JP2006083085A - Method for producing bicyclic pyrimidine derivative and its synthetic intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for simply and efficiently producing a bicyclic pyrimidine derivative useful for treating and/or preventing various T-cell-related diseases such as allergic diseases and autoimmune diseases and its synthetic intermediate, respectively, and the like. <P>SOLUTION: This method for producing the bicyclic pyrimidine derivative represented by the general formula (I) is characterized by treating an amine represented by the general formula (II) [(m) and (n) are each identically or differently an integer of 1 to 3, and (m)+(n) is an integer of ≤4] with a base, reacting the product with a compound represented by the general formula (III) (R<SP>1</SP>is a substituted or non-substituted lower alkyl, a substituted or non-substituted cycloalkyl, -NR<SP>2</SP>R<SP>3</SP>, -OR<SP>4</SP>, or the like; X is a halogen or the like) or a compound represented by the general formula (IV) to obtain a compound represented by the general formula (V), and then reacting the obtained compound represented by the general formula (V) with carbon dioxide in the presence of an organic base. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a bicyclic pyrimidine derivative useful for the treatment and / or prevention of various diseases involving T cells such as allergic diseases and autoimmune diseases, and a method for producing a synthetic intermediate thereof.

  Formula (IX)

{Where,
m and n are the same or different and represent an integer of 1 to 3 and m + n is 4 or less;
R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted Or an unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl, a substituted or unsubstituted alicyclic heterocyclic alkyl, -NR ² R ³ (Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted Or an unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl or a substituted or unsubstituted alicyclic heterocyclic alkyl, or R ² and R ³ are adjacent to a nitrogen atom Together to form a heterocyclic group) or —OR ⁴ (wherein R ⁴ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted) Or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic Represents a heterocyclic alkyl group or a substituted or unsubstituted alicyclic heterocyclic alkyl,
R ⁷ and R ⁸ are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic ring Represents alkyl or substituted or unsubstituted alicyclic heterocyclic alkyl, or R ⁷ and R ⁸ together with the adjacent nitrogen atom form a heterocyclic group;
p represents an integer of 1 to 4,
Y ^a and Y ^b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl or halogen,
R ⁹ represents —NR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, Substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted An aromatic heterocyclic alkyl or a substituted or unsubstituted alicyclic heterocyclic alkyl), a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group,
-A- is -O-, -CH = CH-, -C≡C-, phenylene or general formula (X)

[Wherein r represents an integer of 0 to 6,
when r is 1, Y ^c represents a substituted or unsubstituted lower alkyl or halogen;
when r is 2 or more, each Y ^c is the same or different and represents a substituted or unsubstituted lower alkyl or halogen, or two Y ^c on the same carbon atom together represent oxo;
G represents a nitrogen atom, CH, C (OH), C (CO ₂ H) or C (CN);
When G is a nitrogen atom, q represents an integer of 1 to 2, and when G is CH, C (OH), C (CO ₂ H) or C (CN), q represents an integer of 0 to 2. Represent,
Z is a single bond, —C (═O) —, —O—, —CH (OH) —, —CH ₂ CH (OH) —, —C (═O) O— or —C (═O) NR ¹² -In which R ¹² represents a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl] is represented by the following formula: The compound represented by (IX) is referred to as Compound (IX). The same applies to compounds of other formula numbers], which are known to be useful for the treatment and / or prevention of various diseases involving T cells such as allergic diseases and autoimmune diseases. A method for synthesizing such a compound (IX) and an intermediate thereof is known (Patent Document 1).

[Wherein, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are as defined above, and W is —C (═O) Cl, —CO _{2, respectively]} COR ¹ (wherein R ¹ is as defined above) etc.]
According to the description of Patent Document 1, compound (XI) which is a useful synthetic intermediate of compound (IX) is commercially available or in Synthetic Communications, Vol. 26, page 1657 (1996), etc. The compound (A) (for example, ethyl N-benzyl-4-oxo-3-piperidinecarboxylate, etc.) obtained according to the described method is synthesized as a starting material through 5 steps. In this method, for example, multi-step synthesis including steps such as removal of benzyl group unnecessary for the structure of the target compound is necessary, and a simpler and more efficient production method of compound (XI) on the premise of industrialization is required. It has been.
International Publication No. 03/104230 Pamphlet

  An object of the present invention is to provide a simple and efficient production of bicyclic pyrimidine derivatives and synthetic intermediates useful for the treatment and / or prevention of various diseases involving T cells such as allergic diseases and autoimmune diseases. And a synthetic intermediate useful for the simple and efficient production of the bicyclic pyrimidine derivative.

The present invention relates to the following [1] to [21].
[1] General formula (I)

[Where:
m and n are the same or different and represent an integer of 1 to 3 and m + n is 4 or less;
R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted Or an unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl, a substituted or unsubstituted alicyclic heterocyclic alkyl, -NR ² R ³ (Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted Or an unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl or a substituted or unsubstituted alicyclic heterocyclic alkyl, or R ² and R ³ are adjacent to a nitrogen atom Together to form a heterocyclic group) or —OR ⁴ (wherein R ⁴ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted) Or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic Represents a heterocyclic alkyl group or a substituted or unsubstituted alicyclic heterocyclic alkyl group]] or a salt thereof.

[2] The bicyclic pyrimidine derivative or a salt thereof according to the above [1], wherein m is 1 and n is 2.
[3] R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted The bicyclic pyrimidine derivative or a salt thereof according to the above [1] or [2], which is aryl.

[4] R ¹ is —NHR ^2A (wherein R ^2A is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or The bicyclic pyrimidine derivative or the salt thereof according to the above [1] or [2], which represents an unsubstituted aralkyl or a substituted or unsubstituted aryl.
[5] R ¹ is —OR ^4A (wherein R ^4A is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted The bicyclic pyrimidine derivative or the salt thereof according to the above [1] or [2], which represents an unsubstituted aralkyl or a substituted or unsubstituted aryl.

  [6] (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (III)

Wherein R ¹ is as defined above, X is halogen, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted lower alkylsulfonyloxy, substituted or unsubstituted arylsulfonyl Oxy, substituted or unsubstituted lower alkylsulfanyl, substituted or unsubstituted arylsulfanyl, substituted or unsubstituted lower alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted lower alkylsulfonyl, substituted or unsubstituted By reacting with a compound represented by the formula (V): arylsulfonyl or —OCOR ⁵ (wherein R ⁵ represents the same as R ¹ above)

(Wherein R ¹ , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.
[7] (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (IV)

Wherein R ^2B is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Represents aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl, or substituted or unsubstituted alicyclic heterocyclic alkyl ) Is reacted with a compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.
[8] (1) General formula (VI)

(Wherein m and n are as defined above), the compound represented by the general formula (III)

(Wherein R ¹ and X have the same meanings as described above), thereby reacting with the compound represented by the general formula (V)

(Wherein R ¹ , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.
[9] (1) General formula (VI)

(Wherein m and n are as defined above), a compound represented by the general formula (IV)

(Wherein R ^2B has the same ^{meaning as} described above) to react with the compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.
[10] General formula (V)

(Wherein R ¹ , m and n are as defined above), and a compound represented by the general formula (I), which is reacted with carbon dioxide in the presence of an organic base

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.
[11] The organic base used for the reaction with carbon dioxide is 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non-5-ene. The manufacturing method in any one of said [6]-[10].

  [12] (1) General formula (VII)

Wherein R ¹ , m and n are as defined above, and R ⁶ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted (Representing lower alkynyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl) is reacted with urea in the presence of an acid catalyst to give a general formula (VIII)

(Wherein R ¹ , R ⁶ , m and n are as defined above),
Next, (2) the resulting compound is treated with a base, which is represented by the general formula (I)

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.
[13] The production method according to any one of [6] to [12], wherein m is 1 and n is 2.
[14] (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (III)

(Wherein R ¹ and X have the same meanings as described above), thereby reacting with the compound represented by the general formula (V)

(Wherein R ¹ , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above), and the method includes a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

{Wherein R ¹ , m and n are as defined above,
R ⁷ and R ⁸ are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic ring Represents alkyl or substituted or unsubstituted alicyclic heterocyclic alkyl, or R ⁷ and R ⁸ together with the adjacent nitrogen atom form a heterocyclic group;
p represents an integer of 1 to 4,
Y ^a and Y ^b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl or halogen,
R ⁹ represents —NR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, Substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted An aromatic heterocyclic alkyl or a substituted or unsubstituted alicyclic heterocyclic alkyl), a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group,
-A- is -O-, -CH = CH-, -C≡C-, phenylene or general formula (X)

[Wherein r represents an integer of 0 to 6,
when r is 1, Y ^c represents a substituted or unsubstituted lower alkyl or halogen;
when r is 2 or more, each Y ^c is the same or different and represents a substituted or unsubstituted lower alkyl or halogen, or two Y ^c on the same carbon atom together represent oxo;
G represents a nitrogen atom, CH, C (OH), C (CO ₂ H) or C (CN);
When G is a nitrogen atom, q represents an integer of 1 to 2, and when G is CH, C (OH), C (CO ₂ H) or C (CN), q represents an integer of 0 to 2. Represent,
Z is a single bond, —C (═O) —, —O—, —CH (OH) —, —CH ₂ CH (OH) —, —C (═O) O— or —C (═O) NR ¹² -(In which R ¹² represents a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl)] is represented.} A production method of a bicyclic pyrimidine derivative represented by:

  [15] (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (IV)

(Wherein R ^2B has the same ^{meaning as} described above) to react with the compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IXB)

(Wherein, A, R ^2B , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n, and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative.
[16] (1) General formula (VI)

(Wherein m and n are as defined above), the compound represented by the general formula (III)

(Wherein R ¹ and X have the same meanings as described above), thereby reacting with the compound represented by the general formula (V)

(Wherein R ¹ , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above) and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

(Wherein, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative.
[17] (1) General formula (VI)

(Wherein m and n are as defined above), a compound represented by the general formula (IV)

(Wherein R ^2B has the same ^{meaning as} described above) to react with the compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IXB)

(Wherein, A, R ^2B , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n, and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative.
[18] General formula (V)

(Wherein R ¹ , m and n are each as defined above) by reacting with a carbon dioxide in the presence of an organic base, the compound represented by the general formula (I)

(Wherein R ¹ , m and n are as defined above) and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

(Wherein, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative.
[19] The organic base used for the reaction with carbon dioxide is 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non-5-ene. The production method according to any one of [14] to [18] above.

  [20] (1) General formula (VII)

(Wherein R ¹ , R ⁶ , m and n are as defined above), and a compound represented by the general formula (VIII) by reacting with urea in the presence of an acid catalyst.

(Wherein R ¹ , R ⁶ , m and n are as defined above),
(2) The resulting compound is then treated with a base to give a compound of general formula (I)

(Wherein R ¹ , m and n are as defined above) and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

(Wherein, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative.
[21] The production method according to any one of [14] to [20], wherein m is 1 and n is 2.

  According to the present invention, for example, a simple and efficient method for producing bicyclic pyrimidine derivatives useful for the treatment and / or prevention of various diseases involving T cells such as allergic diseases and autoimmune diseases, and synthetic intermediates thereof, Synthetic intermediates useful for the simple and efficient production of bicyclic pyrimidine derivatives are also provided.

In the definition of each group of general formulas (I), (IB), (III) to (V), (VB) and (VII) to (X)
Lower alkyl and lower alkyl of lower alkoxy, lower alkylsulfonyloxy, lower alkylsulfanyl, lower alkylsulfonyl and lower alkylsulfinyl include, for example, linear or branched alkyl having 1 to 10 carbon atoms. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, isooctyl, nonyl, decyl and the like.

Examples of cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Examples of the lower alkenyl include linear, branched or cyclic alkenyl having 2 to 8 carbon atoms, specifically vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, cyclopentenyl. , Cyclohexenyl, 2,6-octadienyl and the like.

Examples of lower alkynyl include linear or branched alkynyl having 2 to 8 carbon atoms, and specific examples include ethynyl, 1-propynyl, 2-propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like.
The aryl moiety of aryl and aryloxy, arylsulfonyloxy, arylsulfanyl, arylsulfinyl, arylsulfonyl and arylcarbonyl includes, for example, monocyclic, bicyclic or tricyclic aryl having 6 to 14 carbon atoms. Specific examples include phenyl, naphthyl, indenyl, anthranyl and the like.

Halogen represents each atom of fluorine, chlorine, bromine and iodine.
Examples of the alkylene part of aralkyl, alicyclic heterocyclic alkyl and aromatic heterocyclic alkyl include those obtained by removing one hydrogen atom from the groups exemplified in the lower alkyl. Examples of the aryl moiety of the aralkyl include, in addition to the groups exemplified in the aryl, bicyclic fused ring groups in which the monocyclic aryl and the cycloalkyl are condensed, such as indanyl, 1 2,3,4-tetrahydronaphthyl, 6,7,8,9-tetrahydro-5H-benzocycloheptyl and the like.

  Examples of the aromatic heterocyclic group part of the aromatic heterocyclic group and the aromatic heterocyclic alkyl include, for example, a 5-membered or 6-membered monocyclic fragrance containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. A heterocyclic heterocyclic group, a bicyclic or tricyclic condensed 3- to 8-membered ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Specifically, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzoimidazolyl, 2-oxobenzoimidazolyl, benzotriazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzodioxolyl, indazolyl, indolyl, isoindolyl, purinyl , Quinolyl, isoquinolyl, phthalazinyl, naphthylridinyl, quinoxalinyl, pyro Le, pyrazolyl, quinazolinyl, cinnolinyl, triazolyl, tetrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thienyl, furyl and the like.

  Examples of the alicyclic heterocyclic group part of the alicyclic heterocyclic group and the alicyclic heterocyclic alkyl include a 5-membered or 6-membered single atom containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. A cyclic alicyclic heterocyclic group, a bicyclic or tricyclic condensed 3- to 8-membered ring containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom A cyclic group, a spiro structure in which a 3- to 8-membered ring is bonded, and an alicyclic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom. Is pyrrolidinyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, pyrrolinyl, thiazolidinyl, oxazolidinyl, azotidinyl, piperidyl, piperidino, 4-oxopiperidino, 2-oxopiperazinyl, perhydroazepi , Perhydroazosinyl, piperazinyl, homopiperazinyl, homopiperidyl, homopiperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, pyranyl, tetrahydropyridyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydroisoquinolyl, octahydroquinolyl, Indolinyl, 1,4-dioxa-8-azaspiro [4.5] decan-8-yl and the like can be mentioned.

  Examples of the heterocyclic group formed together with the adjacent nitrogen atom include a 5-membered or 6-membered monocyclic heterocyclic group containing at least one nitrogen atom (the monocyclic heterocyclic group includes other A nitrogen atom, an oxygen atom or a sulfur atom), a bicyclic or tricyclic condensed 3- to 8-membered ring containing at least one nitrogen atom (the condensed group). The cyclic heterocyclic group may contain other nitrogen atom, oxygen atom or sulfur atom), and specifically, tetrahydropyridyl, indolinyl, isoindolinyl, pyrrolidinyl, thiazolidinyl, oxazolidinyl, piperidino, homopiperidino , Piperazinyl, homopiperazinyl, morpholino, thiomorpholino, perhydroazepinyl, perhydroazosinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, octa And hydroquinolyl.

  Substituents (A) in the substituted lower alkyl are the same or different, for example, cycloalkyl, lower alkanoyl, substituted lower alkanoyl, lower alkoxy, substituted lower alkoxy, aryloxy, substituted aryloxy, aralkyloxy having 1 to 3 substituents. , Substituted aralkyloxy, mono- or di-lower alkylamino, substituted mono- or di-lower alkylamino, lower alkanoyloxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoylamino, mono- or di-lower alkylaminocarbonyl, mono- or di-lower alkyl Aminocarbonyloxy, halogen, cyano, nitro, hydroxy, carboxy, carbamoyl, amino, sulfanyl, oxo, formyl, lower alkylsulfanyl, lower alkyls Honiru, lower alkylsulfinyl, and the like.

Examples of the substituent (a) in the substituted lower alkanoyl and substituted lower alkoxy listed as examples of the substituent (A) are the same or different and include, for example, a halogen having 1 to 3 substituents.
Examples of the substituent (b) in the substituted aryloxy and the substituted aralkyloxy given as examples of the substituent (A) are the same or different, for example, cycloalkyl, lower alkanoyl, substituted lower alkanoyl having 1 to 3 substituents [the substituted The substituent in the lower alkanoyl has the same meaning as the substituent (a)], lower alkoxy, substituted lower alkoxy [the substituent in the substituted lower alkoxy has the same meaning as the substituent (a)], aryloxy, Aralkyloxy, mono- or di-lower alkylamino, substituted mono- or di-lower alkylamino [the substituent in the lower alkyl part of the substituted mono- or di-lower alkylamino has the same meaning as the substituent (c) described later], lower alkanoyloxy Lower alkoxycarbonyl, halogen, cyano, nitro, hydroxy, carboxy, Ruvamoyl, sulfanyl, amino, lower alkyl, substituted lower alkyl [the substituent in the substituted lower alkyl has the same meaning as the substituent (a)], aryl, substituted aryl [the substituent in the substituted aryl is the substituent synonymous with (a)], lower alkylsulfanyl, lower alkylsulfonyl, lower alkylsulfinyl, aromatic heterocyclic group, alicyclic heterocyclic group and the like.

Examples of the substituent (c) in the lower alkyl part of the substituted mono- or di-lower alkylamino exemplified in the substituent (A) are the same or different, for example, halogen, hydroxy, carboxy, lower alkoxy having 1 to 3 substituents. Examples include carbonyl and the like.
Aryl, aryloxy and aryl moiety of aralkyloxy, cycloalkyl, halogen, aromatic heterocyclic group, exemplified in the substituent (A), the substituent (a), the substituent (b) and the substituent (c), The alicyclic heterocyclic group and the lower alkyl part of lower alkyl, lower alkanoyl, lower alkoxy, lower alkanoyloxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoylamino, lower alkylsulfanyl, lower alkylsulfonyl and lower alkylsulfinyl are: Each of these is synonymous with the aryl, cycloalkyl, halogen, aromatic heterocyclic group, alicyclic heterocyclic group and lower alkyl, and the alkylene part of aralkyloxy is, for example, a hydrogen atom from the groups exemplified in the lower alkyl. The one without one is given. The lower alkyl part of mono- or di-lower alkylamino, mono- or di-lower alkylaminocarbonyl and mono- or di-lower alkylaminocarbonyloxy has the same meaning as the aforementioned lower alkyl, di-lower alkylamino, di-lower alkylaminocarbonyl and di-lower alkyl. The two lower alkyl moieties of alkylaminocarbonyloxy may be the same or different.

  Substituted aryl, substituted arylcarbonyl, substituted aralkyl, substituted cycloalkyl, substituted lower alkenyl, substituted lower alkynyl, substituted aromatic heterocyclic group, substituted alicyclic heterocyclic group, substituted aromatic heterocyclic alkyl, substituted alicyclic heterocyclic ring The substituent (B) in the substituted heterocyclic group formed together with alkyl and an adjacent nitrogen atom includes, for example, lower alkyl, substituted lower alkyl, in addition to the groups exemplified in the substituent (A). Lower alkenyl, aryl, substituted aryl, aralkyl, substituted aralkyl, aromatic heterocyclic group, substituted aromatic heterocyclic group, alicyclic heterocyclic group, substituted alicyclic heterocyclic group, aromatic heterocyclic alkyl, substituted aromatic Heterocyclic alkyl, alicyclic heterocyclic alkyl, substituted alicyclic heterocyclic alkyl and the like can be mentioned.

Substituents in the substituted aryl, substituted aralkyl, substituted aromatic heterocyclic group, substituted alicyclic heterocyclic group, substituted aromatic heterocyclic alkyl, and substituted alicyclic heterocyclic alkyl listed as examples of the substituent (B) (d ) Are the same or different and include, for example, lower alkyl, lower alkoxy, halogen and the like having 1 to 3 substituents.
Examples of the substituent (e) in the substituted lower alkyl exemplified in the substituent (B) are the same or different, and examples thereof include halogen, hydroxy, lower alkoxy, cyano and the like having 1 to 3 substituents.

  Lower alkyl part of lower alkyl and lower alkoxy, lower alkenyl, halogen, aryl, aromatic heterocyclic group, and aromatic heterocyclic alkyl listed as examples of substituent (B), substituent (d) and substituent (e) Aromatic heterocyclic group moiety, alicyclic heterocyclic group and alicyclic heterocyclic group part of alicyclic heterocyclic alkyl, aralkyl, aromatic heterocyclic alkyl and alkylene part of alicyclic heterocyclic alkyl and aralkyl The aryl moiety is synonymous with the lower alkyl, lower alkenyl, halogen, aryl, aromatic heterocyclic group, alicyclic heterocyclic group, aralkyl alkylene moiety and aralkyl aryl moiety, respectively.

  Substituents in substituted lower alkoxy, substituted lower alkylsulfonyloxy, substituted lower alkylsulfanyl, substituted lower alkylsulfinyl, substituted lower alkylsulfonyl, substituted aryloxy, substituted arylsulfonyloxy, substituted arylsulfanyl, substituted arylsulfinyl and substituted arylsulfonyl (C Examples of () include the groups exemplified in the substituent (d).

  Examples of the salt of compound (I) include inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate, benzenesulfonate, benzoate, citrate, fumarate, Gluconates, lactates, maleates, malates, oxalates, methanesulfonates, acid addition salts such as organic acid salts such as tartrate, alkali metal salts such as sodium and potassium salts, magnesium salts , Alkaline earth metal salts such as calcium salts, metal salts such as aluminum salts and zinc salts, ammonium salts such as ammonium and tetramethylammonium, organic amine addition salts such as morpholine addition salts and piperidine addition salts, glycine addition salts, phenylalanine Examples include addition salts, lysine addition salts, aspartic acid addition salts, amino acid addition salts such as glutamic acid addition salts, and the like.

Below, the example of the manufacturing method of compound (I) is demonstrated.
Production method 1:

(Wherein R ¹ , R ^2B , X, m and n are as defined above)
[Step 1]
Compound (V) can be obtained by treating compound (II) with a base in an inert solvent and then reacting with compound (III) or compound (IV).
Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, diethylaniline, pyridine. Organic bases such as lutidine, N-methylmorpholine, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, lithium hydroxide, water Metal hydroxides such as sodium oxide, potassium hydroxide and calcium hydroxide, metal hydrides such as sodium hydride and calcium hydride, metals such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide Amides etc. Preferably, a metal alkoxide, more preferably potassium tert-butoxide is used. The base is usually used in an amount of 1 to 50 equivalents, preferably 1.5 to 5 equivalents, relative to compound (II).

  Examples of the inert solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, dimethyl sulfoxide, Non-aromatic organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, diethyl ether, cyclopentyl Methyl ether, 1,2-dimethoxyethane, ethers such as diethylene glycol dimethyl ether, esters such as methyl acetate, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropyl alcohol, etc. Alcohol, water and the like, may employ the solvents alone or as a mixture. The solvent is usually used in an amount of 1 to 100 times, preferably 5 to 20 times the weight of the compound (II).

The treatment with a base is usually performed at a temperature between −20 ° C. and the boiling point of the solvent used, preferably at a temperature between 60 ° C. and 100 ° C. for 5 minutes to 24 hours.
In compound (III), X having a preferred embodiment depending on R ¹ is used, and as compound (III), among them, acid halide, carbamoyl halide or X in which X is a fluorine atom, chlorine atom, bromine atom or iodine atom A monocarbonate ester halide, an acid anhydride or dicarbonate in which X is —OCOR ⁵ (wherein R ⁵ is as defined above) are preferred. Among them, for example, acid halides such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, cyclopropanecarboxylic acid chloride, benzoyl chloride, acid anhydrides such as acetic anhydride, propionic anhydride, butanoic anhydride, methyl chlorocarbonate, chloro Monocarbonate esters such as ethyl carbonate, propyl chlorocarbonate and phenyl chlorocarbonate, carbamoyl halides such as N, N-dimethylcarbamoyl chloride, N, N-diethylcarbamoyl chloride, piperidinocarbamoyl chloride, dimethyl dicarbonate, di tert- Dicarbonate such as butyl dicarbonate is preferred. Examples of the compound (IV) include methyl isocyanate, ethyl isocyanate, propyl isocyanate, benzyl isocyanate, and phenyl isocyanate.

Compound (III) or compound (IV) is usually used in an amount of 0.9 to 50 equivalents, preferably 0.9 to 3 equivalents, relative to compound (II).
The reaction with compound (III) or compound (IV) is usually carried out at a temperature between −50 ° C. and the boiling point of the solvent used, preferably at a temperature between −10 ° C. and 30 ° C. for 5 minutes to 24 hours.
In addition, as a raw material compound (II), (III), and (IV), a commercial item can be used as it is or refine | purified.
[Step 2]
Compound (V) can be obtained by reacting compound (VI) with compound (III) or compound (IV) in an inert solvent in the presence or absence of a base.

  Examples of the inert solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, dimethyl sulfoxide, Non-aromatic organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, diethyl ether, cyclopentyl Methyl ether, 1,2-dimethoxyethane, ethers such as diethylene glycol dimethyl ether, esters such as methyl acetate, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropyl alcohol, etc. Alcohol, water and the like, may employ the solvents alone or as a mixture. The solvent is usually used in an amount of 1 to 100 times, preferably 5 to 20 times the weight of the compound (II).

  A base can be added as needed for the purpose of promoting the reaction. Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, diethylaniline, pyridine. Organic bases such as lutidine, N-methylmorpholine, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, lithium hydroxide, water Metal hydroxides such as sodium oxide, potassium hydroxide and calcium hydroxide, metal hydrides such as sodium hydride and calcium hydride, metals such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide Amides etc. Agerare, preferably organic bases, more preferably triethylamine is used. The base is generally used in an amount of 0.1 to 50 equivalents, preferably 1 to 5 equivalents, relative to compound (VI).

Compound (III) or compound (IV) is generally used in an amount of 1 to 50 equivalents, preferably 1 to 3 equivalents, relative to compound (II).
The reaction is usually carried out at a temperature between −50 ° C. and the boiling point of the solvent used, preferably between −10 ° C. and 30 ° C., and is completed in 5 minutes to 24 hours.
In addition, as a raw material compound (III) and (IV), a commercial item can be used as it is or refine | purified. The starting compound (VI) can be obtained according to the method described in Journal of the Chemical Society (C), Vol. 41, p. 1558 (1967). .
[Step 3]
Compound (I) can be obtained by reacting compound (V) and carbon dioxide in the presence of an organic base, without a solvent or in an inert solvent.

  Examples of the organic base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, diethylaniline, Examples thereof include organic bases such as pyridine, lutidine, N-methylmorpholine, and preferably 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non- 5-ene is used. The organic base is generally used in an amount of 1 to 20 equivalents, preferably 2 to 7 equivalents, relative to compound (V).

There is no restriction | limiting in particular in the usage-amount of the carbon dioxide used for reaction, Reaction can be performed under a normal pressure or pressurization. In the reaction, an inert gas such as nitrogen or argon may coexist, and the partial pressure of carbon dioxide in that case is preferably 0.01 MPa to 20 MPa, more preferably 0.1 MPa to 5 MPa. .
The reaction can be performed without a solvent, but a solvent inert to the reaction can be added as necessary. Examples of the inert solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, dimethyl sulfoxide, Non-aromatic organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, diethyl ether, cyclopentyl Methyl ether, 1,2-dimethoxyethane, ethers such as diethylene glycol dimethyl ether, esters such as methyl acetate, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropyl alcohol, etc. Alcohol, water and the like, may employ the solvents alone or as a mixture. The solvent is usually used in an amount of 0.01 to 50 times the weight of the compound (V).

The reaction is usually carried out at a temperature between 0 ° C. and the boiling point of the organic base or solvent used, preferably at a temperature between 60 ° C. and 130 ° C. for 5 minutes to 24 hours.
Carbon dioxide can be supplied using a commercially available gas cylinder, liquefied carbon dioxide cylinder, dry ice or the like.
Production method 2:
Compound (I) can also be produced by the following steps.

(Wherein R ¹ , R ⁶ , m and n are as defined above)
[Step 4]
Compound (VIII) can be obtained by reacting compound (VII) with urea in the presence of an acid catalyst in an inert solvent.
Examples of the acid catalyst include organic acids such as acetic acid, chloroacetic acid, dichloroacetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and p-toluenesulfonic acid, and inorganic acids such as hydrochloric acid, sulfuric acid, and phosphoric acid. More preferably, hydrochloric acid or sulfuric acid is used. The acid is generally used in an amount of 0.01 to 10 equivalents, preferably 0.1 to 1 equivalents, relative to compound (VII).

Urea is usually used in an amount of 1 to 50 equivalents, preferably 3 to 10 equivalents, relative to compound (VII).
Examples of the inert solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, dimethyl sulfoxide, Non-aromatic organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, dioxane, tetrahydrofuran, diethyl ether, cyclopentyl Methyl ether, 1,2-dimethoxyethane, ethers such as diethylene glycol dimethyl ether, esters such as methyl acetate, ethyl acetate, isopropyl acetate, methanol, ethanol, n-propanol, isopropyl alcohol, etc. Alcohol, water and the like, may employ the solvents alone or as a mixture. The solvent is usually used in an amount of 1 to 100 times, preferably 5 to 20 times the weight of the compound (VII).

The reaction is usually carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably at a temperature between 50 ° C. and 100 ° C. for 5 minutes to 24 hours.
The raw material compound (VII) is disclosed in, for example, JP 2002-143610 A, Journal of the American Chemical Society, Vol. 68, page 1049 (1946). It can be obtained by the method described or a method analogous thereto. As urea and an acid catalyst, commercially available products can be used as they are or after purification.
[Step 5]
Compound (I) can be obtained by treating compound (VIII) with a base in an inert solvent.

  Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, diethylaniline, pyridine. Organic bases such as lutidine, N-methylmorpholine, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, lithium hydroxide, water Metal hydroxides such as sodium oxide, potassium hydroxide and calcium hydroxide, metal hydrides such as sodium hydride and calcium hydride, metals such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide Amides etc. Agerare, preferably carbonate, more preferably potassium carbonate is used. The base is generally used in 1 to 20 equivalents, preferably 1 to 5 equivalents, relative to compound (VIII).

  Examples of the inert solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, dimethyl sulfoxide, Non-aromatic organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, ethers such as dioxane, tetrahydrofuran, diethyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, methyl acetate, acetic acid Examples include esters such as ethyl and isopropyl acetate, alcohols such as methanol, ethanol, n-propanol and isopropyl alcohol, water, and the like. These solvents can be used alone or in combination. Can. The solvent is usually used in an amount of 1 to 100 times, preferably 5 to 30 times the weight of the compound (VIII).

The reaction is usually carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably at a temperature between 50 ° C. and 100 ° C. for 5 minutes to 24 hours.
Production method 3:
Various diseases involving T cells such as allergic diseases and autoimmune diseases disclosed in International Publication No. 03/104230 pamphlet from compound (I) obtained by any of the above production methods, for example, by the following steps A bicyclic pyrimidine derivative [compound (IX)] useful for the treatment and / or prevention of can be prepared.

(In the formula, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are each as defined above)
[Step 6]
Compound (XI) can be obtained by reacting compound (I) with a chlorinating agent in an inert solvent or without a solvent in the presence or absence of a base.
Examples of chlorinating agents include thionyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, triphenylphosphine dichloride, (chloromethylene) dimethylammonium chloride, phenylphosphonic dichloride, phenylphosphoric dichloride, cyanuric chloride, and the like. Preferably, phosphorus oxychloride is used. The chlorinating agent is usually used in an amount of 1 to 100 equivalents, preferably 2 to 10 equivalents, relative to compound (I).

  Examples of the base include triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, diethylaniline, pyridine. Organic bases such as lutidine, N-methylmorpholine, metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, lithium hydroxide, water Metal hydroxides such as sodium oxide, potassium hydroxide and calcium hydroxide, metal hydrides such as sodium hydride and calcium hydride, metals such as lithium diisopropylamide, lithium bis (trimethylsilyl) amide and potassium bis (trimethylsilyl) amide Amides etc. Agerare, preferably organic bases, more preferably diisopropylethylamine or diethylaniline is used. The base is generally used in an amount of 1-50 equivalents, preferably 2-5 equivalents, relative to compound (VI).

  The reaction can be performed without a solvent, but a solvent inert to the reaction can be added as necessary. Examples of the inert solvent include aliphatic hydrocarbons such as pentane, hexane, heptane, and cyclohexane, aromatic hydrocarbons such as toluene and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane, acetonitrile, dimethyl sulfoxide, Non-aromatic organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, ethers such as dioxane, tetrahydrofuran, diethyl ether, cyclopentylmethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, methyl acetate, acetic acid Examples include esters such as ethyl and isopropyl acetate, alcohols such as methanol, ethanol, n-propanol, and isopropyl alcohol. These solvents may be used alone or in combination. Kill. The solvent is usually used in an amount of 1 to 100 times, preferably 5 to 30 times the weight of the compound (I).

The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably at a temperature between 40 ° C. and 100 ° C. for 5 minutes to 24 hours.
[Step 7 and Step 8]
Compound (XII) and compound (IX) can be obtained from compound (XI) by the method described in WO03 / 104230 pamphlet or a method analogous thereto, respectively.

The intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. be able to. The intermediate can be subjected to the next reaction without any particular purification.
Some compounds (I) may have stereoisomers such as geometrical isomers, tautomers, optical isomers, rotational isomers, etc., but the present invention includes all such possibilities. Isomers and mixtures thereof.

When it is desired to obtain a salt of compound (I), it can be purified as it is when compound (I) is obtained in the form of a salt. When it is obtained in a free form, compound (I) can be obtained in an appropriate solvent. It may be dissolved or suspended and isolated and purified by adding acid or base.
Compound (I) and salts thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

  Specific examples of the compound (I) obtained by the present invention are shown in Table 1.

  Below, the aspect of this invention is demonstrated with an Example and a reference example.

Synthesis of 6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ia) (Step 1) 4-amino- 3-cyano-1-cyclopropylcarbonyl-1,2,5,6-tetrahydropyridine (compound Va)
Bis (2-cyanoethyl) amine (Compound IIa: 20.0 g, 162 mmol) and potassium tert-butoxide (36.2 g, 323 mmol) were suspended in toluene (400 mL) and stirred at 90 ° C. for 1 hour. After adding water (200 mL) to the reaction mixture, cyclopropanecarboxylic acid chloride (Compound IIIa: 15.0 mL, 165 mmol) was added under ice cooling. The reaction mixture was stirred for 1 hour under ice-cooling, and then stirred at room temperature for 1 hour. Ethyl acetate (400 mL) and methanol (200 mL) were added to the reaction mixture for liquid separation, and the organic layer was washed with a saturated aqueous sodium chloride solution (200 mL) and concentrated under reduced pressure. Toluene (50 mL) and methanol (10 mL) were added to the obtained residue, and the mixture was concentrated under reduced pressure. Toluene (200 mL) was added, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with toluene (50 mL), and dried under reduced pressure to obtain compound Va (26.2 g, yield 80%) as white crystals.

Melting point 183 ℃
¹ H NMR (DMSO-d ₆ , 300 MHz) (inside brackets are chemical shift values of minor rotational isomers, isomer ratio is 6: 4) δ (ppm) 6.24 (br s, 2H), 3.93 [4.21] (Respectively br s, total 2H), 3.72 [3.50] (respectively br s, total 2H), 2.29 [2.15] (respectively br s, total 2H), 1.98 (m, 1H), 0.72-0.66 (m, 4H) .
MS (ESI (+)) m / z 214 (M + Na) ⁺ , 192 (M + H) ⁺
HR-MS calculated (C ₁₀ H ₁₃ N ₃ ONa): 214.0956 (M + Na) ⁺ , measured value: 214.0958 (+0.2 mDa).

(Step 2) 6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ia)
The compound Va (24.0 g, 126 mmol) obtained in Step 1 is dissolved in 1,8-diazabicyclo [5.4.0] undec-7-ene (75.0 mL, 502 mmol), and the inside of the reaction vessel is dioxide. The atmosphere was replaced with a carbon atmosphere. The reaction mixture was stirred at 120 ° C. for 9 hours under normal pressure, and then acetic acid (96 mL) and ethyl acetate (480 mL) were added under ice cooling, followed by stirring for 3 hours. The precipitated crystals were collected by filtration, washed with ethyl acetate (40 mL), and dried under reduced pressure to obtain Compound Ia (26.4 g, yield 87%) as white crystals.

Melting point 287 ℃
¹ H NMR (DMSO-d ₆ , 300 MHz) ([] is the chemical shift value of minor rotational isomer, isomer ratio is 11: 9) δ (ppm) 11.03 (br s, 1H), 10.09 (br s , 1H), 4.06 [4.30] (respectively br s, total 2H), 3.84 [3.64] (respectively br s, total 2H), 2.49 [2.36] (respectively br s, total 2H), 2.02 [1.94] (respectively br s, total 1H), 0.80-0.65 (m, 4H).
MS (ESI (+)) m / z 236 (M + H) ⁺
HR-MS calculated (C ₁₁ H ₁₄ N ₃ O ₃ ): 236.1035 (M + H) ⁺ , measured: 236.1025 (-1.0 mDa).

Synthesis of 6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ia) (Step 1) 4-amino- 3-cyano-1-cyclopropylcarbonyl-1,2,5,6-tetrahydropyridine (compound Va)
4-Amino-3-cyano-1,2,5,6-tetrahydropyridine (Compound VIa: 158 mg, 1.28 mmol) obtained in Reference Example 1 was dissolved in N, N-dimethylformamide (2.0 mL). , Triethylamine (0.200 mL, 1.44 mmol) and cyclopropanecarboxylic acid chloride (Compound IIIa: 0.120 mL, 1.32 mmol) were added and stirred at room temperature for 1 hour. Ethyl acetate (2.0 mL) was added to the reaction mixture, and the precipitated solid was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 to 1/2 to 1/3) to give compound Va (120 mg, yield 49% ) Was obtained as white crystals.

(Step 2) 6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ia)
Compound Va (100 mg, 0.52 mmol) obtained in Step 1 was dissolved in 1,8-diazabicyclo [5.4.0] undec-7-ene (0.48 mL, 3.21 mmol). The obtained solution was sealed in an autoclave together with dry ice and stirred at 60 ° C. and 1 MPa for 5 hours. Ethyl acetate (2 mL) and methanol (0.2 mL) were added to the reaction mixture under ice cooling, and the mixture was stirred for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystals were suspended in a mixed solvent of acetic acid (0.2 mL) and ethyl acetate (1.0 mL), stirred at 60 ° C. for 1 hour, and further stirred under ice cooling for 3 hours. The crystals were collected by filtration, washed with ethyl acetate (0.2 mL), and dried under reduced pressure to give Compound Ia (91 mg, 75% yield) as white crystals.

Synthesis of 6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ia) (Step 1) 1-cyclopropyl Carbonyl-4-ureido-1,2,5,6-tetrahydropyridine-3-carboxylate (compound VIIIa)
Ethyl 1-cyclopropylcarbonyl-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate (Compound VIIa) (125 mg, 0.522 mmol) obtained in Reference Example 2 and urea (157 mg, 2.61 mmol) and concentrated hydrochloric acid (0.030 mL) were dissolved in methanol (1.0 mL) and stirred at reflux for 10 hours. Water (2.0 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration, washed with water (2.0 mL), and dried under reduced pressure to give compound VIIIa (108 mg, yield 74%) as white crystals.

Melting point 206-207 ° C (decomposition)
¹ H NMR (DMSO-d ₆ , 300 MHz) ([] is the chemical shift value of minor rotational isomer, isomer ratio is 2: 1) δ (ppm) 10.41 (br s, 1H), 6.71 (br s , 1H), 4.15 (q, J = 7.0 Hz, 2H), 4.14 [4.34] (respectively br s, total 2H), 3.71 [3.48] (respectively br s, total 2H), 3.02 [2.89] (respectively br s , Total 2H), 2.00 [1.90] (br s, total 1H), 1.22 (t, J = 7.0 Hz, 3H), 0.80-0.64 (m, 4H).
MS (ESI (+)) m / z 304 (M + Na) ⁺
HR-MS calculated (C ₁₃ H ₁₉ N ₃ O ₄ Na): 304.1273 (M + Na) ⁺ , measured value: 304.1273 (0.0 mDa).

(Step 2) 6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ia)
Compound VIIIa (100 mg, 0.355 mmol) and potassium carbonate (98 mg, 0.709 mmol) were dissolved in methanol (2.0 mL) and stirred under reflux for 1 hour. Trimethylamine hydrochloride (136 mg, 1.42 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration, washed with ethanol (2.0 mL), and dried under reduced pressure. The obtained crystals were suspended in a mixed solvent of methanol (1.0 mL) and water (1.0 mL), and stirred at room temperature for 2 hours. The crystals were collected by filtration, washed with water (2.0 mL), and dried under reduced pressure to obtain Compound Ia (54.0 mg, yield 65%) as white crystals.

Synthesis of 6-ethylaminocarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ib) (Step 1) 4-amino- 3-Cyano-1-ethylaminocarbonyl-1,2,5,6-tetrahydropyridine (Compound Vb)
Bis (2-cyanoethyl) amine (Compound IIa: 200 mg, 1.62 mmol) and potassium tert-butoxide (363 mg, 3.23 mmol) were suspended in toluene (2.0 mL) and stirred at 90 ° C. for 30 minutes. Under ice-cooling, water (2.0 mL) and ethyl acetate (2.0 mL) were added to the reaction mixture and stirred for 20 minutes, and then ethyl isocyanate (Compound IVb: 0.130 mL, 1.64 mmol) was added. The reaction mixture was stirred for 1 hour under ice-cooling, and then stirred at room temperature for 1 hour. Ethyl acetate (5.0 mL) and methanol (2.0 mL) were added to the reaction mixture for liquid separation, and the organic layer was washed with saturated aqueous sodium chloride solution (2.0 mL) and concentrated under reduced pressure. Toluene (2.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with toluene (1.0 mL), and dried under reduced pressure to obtain compound Vb (279 mg, yield 88%) as white crystals.

Melting point 196-197 ℃ (decomposition)
¹ H NMR (DMSO-d ₆ , 300 MHz) δ (ppm) 6.52 (t, J = 1.7 Hz, 1H), 6.13 (br s, 2H), 3.80 (s, 2H), 3.36 (t, J = 5.9 Hz, 2H), 3.03 (tq, J = 1.7, 7.2 Hz, 2H), 2.12 (t, J = 5.9 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H).
MS (ESI (+)) m / z 217 (M + Na) ⁺ , 195 (M + H) ⁺ , 124
HR-MS calculated (C ₉ H ₁₅ N ₄ O): 195.1246 (M + H) ⁺ , measured value: 195.1252 (+0.6 mDa).

(Step 2) 6-ethylaminocarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ib)
Compound Vb (200 mg, 1.03 mmol) obtained in step 1 was dissolved in 1,8-diazabicyclo [5.4.0] undec-7-ene (0.770 mL, 5.14 mmol), and the inside of the reaction vessel was carbon dioxide. With three replacements. After the reaction mixture was stirred at 120 ° C. for 6 hours, acetic acid (0.80 mL) and ethyl acetate (4.0 mL) were added at room temperature, stirred at room temperature for 2 hours, and further stirred for 1 hour under ice cooling. The precipitated crystals were collected by filtration, washed with ethyl acetate (1.0 mL), and dried under reduced pressure to obtain Compound Ib (105 mg, 43% yield) as white crystals.

Melting point 256-257 ℃ (decomposition)
¹ H NMR (DMSO-d ₆ , 300 MHz) δ (ppm) 11.0 (br s, 1H), 10.8 (br s, 1H), 6.63 (t, J = 1.7 Hz, 1H), 3.93 (s, 2H) , 3.46 (t, J = 5.6 Hz, 2H), 3.04 (tq, J = 1.8, 7.2 Hz, 2H), 2.34 (t, J = 5.6 Hz, 2H), 0.99 (t, J = 7.2 Hz, 3H) .
MS (ESI (+)) m / z 261 (M + Na) ⁺ , 239 (M + H) ⁺ , 168
HR-MS calculated (C ₁₀ H ₁₅ N ₄ O ₃ ): 239.1144 (M + H) ⁺ , measured: 239.1141 (-0.3 mDa).

Synthesis of 6- (1,1-dimethylethoxycarbonyl) -5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (compound Ic) (process) 1) 4-Amino-3-cyano-1- (1,1-dimethylethoxycarbonyl) -1,2,5,6-tetrahydropyridine (Compound Vc)
Bis (2-cyanoethyl) amine (Compound IIa: 200 mg, 1.62 mmol) and potassium tert-butoxide (363 mg, 3.23 mmol) were added to toluene (4.00 mL), and the mixture was stirred at 90 ° C. for 30 minutes. Under ice cooling, water (2.00 mL) and ditert-butyl dicarbonate (Compound IIIc: 0.370 mL, 1.61 mmol) were added, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (5.0 mL) was added to the reaction mixture and the phases were separated, and the organic layer was washed with saturated aqueous sodium chloride solution (2.0 mL) and concentrated under reduced pressure. Toluene (2.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with toluene (1.0 mL), and dried under reduced pressure to obtain compound Vc (233 mg, yield 64%) as white crystals.

Melting point 132-133 ℃
¹ H NMR (CDCl ₃ , 300 MHz) δ (ppm) 4.39 (br s, 2H), 3.99 (s, 2H), 3.55 (t, J = 5.8 Hz, 2H), 2.25 (t, J = 5.8 Hz, 2H), 1.47 (s, 9H).
MS (ESI (+)) m / z 246 (M + Na) ⁺ , 224 (M + H) ⁺ , 168, 124
HR-MS calculated (C ₁₁ H ₁₈ N ₃ O ₂ ): 224.1399 (M + H) ⁺ , measured value: 224.1408 (+0.9 mDa).

(Step 2) 6- (1,1-dimethylethoxycarbonyl) -5,6,7,8-tetrahydro-1H-pyrido [4,3-d] pyrimidine-2,4-dione (Compound Ic)
Compound Vc (200 mg, 0.896 mmol) obtained in Step 1 was dissolved in 1,8-diazabicyclo [5.4.0] undec-7-ene (0.670 mL, 4.48 mmol), and the reaction system was carbon dioxide. With three replacements. The reaction mixture was stirred at 100 ° C. for 6 hr, acetic acid (0.80 mL) and ethyl acetate (4.0 mL) were added at room temperature, and the mixture was stirred under ice-cooling for 2 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate (1.0 mL), and dried under reduced pressure to obtain Compound Ic (139 mg, yield 58%) as white crystals.

Melting point 243-244 ° C (decomposition)
¹ H NMR (DMSO-d ₆ , 300 MHz) δ (ppm) 3.95 (s, 2H), 3.49 (t, J = 5.8 Hz, 2H), 2.38 (t, J = 5.8 Hz, 2H), 1.40 (s , 9H).
MS (ESI (+)) m / z 290 (M + Na) ⁺ , 268 (M + H) ⁺ , 212, 168
HR-MS calculated (C ₁₂ H ₁₇ N ₃ O ₄ Na): 290.1117 (M + Na) ⁺ , found: 290.1114 (-0.3 mDa).

Synthesis of 6-ethoxycarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Id) (Step 1) 4-amino-3 -Cyano-1-ethoxycarbonyl-1,2,5,6-tetrahydropyridine (Compound Vd)
Bis (2-cyanoethyl) amine (Compound IIa: 200 mg, 1.62 mmol) and potassium tert-butoxide (363 mg, 3.23 mmol) were suspended in toluene (2.0 mL) and stirred at 90 ° C. for 1 hour. Under ice-cooling, water (2.0 mL), ethyl acetate (2.0 mL) and ethyl chlorocarbonate (Compound IIId: 0.130 mL, 1.62 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 3 hours. Ethyl acetate (5.0 mL) was added to the reaction mixture and the phases were separated, and the organic layer was washed with saturated aqueous sodium chloride solution (2.0 mL) and concentrated under reduced pressure. Toluene (2.0 mL) was added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with toluene (1.0 mL), and dried under reduced pressure to give compound Vd (279 mg, yield 88%) as white crystals.

Melting point 134-135 ℃
¹ H NMR (CDCl ₃ , 300 MHz) δ (ppm) 4.42 (br s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.05 (s, 2H), 3.60 (t, J = 5.9 Hz, 2H), 2.27 (t, J = 5.9 Hz, 2H), 1.28 (t, J = 7.2 Hz, 3H).
MS (ESI (+)) m / z 218 (M + Na) ⁺ , 196 (M + H) ⁺
HR-MS calculated (C ₉ H ₁₄ N ₃ O ₂ ): 196.1086 (M + H) ⁺ , measured value: 196.1082 (-0.4 mDa).

(Step 2) 6-Ethoxycarbonyl-5,6,7,8-tetrahydro-1H-pyrido [4,3-d] -pyrimidine-2,4-dione (Compound Id)
Compound Vd (180 mg, 0.922 mmol) obtained in step 1 was dissolved in 1,8-diazabicyclo [5.4.0] undec-7-ene (0.690 mL, 4.61 mmol), and the inside of the reaction vessel was carbon dioxide. With three replacements. The reaction mixture was stirred at 100 ° C. for 8 hr, acetic acid (0.60 mL) and ethyl acetate (4.0 mL) were added at room temperature, and the mixture was stirred under ice-cooling for 2 hr. The precipitated crystals were collected by filtration, washed with ethyl acetate (1.0 mL), and dried under reduced pressure to obtain Compound Id (176 mg, yield 80%) as white crystals.

Melting point 282-283 ℃ (decomposition)
¹ H NMR (DMSO-d ₆ , 300 MHz) δ (ppm) 4.06 (q, J = 7.2 Hz, 2H), 4.01 (s, 2H), 3.55 (t, J = 5.6 Hz, 2H), 2.41 (t , J = 5.6 Hz, 2H), 1.19 (t, J = 7.2 Hz, 3H).
MS (ESI (+)) m / z 262 (M + Na) ⁺ , 240 (M + H) ⁺
HR-MS calculated (C ₁₀ H ₁₄ N ₃ O ₄ ): 240.0984 (M + H) ⁺ , measured value: 240.0988 (+0.4 mDa).

Reference Example 1: Synthesis of 4-amino-3-cyano-1,2,5,6-tetrahydropyridine (Compound VIa) Bis (2-cyanoethyl) amine (Compound IIa: 1.00 g, 8.12 mmol) and potassium tert-butoxide (1.82 g, 16.2 mmol) was suspended in toluene (20 mL) and stirred at 90 ° C. for 1 hour. Water (5.0 mL), methanol (2.0 mL) and ethyl acetate (10 mL) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The organic layer was separated, and the crystals precipitated in the aqueous layer were collected by filtration, washed with water (2.0 mL), and dried under reduced pressure to give Compound VIa (624 mg, yield 62%) as white crystals. Got as.

Melting point 175-176 ° C (decomposition)
¹ H NMR (DMSO-d ₆ , 300 MHz) δ (ppm) 5.88 (br s, 2H), 3.18 (s, 2H), 2.72 (t, J = 5.9 Hz, 2H), 2.00 (t, J = 5.9 Hz, 2H).
MS (ESI (+)) m / z 124 (M + H) ⁺
HR-MS calculated (C ₆ H ₁₀ N ₃ ): 124.0875 (M + H) ⁺ , measured value: 124.0878 (+0.3 mDa).

Reference Example 2: Synthesis of ethyl 1-cyclopropylcarbonyl-4-hydroxy-1,2,5,6-tetrahydropyridine-3-carboxylate (Compound VIIa) N, N-bis (2-ethoxycarbonylethyl) cyclopropane Carboxylic acid amide (200 mg, 0.700 mmol) was dissolved in tetrahydrofuran (1.0 mL). Under ice cooling, a 1.0 mol / L tetrahydrofuran solution (1.40 mL, 1.40 mmol) of lithium hexamethyldisilazane was added to the mixture, and the mixture was stirred for 1 hour under ice cooling. Ethyl acetate (10 mL) and water (2.0 mL) were added to the reaction mixture, and then the pH value of the aqueous layer was adjusted to 1 to 2 with 1 mol / L hydrochloric acid. After separating the reaction mixture, the organic layer was washed successively with a saturated aqueous ammonium chloride solution (2.0 mL) and a saturated aqueous sodium chloride solution (2.0 mL), and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (silica gel 10 g, hexane / ethyl acetate = 10 / 1-5 / 1-3 / 1) to give compound VIIa (126 mg, 75% yield) as a colorless oil Obtained as a thing.

¹ H NMR (CDCl ₃ , 300 MHz) ([] is the chemical shift value of minor rotational isomer, isomer ratio is 11: 9) δ (ppm) 12.04 (br s, 1H), 4.38-4.17 (m, 4H), 3.83-3.70 (m, 2H), 2.36 [2.45] (respectively br s, total 2H), 1.76 (m, 1H), 1.28 [1.26] (respectively t, J = 7.2 Hz, total 3H), 1.03 -0.94 (m, 2H), 0.88-0.60 (m, 2H).
MS (ESI (+)) m / z 240 (M + H) ⁺
HR-MS calculated (C ₁₂ H ₁₈ NO ₄ ): 240.1236 (M + H) ⁺ , found: 240.1233 (-0.3 mDa).

Reference Example 3: Synthesis of 2,4-dichloro-6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine (Compound XIa) 6- obtained in Example 1 Cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido [4,3-d] pyrimidine-2,4 (1H, 3H) -dione (Compound Ia: 2.00 g, 8.50 mmol) in toluene (40 mL) Diisopropylethylamine (3.30 mL, 18.9 mmol) and phosphorus oxychloride (4.00 mL, 42.9 mmol) were added, and the mixture was stirred at 40 ° C for 2 hours, and then stirred at 80 ° C for 4 hours. Ethyl acetate (20 mL), toluene (20 mL) and water (20 mL) were added to the reaction mixture to separate the layers. The organic layer was washed successively with water (20 mL) and saturated aqueous sodium chloride solution (20 mL), and concentrated under reduced pressure. N, N-dimethylacetamide (8 mL) and water (14 mL) were added to the resulting residue, and the mixture was stirred for 1 hour under ice cooling. The precipitated crystals were collected by filtration, washed with water (4 mL), and dried under reduced pressure to give compound XIa (1.56 g, yield 70%) as white crystals.

Melting point 107-108 ℃ (decomposition)
¹ H NMR (CDCl ₃ , 300 MHz) δ (ppm) 4.73 (br s, 2H), 3.97 (br s, 2H), 3.04 (br s, 2H), 1.82 (m, 1H), 1.07-0.99 (m , 2H), 0.89-0.82 (m, 2H).
MS (ESI (+)) m / z 272 (M + H) ⁺
HR-MS calculated (C ₁₁ H ₁₂ Cl ₂ N ₃ O): 272.0357 (M + H) ⁺ , measured value: 272.0364 (+0.7 mDa).

Claims (21)

Formula (I)

[Where:
m and n are the same or different and represent an integer of 1 to 3 and m + n is 4 or less;
R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted Or an unsubstituted aromatic heterocyclic group, a substituted or unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl, a substituted or unsubstituted alicyclic heterocyclic alkyl, -NR ² R ³ (Wherein R ² and R ³ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, Substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted Or an unsubstituted alicyclic heterocyclic group, a substituted or unsubstituted aromatic heterocyclic alkyl or a substituted or unsubstituted alicyclic heterocyclic alkyl, or R ² and R ³ are adjacent to a nitrogen atom Together to form a heterocyclic group) or —OR ⁴ (wherein R ⁴ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted) Or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic Represents a heterocyclic alkyl group or a substituted or unsubstituted alicyclic heterocyclic alkyl group]] or a salt thereof.   The bicyclic pyrimidine derivative or a salt thereof according to claim 1, wherein m is 1 and n is 2. R ¹ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, or substituted or unsubstituted aryl The bicyclic pyrimidine derivative or a salt thereof according to claim 1 or 2. R ¹ is -NHR ^2A (wherein R ^2A is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted The bicyclic pyrimidine derivative or a salt thereof according to claim 1 or 2, which represents aralkyl or substituted or unsubstituted aryl. R ¹ is —OR ^4A (wherein R ^4A is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted The bicyclic pyrimidine derivative or a salt thereof according to claim 1 or 2, which represents aralkyl or substituted or unsubstituted aryl. (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (III)

Wherein R ¹ is as defined above, X is halogen, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryloxy, substituted or unsubstituted lower alkylsulfonyloxy, substituted or unsubstituted arylsulfonyl Oxy, substituted or unsubstituted lower alkylsulfanyl, substituted or unsubstituted arylsulfanyl, substituted or unsubstituted lower alkylsulfinyl, substituted or unsubstituted arylsulfinyl, substituted or unsubstituted lower alkylsulfonyl, substituted or unsubstituted By reacting with a compound represented by the formula (V): arylsulfonyl or —OCOR ⁵ (wherein R ⁵ represents the same as R ¹ above)

(Wherein R ¹ , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative. (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (IV)

Wherein R ^2B is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted Represents aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic alkyl, or substituted or unsubstituted alicyclic heterocyclic alkyl ) Is reacted with a compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative. (1) General formula (VI)

(Wherein m and n are as defined above), the compound represented by the general formula (III)

(Wherein R ¹ and X have the same meanings as described above), thereby reacting with the compound represented by the general formula (V)

(Wherein R ¹ , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative. (1) General formula (VI)

(Wherein m and n are as defined above), a compound represented by the general formula (IV)

(Wherein R ^2B has the same ^{meaning as} described above) to react with the compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative. General formula (V)

(Wherein R ¹ , m and n are as defined above), and a compound represented by the general formula (I), which is reacted with carbon dioxide in the presence of an organic base

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.   The organic base used for the reaction with carbon dioxide is 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non-5-ene. The manufacturing method in any one of -10. (1) General formula (VII)

Wherein R ¹ , m and n are as defined above, and R ⁶ is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted (Representing lower alkynyl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl) is reacted with urea in the presence of an acid catalyst to give a general formula (VIII)

(Wherein R ¹ , R ⁶ , m and n are as defined above),
Next, (2) the resulting compound is treated with a base, which is represented by the general formula (I)

(Wherein R ¹ , m and n are as defined above), a method for producing a bicyclic pyrimidine derivative.   The production method according to claim 6, wherein m is 1 and n is 2. (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (III)

(Wherein R ¹ and X have the same meanings as described above), thereby reacting with the compound represented by the general formula (V)

(Wherein R ¹ , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above), and the method includes a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

{Wherein R ¹ , m and n are as defined above,
R ⁷ and R ⁸ are the same or different and are a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylcarbonyl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aromatic heterocyclic ring Represents alkyl or substituted or unsubstituted alicyclic heterocyclic alkyl, or R ⁷ and R ⁸ together with the adjacent nitrogen atom form a heterocyclic group;
p represents an integer of 1 to 4,
Y ^a and Y ^b are the same or different and each represents a hydrogen atom, a substituted or unsubstituted lower alkyl or halogen,
R ⁹ represents —NR ¹⁰ R ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, Substituted or unsubstituted lower alkynyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted An aromatic heterocyclic alkyl or a substituted or unsubstituted alicyclic heterocyclic alkyl), a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group,
-A- is -O-, -CH = CH-, -C≡C-, phenylene or general formula (X)

[Wherein r represents an integer of 0 to 6,
when r is 1, Y ^c represents a substituted or unsubstituted lower alkyl or halogen;
when r is 2 or more, each Y ^c is the same or different and represents a substituted or unsubstituted lower alkyl or halogen, or two Y ^c on the same carbon atom together represent oxo;
G represents a nitrogen atom, CH, C (OH), C (CO ₂ H) or C (CN);
When G is a nitrogen atom, q represents an integer of 1 to 2, and when G is CH, C (OH), C (CO ₂ H) or C (CN), q represents an integer of 0 to 2. Represent,
Z is a single bond, —C (═O) —, —O—, —CH (OH) —, —CH ₂ CH (OH) —, —C (═O) O— or —C (═O) NR ¹² -(In which R ¹² represents a hydrogen atom, substituted or unsubstituted lower alkyl or substituted or unsubstituted cycloalkyl)] is represented.} A production method of a bicyclic pyrimidine derivative represented by: (1) General formula (II)

(Wherein, m and n are as defined above), and an amine is treated with a base,
Next, (2) the obtained compound is represented by the general formula (IV)

(Wherein R ^2B has the same ^{meaning as} described above) to react with the compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (3) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IXB)

(Wherein, A, R ^2B , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n, and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative. (1) General formula (VI)

(Wherein m and n are as defined above), the compound represented by the general formula (III)

(Wherein R ¹ and X have the same meanings as described above), thereby reacting with the compound represented by the general formula (V)

(Wherein R ¹ , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base.

(Wherein R ¹ , m and n are as defined above) and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

(Wherein, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative. (1) General formula (VI)

(Wherein m and n are as defined above), a compound represented by the general formula (IV)

(Wherein R ^2B has the same ^{meaning as} described above) to react with the compound represented by the general formula (VB)

(Wherein R ^2B , m and n are as defined above),
Next, (2) the obtained compound is reacted with carbon dioxide in the presence of an organic base, and is represented by the general formula (IB)

(Wherein R ^2B , m and n are as defined above), and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IXB)

(Wherein, A, R ^2B , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n, and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative. General formula (V)

(Wherein R ¹ , m and n are each as defined above) by reacting with a carbon dioxide in the presence of an organic base, the compound represented by the general formula (I)

(Wherein R ¹ , m and n are as defined above) and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

(Wherein, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative.   15. The organic base used in the reaction with carbon dioxide is 1,8-diazabicyclo [5.4.0] undec-7-ene or 1,5-diazabicyclo [4.3.0] non-5-ene. The manufacturing method in any one of -18. (1) General formula (VII)

(Wherein R ¹ , R ⁶ , m and n are as defined above), and a compound represented by the general formula (VIII) by reacting with urea in the presence of an acid catalyst.

(Wherein R ¹ , R ⁶ , m and n are as defined above),
(2) The resulting compound is then treated with a base to give a compound of general formula (I)

(Wherein R ¹ , m and n are as defined above) and a step of obtaining a bicyclic pyrimidine derivative represented by the general formula (IX)

(Wherein, A, R ¹ , R ⁷ , R ⁸ , R ⁹ , Y ^a , Y ^b , m, n and p are as defined above), respectively, for producing a bicyclic pyrimidine derivative.   The production method according to any one of claims 14 to 20, wherein m is 1 and n is 2.