t, J = 7.1 Hz), 1.50-1.95 (8H, m), 3.22 (3H, s), 3.62 (2H, q, J = 7.1 Hz), 4.00-4.15 (1H, m), 7.17 (1H, s), 7.61 (2H, dd, J = 4.6 Hz, 1.5 Hz), 7.75 (2H, d, J = 8.8 Hz), 7.86 (2H, d, J = 8.8 Hz), 7.93 (1H, s ), 8.55 (2H, dd, J = 4.6 Hz, 1.5 Hz)

Example 24
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (thiophen-2-ylmethylcarbamoyl) phenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2,4 Synthesis of triazin-3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,2] obtained in Reference Example 25 above. 4] 228 mg of the title compound was obtained from 300 mg of triazin-3-one and 99 μl of 2-aminomethylthiophene according to the method of Example 20.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 3.21 (3H, s), 3.60 (2H, q, J = 7.1 Hz), 4.00-4.15 (1H, m), 4.82 (2H, d, J = 6.4 Hz), 6.30-6.40 (1H, m), 6.98 (1H, dd, J = 5.1 Hz, 3.7 Hz), 7.05 (1H, d, J = 3.7 Hz), 7.09 (1H , s), 7.240-7.26 (2H, m), 7.66 (2H, d, J = 8.5 Hz), 7.77 (2H, d, J = 8.5 Hz), 7.77 (1H, s)

Example 25
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (pyridin-3-ylmethylcarbamoyl) phenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2,4 Synthesis of triazin-3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained by Reference Example 25 According to the method of Example 20, 40.9 mg of the title compound was obtained from 40 mg of triazin-3-one and 13 μl of 3-aminomethylpyridine.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 3.20 (3H, s), 3.59 (2H, q, J = 7.1 Hz), 3.95-4.10 (1H, m), 4.55 -4.75 (2H, m), 6.80-7.10 (1H, m), 7.25-7.30 (1H, m), 7.30-7.50 (1H, m), 7.60-7.95 (6H, m), 8.45-8.60 (2H, m)

Example 26
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (2- (pyridin-2-yl) ethylcarbamoyl) phenyl] amino-1,2-dihydropyrimido [5,4-e] [1 , 2,4] Triazin-3-one

  7- (4-Carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained by Reference Example 25 According to the method of Example 20, 29.2 mg of the title compound was obtained from 40 mg of triazin-3-one and 14 μl of 2- (2-amino) ethylpyridine.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.11 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 3.11 (2H, t, J = 6.1 Hz), 3.21 (3H, s), 3.61 (2H, q, J = 7.1 Hz ), 3.87 (2H, q, J = 6.1 Hz), 4.00-4.10 (1H, m), 7.15-7.25 (3H, m), 7.30-7.50 (1H, m), 7.55-7.90 (5H, m), 8.58 (1H, dd, J = 4.9 Hz, 0.73 Hz)

Example 27
1-cyclopentyl-2-ethyl-4-methyl-7- [4-((2- (1-pyrrolidinylmethyl) phenyl) methylcarbamoyl) phenyl] amino-1,2-dihydropyrimido [5,4- e] Synthesis of [1,2,4] triazin-3-one

  980 mg of 2-cyanobenzyl bromide was dissolved in 10 ml of chloroform, and 1 ml of piperidine was added and stirred for 30 minutes. Water was added to the reaction solution, extracted with chloroform, washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 940 mg of intermediate 2- (1-pyrrolidinylmethyl) benzonitrile. 211 mg of this intermediate was dissolved in 18 ml of THF, and 700 μl of 2.4 M lithium aluminum hydride THF solution was added dropwise under ice cooling. Thereafter, the mixture was stirred for 2 hours under ice cooling, 12 hours at room temperature, and 1 hour under heating to reflux, and then cooled to room temperature. Subsequently, water was added to the reaction solution, extracted with chloroform, washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. To this residue, 2 ml of THF was added to the 7- (4-carboxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5] obtained in Reference Example 25 above. , 4-e] [1,2,4] Triazin-3-one 50 mg, TBTU 38.1 mg, and DIPEA 56 μl in DMF (1 ml), the title compound 62.4 mg was obtained according to the method of Example 20.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.09 (3H, t, J = 7.1 Hz), 1.50-2.00 (12H, m), 3.21 (3H, s), 3.59 (2H, q, J = 7.1 Hz), 3.68 (1H, s), 3.95-4.10 (1H, m), 4.67 (2H, d, J = 4.9 Hz), 7.05-7.15 (1H, m), 7.25-7.35 (2H, m), 7.45 (1H, d, J = 6.8 Hz), 7.60 ( 2H, d, J = 8.5 Hz), 7.73 (2H, d, J = 8.5 Hz), 7.77 (1H, s), 9.28 (1H, brs)

Example 28
Synthesis of 1-cyclopentyl-2-ethyl-7- (4-hydroxyphenyl) amino-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one

  7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 500 mg obtained according to Reference Example 19 According to the method of Reference Example 25, 459 mg of the title compound was obtained from 200 mg of 4-hydroxyaniline.

¹ H-NMR (DMSOd ₆ ) δ (ppm):
0.97 (3H, t, J = 7.1 Hz), 1.45-1.85 (8H, m), 3.11 (3H, s), 3.30-3.50 (2H, m), 3.90-4.00 (1H, m), 6.66 (2H, d, J = 8.8 Hz), 7.43 (2H, d, J = 8.8 Hz), 7.92 (1H, s), 8.32 (1H, s), 9.06 (1H, s)

Example 29
1-cyclopentyl-2-ethyl-4-methyl-7- (4- (1-methylpiperidin-4-ylmethoxy) phenyl) amino-1,2-dihydropyrimido [5,4-e] [1,2, 4] Synthesis of triazin-3-one

  To 1.39 g of 4-nitrophenol, 40 ml of methylene chloride, 3.4 g of triphenylphosphi, 2.37 g of 1-Boc-4-hydroxymethylpiperidine, and 6.8 ml of 1.9 MDIAD-toluene solution were sequentially added and stirred at room temperature overnight. did. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 2.72 g of intermediate 4- (1-Boc-piperidin-4-ylmethoxy) nitrobenzene. To 2.74 g of this intermediate, 40 ml of methylene chloride and 7.5 ml of TFA were added and stirred for 1 hour. The solvent was distilled off under reduced pressure, basified with sodium carbonate, extracted 6 times with chloroform, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.57 g of intermediate 4- (piperidin-4-ylmethoxy) nitrobenzene. To 1.57 g of this intermediate, 11 ml of THF, 11 ml of methanol and 1.1 ml of formalin were added, and then 500 mg of sodium cyanoborohydride was added and stirred at room temperature overnight. The organic solvent was distilled off under reduced pressure, extracted six times with chloroform, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1.40 g of intermediate 4- (1-methylpiperidine-4-lmethoxy) nitrobenzene (yield) 85%). 200 mg of this intermediate was dissolved in 4 ml of methanol, 40 mg of palladium carbon was added, and the mixture was stirred overnight under a hydrogen atmosphere under normal pressure. The solution obtained by filtering the precipitate was distilled off under reduced pressure to obtain 164 mg of intermediate 4- (1-methylpiperidin-4-ylmethoxy) aniline. 41 mg of this intermediate and 7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,2] obtained according to Reference Example 19 above. 4] From 500 mg of triazin-3-one, 4.4 mg of the title compound was obtained according to the method of Reference Example 25.

H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.00 (15H, m), 2.40 (1H, s), 2.95-3.10 (2H, m), 3.19 (3H, s), 3.59 (2H, q, J = 7.1 Hz), 3.81 (2H, d, J = 6.1 Hz), 3.95-4.10 (1H, m), 6.86 (2H, d, J = 8.8 Hz), 6.98 (1H, s), 7.43 (2H, d, J = 8.8 Hz), 7.72 (1H, s)

Example 30
1-cyclopentyl-2-ethyl-4-methyl-7- (4- (thiophen-2-ylmethoxy) phenyl) amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine Synthesis of -3-one

  1-cyclopentyl-2-ethyl-7- (4-hydroxyphenyl) amino-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained according to Example 28 To 46 g of triazin-3-one, 1 ml of methylene chloride, 43 mg of triphenylphosphine, 14 μl of 2-thiophenemethanol, and 86 μl of a 1.9M DIAD-toluene solution were sequentially added and stirred overnight at room temperature. Subsequently, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 16 mg of the title compound.

H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-1.90 (8H, m), 3.19 (3H, s), 3.59 (2H, q, J = 7.1 Hz), 3.95-4.10 (1H, m), 5.21 (2H, s), 6.78 (1H, s), 6.96 (2H, d, J = 9.0 Hz), 7.00 (1H, dd, J = 5.1 Hz, 3.4 Hz), 7.10 (1H, dd, J = 3.4 Hz , 1.2 Hz), 7.32 (1H, dd, J = 5.1 Hz, 1.2 Hz), 7.46 (2H, d, J = 9.0 Hz), 7.73 (1H, s)

Example 31
1-cyclopentyl-2-ethyl-4-methyl-7- (3-oxoindoline-5-yl) amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3 -On synthesis

  7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 360 mg obtained according to Reference Example 19 And 151.6 mg of 5-amino-3-oxoindoline were obtained according to the method of Reference Example 25 (melting point: 229.4-230.6 ° C.).

H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 3.20 (3H, s), 3.56 (2H, s), 3.60 (2H, q, J = 7.1 Hz), 3.95-4.10 (1H, m), 6.81 (1H, s), 7.25-7.35 (2H, m), 7.48 (1H, s), 7.58 (1H, s), 7.73 (1H, s)

Example 32
Synthesis of 7- (4-aminophenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one

  621 mg of 7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one obtained in Reference Example 19 And 4-Boc-aminoaniline from 481 mg according to the method of Reference Example 25, intermediate 7- (4-Boc-aminophenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyri 628.8 mg of mid [5,4-e] [1,2,4] triazin-3-one was obtained. To 130 mg of this intermediate, 0.5 ml of methylene chloride and 0.1 ml of TFA were added and stirred for 2 hours. The solvent was distilled off under reduced pressure, basified with sodium carbonate, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 90.1 mg of the title compound.

H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-1.90 (8H, m), 3.18 (3H, s), 3.45-3.65 (4H, m), 3.95-4.10 (1H, m), 6.68 (2H, d, J = 8.5 Hz), 7.31 (1H, d, J = 8.5 Hz), 7.71 (1H, s)

Example 33
Of 1-cyclopentyl-2-ethyl-4-methyl-7- (piperidin-4-yl) amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one Composition

  792-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 592 mg obtained in Reference Example 19 Then, 1.4 g of 4-amino-1-Boc-piperidine was dissolved in 10 ml of dimethyl sulfoxide (hereinafter, DMSO) and stirred at 150 ° C. for 20 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate 1-cyclopentyl-2-ethyl-4-methyl-7- (1-Boc-piperidin-4-yl) amino-1,2- 938 mg of dihydropyrimido [5,4-e] [1,2,4] triazin-3-one was obtained. To 874 mg of this intermediate were added 9.5 ml of methylene chloride and 1.7 ml of TFA, and the mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure, basified with sodium carbonate, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 392 mg of the title compound.

H-NMR (CDCl ₃ ) δ (ppm):
1.08 (3H, t, J = 7.1 Hz), 1.50-2.50 (13H, m), 2.75-2.85 (2H, m), 3.10-3.25 (5H, m), 3.57 (2H, q, J = 7.1 Hz) , 3.75-4.00 (2H, m), 7.65 (1H, s)

Example 34
1-cyclopentyl-2-ethyl-4-methyl-7- (1- (1-methylpiperidin-4-yl) carbamoylpiperidin-4-yl) amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one Dissolved in 288.7 mg of 4-amino-1-methylpiperidine and 12 ml of THF, 351 μl of TEA was added to a solution of 559 mg of paranitrophenyl chloroformate in THF (under ice cooling). 4 ml) solution was added. Thereafter, the reaction solution was stirred at room temperature overnight. The precipitate was filtered, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 376 mg of intermediate 1-methyl-4- (4-nitrophenoxycarbonyl) aminopiperidine. 33.5 mg of this intermediate and 1-cyclopentyl-2-ethyl-4-methyl-7- (piperidin-4-yl) amino-1,2-dihydropyrimido [5,4-e] obtained according to Example 33 ] 35.9 mg of [1,2,4] triazin-3-one was dissolved in 1 ml of THF, 28 μl of TEA was added, and the mixture was stirred at 60 ° C. for 1.5 hours. Water was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain 27.6 mg of the title compound.

H-NMR (CDCl ₃ ) δ (ppm):
1.08 (3H, t, J = 7.1 Hz), 1.35-2.25 (18H, m), 2.28 (3H, s), 2.70-2.90 (2H, m), 2.95-3.05 (2H, m), 3.17 (3H, s), 3.57 (2H, q, J = 7.1 Hz), 3.60-3.75 (1H, m), 3.80-4.00 (4H, m), 4.30-4.45 (1H, m), 4.75-4.90 (1H, m) , 7.65 (1H, s)

Example 35
1-cyclopentyl-2-ethyl-4-methyl-7- (4- (pyridin-4-ylcarbonyl) aminophenyl) amino-1,2-dihydropyrimido [5,4-e] [1,2,4 Synthesis of triazin-3-one

  7- (4-Aminophenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained according to Example 32 According to the method of Example 19, 45.2 mg of the title compound was obtained from 36.7 mg of triazin-3-one and 15 mg of isonicotinic acid.

H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-1.95 (8H, m), 3.20 (3H, s), 3.60 (2H, q, J = 7.1 Hz), 4.00-4.10 (1H, m), 7.01 (1H, s), 7.55-7.65 (4H, m), 7.72 (1H, d, J = 6.1 Hz), 7.76 (1H, s), 8.00-8.10 (1H, m), 8.78 (2H, d, J = 5.4 Hz)

Example 36
1-cyclopentyl-2-ethyl-7- (4-methanesulfonylaminophenyl) amino-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one Synthesis of

  7- (4-Aminophenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] obtained according to Example 32 36.7 mg of triazin-3-one was dissolved in 1 ml of THF, 42 μl of TEA was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 32.8 mg of the title compound.

H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.00 (8H, m), 2.98 (3H, s), 3.21 (3H, s), 3.60 (2H, q, J = 7.1 Hz), 4.00-4.10 (1H, m), 6.60 (1H, s), 7.18 (1H, s), 7.23 (2H, d, J = 9.0 Hz), 7.59 (2H, d, J = 9.0 Hz), 7.72 (1H, s)

Example 37
1-cyclopentyl-2-ethyl-4-methyl-7- [2-methoxy-4- (1,2,2,6,6-pentamethylpiperidin-4-yl) carbamoylphenyl] amino-1,2-dihydro Synthesis of pyrimido [5,4-e] [1,2,4] triazin-3-one

  7- (4-Carboxy-2-methoxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1, obtained by Reference Example 26 According to the method of Example 20, 313.1 mg of the title compound was obtained from 298 mg of 2,4] triazin-3-one and 200 μl of 1,2,2,6,6-pentamethylpiperidine.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.00-1.30 (15H, m), 1.40-2.00 (12H, m), 2.30 (1H, s), 3.32 (3H, s), 3.61 (2H, q, J = 7.1 Hz), 3.96 (3H, s) , 4.30-4.50 (1H, m), 5.90-6.00 (1H, m), 7.25-7.27 (1H, m), 7.46 (1H, d, J = 2.0 Hz), 7.75-7.90 (2H, m), 8.54 (1H, d, J = 8.5 Hz)

Example 38
1-cyclopentyl-2-ethyl-4-methyl-7- (4- (pyridin-4-yl) carbamoyl-2-methoxyphenyl) amino-1,2-dihydropyrimido [5,4-e] [1, Synthesis of 2,4] triazin-3-one

  7- (4-Carboxy-2-methoxyphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1, obtained by Reference Example 26 According to the method of Example 20, 32.6 mg of the title compound was obtained from 37 mg of 2,4] triazin-3-one and 12 mg of 4-aminopyridine.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.12 (3H, t, J = 7.1 Hz), 1.50-1.95 (8H, m), 3.22 (3H, s), 3.62 (2H, q, J = 7.1 Hz), 3.95-4.10 (1H, m), 7.43 (1H, dd, J = 8.5 Hz, 1.7 Hz), 7.53 (1H, d, J = 1.7 Hz), 7.63 (2H, d, J = 6.1 Hz), 7.82 (1H, s), 7.86 (1H, s ), 8.05-8.15 (1H, m), 8.55 (2H, d, J = 6.1 Hz), 8.64 (1H, d, J = 8.5 Hz)

Example 39
1-cyclopentyl-2-ethyl-4-methyl-7- [3- (N-methylpiperidin-4-yl) carbamoylphenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2 , 4] Synthesis of triazin-3-one

  7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 100 mg obtained according to Reference Example 19 And 1-cyclopentyl-2-ethyl-4-methyl-7- (3-carboxyphenyl) amino-1,2-dihydropyrimido from 46.4 mg of 3-aminobenzoic acid according to the method of Example 2 [5,4-e] 70 mg of [1,2,4] triazin-3-one was obtained. From 50 mg of this intermediate, 39.4 mg of the title compound was obtained according to the method of Example 2 (melting point: 161.8 to 163.8 ° C.).

¹ H-NMR (DMSO-d ₆ ) δ (ppm):
0.97 (3H, t, J = 7.1 Hz), 1.40-2.10 (14H, m), 2.18 (3H, s), 2.75-2.90 (2H, m), 3.12 (3H, s), 3.46 (2H, q, J = 7.1 Hz), 3.70-3.80 (1H, m), 3.95-4.10 (1H, m), 7.25-7.35 (2H, m), 7.65-7.80 (1H, m), 7.98 (1H, s), 8.10 -8.20 (2H, m), 9.51 (1H, s)

Example 40
1-cyclopentyl-2-ethyl-4-methyl-7- (3- (N-methylpiperidin-4-yl) carbamoylmethylphenyl) amino-1,2-dihydropyrimido [5,4-e] [1, Synthesis of 2,4] triazin-3-one

  7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 200 mg obtained according to Reference Example 19 And 2-aminophenylacetic acid 102 mg according to the method of Example 2, intermediate 1-cyclopentyl-2-ethyl-4-methyl-7- (3-carboxymethylphenyl) amino-1,2-dihydropyrimido [ 5,4-e] [1,2,4] Triazin-3-one 80 mg was obtained. From 30 mg of this intermediate, 15 mg of the title compound was obtained according to the method of Example 2 (melting point: 143.5-145.5 ° C.).

¹ H-NMR (DMSO-d ₆ ) δ (ppm):
0.97 (3H, t, J = 7.1 Hz), 1.40-2.00 (14H, m), 2.13 (3H, s), 2.60-2.75 (2H, m), 3.11 (3H, s), 3.40-3.55 (2H, m), 3.95-4.10 (1H, m), 6.78 (1H, d, J = 8.5 Hz), 7.10-7.20 (1H, m), 7.50-7.60 (2H, m), 7.93 (1H, d, J = 7.5 Hz), 7.96 (1H, s), 9.37 (1H, s)

Example 41
1-cyclopentyl-2-ethyl-4-methyl-7- (4-carboxymethylthiazol-2-yl) amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- Synthesis of 3-one

  7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 100 mg obtained according to Reference Example 19 Intermediate 1-cyclopentyl-2-ethyl-7- (4-ethoxycarbonylmethylthiazol-2-yl) amino-4 from 88.2 mg of ethyl 2-amino-4-thiazole acetate according to the method of Reference Example 32 15 mg of methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one was obtained. To 15 mg of this intermediate, 5 ml of methanol and 0.2 ml of 4N aqueous sodium hydroxide solution were added and heated under reflux for 3 hours. The reaction solution was cooled to room temperature, acidified with 6N hydrochloric acid, and the precipitate was collected by filtration under reduced pressure and dried to obtain 11 mg of the title compound (melting point: 110.3-114.3 ° C.).

¹ H-NMR (DMSO-d ₆ ) δ (ppm):
0.97 (3H, t, J = 7.1 Hz), 1.40-1.90 (8H, m), 3.13 (3H, s), 3.47 (2H, q, J = 7.1 Hz), 3.54 (3H, s), 4.00-4.15 (1H, m), 6.79 (1H, s), 8.05 (1H, s), 11.4 (1H, brs)

Example 42
1-cyclopentyl-2-ethyl-4-methyl-7- (3,4,5-trimethoxyphenyl) amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine- Synthesis of 3-one

  7-Chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 53 obtained according to Reference Example 19 According to the method of Example 2, 37 mg of the title compound was obtained from 2 mg and 41,3,4,5-trimethoxyaniline (melting point: 142.2 to 148.0 ° C.).

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-1.90 (8H, m), 3.21 (3H, s), 3.59 (2H, q, J = 7.1 Hz), 3.82 (3H, s), 3.88 (6H , s), 4.00-4.10 (1H, m), 6.82 (1H, s), 6.89 (2H, s), 7.76 (1H, s)

Example 43
1-cyclopentyl-2-ethyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-3-trifluoromethylphenyl] amino-1,2-dihydropyrimido [5,4- e] Synthesis of [1,2,4] triazin-3-one

  7- (4-Carboxy-3-trifluoromethylphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [5] obtained according to Reference Example 27 According to the method of Example 20, 40.4 mg of the title compound was obtained from 34 mg of 1,2,4] triazin-3-one and 14 μl of 4-amino-1-methylpiperidine.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.50-2.25 (14H, m), 2.34 (3H, s), 2.75-3.00 (2H, m), 3.22 (3H, s), 3.60 (2H, q, J = 7.1 Hz), 3.95-4.15 (2H, m), 5.66 (1H, d, J = 7.8 Hz), 7.09 (1H, s), 7.49 (1H, d, J = 8.90 Hz), 7.67 (1H, dd, J = 8.9 Hz, 2.4 Hz), 7.76 (1H, s), 8.12 (1H, s)

Example 44
1-cyclopentyl-2-ethyl-4-methyl-7- [2-methyl-4- (N-methylpiperidin-4-yl) carbamoylphenyl] amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7- (4-Carboxy-2-methylphenyl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1, obtained by Reference Example 28 According to the method of Example 20, 30.3 mg of the title compound was obtained from 30 mg of 2,4] triazin-3-one and 14 μl of 4-amino-1-methylpiperidi.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.11 (3H, t, J = 7.1 Hz), 1.50-2.30 (14H, m), 2.37 (6H, s), 2.90-3.00 (2H, m), 3.22 (3H, s), 3.61 (2H, q, J = 7.1 Hz), 4.00-4.10 (2H, m), 5.93 (1H, d, J = 7.6 Hz), 6.87 (1H, s), 7.55-7.75 (2H, m) 7.78 (1H, s), 8.80 -8.95 (1H, m)

Example 45
1-cyclopentyl-2-ethyl-4-methyl-7- (3- (1-methylpiperidin-4-yl) carbamoylphenyl) -1,2-dihydropyrimido [5,4-e] [1,2, 4] Synthesis of triazin-3-one

  7-Chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 29 obtained according to Reference Example 19 1 mg of dimethoxyethane (DME) and 1 ml of 2N aqueous sodium carbonate solution were added to 6 mg, 3 carboxyphenylboronic acid 33.2 mg and tetrakistriphenylphosphine palladium 6 mg, and the mixture was stirred at 90 ° C. overnight. The reaction mixture was acidified with 2N hydrochloric acid, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate 1-cyclopentyl-2-ethyl-4-methyl-7- (3-carboxyphenyl) -1,2-dihydropyrimido [5, 4-e] 11.9 mg of [1,2,4] triazin-3-one was obtained. According to the method of Example 20, 5.2 mg of the title compound was obtained from 7.5 mg of this intermediate and 4 μl of 4-amino-1-methylpiperidine.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.13 (3H, t, J = 7.1 Hz), 1.50-2.35 (14H, m), 2.39 (3H, s), 2.85-3.05 (2H, m), 3.66 (2H, q, J = 7.1 Hz), 4.00 -4.15 (2H, m), 6.20-6.35 (1H, m), 7.54 (1H, t, J = 7.8 Hz), 7.85-7.95 (1H, m) 8.09 (1H, s), 8.45-8.55 (1H, m), 8.60-8.70 (1H, m)

Example 46
Synthesis of 7-benzylamino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one

  7-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 50 mg obtained according to Reference Example 19 And 65 μl of benzylamine were dissolved in 1 ml of DMSO and stirred at 150 ° C. for 20 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 17 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.09 (3H, t, J = 7.1 Hz), 1.45-1.85 (8H, m), 3.16 (3H, s), 3.57 (2H, q, J = 7.1 Hz), 3.85-4.00 (2H, m), 4.59 (2H, d, J = 5.9 Hz), 5.25-5.30 (1H, m) 7.26-7.90 (5H, m), 7.66 (1H, s)

Example 47
1-cyclopentyl-2-ethyl-4-methyl-7- (5- (N-methylpiperidin-4-yl) carbamoylpyridin-2-yl) amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7- (5-Carboxyridin-2-yl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1, obtained by Reference Example 34 According to the method of Example 20, 23.3 mg of the title compound was obtained from 35 mg of 2,4] triazin-3-one.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.11 (3H, t, J = 7.1 Hz), 1.50-2.30 (14H, m), 2.35 (3H, s), 2.80-3.00 (2H, m), 3.23 (3H, s), 3.61 (2H, q, J = 7.1 Hz), 4.00-4.10 (2H, m), 6.00-6.10 (1H, m), 7.87 (1H, d, J = 2.4 Hz), 8.05 (1H, dd, J = 9.0 Hz, 2.4 Hz) , 8.41 (1H, d, J = 9.0 Hz), 8.50 (1H, s), 8.72 (1H, s)

Example 48
1-cyclopentyl-2-ethyl-4-methyl-7- (5- (N-methylpiperidin-4-yl) carbamoylthiophen-2-yl) amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7- (5-Carboxythiophen-2-yl) amino-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1, obtained by Reference Example 35 According to the method of Example 20, 20 mg of the title compound was obtained from 24 mg of 2,4] triazin-3-one.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.09 (3H, t, J = 7.1 Hz), 1.50-2.30 (14H, m), 2.35 (3H, s), 2.80-3.00 (2H, m), 3.21 (3H, s), 3.60 (2H, q, J = 7.1 Hz), 4.15-4.25 (2H, m), 5.66 (1H, d, J = 8.1), 6.49 (1H, d, J = 4.1 Hz), 7.29 (1H, d, J = 4.1 Hz), 7.63 (1H, s), 7.78 (1H, s)

Example 49
1-cyclopentyl-2-ethyl-4-methyl-7- (4- (N-methylpiperidin-4-yl) carbamoylphenyl) oxy-1,2-dihydropyrimido [5,4-e] [1,2 , 4] Synthesis of triazin-3-one

  792-chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 592 mg obtained in Reference Example 19 DMSO (10 ml) was added to methyl 4-hydroxybenzoate (335 mg) and potassium carbonate (552 mg), and the mixture was stirred at 120 ° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography, and the intermediate 1-cyclopentyl-2-ethyl-7- (4-methoxycarbonylphenyl) oxy-4-methyl-1,2-dihydropyrimido [ 5,4-e] [1,2,4] Triazin-3-one 750 mg was obtained. 2 ml of methanol and 2 ml of 2M aqueous sodium carbonate solution were added to 140 mg of this intermediate and stirred at 95 ° C. for 1 hour. The reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to adjust the pH to 5, and the mixture was extracted 3 times with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. Chloroform was added to the residue, and the precipitate was collected by filtration under reduced pressure, whereby the intermediate 7- (4-carboxyphenyl) oxy-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4 -E] 92.2 mg of [1,2,4] triazin-3-one was obtained. In accordance with the method of Example 20, 39.6 mg of the title compound was obtained from 38 mg of this intermediate.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.45-2.30 (14H, m), 2.33 (3H, s), 2.80-3.00 (2H, m), 3.19 (3H, s), 3.59 (2H, q, J = 7.1 Hz), 3.95-4.20 (2H, m), 5.98 (1H, d, J = 7.6), 7.24 (2H, d, J = 8.5 Hz), 7.63 (1H, s), 7.81 (2H, d , J = 8.5 Hz)

Example 50
1- (3,4-Dimethoxybenzyl) -2-ethyl-4-methyl-7- (4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl) amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7-Chloro-1- (3,4-dimethoxybenzyl) -2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4 obtained by Reference Example 23 According to the method of Example 2, 39.5 mg of the title compound was obtained from 40 mg of triazin-3-one.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.18 (3H, t, J = 7.1 Hz), 1.50-2.30 (6H, m), 2.35 (3H, s), 2.80-3.05 (5H, m), 3.61 (2H, q, J = 7.1 Hz), 3.75 (3H, s), 3.85 (3H, s), 3.95-4.15 (4H, m), 4.60 (2H, s), 6.00-6.25 (1H, m), 6.75-6.80 (3H, m), 7.24 (1H , dd, J = 8.5 Hz, 1.7 Hz), 7.45 (1H, d, J = 1.7 Hz), 7.76 (1H, s), 8.49 (1H, d, J = 8.5)

Example 51
2-Ethyl-1-isopropyl-4-methyl-7- (4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl) amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazin-3-one

  7-chloro-2-ethyl-1-isopropyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 30 mg obtained according to Reference Example 22 Thus, 24.6 mg of the title compound was obtained according to the method of Example 2.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.11 (3H, t, J = 7.1 Hz), 1.28 (6H, d, J = 6.6 Hz), 1.50-2.20 (4H, m), 2.21 (2H, t, J = 11.2 Hz), 2.33 (3H, s ), 2.80-3.00 (2H, m), 3.21 (3H, s), 3.62 (2H, q, J = 7.1 Hz), 3.95-4.10 (5H, m), 6.03 (1H, d, J = 8.3 Hz) , 7.24-7.27 (1H, m), 7.44 (1H, d, J = 1.7Hz), 7.77 (1H, s), 7.79 (1H, s), 8.34 (1H, d, J = 8.5)

Example 52
1- (2-adamantyl) -2-ethyl-4-methyl-7- (4-N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl) amino-1,2-dihydropyrimido [5,4 -E] Synthesis of [1,2,4] triazin-3-one

  1- (2-adamantyl) -7-chloro-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-obtained by Reference Example 21 12.7 mg of the title compound was obtained from 54 mg of 3-one according to the method of Example 2 (melting point: 200.9 ° C., decomposition).

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.10 (3H, t, J = 7.1 Hz), 1.40-2.35 (21H, m), 2.38 (3H, s), 2.55-2.65 (1H, m), 2.80-3.05 (2H, m), 3.10-3.20 ( 1H, m), 3.27 (3H, s), 3.40 (1H, s), 3.75 (1H, t, J = 6.6 Hz), 3.95-4.15 (5H, m), 6.01 (1H, d, J = 7.1 Hz ), 7.25-7.27 (1H, m), 7.44 (1H, d, J = 1.7Hz), 7.83 (1H, s), 7.98 (1H, s), 8.56 (1H, d, J = 8.5)

Example 53
1-cyclopentyl-2-ethyl-3,3,4-trimethyl-7- (4-N-methylpiperidin-4-yl) carbamoylphenyl) amino-1,2,3,4-tetrahydropyrimido [5,4 -E] Synthesis of [1,2,4] triazin-3-one

  487 mg of 1- (2-chloro-5-methylaminopyrimidin-4-yl) -1-cyclopentyl-2-ethylhydrazine obtained in Reference Example 29 was dissolved in 10 ml of THF, 1.8 ml of acetone, 4N hydrogen chloride-dioxane. The reaction solution to which 3 drops of the solution was added was stirred at 60 ° C. for 2 hours. The reaction solution was cooled to room temperature, and the solvent was distilled off under reduced pressure. The mixture was made basic by adding an aqueous sodium carbonate solution, extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain intermediate 7-chloro-1-cyclopentyl-2-ethyl-3,3,4-trimethyl-1,2,3,4-tetrahydropyrimido. [5,4-e] 560 mg of [1,2,4] triazin-3-one was obtained. According to the method of Reference Example 32, from this intermediate 250 mg and ethyl 4-aminobenzoate 159 mg, the intermediate 1-cyclopentyl-2-ethyl-7- (4-methoxycarbonylphenyl) amino-3,3,4- 161 mg of trimethyl-1,2,3,4-tetrahydropyrimido [5,4-e] [1,2,4] triazin-3-one was obtained. To 161 mg of this intermediate, 5 ml of methanol and 2 ml of 2N aqueous sodium hydroxide solution were added and stirred at 50 ° C. overnight. The reaction mixture was cooled to room temperature, 2N hydrochloric acid was added to pH 5, and the precipitate was collected by filtration under reduced pressure and dried to give intermediate 7- (4-carboxyphenyl) amino-1-cyclopentyl-2-ethyl-3, 121 mg of 3,4-trimethyl-1,2,3,4-tetrahydropyrimido [5,4-e] [1,2,4] triazin-3-one was obtained. According to the method of Example 20, 89.9 mg of the title compound was obtained from 77 mg of this intermediate.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.00 (3H, s), 1.16 (3H, t, J = 7.3 Hz), 1.46 (3H, s), 1.55-2.30 (14H, m), 2.33 (3H, s), 2.56 (1H, sex, J = 7.3Hz), 2.71 (3H, s), 2.85-2.95 (2H, m), 3.18 (1H, sex, J = 7.3 Hz), 3.95-4.10 (1H, m), 5.91 (1H, d, J = 8.1 Hz), 6.96 (1H, s), 7.36 (1H, s), 7.64 (2H, d, J = 9.0Hz), 7.68 (2H, d, J = 9.0Hz)

Example 54
4-Cyclopentyl-3-ethyl-1-methyl-6- (4- (N-methylpiperidin-4-yl) carbamoylphenyl) amino-3,4-dihydropyrimido [4,5-d] [1,2 , 3,6] Synthesis of thiatriazin-2-one

  6-Chloro-4-cyclopentyl-3-ethyl-1-methyl-3,4-dihydropyrimido [4,5-d] [1,2,3,6] thiatriazine-2 obtained by Reference Example 36 In accordance with the method of Reference Example 32, the intermediate 4-cyclopentyl-3-ethyl-6- (4-methoxycarbonylphenyl) amino-1-methyl-3,4 was obtained from 163 mg of -one and 159 mg of methyl 4-aminobenzoate. -Dihydropyrimido [4,5-d] [1,2,3,6] thiatriazin-2-one was obtained and according to the method of Reference Example 35, the intermediate 6- (4-carboxyphenyl) amino- There was obtained 33 mg of 4-cyclopentyl-3-ethyl-1-methyl-3,4-dihydropyrimido [4,5-d] [1,2,3,6] thiatriazin-2-one. According to the method of Example 20 from 16.33 mg of this intermediate, 16.2 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.24 (3H, td, J = 7.1 Hz, 2.2Hz), 1.50-2.30 (14H, m), 2.35 (3H, s), 2.70-3.05 (4H, m), 3.24 (3H, s), 3.95-4.10 (1H, m), 4.95-5.05 (1H, m), 5.95 (1H, d, J = 7.6Hz), 7.08 (1H, s), 7.60-7.85 (5H, m)

Example 55
1-cyclopentyl-2-ethyl-4-methyl-7- (4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl) amino-1,2-dihydropyrimido [5,4-e] Synthesis of [1,2,4] triazine-3-thione

  7-Chloro-1-cyclopentyl-2-ethyl-4-methyl-1,2-dihydropyrimido [5,4-e] [1,2,4] triazine-3-thione 205 mg obtained by Reference Example 37 Thus, 100 mg of the title compound was obtained according to the method of Example 2.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.21 (3H, t, J = 7.1 Hz), 1.50-2.30 (14H, m), 2.34 (3H, s), 2.80-2.95 (2H, m), 3.63 (3H, s), 3.75-3.90 (1H, m), 3.95-4.25 (6H, m), 5.98 (1H, d, J = 7.8 Hz), 7.25-7.30 (1H, m), 7.46 (1H, d, J = 1.7Hz), 7.91 (1H, s ), 7.99 (1H, s), 8.55 (1H, d, J = 8.5 Hz)

Example 56
7-ethyl-5-methyl-2- (4-N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl) amino-8-phenyl-5,6-dihydropyrido [3,2-d] pyrimidine-6 -On synthesis

  To 983 mg of 4-benzoyl-5-bromo-2-methoxypyrimidine obtained in Reference Example 38, 6 ml of methanol and 6 ml of concentrated hydrochloric acid were added, and the mixture was heated to reflux for 2 hours. The solvent was distilled off under reduced pressure, ethyl acetate was added, and the mixture was dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 808 mg of intermediate 4-benzoyl-5-bromo-2-hydroxypyrimidine. To 808 mg of this intermediate, 30 ml of phosphorus oxychloride and 120 μl of N, N-dimethylaniline were added and heated to reflux overnight. The reaction solution was poured into ice water, extracted three times with ether, washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 799 mg of intermediate 4-benzoyl-5-bromo-2-chloropyrimidine. 671 mg of this intermediate and 940 mg of 4-amino-3-methoxybenzoic acid were mixed and heated at 190 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with a mixed solvent of THF and ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 318 mg of intermediate 4-benzoyl-5-bromo-2- (4-carboxy-2-methoxyphenyl) aminopyrimidine.

  To 250 mg of this intermediate and 15 mg of copper (II) sulfate pentahydrate, 5 ml of 40% aqueous methylamine solution was added, sealed, and stirred at 90 ° C. for 6 hours. The reaction mixture was evaporated under reduced pressure, 2N hydrochloric acid and THF were added, and the mixture was allowed to stand at room temperature for 30 min. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. Ethanol was added to the residue and crystallized to obtain 69 mg of intermediate 4-benzoyl-2- (4-carboxy-2-methoxyphenyl) amino-5-methylaminopyrimidine. 62.4 mg of this intermediate was dissolved in 2.3 ml of nitromethane, 52 μl of butyryl chloride was added, and the mixture was heated to reflux for 30 minutes. Further, 52 μl of butyryl chloride was added and heated to reflux for 30 minutes. The suspension was made into a solution by adding 0.5 ml of DMA, and 52 μl of butyryl chloride was further added, followed by heating under reflux for 30 minutes. The reaction suspension was cooled to room temperature, water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 84 mg of intermediate N-methyl-N- (4-benzoyl-2- (4-carboxy-2-methoxyphenyl) aminopyrimidin-5-yl) butanamide. To 84 mg of this intermediate was added 4 ml of 1N sodium ethoxide-ethanol solution, and the mixture was heated to reflux for 20 minutes. The reaction suspension was cooled to room temperature, the precipitate was filtered under reduced pressure, washed successively with ethanol and ether to give intermediate 2- (4-carboxy-2-methoxyphenyl) amino-7-ethyl-5-methyl-8. -45 mg of phenyl-5,6-dihydropyrido [3,2-d] pyrimidin-6-one was obtained. According to the method of Example 20 from 22 mg of this intermediate, 22 mg of the title compound was obtained.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.12 (3H, t, J = 7.3 Hz), 1.50-1.75 (2H, m), 2.00-2.15 (1H, m), 2.19 (2H, t, J = 10.5 Hz), 2.33 (3H, s), 3.62 (2H, q, J = 7.3 Hz), 3.75-3.95 (2H, m), 3.81 (3H, s), 3.93 (3H, s), 3.95-4.05 (1H, m), 5.80-5.95 (1H, s ), 6.75-6.85 (1H, m), 7.25-7.40 (3H, m), 7.50-7.60 (3H, s), 7.81 (1H, d, J = 8.5 Hz), 7.92 (1H, s), 8.65 ( 1H, s)

Example 57
Synthesis of 7-ethyl-5-methyl-2-methylamino-8-phenyl-5,6-dihydropyrido [3,2-d] pyrimidin-6-one

  To 354 mg of 4-benzoyl-5-bromo-2-methoxypyrimidine obtained in Reference Example 38 and 30 mg of copper (II) sulfate pentahydrate, 4 ml of 40% aqueous methylamine solution was added, sealed, and stirred at 90 ° C. overnight. did. The reaction mixture was evaporated under reduced pressure, 2N hydrochloric acid and THF were added, and the mixture was allowed to stand at room temperature for 30 min. An aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 63.9 mg of intermediate 4-benzoyl-2,5-bis (aminomethyl) pyrimidine. 63.9 mg of this intermediate was dissolved in 3 ml of nitromethane, 62 μl of butyryl chloride was added, and the mixture was heated to reflux for 30 minutes. Further, 62 μl of butyryl chloride was added and heated to reflux for 30 minutes. The reaction solution was cooled to room temperature, an aqueous sodium carbonate solution was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 32.5 mg of intermediate N-methyl-N- (4-benzoyl-2-methylaminopyrimidin-5-yl) butanamide. To 32.5 mg of this intermediate was added 2 ml of 1N sodium ethoxide-ethanol solution, and the mixture was heated to reflux for 1 hour. The reaction solution was cooled to room temperature, water was added, extracted with ethyl acetate, washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 31.3 mg of the title compound.

¹ H-NMR (CDCl ₃ ) δ (ppm):
1.09 (3H, t, J = 7.6 Hz), 1.56 (2H, q, J = 7.6 Hz), 2.83 (3H, d, J = 4.9 Hz), 3.75 (3H, s), 4.88 (1H, brs), 7.25-7.30 (2H, m), 7.35-7.55 (3H, m), 8.52 (1H, s)

Comparative Example 1
4-(((7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-6-oxo-2-pteridinyl) amino) -3-methoxy-N- (1- Synthesis of methyl-4-piperidinyl) benzamide The title compound was synthesized by the method described in WO 2006/018185.

Table 1 below lists the compounds obtained above using R ^{1 to} R ⁶ and X ^{1 to} X ³ of the general formula (I).

The pharmacological test results of typical compounds are shown below.
Test Example 1 PKL1 Enzyme Inhibition Test The inhibitory activity of the above compounds on PLK1 phosphorylase was measured according to a method described in the literature (J. Biomolo. Science vol. 10, No. 7, pp730-737 (2005)). That is, using a biotinylated peptide containing a consensus sequence of PLK1 (D / EXS / T-Φ-XD / E) as a substrate according to the literature description of J. Biol Chem, vol. 278, No. 28, pp25277-25280 (2003). In the reaction buffer, the reaction was carried out with PLK1 (CP-0094, Cyclex Co., Ltd) in the presence of the test compound. Simultaneously with the termination of the reaction, a mixture containing a phosphorylated serine / threonine-specific recognition antibody and AlphaScreen reagent (6760617C, Perkin Elmer) was added, and the amount of fluorescence after the reaction was measured for 1 hour. The compound concentration at which the phosphorylation reaction can be inhibited by 50% as compared with the control group was defined as the IC ₅₀ value, and is shown in Table 2 below.

表２の結果より、本発明化合物はいずれもＰＬＫ１に対する優れた阻害活性を有することが明らかとなった。

From the results in Table 2, it was revealed that all of the compounds of the present invention have excellent inhibitory activity against PLK1.

Test Example 2 Oral absorbability test
A test on oral absorbability was carried out from the blood concentration when the compound was orally administered to BALB / cA-nu mice (CLEA Japan).
On the test day, the compound (25 μmol / kg, 0.5% hydroxypropylmethylcellulose: dimethylsulfoxide = 3: 1 solution or suspension) was orally administered in the morning, and the fundus vein was injected 0.5, 1, 2, 4 and 6 hours later Alternatively, blood was collected from the jugular vein to obtain plasma. The compound concentration in the obtained plasma was measured by HPLC, and the average blood concentration and the blood concentration after 6 hours were calculated. The blood concentration after 6 hours is shown in Table 3.

表３より、比較例化合物に対し、本発明化合物が経口吸収性に優れていることが示された。

From Table 3, it was shown that the compound of the present invention is excellent in oral absorbability with respect to the comparative compound.

Formulation Example 1 Tablet compound (1) 50 mg
Corn starch 50mg
Microcrystalline cellulose 50mg
Hydroxypropylcellulose 15mg
Lactose 47mg
Talc 2mg
Magnesium stearate 2mg
Ethylcellulose 30mg
Unsaturated glyceride 2mg
Titanium dioxide 2mg
According to a conventional method at the above blending ratio, 250 mg tablets per tablet were prepared.

Formulation Example 2 Granule compound (2) 300 mg
Lactose 540mg
Corn starch 100mg
Hydroxypropylcellulose 50mg
Talc 10mg
In the above blending ratio, 1000 mg of a granule was prepared per package according to a conventional method.

Formulation Example 3 Capsule Compound (3) 100 mg
Lactose 30mg
Corn starch 50mg
Microcrystalline cellulose 10mg
Magnesium stearate 3mg
193 mg capsules per capsule were prepared according to a conventional method at the above blending ratio.

Formulation Example 4 Injection Compound (4) 100 mg
Sodium chloride 3.5mg
Appropriate amount of distilled water for injection (2 ml per ampoule)
An injection was prepared according to a conventional method at the above blending ratio.

Formulation Example 5 Syrup Compound (6) 200 mg
60g refined white sugar
Ethyl parahydroxybenzoate 5mg
Butyl parahydroxybenzoate 5mg
Fragrance Appropriate amount Colorant Appropriate amount Purified water Appropriate amount A syrup was prepared according to a conventional method at the above blending ratio.

Formulation Example 6 Suppository Compound (8) 300 mg
Witepsol W-35 ^{* 1} 1400mg
* 1: Registered trademark, mono-, di- and tri-glyceride mixture of saturated fatty acids from lauric acid to stearic acid; manufactured by Dynamite Nobel, Inc. A suppository was prepared according to a conventional method at the above blending ratio.

Claims (8)

The following general formula (I)

(In the formula, —X ¹ —X ² — represents an —N—N— bond or —C═C— bond,
X ³ represents a carbon atom or a sulfur atom,
R ¹ represents a hydrogen atom or an optionally substituted lower alkyl group,
R ² and R ³ , when X ³ represents a carbon atom, are the same or different and represent a lower alkyl group which may have a substituent, or together represent an oxygen atom or a sulfur atom. Or when X ³ represents a sulfur atom, each represents an oxo group or together represents an oxygen atom,
R ⁴ represents a C 1-10 alkyl group which may have a substituent,
R ⁵ represents an optionally substituted lower alkyl group, a C 3-10 cyclic alkyl group, or an aryl group,
R ⁶ represents a halogen atom, an aryl group which may have a substituent, —NR ⁷ R ⁸ or —OR ⁹ ;
R ⁷ and R ⁸ are the same or different and each represents a hydrogen atom, a lower alkyl group which may have a substituent, a saturated or unsaturated heterocyclic group which may have a substituent, or a substituent. An aryl group which may have,
R ⁹ represents an aryl group which may have a substituent)
A condensed cyclic pyrimidine compound represented by the formula: In the formula, —X ¹ —X ² — represents an —N—N— bond or —C═C— bond,
X ³ represents a carbon atom or a sulfur atom,
R ¹ represents an optionally substituted methyl group or ethyl group,
R ² and R ³ are the same or different when X ³ represents a carbon atom and represent a lower alkyl group or together represent an oxygen atom or a sulfur atom, or X ³ represents a sulfur atom. When indicating, each represents an oxo group or together represents an oxygen atom,
R ⁴ represents a methyl group, an ethyl group, an isopropylmethyl group, a cyclobutylmethyl group, or an n-octyl group, and the alkyl group has a halogen atom, a cyano group, an alkoxy group, a mono- or dialkylamino group, a non-alkyl group as a substituent. A substituted carbamoyl group, an optionally substituted aryl group, or a heteroaryl group,
R ⁵ represents an optionally substituted methyl group, isopropyl group, cyclopentyl group, adamantyl group or phenyl group,
R ⁶ represents a halogen atom, an optionally substituted phenyl group, —NR ⁷ R ⁸ or —OR ⁹ ;
R ⁷ represents a hydrogen atom, R ⁸ represents a methyl group which may have a substituent, a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may have a substituent, substituted Any phenyl group optionally having a group;
The fused cyclic pyrimidine compound or a salt thereof according to claim 1, wherein R ⁹ represents a phenyl group which may have a substituent. In the formula, —X ¹ —X ² — represents an —N—N— bond or —C═C— bond,
X ³ represents a carbon atom or a sulfur atom,
R ¹ represents a methyl group,
R ² and R ³ together represent an oxygen atom or a sulfur atom when X ³ represents a carbon atom, or each other represents an oxo group or together when X ³ represents a sulfur atom. Indicating oxygen atoms,
R ⁴ is a cyano group, an unsubstituted carbamoyl group, a phenyl group optionally having a substituent, a methyl group optionally having a pyridyl group as a substituent, a halogen atom, an alkoxy group as a substituent Represents an ethyl group, an isopropylmethyl group, a cyclobutylmethyl group, or an n-octyl group, which may have either a mono- or dialkylamino group,
R ⁵ represents a cyclopentyl group, an adamantyl group or a phenyl group,
R ⁶ represents a chlorine atom, a phenyl group optionally having an N-substituted or unsubstituted carbamoyl group as a substituent, —NR ⁷ R ⁸ or —OR ⁹ ;
R ⁷ represents a hydrogen atom, R ⁸ represents a methyl group which may have an aryl group as a substituent, a piperidinyl group which may have an N-substituted or unsubstituted carbamoyl group, or a substituent. A monocyclic or bicyclic unsaturated heterocyclic group which may have a phenyl group which may have a substituent,
The condensed cyclic pyrimidine compound or a salt thereof according to claim 1 or 2, wherein R ⁹ represents a phenyl group which may have an N-substituted or unsubstituted carbamoyl group as a substituent. In the formula, —X ¹ —X ² — represents an —N—N— bond or —C═C— bond,
X ³ represents a carbon atom, R ¹ represents a methyl group, R ² and R ³ together represent an oxygen atom, R ⁴ represents an ethyl group, and R ⁵ represents a cyclopentyl group or a phenyl group. R ⁶ represents -NR ⁷ R ⁸ ,
R ⁷ represents a hydrogen atom, R ⁸ has a thienyl group which may have an N-substituted or unsubstituted carbamoyl group as a substituent, and a methyl group which may have a substituent as a substituent. An optionally substituted thiazolyl group, a pyridyl group optionally having an N-substituted or unsubstituted carbamoyl group, an indolinyl group optionally having an oxo group, a hydroxy group, a substituent An alkyl group which may have a substituent, an alkoxy group which may have a substituent, an amino group which may have a substituent, an N-substituted or an unsubstituted carbamoyl group The condensed cyclic pyrimidine compound or a salt thereof according to any one of claims 1 to 3, which shows a good phenyl group. In the formula, —X ¹ —X ² — represents an —N—N— bond or —C═C— bond,
X ³ represents a carbon atom, R ¹ represents a methyl group, R ² and R ³ together represent an oxygen atom, R ⁴ represents an ethyl group, and R ⁵ represents a cyclopentyl group or a phenyl group. R ⁶ represents -NR ⁷ R ⁸ ,
R ⁷ represents a hydrogen atom, R ⁸ represents a thienyl group having (N-methylpiperidinyl-4-yl) carbamoyl group as a substituent, a thiazolyl group having a carboxymethyl group as a substituent, and (N -Methylpiperidinyl-4-yl) pyridyl group having a carbamoyl group, an indolinyl group having an oxo group as a substituent, or a phenyl group, the phenyl group being a hydroxy group, a fluorine atom as a substituent or (N- Methyl group optionally having methylpiperidinyl-4-yl) carbamoyl group, methoxy group, amino group optionally having methanesulfonyl group, (1-methylpiperidin-4-yl) carbamoyl group, (N-methylazetidin-3-yl) carbamoyl group, 2- (diethylamino) ethylcarbamoyl group, 3-pyridylcarbamoyl 4-pyridylcarbamoyl group, thiophen-2-methylcarbamoyl group, 3-pyridylmethylcarbamoyl group, 2- (pyridin-2-yl) ethylcarbamoyl group, 2- (1-pyrrolidinylmethyl) phenylmethylcarbamoyl group, The structure according to claim 1, which may have 1 to 3 of (1,2,2,6,6-pentamethylpiperidin-4-yl) carbamoyl group and 4-pyridylcarbonylamino group. The condensed cyclic pyrimidine compound or a salt thereof according to any one of the above. The fused cyclic pyrimidine compound or a salt thereof according to claim 1, selected from the following group:
1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (2,2,2-trifluoroethyl) -1,2 -Dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 1-cyclopentyl-2-ethyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) ) Carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one / 1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-2- (2-methylpropan-1-yl) -1,2-dihydropyrimido [5,4-e] [1,2 , 4] Triazin-3-one, 2-sia Methyl-1-cyclopentyl-4-methyl-7- [4- (N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl] amino-1,2-dihydropyrimido [5,4-e] [1 , 2,4] triazin-3-one / 1-cyclopentyl-2-ethyl-4-methyl-7- [4- (N-methylazetidin-3-yl) carbamoyl] phenyl] amino-1,2-dihydro Pyrimido [[5,4-e] [1,2,4] triazin-3-one 1-cyclopentyl-2-ethyl-7- (4-hydroxyphenyl) amino-4-methyl-1,2-dihydro Pyrimido [5,4-e] [1,2,4] triazin-3-one / 1-cyclopentyl-2-ethyl-4-methyl-7- (4- (1-methylpiperidin-4-ylmethoxy) phenyl Amino-1,2-dihydro Rimido [5,4-e] [1,2,4] triazin-3-one 1-cyclopentyl-2-ethyl-4-methyl-7- (3-oxoindoline-5-yl) amino-1,2 -Dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 1-cyclopentyl-2-ethyl-7- (4-methanesulfonylaminophenyl) amino-4-methyl-1, 2-Dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 1-cyclopentyl-2-ethyl-4-methyl-7- [2-methoxy-4- (1,2 , 2,6,6-pentamethylpiperidin-4-yl) carbamoylphenyl] amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one / 1-cyclopentyl -2-ethyl-4-methyl-7- (5- (N- Tilpiperidin-4-yl) carbamoylthiophen-2-yl) amino-1,2-dihydropyrimido [5,4-e] [1,2,4] triazin-3-one 1- (2-adamantyl) -2-ethyl-4-methyl-7- (4-N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl) amino-1,2-dihydropyrimido [5,4-e] [1,2 , 4] triazin-3-one-7-ethyl-5-methyl-2- (4-N-methylpiperidin-4-yl) carbamoyl-2-methoxyphenyl) amino-8-phenyl-5,6-dihydropyrido [, 3,2-d] pyrimidin-6-one.   The pharmaceutical composition which uses the condensed cyclic pyrimidine compound or its salt of any one of Claims 1-6 as an active ingredient.   The antitumor agent which uses the condensed cyclic pyrimidine compound or its salt of any one of Claims 1-6 as an active ingredient.