JPWO2001002400A1 - Condensed imidazole compounds and antidiabetic drugs - Google Patents

Abstract

(57) [Summary] The present invention provides a new type of agent for preventing and treating diabetes and diabetic complications based on adenosine A2 receptor antagonism. That is, a compound represented by the general formula (I): (wherein ^R1 is an amino group or the like which may be substituted with an alkyl group; ^R2 is an alkyl group, alkenyl group, alkynyl group or the like which may be substituted with a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyl group or the like; ^R3 is an alkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, pyridinone group, pyrimidinone group, pyrazinone group or the like which may have a substituent; Ar is an aryl group, heteroaryl group or the like which may have a substituent; and Q and W are the same or different and each represents N or CH), which has an adenosine A2 receptor antagonistic activity and is effective for the prevention and treatment of diabetes and diabetic complications, or a pharmacologically acceptable salt or hydrate of the same.

Description

[Detailed Description of the Invention] Technical Field The present invention relates to a compound having a blood glucose lowering effect based on the inhibitory effect on glucose production and the promotion of glucose utilization in the periphery.
The present invention relates to a novel purine compound having a glucose tolerance-improving effect, and a prophylactic/therapeutic agent for diabetes and diabetic complications using the compound. More specifically, the present invention relates to a novel purine compound that is an adenosine A2 receptor antagonist, and a prophylactic/therapeutic agent for diabetes and diabetic complications based on the adenosine A2 receptor antagonistic effect.

PRIOR ART Various biguanide compounds and sulfonylurea compounds have been used as therapeutic agents for diabetes. However, the use of biguanide compounds is limited because they can cause lactic acidosis, and sulfonylurea compounds must be used with caution because they often cause severe hypoglycemia due to their strong hypoglycemic effect.

Diabetes is associated with a variety of frequent complications affecting the eyes, kidneys, nervous system, cardiovascular system, and skin, among others. Complications specific to diabetes include retinopathy, nephropathy, and neuropathy. In general, complications are thought to decrease with the achievement of near-normal blood sugar control (Latest Medical Dictionary, Ishiyaku Publishing, 1988). Diabetic retinopathy (
In particular, angiogenesis is a key factor in the pathogenesis of proliferative retinopathy, and activation of adenosine A2 receptors promotes angiogenesis due to hypoxia in the retina (Takag
i,H. et al. , Invest. Ophthalmol. Vis. Sci
, Vol. 37, pp. 1311-1321 and 2165-2176, 1996).

Adenosine is a nucleoside that is widely present in the body and is involved in the cardiovascular system, central nervous system,
It has physiological effects on the respiratory system, kidneys, immune system, etc. The action of adenosine is mediated by at least four receptors, A1, A2a, A2b, and A3, which are G protein-mediated.
(Fredholm, B.B. et al., (1994), Pharmacol. Rev., vol. 46, pp. 143-156). In 1979, adenosine receptors were first classified into A1 and A2 based on pharmacological action and adenylate cyclase involvement (Van Calker, D. et al., (1994), Pharmacol. Rev., vol. 46, pp. 143-156).
979, J. Neurochem., 33, 999-1003). Furthermore, A2 receptors are classified as A2a and A2 receptors based on their high or low affinity for adenosine and the adenosine A2 agonists NECA and CGS-21680.
b subtype (Burns, R.F. et al., (1986
Pharmacol., vol. 29, pp. 331-346; Wan, W
et al., (1990), J. Neurochem., Vol. 55, 176
3-1771) The physiological and pathological significance of these receptors in the central nervous system, circulatory system, etc. is gradually becoming clear.

Regarding glucose metabolism, the following reports have been reported: In experiments using skeletal muscle samples, adenosine acts as an agonist on the A1 receptor, reducing insulin sensitivity and inhibiting glucose uptake, while A1 receptor antagonists increase insulin sensitivity [Challis, R. A., Biochem. J., (1984), 2
21, pp. 915-917; Challis, R. A. , Eur. J. Phar
macol., (1992), vol. 226, pp. 121-128]. In adipocytes, adenosine enhances insulin sensitivity via A1 receptors and promotes glucose uptake [Vannucci, S. J., (1992), vol. 288, pp. 321-322].
5-330]. Also, WO95/18128 and WO98/03507 disclose antidiabetic agents that are A1 receptor antagonists, and there are many reports on A1 receptors. On the other hand, WO9701551 discloses an A2 receptor antagonist.
Although there is a brief description suggesting that 2a receptor antagonists may be used as antidiabetic agents, no evidence is provided. TIPS., (1993), Vol. 14, 360-36
On page 6, the involvement of adenosine A2 receptors in promoting gluconeogenesis in hepatocytes is suggested, but no specific details are given. In contrast to these, WO9801459 describes A2 receptor agonists as antidiabetic agents, but makes no mention of adenosine A2 receptor antagonists. Thus, the positioning of adenosine A2 receptor antagonists as antidiabetic agents is chaotic.

An object of the present invention is to provide an agent for the prophylaxis and treatment of diabetes and diabetic complications based on a new mechanism of action different from that of conventional biguanide compounds and sulfonylurea antidiabetic agents which have various limitations in use.

DISCLOSURE OF THE INVENTION After extensive investigations, the present inventors have discovered that adenosine receptor antagonists can be used as a new type of preventive and therapeutic agent for diabetes. Specifically, adenosine receptor antagonists improved hyperglycemia in spontaneously diabetic mice. This effect was presumably due to the antagonist's inhibition of hepatic glycogenolysis and gluconeogenesis, which are promoted by endogenous adenosine. Based on this finding, the present inventors have conducted extensive research to identify compounds with excellent hypoglycemic and glucose tolerance-improving effects as preventive and therapeutic agents for diabetes, and have discovered a novel fused imidazole compound represented by the following general formula (I). Further detailed investigations into its mechanism of action revealed that, among adenosine receptor antagonist actions, adenosine A2 receptor antagonist action is the essence of the hypoglycemic and glucose tolerance-improving effects. Based on this, the present invention has been completed, in which an adenosine A2 receptor antagonist is used as a new preventive and therapeutic agent for diabetes and diabetic complications.

The novel fused imidazole compound according to the present invention is represented by the following general formula (I):
In the formula, R ¹ is 1) a hydrogen atom, 2) a hydroxyl group, 3) a halogen atom, 4) a C1 to C8 alkyl group which may have a substituent, or 5) a group of the formula -NR ⁴ R ⁵ (in the formula, R ⁴ and R ⁵ are the same or different and each represent a hydrogen atom, a C1 to C8 alkyl group, or a C
R2 means 1) a hydrogen atom, 2) a halogen atom, 3) a C2-C5 acyl group, C1-C8 alkyl group, or C3-C8 cycloalkyl group, or a C2-C5 saturated cyclic amino group formed together with the nitrogen atom to which it is bonded. This ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom in addition to the nitrogen atom, and may be further substituted with a C1-C4 alkyl group which may be substituted with a halogen atom.), and ^R2 means 1) a hydrogen atom, 2) a halogen atom, ³ ) a group of the formula ^-NR6R7 (wherein ^R6 and ^R7 are the same or different and represent a hydrogen atom, a C2-C5 acyl group, a C1-C8 alkyl group, or a C3-C8 cycloalkyl group, or ^R6 and ^R7 mean a C2-C5 saturated cyclic amino group formed together with the nitrogen atom to which it is bonded. This ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom in addition to the nitrogen atom, and may be further substituted with a C1-C4 alkyl group which may be substituted with a halogen atom.
4) a halogen atom, a hydroxyl group, a C1 alkyl group, or a C2 alkyl group;
C optionally substituted by a C to C alkyl group or a C to C cycloalkyl group
R3 represents 1) a C3-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 2) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 3) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or ⁴ ) a C1-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group,
1) a C1-C6 alkyl group optionally substituted with an alkyl group, 2) a C1-C8 alkenyl group optionally substituted with an alkyl group, 3) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 4) an aryl group optionally having a substituent, 5) a heteroaryl group optionally having a substituent, 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C6 optionally having a substituent
4 alkyl group, or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C3 to C6 cycloalkyl group which may have a substituent; 7)
a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-1) a C1-C6 alkyl group optionally having a substituent, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-
3) a dihydrooxopyrimidyl group substituted with a C3 to C6 cycloalkyl group, or 8) a) a C1 to C6 alkyl group optionally substituted with a halogen atom or a C1 to C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group,
a) an optionally substituted C3-C6 cycloalkyl-C1-C4 alkyl group, or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3-C6 cycloalkyl group, wherein Ar is 1) an optionally substituted aryl group, 2) an optionally substituted heteroaryl group, 3) an oxopyridyl group optionally substituted with a halogen atom or a C1-C6 alkyl group and further substituted at the nitrogen atom with a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or 4) an optionally substituted with a halogen atom or a C1-C6 alkyl group and further substituted at the nitrogen atom with a C1-C6 alkyl group or a C3-C6 cycloalkyl group.
and Q and W are the same or different and represent N or CH. However, in the above, when ^R2 is 4) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group or a C3-C6 cycloalkyl group, 5) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or 6) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, ^R3 is 3) a halogen atom,
a) a C1-C8 alkyl group optionally substituted with a hydroxyl group or a C1-C4 alkyl group, or 4) an aryl group optionally having a substituent; a fused imidazole compound or a pharmacologically acceptable salt or hydrate thereof in which ^R2 is a hydrogen atom; a fused imidazole compound or a pharmacologically acceptable salt or hydrate thereof in which ^R3 is 1) a heteroaryl group optionally having a substituent, 2) a) a halogen atom or a C1-C6 alkyl group optionally having a substituent;
The nitrogen atom may be substituted with an alkyl group, and b-1) a halogen atom,
b-1) a C1-C6 alkyl group optionally substituted with a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent.
3) a) a C1 to C6 alkyl group optionally substituted with a halogen atom or a C1 to C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group;
b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group which may have a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or 4) a) a C1-C6 alkyl group which may be substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom is b-1) a C1-C6 alkyl group which may be substituted with a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group, or b-2) a C3-C6 cycloalkyl-C1-C4
a) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-1) a ^C1- C6 cycloalkyl-C1-C6 alkyl group optionally having a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C1-C6 cycloalkyl-C1-C6 alkyl group optionally having a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-3) a C1-C6 cycloalkyl-C1-C6 alkyl group optionally having a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group,
a-4 alkyl group, or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C3 to C6 cycloalkyl group which may have a substituent, or 4) a) optionally substituted with a halogen atom or a C1 to C6 alkyl group,
Further, a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein the nitrogen atom is b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group; a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein Ar is an aryl group optionally having a substituent; a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein Ar is a phenyl group substituted with a halogen atom; a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein R ¹ is a group represented by the formula -NR ⁴ R ⁵ (wherein R ⁴ and R ^{The 5} may be the same or different and represent a hydrogen atom, a C1-C8 alkyl group, or a C3-C8 cycloalkyl group, or a C2-C5 saturated cyclic amino group formed together with the nitrogen atom to which it is bonded. This ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom in addition to the nitrogen atom, and may further include a C1-C8 cycloalkyl group optionally substituted with a halogen atom.
a condensed imidazole compound or a pharmacologically acceptable salt thereof, or a hydrate thereof, in which R ¹ is an amino group; a condensed imidazole compound or a pharmacologically acceptable salt thereof, or a hydrate thereof, in which R ¹ is an amino group, R ² is a hydrogen atom, and R ³ is 1)
a pyridyl group optionally substituted with a hydroxyl group or a C1-C6 alkyl group, or 2) a) a pyridyl group optionally substituted with a halogen atom or a C1-C6 alkyl group,
a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein the nitrogen atom is b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C3-C6 cycloalkyl group optionally having a substituent; a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein Q or W is N; a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein R ¹ is an amino group, R ² is a hydrogen atom, and R ³ is a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C1-C6 alkyl group whose nitrogen atom may be substituted with a halogen atom; a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein R ¹ is an amino group, R a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, wherein ^{R 2} is a C2 alkynyl group substituted with a hydroxyl group and a C4-C6 cycloalkyl group, R ³ is a C3 alkenyl group, and Ar is a phenyl group substituted with a halogen atom; a fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof, selected from the following group: 1) 5-
[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone, 2) 1-{2-[6-amino-8-
(3-fluorophenyl)-9-(2-propenyl)-9H-2-purinyl]-
1-ethynyl}-1-cyclobutanol.

The present invention provides a fused imidazole compound, or a pharmacologically acceptable salt or hydrate thereof, which is a purine compound represented by the above formula (I) in which Q and W represent a nitrogen atom. The present invention also provides a fused imidazole compound, or a pharmacologically acceptable salt or hydrate thereof, which is a benzimidazole compound represented by the above formula (I) in which Q and W represent -CH. Furthermore, the present invention provides a fused imidazole compound, or a pharmacologically acceptable salt or hydrate thereof, which is a benzimidazole compound represented by the above formula (I) in which Q and W represent -CH.
wherein one of Q and W is N and the other is —CH, or a pharmacologically acceptable salt or hydrate thereof.

The present invention provides a prophylactic or therapeutic agent for diabetes, which contains the above-mentioned condensed imidazole compound, a pharmacologically acceptable salt thereof, or a hydrate of these as an active ingredient; a prophylactic or therapeutic agent for diabetic complications, which contains the above-mentioned condensed imidazole compound, a pharmacologically acceptable salt thereof, or a hydrate of these as an active ingredient; a prophylactic or therapeutic agent for diseases for which the above-mentioned condensed imidazole compound, a pharmacologically acceptable salt thereof, or a hydrate of these is effective; a prophylactic or therapeutic agent for diabetic retinopathy, which contains the above-mentioned condensed imidazole compound, a pharmacologically acceptable salt thereof, or a hydrate of these as an active ingredient; an adenosine A2 receptor antagonist comprising the above-mentioned condensed imidazole compound, a pharmacologically acceptable salt thereof, or a hydrate of these; and a pharmaceutical composition comprising the above-mentioned condensed imidazole compound, a pharmacologically acceptable salt thereof, or a hydrate of these, and a pharmacologically acceptable carrier.

The present invention provides a method for preventing and treating diabetes, diabetic complications, diabetic retinopathy, or a disease for which the fused imidazole compound, its pharmacologically acceptable salt, or its hydrate is effective, or a disease for which adenosine A2 receptor antagonism is effective, by administering to a patient a pharmacologically effective amount of the fused imidazole compound, its pharmacologically acceptable salt, or its hydrate.

The present invention also provides use of the above-mentioned fused imidazole compound, or a pharmacologically acceptable salt thereof, or a hydrate thereof for use in producing an agent for the prophylaxis or treatment of diabetes, diabetic complications, diabetic retinopathy, or a disease for which the above-mentioned fused imidazole compound, or a pharmacologically acceptable salt thereof, or a hydrate thereof is effective, or an adenosine A2 receptor antagonist.

The present invention relates to a compound of the following formula, which is a useful intermediate for synthesizing the compound of the present invention:5-amino-1-methyl-2(1H)-pyridone oxalate represented by the formula:
and a method for producing the compound of the present invention and a synthetic intermediate of the compound of the present invention, which is represented by the following general formula:(In the formula, L¹represents a halogen atom, R²is 1) a hydrogen atom, 2) a halogen atom, or 3) a group of the formula -NR⁶R⁷(In the formula, R⁶oh
Yobi R⁷are the same or different and are a hydrogen atom, a C2 to C5 acyl group, a C1 to C8 acyl group,
or R⁶Oh
BiR⁷is a saturated C2-C5 ring formed together with the nitrogen atom to which it is attached.
In addition to the nitrogen atom, this ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom.
C1 to C2 alkyl groups which may contain hydrogen atoms and which may be further substituted with halogen atoms.
4) a halogen atom, a hydroxyl group, a C1 alkyl group, or a C2 alkyl group;
C optionally substituted by a C to C alkyl group or a C to C cycloalkyl group
2) a C8 alkynyl group, 5) a halogen atom, a hydroxyl group, or a C1-C4 alkyl group.
6) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or
or a C1-C8 alkyl group optionally substituted with a C1-C4 alkyl group,
7) may be substituted with a halogen atom, a hydroxyl group, or a C1-C4 alkyl group.
R means a C1-C8 alkoxy group.³1) is substituted with a halogen atom, a hydroxyl group, or a C1-C4 alkyl group;
2) a C3 to C8 alkynyl group optionally containing a halogen atom, a hydroxyl group, or a C1 to C4
a C3-C8 alkenyl group optionally substituted with an alkyl group; 3) a halogen atom;
, C1-C8 alkyl optionally substituted with a hydroxyl group or a C1-C4 alkyl group;
4) an aryl group which may have a substituent; 5) an aryl group which may have a substituent;
6) a) a heteroaryl group substituted with a halogen atom or a C1-C6 alkyl group;
The nitrogen atom may have b-1) a halogen atom, a hydroxyl group or a protecting group.
a C1-C6 alkyl group optionally substituted with an optionally substituted carboxyl group;
b-2) optionally substituted C3-C6 cycloalkyl-C1-C4 alkyl
b-3) an optionally substituted C3-C6 cycloalkyl group;
7) a) a 1,2-dihydro-2-oxopyridyl group optionally substituted with
The nitrogen atom may be substituted with a halogen atom or a C1-C6 alkyl group,
-1) a halogen atom, a hydroxyl group, or a carboxyl group which may have a protecting group
b-2) an optionally substituted C1-C6 alkyl group;
b-3) a C3-C6 cycloalkyl-C1-C4 alkyl group; or b-4) a C3-C6 cycloalkyl-C1-C4 alkyl group;
6) a dihydrooxopyrimidinyl group substituted with a cycloalkyl group, or 8)
a) a nitrogen atom which may be substituted with a halogen atom or a C1-C6 alkyl group;
b-1) a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group
b-1) a C1-C6 alkyl group optionally substituted with a methyl group; b-2) a C1-C6 alkyl group optionally substituted with a methyl group;
b-3) a C3-C6 cycloalkyl-C1-C4 alkyl group, or b-4) a C
Dihydrooxo or tetrahydroxo, each substituted with a 3-C6 cycloalkyl group
and Q and W are the same or different and represent N or CH.
a pyridine derivative (A2) and a compound represented by the general formula ArCOX (wherein X represents a halogen atom,
Ar is 1) an aryl group which may have a substituent;
3) a heteroaryl group substituted with a halogen atom or a C1-C6 alkyl group;
The nitrogen atom may be a C1-C6 alkyl group or a C3-C6 cycloalkyl group.
4) an oxopyridyl group substituted with a halogen atom or a C1-C
The nitrogen atom may be substituted with a C1 to C6 alkyl group or a C
means an oxopyrimidyl group substituted with a 3-C6 cycloalkyl group.
The compound is characterized by reacting an acyl compound represented by the following general formula:(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
or a salt thereof.
The method for producing these hydrates is shown below.(In the formula, L¹, R², R³, Q and W each represent the same group as defined above.
.) and an aminopyridine derivative (A2) represented by the general formula ArCOX (wherein X
and Ar are the same as defined above,
The following general formula, characterized by reacting in the presence of pyridine:(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
or a salt thereof.
means a method for producing a hydrate thereof;³is N-C1-C8 alkyl-2
- an acylaminopyridine derivative (A3) which is an oxopyridinyl group, or a salt thereof
Or a method for producing their hydrates; the following general formula: (In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The acylaminopyridine derivative (A3) represented by the formula (I) is reacted with POCl₃in the presence
, characterized by undergoing a ring-closure reaction, as shown by the following general formula: (In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The imidazopyridine derivative (A4) represented by the formula (I) or a salt thereof
The method for producing these hydrates is as follows:(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The acylaminopyridine derivative (A3) represented by the formula (I) is reacted with the acylaminopyridine derivative (A4) in the presence of hydrochloric acid or
is subjected to a ring-closing reaction using the hydrochloride of the acylaminopyridine derivative (A3).
The following general formula is characterized by:(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The imidazopyridine derivative (A4) represented by the formula (I) or a salt thereof
The method for producing these hydrates is as follows:(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The acylaminopyridine derivative (A3) represented by the formula (I) is reacted with NMP (1-methyl-
The method is characterized in that the ring-closing reaction is carried out in a solvent containing 1,2-dichloro-2-pyrrolidone under heating.
expression(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The imidazopyridine derivative (A4) represented by the formula (I) or a salt thereof
A method for producing these hydrates;³is N-C1-C8 alkyl-2-ol
an imidazopyridine derivative (A4) having a xopyridinyl group, or a salt thereof; or
The method for producing these hydrates is shown below:(In the formula, L¹, R², R³, Q and W each represent the same group as defined above.
.) and an aminopyridine derivative (A2) represented by the general formula ArCOX (wherein X
and Ar are the same as defined above.
and then subjecting it to a ring-closure reaction,(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The imidazopyridine derivative (A4) represented by the formula (I) or a salt thereof
A method for producing these hydrates:
The imidazopyridine derivative (A4) is obtained by a HO reaction.
A method for producing a lysine derivative (A4), a salt thereof, or a hydrate thereof, comprising the steps of:
general ceremony(In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The present invention is characterized by amminating an imidazopyridine derivative (A4) represented by the formula:
General formula (In the formula, L¹, R², R³, Ar, Q and W each represent the same group as defined above.
The aminoimidazopyridine derivative (A5) or a salt thereof represented by the formula:
or a method for producing a hydrate thereof;³is N—C1 to C8 alkyl-
Aminoimidazopyridine derivative (A5) which is a 2-oxopyridinyl group or
A method for producing a salt or hydrate thereof; and the following general formula:(In the formula, R¹is 1) a hydrogen atom, 2) a hydroxyl group, 3) a halogen atom, or 4) a group having a substituent.
or 5) a C1 to C8 alkyl group of the formula -NR⁴R⁵(In the formula, R⁴
and R⁵are the same or different and represent a hydrogen atom, a C1-C8 alkyl group, or
means a C3-C8 cycloalkyl group, or together with the nitrogen atom to which it is attached
This ring is a saturated cyclic amino group of C2 to C5 formed by the nitrogen.
In addition to the hydrogen atoms, the alkyl group may contain oxygen atoms, sulfur atoms, or nitrogen atoms.
and optionally substituted with a C1-C4 alkyl group optionally substituted with a halogen atom.
) means the expression is a dihydrooxopyridinyl or pyrimidyl group, or a dihydro or tetra
means a hydropyrazinyl group, and R²Ar, Q and W are the same groups as defined above.
The imidazopyridine derivative (C2) represented by the formula (C1) is alkylated to
The general formula is(In the formula, R¹³is a halogen atom, a hydroxyl group or a carbo
a C1-C6 alkyl group optionally substituted with an xyl group;
C3-C6 cycloalkyl-C1-C4 alkyl group or
R means a C3-C6 cycloalkyl group which may be optionally substituted;¹, expressionR², Ar, Q and W each represent the same group as defined above.
Method for producing imidazopyridine derivative (C3) or its salt or hydrate thereof
Regarding the law.

In general formula (I), the term "optionally substituted" in the definitions of R ¹ , R ³ and Ar - for example, an aryl group which may have a substituent, a heteroaryl group which may have a substituent, a C1-C8 alkyl group which may have a substituent, and the like - means that each group is, for example, a hydroxyl group; a thiol group; a nitro group; a cyano group; a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a C1-C8 alkyl group such as methyl, ethyl, n-propyl or isopropyl;
C1 groups such as methoxy, ethoxy, n-propoxy, isopropoxy, and butoxy groups
to C8 alkoxy groups; halogenated alkyl groups such as a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, and a 2,2,2-trifluoroethyl group; alkylthio groups such as a methylthio group, an ethylthio group, and an isopropylthio group; acyl groups such as an acetyl group, a propionyl group, and a benzoyl group; hydroxyalkyl groups such as a hydroxymethyl group, a hydroxyethyl group, and a hydroxypropyl group; amino groups; monoalkylamino groups such as a methylamino group, an ethylamino group, and an isopropylamino group, and dialkylamino groups such as a dimethylamino group and a diethylamino group; cyclic amino groups such as an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, a perhydroazepinyl group, and a piperazinyl group; carboxyl groups; alkoxycarbonyl groups such as a methoxycarbonyl group, an ethoxycarbonyl group, and a propylcarbonyl group; a carbamoyl group; alkylcarbamoyl groups such as a methylcarbamoyl group and a dimethylcarbamoyl group; acetonitrile acylamino groups such as a methylamino group and a benzoylamino group; alkylsulfonyl groups unsubstituted or substituted with a C1 to C4 alkyl group, such as a sulfamoyl group, a methylsulfonyl group, and an ethylsulfonyl group; unsubstituted or substituted arylsulfonyl groups such as a benzenesulfonyl group and a p-toluenesulfonyl group; unsubstituted or substituted aryl groups such as a phenyl group, a tolyl group, and an anisolyl group; unsubstituted or substituted heteroaryl groups such as a pyrrole group, a pyrazolyl group, an imidazolyl group, a triazolyl group, a tetrazolyl group, a thiazolyl group, a pyridyl group, a pyrimidyl group, and a pyrazinyl group; carboxyalkyl groups; alkyloxycarbonylalkyl groups such as a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, and a methoxycarbonylethyl group; carboxyalkoxy groups such as a carboxymethoxy group; arylalkyl groups such as a benzyl group and a 4-chlorobenzyl group; heteroarylalkyl groups such as a pyridylmethyl group and a pyridylethyl group;
This means that the group may be substituted with a group selected from alkylenedioxy groups such as methylenedioxy and ethylenedioxy groups; oxo groups, and the like.

The halogen atom in the definitions of R ¹ , R ² and R ³ means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

C1-C4, C1-C6 or C1-C6 as defined in the definitions of R ¹ , R ² and R ³
The C8 alkyl group means a linear or branched alkyl group having 1 to 4, 1 to 6, or 1 to 8 carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.
butyl group, n-pentyl group, 1,2-dimethylpropyl group, 1,1-dimethylpropyl group, 2,2-dimethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1,2-dimethylbutyl group, 2,3-dimethylbutyl group, 1,3-dimethylbutyl group, 1-ethyl-2-methylpropyl group, 1-methyl-2-ethylpropyl group, n-heptyl group, 1,1-dimethylpentyl group, 2-ethylpentyl group, 1-methyl-2-ethylbutyl group, n-octyl group, 1,1-dimethylhexyl group, 2-ethylhexyl group, 1-methyl-2-ethylpentyl group, and the like.

The cycloalkyl group defined for R ¹ , R ² and R ³ means a cycloalkyl group having 3 to 8 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group.

The C3-C6 cycloalkyl-C1-C4 alkyl group in the definition of ^R3 means a group in which a cycloalkyl group having 3 to 6 carbon atoms, such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group, is bonded to the above-mentioned C1-C4 alkyl group.

C3-C8 alkenyl groups as defined for ^R2 and ^R3 , and straight-chain or branched alkenyl groups, such as 1-propenyl group, 2-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 3-methyl-1-propenyl group, 2-
methyl-2-propenyl group, 3-methyl-2-propenyl group, 1-butenyl group,
It means a 2-butenyl group, a 3-butenyl group, and the like.

The acyl group in the definition of ^R2 means, for example, a group derived from an aliphatic saturated monocarboxylic acid such as an acetyl group, a propionyl group, a butyryl group, a valeryl group, an isovaleryl group, or a pivaloyl group; a group derived from an aliphatic unsaturated carboxylic acid such as an acryloyl group, a propioloyl group, a methacryloyl group, a crotonoyl group, or an isocrotonoyl group; a group derived from a carbocyclic carboxylic acid such as a benzoyl group, a naphthoyl group, a toluoyl group, a hydratropoyl group, an atropoyl group, or a cinnamoyl group; a group derived from a heterocyclic carboxylic acid such as a furoyl group, thenoyl group, a nicotinoyl group, or an isonicotinoyl group; a group derived from a hydroxycarboxylic acid or an alkoxycarboxylic acid such as a glycoloyl group, a lactoyl group, a glyceroyl group, a tropoyl group, a benzyloyl group, a salicyloyl group, anisoyl group, a vanilloyl group, a piperonyloyl group, or a galloyl group; or a group derived from various amino acids.

The aryl group in the aryl group which may have a substituent as defined for ^R3 and Ar means a phenyl group, a 1-naphthyl group, a 2-naphthyl group, an anthracenyl group, or the like.

The heteroaryl group in the heteroaryl group which may have a substituent as defined in the definitions of ^R3 and Ar means a group derived from a monocyclic or condensed ring containing 1 to 4 atoms of at least one selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms, such as a pyrrolyl group, a thienyl group, a furyl group, a thiazolyl group, an oxazolyl group, an isothiazolyl group, an isoxazolyl group, an imidazolyl group,
It means a pyrazolyl group, a thiadiazolyl group, an oxadiazolyl group, a triazolyl group, a tetrazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an indolyl group, an isoindolyl group, a benzothienyl group, a benzofuranyl group, an isobenzofuranyl group, a benzimidazolyl group, an indazolyl group, a benzotriazolyl group, a benzothiazolyl group, a benzoxazolyl group, a quinolyl group, an isoquinolyl group, a cinnolinyl group, a phthalazyl group, a quinoxalyl group, a naphthyridinyl group, a quinazolinyl group, an imidazopyridinyl group, and the like.

Among the above heteroaryl groups, when a nitrogen atom-containing heteroaryl group has a hydroxyl group bonded to the carbon atom adjacent to the nitrogen atom, the heteroaryl group also refers to its tautomer, —NH-oxo form.

In the carboxyl group which may have a protecting group as defined for ^R3 , examples of the protecting group include C1 to C8 alkyl groups such as methyl, ethyl, and tert-butyl groups; C1 to C8 alkyl groups substituted with phenyl groups which may have a substituent such as p-methoxybenzyl, p-nitrobenzyl, 3,4-dimethoxybenzyl, diphenylmethyl, trityl, and phenethyl; halogenated C1 to C8 alkyl groups such as 2,2,2-trichloroethyl and 2-iodoethyl; pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, valeryloxymethyl, 1-acetoxyethyl, 2-acetoxyethyl, and 1-methyl-2 ...
-C1-C8 alkanoyloxy C1-C8 alkyl groups such as pivaloyloxyethyl and 2-pivaloyloxyethyl; higher alkanoyloxy C1-C8 alkyl groups such as palmitoyloxyethyl, heptadecanoyloxymethyl and 1-palmitoyloxyethyl; C1-C8 alkyl groups such as methoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl and 1-(isopropoxycarbonyloxy)ethyl;
1-C8 alkoxycarbonyloxy C1-C8 alkyl groups, carboxy C1-C8 alkyl groups such as carboxymethyl and 2-carboxyethyl, heteroaryl groups such as 3-phthalidyl, benzoyloxy C1-C8 alkyl groups which may have a substituent such as 4-glycyloxybenzoyloxymethyl, (substituted dioxolene) C1-C8 alkyl groups such as (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl, cycloalkyl-substituted C1-C8 alkanoyloxy C1-C8 alkyl groups such as 1-cyclohexylacetyloxyethyl, 1-
Examples include cycloalkyloxycarbonyloxy C1-C8 alkyl groups such as cyclohexyloxycarbonyloxyethyl. They may also be in the form of various acid amides. In other words, anything that can be decomposed in vivo to a carboxylic acid can be used as a protecting group for a carboxyl group.

The definition of ^R3 , ^R4 , ^R6 , and ^R7 , "a C2 to C5 saturated cyclic amino group formed together with the nitrogen atom to which it is bound," means aziridine, azetidine, pyrrolidine, piperidine, piperazine, homopiperazine, morpholine, thiomorpholine, or the like. These rings may be substituted with a C1 to C4 alkyl group optionally substituted with a halogen atom.

Q and W may be the same or different and each represent N or CH, with a nitrogen atom being more preferred.

Here, R¹represents 1) a hydrogen atom, 2) a hydroxyl group, 3) a halogen atom, or 4) a substituent.
5) a C1 to C8 alkyl group optionally having the formula —NR⁴R⁵(In the formula, R
⁴and R⁵are the same or different and each represents a hydrogen atom, a C1-C8 alkyl group, or
means a C3-C8 cycloalkyl group or a group that is bonded to the nitrogen atom
The term "amino group" refers to a saturated cyclic amino group of C2 to C5 formed by the combination of the two amino groups.
In addition to the nitrogen atom, the group may contain an oxygen atom, a sulfur atom, or a nitrogen atom,
may be substituted with a C1-C4 alkyl group optionally substituted with a halogen atom;
) and preferably 2) a hydroxyl group, 3) a halogen atom, 4) a group having a substituent.
or 5) a C1 to C8 alkyl group of the formula -NR⁴R⁵(In the formula, R⁴
and R⁵are the same or different and represent a hydrogen atom, a C1-C8 alkyl group, or
means a C3-C8 cycloalkyl group, or together with the nitrogen atom to which it is attached
This ring is a saturated cyclic amino group of C2 to C5 formed by the nitrogen.
In addition to the hydrogen atoms, the alkyl group may contain oxygen atoms, sulfur atoms, or nitrogen atoms.
and optionally substituted with a C1-C4 alkyl group optionally substituted with a halogen atom.
) and more preferably 2) a hydroxyl group, 4) a C
1 to C8 alkyl group, or 5) a group of the formula -NR⁴R⁵(In the formula, R⁴and R⁵are the same
or differently, a hydrogen atom, a C1-C8 alkyl group, or a C3-C8 cyclo
It means an alkyl group or is formed together with the nitrogen atom to which it is attached.
The ring is a saturated cyclic amino group having C2 to C5 carbon atoms, and oxygen atoms are present in addition to the nitrogen atom.
may contain atoms, sulfur atoms or nitrogen atoms, and may be further substituted with halogen atoms.
and optionally substituted with a C1-C4 alkyl group,
More preferably, 4) an optionally substituted C1 to C8 alkyl group, or
5) Formula-NR⁴R⁵(In the formula, R⁴and R⁵are the same or different hydrogen atoms,
It means a C1-C8 alkyl group or a C3-C8 cycloalkyl group, or
or a saturated cyclic alkyl group of C2 to C5 formed together with the nitrogen atom to which it is attached
In addition to the nitrogen atom, this ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom.
C1 to C4 alkyl groups which may contain alkyl groups and which may be further substituted with halogen atoms
and more preferably 5) a group represented by the formula
-NR⁴R⁵(In the formula, R⁴and R⁵are the same or different and may be a hydrogen atom,
C8 alkyl group, or C3-C8 cycloalkyl group, or
A saturated cyclic amino group of C2 to C5 formed together with the nitrogen atom to which it is attached
This ring contains an oxygen atom, a sulfur atom or a nitrogen atom in addition to the nitrogen atom.
and C1-C4 alkyl optionally substituted with a halogen atom.
The group may be substituted with a methyl group.

wherein ^R2 is 1) a hydrogen atom, 2) a halogen atom, ³ ) a group of the formula ^-NR6R7 (wherein ^R6 and ^R7 are the same or different and represent a hydrogen atom, a C2 to C5 acyl group, a C1
or ^R6 and ^R7 together with the nitrogen atom to which they are bonded represent a saturated C2-C5 cyclic amino group. This ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom in addition to the nitrogen atom, and may be further substituted with a C1-C4 alkyl group optionally substituted with a halogen atom.), 3) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group, or a C3-C6 cycloalkyl group, 5) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group, or a C1-C4 alkyl group, 6) a halogen atom,
1) a C1-C8 alkyl group optionally substituted with a hydroxyl group or a C1-C4 alkyl group, or 7) a C1-C8 alkoxy group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, and preferably 1) a hydrogen atom, 2) a halogen atom, 4) a halogen atom, a hydroxyl group, a C1-C4 alkyl group or a C3-C
6) a C2-C8 alkynyl group optionally substituted with a cycloalkyl group; 5) a C3-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group;
1) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, or a C1-C4 alkyl group; 2) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group, or 3) a C1-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group, or a C3-C6 cycloalkyl group; 3) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group, or a C1-C4 alkyl group; or 4) a C1-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group, or 5) a C1-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group, or 6) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group, or a C1-C4 alkyl group; alkoxy group, more preferably 1) a hydrogen atom, 4) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group or a C3-C6 cycloalkyl group, 6) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or 7) a C1-C8 alkoxy group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, and even more preferably 1) a hydrogen atom, 4) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group or a C3-C6 cycloalkyl group, or 6) a halogen atom, a hydroxyl group or a C1-C8 alkoxy group
It means a C1 to C8 alkyl group optionally substituted with a C4 alkyl group, more preferably 1) a hydrogen atom, or 6) a halogen atom, a hydroxyl group, or a C1 to C4 alkyl group.
It means a C1-C8 alkyl group which may be substituted with an alkyl group, and most preferably means a hydrogen atom.

Here, ^R3 is 1) a C3 to C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, or a C1 to C4 alkyl group;
3) a C3-C8 alkenyl group optionally substituted with a C1-C4 alkyl group, a halogen atom, a hydroxyl group or a C1-C4 alkyl group,
1) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group;
b-2) an optionally substituted C3-C6 cycloalkyl-
a) a C1-C4 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or 8) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or a) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C6 alkyl group, or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3-C6 cycloalkyl group, and preferably 2) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 3) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 4) an aryl group optionally having a substituent, 5) a heteroaryl group optionally having a substituent, 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a C3-C6 cycloalkyl group optionally substituted with a C3-C6 cycloalkyl group
, 2-dihydro-2-oxopyridyl group, 7) a) a halogen atom or a C1-C
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or 8) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group and further wherein the nitrogen atom is b-1)
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-2) a C3
b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3 to C6 cycloalkyl-C1 to C4 alkyl group, and more preferably b-4) a halogen atom, a hydroxyl group, or a C1 to C6 cycloalkyl-C1 to C4 alkyl group.
4) a C3-C8 alkenyl group optionally substituted with a C1-C4 alkyl group; 5) a heteroaryl group optionally substituted with a halogen atom or a C1-C6 alkyl group;
The nitrogen atom may be substituted with an alkyl group, and b-1) a halogen atom,
b-1) a C1-C6 alkyl group optionally substituted with a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent.
7) a) a C1 to C6 alkyl group optionally substituted with a halogen atom or a C1 to C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group;
b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or 8) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, or b-2) a C3-C6 cycloalkyl-C1
and b-1) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group optionally substituted with a C3-C6 cycloalkyl group, more preferably 5) an optionally substituted heteroaryl group, 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a C3-C6 cycloalkyl group optionally having a substituent.
2-dihydro-2-oxopyridyl group, 7) a) a halogen atom or a C1 to C6
The nitrogen atom may be substituted with an alkyl group, and b-1) a halogen atom,
b-1) a C1-C6 alkyl group optionally substituted with a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or 8) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent
or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group each substituted with a C6 cycloalkyl-C1-C4 alkyl group, and even more preferably 6) a) a halogen atom or a C1
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a 1,2-dihydro-2-
7) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-1) a C3-C6 cycloalkyl-C1-C4 optionally substituted
or b-3) a dihydrooxopyrimidyl group substituted with a C3 to C6 cycloalkyl group, or 8) a) a C1 to C6 alkyl group optionally substituted with a halogen atom or a C1 to C6 alkyl group, the nitrogen atom of which may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group.
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent; or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3-C6 cycloalkyl group, and more preferably 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group;
or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C3 to C6 cycloalkyl group optionally having a substituent; or 7) a) a C1 to C6 alkyl group optionally substituted with a halogen atom or a C1 to C6 alkyl group and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3 to C6 cycloalkyl-C1 to C4 alkyl group optionally having a substituent; or b-3) a dihydrooxopyrimidyl group substituted with a C3 to C6 cycloalkyl group, and even more preferably 6) a) a halogen atom or a C1 to C6 alkyl group optionally having a halogen atom or a C1 to C6 cycloalkyl group
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C3-C6 cycloalkyl group optionally having a substituent, and even more preferably 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and b-1) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and
It is a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group, or a carboxyl group optionally having a protecting group, and most preferably a 1,2-dihydro-2-oxopyridyl group or a 1-methyl-1,2-dihydro-2-oxopyridyl group.

^R3 has the same meaning as defined above, except that ^R2 is i) a halogen atom, a hydroxyl group,
When R 3 means i) a C2-C8 alkynyl group optionally substituted with a C1-C4 alkyl group or a C3-C6 cycloalkyl group, ii) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or iii) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, R ³ means i) a halogen atom, a hydroxyl group or a C1-C4 alkyl group,
It does not mean ii) a C1-C8 alkyl group optionally substituted with an alkyl group, or ii) an aryl group optionally having a substituent.

In this case, when ^R2 represents i) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group or a C3-C6 cycloalkyl group, ii) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or iii) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, ^R3 represents 1) a C3-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 2) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 5) a heteroaryl group optionally having a substituent, 6) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group
b-2) an optionally substituted C3-C6 cycloalkyl-
a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or 8) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, a) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3-C6 cycloalkyl group, and preferably 5) a heteroaryl group optionally having a substituent, 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-2) a C3-C6 cycloalkyl-C1-C6 alkyl group optionally having a substituent;
a) a halogen atom or a C1 to C6 alkyl group, or b-3) a dihydrooxopyrimidyl group substituted with a C3 to C6 cycloalkyl group, or
The nitrogen atom may be substituted with an alkyl group, and b-1) a halogen atom,
b-1) a C1-C6 alkyl group optionally substituted with a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3-C6 cycloalkyl group, more preferably 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and further wherein the nitrogen atom is b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group
b-2) an alkyl group having an optionally substituted C3 to C6 cycloalkyl-C
a) a C1 to C4 alkyl group, or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C3 to C6 cycloalkyl group which may have a substituent; 7) a) optionally substituted with a halogen atom or a C1 to C6 alkyl group,
a dihydrooxopyrimidyl group in which the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group which may have a substituent, or b-3) a C3-C6 cycloalkyl group, or 8) a) a C1-C6 alkyl group which may be substituted with a halogen atom or a C1-C6 alkyl group and in which the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group,
b-2) a C3 to C6 cycloalkyl-C1 to C4 alkyl group optionally having a substituent, or b-3) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3 to C6 cycloalkyl group, and even more preferably 6) a) a C1 to C6 alkyl group optionally substituted with a halogen atom or a C1 to C6 alkyl group, and the nitrogen atom thereof may be b-1) a C1 to C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group;
2) an optionally substituted C3-C6 cycloalkyl-C1-C4 alkyl group, or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with an optionally substituted C3-C6 cycloalkyl group, or 7) a)
b-1) a C1-C6 alkyl group which may be substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group; b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group which may have a substituent; or b-3)
and more preferably 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-2) a C3-C6 cycloalkyl-C1 optionally having a substituent;
b-1) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C1 to C4 alkyl group, or b-3) a C3 to C6 cycloalkyl group optionally having a substituent, more preferably 6) a C1 to C6 alkyl group optionally substituted with a halogen atom or a C1 to C6 alkyl group, and further preferably b-2) a C1 to C6 cycloalkyl group optionally having a nitrogen atom optionally substituted with a halogen atom, a hydroxyl group, or a carboxyl group optionally having a protecting group.
It is a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C6 alkyl group, and most preferably a 1,2-dihydro-2-oxopyridyl group or a 1-methyl-1,2-dihydro-2-oxopyridyl group.

wherein Ar is 1) an aryl group which may have a substituent, 2) a heteroaryl group which may have a substituent, or 3) a group which may be substituted with a halogen atom or a C1-C6 alkyl group and in which the nitrogen atom is further substituted with a C1-C6 alkyl group or a C3-C6 alkyl group.
3) an oxopyridyl group substituted with a C6 cycloalkyl group, or 4) an oxopyridyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and further wherein the nitrogen atom is C
1) an aryl group which may have a substituent;
2) an optionally substituted heteroaryl group; 3) a halogen atom or a C1
[0033] The term "oxopyridyl group" refers to an oxopyridyl group which may be substituted with a C1-C6 alkyl group and whose nitrogen atom is further substituted with a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or 4) an oxopyrimidyl group which may be substituted with a halogen atom or a C1-C6 alkyl group and whose nitrogen atom is further substituted with a C1-C6 alkyl group or a C3-C6 cycloalkyl group, more preferably 1) an aryl group which may be substituted, 2) a heteroaryl group which may be substituted, or 3) an oxopyridyl group which may be substituted with a halogen atom or a C1-C6 alkyl group and whose nitrogen atom is further substituted with a C1-C6 alkyl group or a C3-C6 cycloalkyl group, even more preferably 1) an aryl group which may be substituted, or 2) a heteroaryl group which may be substituted, even more preferably an aryl group which may be substituted, and most preferably an aryl group which may be substituted.

In the present invention, it goes without saying that optically active compounds having asymmetric atoms are also included in the present invention, including hydrates thereof.

The pharmacologically acceptable salts in the present invention include, for example, hydrochlorides, hydrobromides,
Examples include inorganic salts such as sulfates and phosphates; organic salts such as acetates, maleates, tartrates, methanesulfonates, benzenesulfonates and toluenesulfonates; and salts with amino acids such as aspartic acid and glutamic acid.

Furthermore, the compounds of the present invention are useful in that they are low in toxicity and highly safe.

When the compound of the present invention is used for the above-mentioned diseases, it may be administered orally or parenterally. It may be administered in the form of tablets, powders, granules, capsules, syrups, lozenges, inhalants, etc.
They can be administered as preparations such as suppositories, injections, ointments, eye ointments, eye drops, nasal drops, ear drops, poultices, lotions, and the like.

The dosage varies significantly depending on the type of disease, severity of symptoms, age, sex, and sensitivity to drugs of the patient, but is usually about 0.03-100 mg/day for adults.
1000 mg, preferably 0.1-500 mg, more preferably 0.1-10
0 mg once a day or in divided doses. In the case of injections, the usual dose is about 1 μg/kg
-3000 μg/kg, preferably about 3 μg/kg-1000 μg/kg
is.

The compound of the present invention can be formulated into a pharmaceutical preparation by a conventional method using a conventional pharmaceutical carrier.

That is, when preparing a solid oral preparation, the main excipient, binder, disintegrant, lubricant, colorant, flavoring agent, antioxidant, etc. are added, and then the mixture is formed into tablets or tablets by the usual method.
It is available in coated tablets, granules, powders, capsules, etc.

Examples of the excipients that can be used include lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose, and silicon dioxide.

Examples of binders include polyvinyl alcohol, polyvinyl ether,
Ethyl cellulose, methyl cellulose, gum arabic, tragacanth, gelatin,
Examples of lubricants that can be used include shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, calcium citrate, dextrin, and pectin, and examples of lubricants that can be used include magnesium stearate, talc, polyethylene glycol, silica, and hardened vegetable oil.

Coloring agents may be any that are permitted to be added to pharmaceuticals, and flavoring agents may include cocoa powder, peppermint, aromatic acids, peppermint oil, borneol, cinnamon powder, etc. Antioxidants may be any that are permitted to be added to pharmaceuticals, such as ascorbic acid and α-tocopherol. Furthermore, tablets and granules may be coated with sugar, gelatin, or other coatings as needed.

On the other hand, when manufacturing injections, eye drops, etc., the main drug may contain a pH adjuster, if necessary.
The injections can be prepared by conventional methods by adding buffers, suspending agents, solubilizing agents, stabilizers, isotonicity agents, antioxidants, preservatives, etc. In this case, they can also be lyophilized as needed. The injections can be administered intravenously, subcutaneously, or intramuscularly.

Examples of the suspending agent include methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, powdered tragacanth, sodium carboxymethyl cellulose, and polyoxyethylene sorbitan monolaurate.

Examples of solubilizing agents include polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, and polyoxyethylene sorbitan monolaurate.

Examples of stabilizers that can be used include sodium sulfite, sodium metasulfite, and ether, and examples of preservatives that can be used include methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol, and chlorocresol.

When an ointment is produced, a stabilizer, an antioxidant, a preservative, etc. may be added as needed, and the ointment can be produced by a conventional method.

The novel purine compounds of the present invention can be produced by combining generally known methods. The main general methods for producing the compounds of the present invention are listed below.

[Manufacturing method A] (wherein ^L1 represents a halogen atom, and ^R1 , ^R2 , ^R3 , Ar, Q and W represent the same groups as defined above.) Step A1 : This step is carried out by reacting a compound 5-amino-4,6
In this step, 4,5-dihalogeno-2-pyrimidine 1 is reacted with various primary amine derivatives in a solvent to substitute only the halogen atom at the 4-position with an amine derivative to produce 4,5-diaminopyrimidine derivative 2 .

The reaction is carried out using an excess of amine, or when the amine to be reacted is an alkylamine, an alkynylamine, an alkynylamine, or an allylamine, triethylamine,
The reaction is carried out in the presence of a tertiary amine such as diisopropylethylamine, and when the amine to be reacted is an arylamine or heteroarylamine, in the presence of a catalytic amount of a mineral acid, preferably hydrochloric acid, but the reaction can also be carried out using a carboxylic acid salt thereof to avoid the coexistence of hydrochloric acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Suitable solvents include NMP (1-methyl-2-pyrrolidone); ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; and halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane. When the amine to be reacted is an arylamine or heteroarylamine, a mixed solvent of alcohol and water can be used. The reaction temperature varies depending on the reactivity of the amine derivative used; room temperature to the boiling point of the solvent is preferred, with reflux temperature being more preferred. Step A2 : This step involves reacting 4,5-diaminopyrimidine derivative 2 with ArCOX (where X is a halogen atom and Ar has the same meaning as above) to produce 5-acylaminopyrimidine derivative 3 .

The reaction is carried out in pyridine or in the presence of a base using a reaction-inert solvent such as methylene chloride, chloroform, ethyl acetate, tetrahydrofuran, dioxane, dimethoxyethane, benzene, toluene, etc. at temperatures from 0° C. to room temperature. Step A3 : This step is a step in which the adjacent acylamino group and substituted amino group on the pyrimidine ring are subjected to dehydration condensation to form an imidazole ring, thereby producing purine derivative 4 .

The reaction is carried out in phosphorus oxychloride under reflux, or in the presence of hydrochloric acid, or by heating in NMP.

Steps A2 and A3 can also be carried out as a one-pot reaction. Step A4 : This step is a step of producing a 6-amino-8,9-disubstituted purine derivative 5 by reacting the halogen atom at the 6-position of the purine derivative 4 with an amine derivative.

When the amine derivative is a gas or has a low boiling point, the reaction is preferably carried out in a sealed tube or an autoclave.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferred examples include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; dimethylformamide, 1-
Methylpyrrolidinone and the like can be mentioned.

The reaction temperature is preferably 0 to 150°C, more preferably 50 to 100°C.
[Manufacturing method B] (wherein ^L2 , ^R1 , ^R2 , ^R3 , Ar, Q and W are the same as defined above. ^R11 is a C1-C4 alkyl group.) Step B1 : This step involves reducing the nitro group of 2-acylamino-4,6-dichloro-5-nitropyrimidine derivative 1 , which is produced by a known method, with catalytic reduction, metal and metal salt reduction, or metal hydride to give 2-acylamino-5-amino-4,
This is a process for producing 6-dichloropyrimidine derivative 2 .

Catalytic reduction is carried out under a hydrogen atmosphere in the presence of a catalyst such as Raney Ni, Pd-C, or _PtO2 at normal pressure or under pressure, at room temperature or under elevated temperature. Preferably, it is carried out at normal pressure and room temperature, more preferably using Raney Ni as the catalyst. The solvent used is not particularly limited as long as it is not a catalyst poison and dissolves the starting material to some extent, but preferred examples include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid, dimethylformamide, etc., or mixed solvents thereof. Metal and metal salt reduction is carried out in an alcoholic system such as hydrous or anhydrous methanol or ethanol, or in a dioxane or tetrahydrofuran solvent with zinc powder-hydrochloric acid, stannous chloride-hydrochloric acid, iron-hydrochloric acid, etc. Reduction with a metal hydride is carried out in a methanol, ethanol, or tetrahydrofuran solvent with P
This is carried out using sodium d-borohydride, _NiCl2 ( _PPh3 ) ₂ -sodium borohydride, stannous chloride-sodium borohydride, etc. Step B2 : This step is a step of producing a 4,5-diaminopyrimidine derivative 3 by reacting a 2-acylamino-5-amino-4,6-dichloropyrimidine derivative 2 with a primary amine derivative to substitute only the chlorine atom at the 4-position with an amino derivative.

The reaction is carried out using an excess of amine, or when the amine to be reacted is an alkylamine, an alkynylamine, an alkynylamine, or an allylamine, triethylamine,
The reaction is preferably carried out in the presence of a tertiary amine such as diisopropylethylamine, and when the amine to be reacted is an arylamine or heteroarylamine, in the presence of a catalytic amount of a mineral acid, particularly hydrochloric acid.

The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferred examples include ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; and halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane. The reaction temperature varies depending on the reactivity of the amine derivative used, and is preferably room temperature to reflux, more preferably reflux. Step B3 : This step is a step of producing 2-aminopyrimidine derivative 4 by removing the acyl group that is the protecting group for the amino group at the 2-position of the above 2-acylaminopyrimidine derivative 3 .

The reaction is carried out in a solvent such as methanol, ethanol, dioxane, tetrahydrofuran, etc., by reacting with a mineral acid or an aqueous alkali solution. The reaction proceeds at room temperature, but is preferably carried out under heating.

This step may be completed in the previous step B2 depending on the substitution conditions with the amino derivative in step B2, in which case it is omitted. Step B4 : This step is a step in which the amino groups at the adjacent 4- and 5-positions on the pyrimidine ring are subjected to dehydration condensation with an aldehyde to form an imidazole ring, thereby producing purine derivative 5 .

The reaction is carried out by condensing the amino group at the 5-position with an aldehyde derivative to form a Schiff's base, and then by reacting it with ferric chloride or the like to close the ring.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferred solvents include alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether, and dimethylformamide.
The reaction is carried out at 0 to 100°C, preferably at room temperature. It is preferable to add acetic acid during the preparation of Schiff's base. Step B5 : This step is a step of converting the amino group of the 2-aminopurine derivative 6 to a halogen atom by the Sandmeyer reaction to prepare a 2,6-dihalogenopurine derivative 6 .

The reaction is carried out by diazotizing the amino group with sodium nitrite or a nitrite ester such as amyl nitrite or isoamyl nitrite to form a diazonium group, and then converting the diazonium group to a halogen atom using cuprous halide. When using a nitrite ester such as isoamyl nitrite in the diazotization reaction, no acid is required; instead, the amino group can be converted to a halogen atom by adding cuprous halide and methylene halide to a solvent such as dioxane or tetrahydrofuran and heating. In the present invention, it is most preferable to use cuprous iodide as the cuprous halide and diiodomethane as the methylene halide to convert to a 2-iodopurine derivative. Step B6 : This step is a step in which the chlorine atom at the 6-position of the 6-chloro-2-iodopurine derivative 6 is reacted with an amine derivative to produce a 6-amino-2-iodopurine derivative 8 .

When the amine derivative is a gas or has a low boiling point, the reaction is preferably carried out in a sealed tube or an autoclave.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferred examples include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; dimethylformamide, 1-
Methylpyrrolidinone and the like can be mentioned.

The reaction temperature is preferably 0 to 150°C, more preferably 50 to 100°C.
Step B7 : This is a step for producing a 2-ethynylene-6-halogenopurine derivative 8 by selectively coupling the halogen atom at the 2-position of the 2-halogenopurine derivative 7 with an ethynyl side chain.

The reaction is carried out at room temperature or under heating in the presence of catalytic amounts of dichlorobistriphenylphosphinepalladium(II), cuprous iodide, and a tertiary amine. Examples of solvents used include ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether, as well as dimethylformamide and 1-methylpyrrolidinone. Examples of tertiary amines used include triethylamine, diisopropylethylamine, DBU, and dimethylaniline. The reaction temperature is preferably 0 to 100°C, more preferably room temperature.

[Manufacturing method C] wherein R ¹ , R ² , Ar, Q and W are the same groups as defined above, R ¹² is a C1-C6 alkyl group;
R ¹³ represents a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or a C3-C6 cycloalkyl group optionally having a substituent. means a pyridinyl group, a pyrimidyl group or a pyrazinyl group, and the formula means a dihydrooxopyridinyl or pyrimidyl group, or a dihydro or tetrahydropyrazinyl group.) This production method C is a method for producing an α-hydroxy nitrogen-containing heteroaryl derivative by hydrolyzing the alkoxy group of a nitrogen-containing heteroaryl compound where ^R3 is α-alkoxy, obtained by production method A or B, or a production method for introducing a substituent into the nitrogen atom of these rings. Step C1 : This step is a step for hydrolyzing the alkoxy group of a 9-α-alkoxy nitrogen-containing heteroaryl purine derivative 1 to produce a 9-α-hydroxy nitrogen-containing heteroaryl purine derivative 2 .

The reaction is carried out in the presence of an aqueous solution of a mineral acid such as hydrochloric acid, hydrobromic acid, or sulfuric acid at room temperature to 100° C. Step C2 : This step is a step of introducing a substituent into the nitrogen atom of the 9-α-hydroxy nitrogen-containing heteroaryl purine derivative 2 obtained above.

The reaction is carried out in the presence of a base in a solvent by reacting with an alkyl halide compound, a fluoroalkyl halide compound, an alkoxycarbonylalkyl halide compound, various sulfonate compounds, or the like.

Examples of the base include sodium hydride, sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, or sodium alkoxide, and examples of the solvent include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; N,N-dimethylformamide, dimethyl sulfoxide, and 1-methylpyrrolidinone. The reaction temperature is 0° C. to 10° C.
It is carried out at 0°C.

[Manufacturing method D] (Wherein ^R2 " means a C1-C8 alkoxy group, ^R1 , ^R3 , ^L2 , Ar,
Q and W have the same meanings as defined above. In this production method D, the halogen atom at the 2-position of compound 7 obtained in production method B is substituted with a C1
This is a method for converting a C1 to C8 alkoxy group.

The reaction proceeds when ^L2 is any halogen atom, but a bromo atom is preferred. The iodo derivative is readily converted to the bromo derivative by treatment with hydrobromic acid solution.

The reaction is carried out by reaction with sodium or potassium alkoxide.

[Manufacturing method E] (wherein ^R8 represents a C1-C4 alkyl group, and ^R1 , ^R3 , Ar, Q and W
means the same group as defined above.) This production method is a method in which the ethynylene group of compound 8 obtained by production method B is reduced by catalytic reduction to obtain an alkyl derivative.

The catalytic reduction is carried out in a hydrogen atmosphere in the presence of a catalyst such as Raney Ni, Pd-C, or _PtO2 at normal pressure or under pressure, at room temperature or under elevated temperature. Preferably, it is carried out at normal pressure and room temperature, more preferably using Raney Ni as the catalyst. The solvent used is not particularly limited as long as it is not a catalyst poison and can dissolve the starting materials to some extent, but preferred examples include methanol, ethanol, tetrahydrofuran, dioxane, acetic acid, dimethylformamide, etc., or mixed solvents of these.

Next, pharmacological experimental examples will be given to illustrate the excellent effects of the purine compounds of the present invention.

Effects of Novel Purine Compounds 1) Adenosine A2a Receptor Binding Experiments Adenosine A2a receptor-overexpressing membrane preparations were purchased from Receptor Biology Inc. and used to conduct adenosine A2a receptor binding experiments. The purchased membrane preparations were diluted with I to a concentration of 22.2 μg/ml.
incubation buffer (20mM HEPES, 10mM MgC
_1.2 ml of 100 mM NaCl, pH 7.4) was added and suspended.
To 45 ml of the solution, tritium-labeled ^3H -CGS21680 (500 nM;
The test compound solution was first dissolved in DMSO to a compound concentration of 20 mM.
The mixture was allowed to stand at 25°C for 90 minutes, and then filtered through a glass fiber filter (GF/B; Whatman).
The filter was then rapidly filtered by suction and immediately washed twice with 5 ml of ice-cold 50 mM Tris-HCl buffer.The glass fiber filter was then transferred to a vial, a scintillator was added, and the amount of radioactivity on the filter was measured using a liquid scintillation counter.
The inhibition rate of the test compound against A2a receptor binding ( ³ H-CGS21680) was calculated by the following formula, and IC ₅₀ was calculated based on this.

Inhibition rate (%) = [1 - {(binding amount in the presence of drug - non-specific binding amount) / (total binding amount - non-specific binding amount)}] x 100. The total binding amount is the amount of radioactivity bound to ^3H -CGS21680 in the absence of a test compound. The non-specific binding is the amount of radioactivity bound to ^3H -CGS21680 in the presence of 100 μM RPIA.
The amount of binding in the presence of a drug is the amount of radioactivity bound to ³ H-CGS21680 in the presence of various concentrations of the test compound.

The inhibition constant (Ki value) was calculated using the Cheng-Prusoff equation.

The compounds of Example 5 and Example 20 each had an inhibition constant (Ki value) of 0.0.
2) Inhibition of NECA-stimulated cAMP production in adenosine A2b receptor-expressing cells
Evaluation of test compounds using inhibition as an index Human adenosine A2b receptor cDNA was overexpressed in CHOK1 cells. The cells were uniformly seeded on a 24-well plate at 1.5 x ¹⁰⁵ cells/well, cultured overnight, and then used in the experiment.
The amount of cAMP produced by stimulation with Krebs-Ringer-Bicarbonate buffer (30 nM) was suppressed in the presence of the test compound, and the affinity of the test compound for the A2b receptor was evaluated based on this.
fer(KRB) (:mM) (NaCl 118, KCl 4.8, KH ₂ PO
₄ 1.2, MgSO ₄ 1.2, CaCl ₂ 3.4, HEPES 10, N
aHCO ₃ 25, pH: 7.4) 2 ml/well, washed twice, then 0.5 ml
Pre-incubation was performed for 30 minutes in each well.
724 (phosphodiesterase inhibitor) 600μ
A mixed solution containing NECA (180 nM) and a test compound at a concentration 6 times higher than that of the reaction solution was added at 100 μl/well. After 15 minutes, 0.1 N HCl (3
The reaction is stopped by replacing the reaction solution with 000 μl/well of cAMP.
Measurement was carried out using Amersham cAMP EIA Kit.

The inhibition rate of the test compound against NECA-stimulated cAMP production was calculated according to the following formula.

Inhibition rate (%) = [1 - {(cAMP amount in the presence of NECA and test compound - Bas
Basal cAMP level)/(cAMP level stimulated by NECA alone - Basal cAMP
Amount)} × 100 From this, IC ₅₀ was calculated.

The _IC50 of the compound of Example 5 was 0.011 μM. 3) Inhibitory effect on NECA-stimulated glucose production in primary cultured rat hepatocytes Hepatocytes were isolated from the livers of male Wistar rats by collagenase perfusion and primary cultured in William's Medium E containing 5% calf serum, ^10-6 M insulin, and ^10-7 M dexamethasone. After one day, the hepatocytes were cultured in Krebs-Rin containing 10 mM HEPES and 0.1% bovine serum albumin.
ger-Bicarbonate buffer (mM) (NaCl 118,
KCl 4.8, KH ₂ PO ₄ 1.2, MgSO ₄ 1.2, CaCl ₂ 3
After washing with KRB (Korean broth, 100 ml of PBS, 100 ml of HEPES, 25 _{ml of} NaHCO3, pH 7.4), KRB was added and the cells were incubated at 37°C. After 30 minutes, NECA (Ne-e
thylcarboxamide adenosine) (final concentration; 0.1μ
M) and the test compound were added simultaneously, and the mixture was further incubated for 1 hour, after which the amount of glucose released into the incubation medium was measured.

IC of the compounds of Example 5 and Example 20 for inhibition of NECA-stimulated glucose release
₅₀ (μM) were 0.0076 and 0.0084, respectively. 4) Effect on hyperglycemia in spontaneously diabetic mice (KK-A ^y /Ta Jcl)
(Single administration) Animals: 7 male KK-A ^y /Ta Jcl mice per group (purchased from CLEA Japan)
.

Preparation and administration of test compounds: Test compounds at the doses shown in Table 1 were suspended in a 0.5% aqueous methylcellulose solution and orally administered at a volume of 10 ml/kg.

Blood collection and measurement of blood glucose level: Blood was collected from the tail vein immediately before and 5 hours after administration of the test compound, and blood glucose level was measured.

Method: Under no anesthesia, the tail vein of the mouse was incised with a razor to induce slight bleeding.
Immediately mix 135 μl of 0.6 M perchloric acid with 135 μl of 0.6 M perchloric acid.
The supernatant was centrifuged at 1000g for 10 minutes at 4°C using a refrigerated centrifuge GS-6KR (Beckman Co., Ltd.) and the glucose in the supernatant was measured using Glucose CII Test Wako (Wako Pure Chemical Industries, Ltd.).

The results are shown in Table 1.

The results are shown as a percentage ratio of the blood glucose level 5 hours after administration to the blood glucose level before administration ± standard error.
Data was subjected to one-way analysis of variance followed by Dunnett's multiple comparison, and p<0.05 was determined to be a significant difference.

As described above, the compound of the present invention has an adenosine A2 receptor antagonistic action and exhibits a clear effect on diabetic pathological models.
It also showed an improving effect on impaired glucose tolerance in a glucose tolerance test, confirming that it acts not only in the liver but also in the periphery.

Next, novel methods for synthesizing purine compounds of the present invention will be listed, but the purpose of these is to facilitate understanding of the present invention, and it goes without saying that the present invention is not limited to these compounds.

Example 1 8-(3-fluorophenyl)-9-(6-methoxy-3-pyridyl)-9H-
6-Purinamine (1) N4-(6-methoxy-3-pyridyl)-6-chloro-4,5-pyrimidinyl
Synthesis of 5-amino-4,6-dichloropyrimidine hydrochloride (10.0 g, 45.2 mmol);
To a suspension of 5-amino-2-methoxypyridine (manufactured by Tokyo Chemical Industry Co., Ltd.) in water (100 ml) and ethanol (15 ml) were added 5-amino-2-methoxypyridine (8.7 g, 70.1 mmol) and concentrated hydrochloric acid (1.5 ml) successively at room temperature, followed by heating under reflux for 3 hours. After cooling, the resulting solid was collected by filtration, washed with water, and air-dried at 50°C to obtain the title compound (6.6 g, 72%) as a reddish-brown solid. ^1H NMR (400 Hz, DMSO- _d6 ) δ ppm: 3.84 (3H, s)
, 6.84 (1H, d, J = 9.6Hz), 7.82 (1H, s), 7.99 (
1H, dd, J = 2.8, 9.6Hz), 8.39 (1H, d, J = 2.8Hz
), 8.78 (1H,s). (2) N1-[4-chloro-6-[(methoxy-3-pyridyl)amino]-5-
Synthesis of [pyrimidinyl]-3-fluorobenzamide (1) (6.6 g, 22.9 mmol) in pyridine (66 ml)
The suspension was treated with 3-fluorobenzoyl chloride (9.6 ml,
79.0 mmol) was added dropwise over 80 minutes, and the mixture was stirred for 5 hours. The reaction mixture was diluted with water and ethyl acetate. The organic layer was washed with 1N hydrochloric acid (x1). The 1N hydrochloric acid layer was extracted with ethyl acetate (x2), and the combined organic layers were washed with saturated aqueous sodium bicarbonate solution (x1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (6.5 g, 76%) as a colorless solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm; 3.84 (3H, s
), 6.84 (1H, d, J = 8.8Hz), 7.47-7.54 (1H, m)
, 7.59-7.66 (1H, m), 7.81-7.94 (3H, m), 8.2
6 (1H, d, J = 2.4Hz), 8.33 (1H, s), 9.38 (1H, s
), 10.16 (1H,s). (3) 6-chloro-8-(3-fluorophenyl)-9-(6-methoxy-3-
Synthesis of (pyridyl)-9H-purine (3)
The resulting suspension (300 ml) was heated to reflux under a nitrogen atmosphere for 4.5 hours. After cooling, the reaction mixture was concentrated. The residue was diluted with ethyl acetate, washed with water (x3), saturated aqueous sodium bicarbonate solution (x2), and saturated brine (x1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (248 mg, 60%) as a colorless solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm; 3.93 (3H, s
), 7.05 (1H, d, J=8.8Hz), 7.38-7.48 (3H, m)
, 7.50-7.56 (1H, m), 7.90 (1H, dd, J=2.8, 8.
(1H, d, J = 2.8 Hz), 8.35 (1H, d, J = 2.8 Hz), 8.79 (1H, s). (4) 8-(3-fluorophenyl)-9-(6-methoxy-3-pyridyl)-
Synthesis of 9H-6-purinamine A suspension of the compound (1.0 g, 2.81 mmol) obtained in (3) in 1,2-dimethoxyethane (40 ml) and concentrated aqueous ammonia (20 ml) was placed in an autoclave for 7 min.
The mixture was stirred at 0°C for 11 hours. After cooling, the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride (x1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in diethyl ether, and the solid matter was collected by filtration and washed with diethyl ether to give the title compound (92
8 mg, 98%) was obtained as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.91 (3H, s
), 6.99 (1H, d, J=8.8Hz), 7.26-7.33 (2H, m)
, 7.34-7.38 (1H, m), 7.43-7.49 (1H, m), 7.5
0 (2H, brs), 7.81 (1H, dd, J=2.8, 8.8Hz), 8.
14 (1H, s), 8.23 (1H, d, J = 2.8 Hz). Example 2 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
,2-dihydro-2-pyridinone A suspension of 8-(3-fluorophenyl)-9-(6-methoxy-3-pyridyl)-9H-6-purinamine (890 mg, 2.65 mmol) obtained in Example 1 in concentrated hydrobromic acid aqueous solution (12 ml) was stirred for 15 minutes at 100° C. After cooling, the reaction solution was neutralized with 5N aqueous sodium hydroxide solution, and the resulting solid was collected by filtration and washed with water, ethyl acetate, and diethyl ether to give the title compound (767 mg, 90%).
was obtained as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm; 6.42 (1H, d
, J=9.2Hz), 7.29-7.36 (1H, m), 7.40-7.56 (
6H, m), 7.70 (1H, d, J = 2.8 Hz), 8.15 (1H, s). This compound (200 mg, 0.621 mmol) was dissolved in methanol-4N hydrochloric acid/ethyl acetate (10 drops) and concentrated. The residue was crystallized from methanol-ethyl acetate-diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the hydrochloride salt (189 mg, 85%) as a colorless solid. ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm; 6.47 (1H, d
, J=9.6Hz), 7.36-7.43 (1H, m), 7.44-7.60 (
4H, m), 7.77 (1H, d, J=2.8Hz), 8.47 (1H, s).
MS m/e (ESI): 323 (MH ⁺ ). Example 3 5-[8-(3-fluorophenyl)-6-(methylamino)-9H-9-purine
Nyl]-1,2-dihydro-2-pyridinone hydrochloride The synthesis was carried out in the same manner as in Example 2, except that monomethylamine was used instead of ammonia in (4) of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.10 (3H, b
r s), 6.47 (1H, d, J = 9.2Hz), 7.34-7.42 (1H
, m), 7.42-7.60 (4H, m), 7.76 (1H, d, J = 2.8H
2, 8.41 (1H, s). MS m/e (ESI): 337 (MH ⁺ ). Example 4 5-[6-(dimethylamino)-8-(3-fluorophenyl)-9H-9-propanol]
Linyl]-1,2-dihydro-2-pyridinone hydrochloride The synthesis was carried out in the same manner as in Example 2, except that dimethylamine was used instead of ammonia in (4) of Example 1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.56 (6H, b
r s), 6.46 (1H, d, J = 9.2Hz), 7.32-7.39 (1H
, m), 7.42-7.57 (4H, m), 7.75 (1H, d, J = 2.8H
z), 8.32 (1H,s). MS m/e (ESI): 351 (MH ⁺ ). Example 5 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
-Methyl-1,2-dihydro-2-pyridinone hydrochloride 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1,2-dihydro-2-pyridinone (1.0 g, 3.10 mmol) from Example 2
To a suspension of the above in N,N-dimethylformamide (10 ml), N,N-dimethylformamide dimethyl acetal (0.5 ml, 3.76 mmol) was added and the mixture was stirred at room temperature under a nitrogen atmosphere. After 1 hour, N,N-dimethylformamide dimethyl acetal (0.5 ml, 3.76 mmol) was added, and the mixture was stirred for an additional 1.5 hours. The reaction mixture was ice-cooled and then added to 60-70% sodium hydride (136 mg,
After 30 minutes, iodomethane (0.29 ml) was added and stirred.
, 4.66 mmol) was added dropwise and the mixture was further stirred. After 20 minutes, concentrated aqueous ammonia (
10 ml) was added and stirred at room temperature. After 16 hours, the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The aqueous layer was extracted with ethyl acetate (x4), and the combined organic layers were washed with 1N aqueous sodium hydroxide solution (x1) and saturated aqueous ammonium chloride solution (x1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in ethyl acetate, and the solid matter was collected by filtration and washed with ethyl acetate.
The title compound (703 mg) was obtained as a free form. The free form was dissolved in methanol-4N hydrochloric acid/ethyl acetate (1.5 ml) and concentrated. The residue was crystallized from methanol-ethyl acetate-diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (697 mg, 60%) as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm; 3.46 (3H, s
), 6.52 (1H, d, J = 9.2Hz), 7.36-7.43 (1H, m)
, 7.44-7.60 (4H, m), 8.15 (1H, d, J=2.8Hz),
8.42 (1H, s). MS m/e (ESI): 337 (MH ⁺ ). Example 6 5-[6-(dimethylamino)-8-(3-fluorophenyl)-9H-9-propanol]
Linyl]-1-methyl-1,2-dihydro-2-pyridinone hydrochloride 5-[6-(dimethylamino)-8-(3-fluorophenyl)- of Example 4
9H-9-purinyl]-1,2-dihydro-2-pyridinone hydrochloride (130 mg
, 0.336 mmol) in N,N-dimethylformamide (3 ml),
Under a nitrogen atmosphere, 60-70% sodium hydride (28 mg, 0.7
1 hour later, iodomethane (23 μl, 0.36 mmol) was added and stirred.
9 mmol) was added dropwise and stirred. After 30 minutes, 60-70% sodium hydride (1
7 mg, 0.425 mmol) and, after a further 30 min, iodomethane (23 μl,
0.369 mmol) was added and stirred. After 30 minutes, the reaction mixture was diluted with saturated aqueous ammonium chloride solution and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride solution (x1) and then extracted with 1N hydrochloric acid (x1). The 1N hydrochloric acid layer was
The pH was adjusted to 9-10 with a N aqueous solution of sodium hydroxide, and ethyl acetate (x1)
The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in methanol-4N hydrochloric acid/ethyl acetate (1.5 ml) and concentrated. The residue was crystallized from methanol-diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (90 mg, 67%) as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm; 3.46 (3H, s
), 3.56 (6H, s), 6.51 (1H, d, J=9.6Hz), 7.33
-7.39 (1H, m), 7.46-7.56 (4H, m), 8.14 (1H,
d, J = 2.4 Hz), 8.31 (1H, s). MS m/e (ESI): 365 (MH ⁺ ). Example 7 8-(3-fluorophenyl)-2-iodo-9-(6-methoxy-3-pyridinyl)
(I)-9H-6-purinamine (1) N1-(5-amino-4,6-dichloro-2-pyrimidinyl)acetamido
Synthesis of N-(4,6-dichloro-5-nitro-2-pyrimidinyl)acetamide (
After suspending Raney nickel (100 g, 0.40 mol) and Raney nickel (100 g, wet) in methanol (1.5 L), the mixture was vigorously stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 5 hours. After filtering off the nickel, the filtrate was concentrated. The residue was crystallized from methanol-ethyl acetate, and the crystals were filtered and washed with ethyl acetate to give the title compound (44
.6 g, 51%) was obtained as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 2.05 (3H, s
), 5.78 (2H,s), 10.53 (1H,s). (2) N4-(6-Methoxy-3-pyridyl)-6-chloro-2,4,5-pyridyl
The compound obtained from 1-(10.0 g, 45.2 mmol) of 1- (1, 200 ml) of water
A suspension of 5-amino-2-methoxypyridine (
After adding 12.4 g (99.9 mmol) and concentrated hydrochloric acid (3.0 ml) in that order,
The mixture was heated under reflux for 3.5 hours, allowed to cool, and then neutralized with a saturated aqueous solution of sodium bicarbonate.
The resulting crystals were collected by filtration, washed with water, and air-dried at 50°C to obtain the title compound (9.25 g,
66%) was obtained as a reddish-brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.83 (3H, s
), 4.16 (2H, br s), 5.89 (2H, br s), 6.78 (1
H, d, J = 9.0Hz), 8.00 (1H, dd, J = 2.6, 9.0Hz)
, 8.36 (1H, s), 8.56 (1H, d, J = 2.6 Hz). (3) 6-chloro-8-(3-fluorophenyl)-9-(6-methoxy-3-
The compound obtained from (2) (6.0 g, 19.4 mmol) of 9H-2-pyridyl-p- rinamine was dissolved in methanol (60 ml
) suspension was added with 3-fluorobenzaldehyde (3.0 g, 24.2 mmol) at room temperature.
After adding 1.8 ml of acetic acid (1.8 ml) and stirring at room temperature for 15 hours, the reaction mixture was concentrated and then azeotroped twice with toluene. The resulting azeotropic residue was suspended in 60 ml of ethanol and diluted with 30 ml of anhydrous iron(III) chloride in ethanol at room temperature.
After adding a solution of 1H-dimethylformamide (DMSO-d 6 ), the mixture was heated under reflux for 3.5 hours. After allowing to cool, the reaction mixture was concentrated. The residue was suspended in a small amount of ethanol, and the solid matter was collected by filtration and washed with ethanol to obtain the title compound (5.2 g, 72%) as a brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm; 3.91 (3H, s
), 7.00 (1H, d, J=8.8Hz), 7.09 (2H, br s), 7
．． 27-7.35 (3H, m), 7.42-7.48 (1H, m), 7.83 (
1H, dd, J = 2.6, 8.8Hz), 8.30 (1H, d, J = 2.6Hz
(4) 6-chloro-8-(3-fluorophenyl)-2-iodo-9-(6-methylphenyl)-
To a solution of the compound obtained by (3-thiazol-3-pyridyl)-9H-purine (3) in tetrahydrofuran (80 ml), copper(I) iodide (2.1 g, 11.0 mmol), diiodomethane (4.4 ml, 5
After adding nitrite (4.4 ml, 32.8 mmol) and isoamyl nitrite (4.4 ml, 32.8 mmol) successively, the mixture was stirred at 70°C for 2 hours. After allowing to cool, insoluble material was removed by filtration. The filtrate was diluted with ethyl acetate and 1N hydrochloric acid, and the organic layer was washed with concentrated aqueous ammonia-saturated aqueous ammonium chloride (1:1) (x1) and saturated aqueous ammonium chloride (x1), then dried over anhydrous sodium sulfate and concentrated. The residue was suspended in diethyl ether, and the solid matter was collected by filtration and washed with diethyl ether to give the title compound (2.9
8 g, 57%) was obtained as a reddish-brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.94 (3H, s
), 7.06 (1H, d, J = 8.8Hz), 7.34-7.44 (3H, m)
, 7.48-7.55 (1H, m), 7.88 (1H, dd, J=2.8, 8.
(1H, d, J = 2.8 Hz), 8.34 (1H, d, J = 2.8 Hz). (5) 8-(3-fluorophenyl)-2-iodo-9-(6-methoxy-3-
A suspension of the compound (2.98 g, 61.9 mmol ) obtained in (4) in 1,2-dimethoxyethane (60 ml) and concentrated aqueous ammonia (30 ml) was stirred in an autoclave at 70° C. for 6 hours. After cooling, the reaction mixture was concentrated. The residue was suspended in methanol, and the solid matter was collected by filtration and washed with methanol to obtain the title compound (2.69 g, 9
4%) was obtained as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.92 (3H, s
), 7.00 (1H, d, J=9.0Hz), 7.24-7.35 (3H, m)
, 7.42-7.49 (1H, m), 7.81 (1H, dd, J=2.6, 9.
0Hz), 7.92 (2H, br s), 8.25 (1H, d, J=2.6Hz
Example 8 5-[6-amino-2-bromo-8-(3-fluorophenyl)-9H-9-propanol]
Linyl]-1,2-dihydro-2-pyridinone A suspension of the compound of Example 7 (100 mg, 0.216 mmol) in concentrated hydrobromic acid (2 ml) was stirred at 100° C. for 15 minutes. After cooling, the reaction mixture was diluted with water, and the solid matter was collected by filtration and washed with water and ether to obtain the title compound (71 mg,
79%) was obtained as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 6.45 (1H, d
, J=9.6Hz), 7.30-7.38 (1H, m), 7.38-7.46 (
2H, m), 7.46-7.66 (2H, m), 7.73 (1H, d, J=2.
8Hz), 8.01 (2H, br s). Example 9 5-[6-amino-8-(3-fluorophenyl)-2-propoxy-9H-9
-purinyl]-1,2-dihydro-2-pyridinone hydrochloride The compound of Example 8 (82 mg, 0.204 mmol) was added to a solution of sodium (30 mg, 1.30 mmol) in 1-propanol (3 ml) at 90° C., and the mixture was then heated to reflux for 4 hours. After cooling, the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride (×1), dried over anhydrous sodium sulfate, and concentrated. The residue was dissolved in 5N hydrochloric acid in methanol (3 drops) and concentrated. The residue was crystallized from methanol-ether, and the solid was collected by filtration and washed with ether to give the title compound (71 mg, 67%).
was obtained as a colorless solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm; 6.45 (1H, d
, J=9.6Hz), 7.30-7.38 (1H, m), 7.38-7.46 (
2H, m), 7.46-7.66 (2H, m), 7.73 (1H, d, J=2.
8 Hz), 8.01 (2H, br s). MS m/e (ESI): 381 (MH ⁺ ). Example 10 8-(3-fluorophenyl)-9-(6-methoxy-3-pyridyl)-2-(
1-pentynyl)-9H-6-purinamine The compound of Example 7 (200 mg, 0.433 mmol), copper(I) iodide (8
mg, 42.0 μmol), dichlorobis(triphenylphosphine)palladium(II) (30 mg, 42.7 μmol), and 1-pentyne (60 mg, 0
Triethylamine (0.2 ml, 1.43 mmol) was added dropwise to a suspension of 1.880 mmol of ammonium hydroxide in N,N-dimethylformamide (3 ml) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 18 hours. The reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The organic layer was diluted with concentrated aqueous ammonia/saturated aqueous ammonium chloride (1:1) solution.
The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (148 mg, 85%) as a pale brown solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm; 0.97 (3H, t
, J=7.2Hz), 1.53 (2H, sex, J=7.2Hz), 2.35(
2H, t, J = 7.2Hz), 3.92 (3H, s), 7.01 (1H, d, J
=8.8Hz), 7.26-7.38 (3H, m), 7.42-7.49 (1H
, m), 7.61 (2H, br s), 7.80 (1H, dd, J = 2.8, 8
.8 Hz), 8.24 (1H, d, J = 2.8 Hz). Example 11 8-(3-fluorophenyl)-9-(6-methoxy-3-pyridyl)-2-phenyl
butyl-9H-6-purinamine The compound of Example 10 (127 mg, 0.316 mmol) was dissolved in methanol (20
To the solution (25 ml) of 10% aqueous palladium on carbon (25 mg) was added, and the mixture was vigorously stirred under a hydrogen atmosphere at room temperature and atmospheric pressure for 4.5 hours. The palladium on carbon was filtered off, and the filtrate was concentrated to obtain the title compound (122 mg, 95%) as a brown solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm; 0.88 (3H, t, J
=7.2Hz), 1.27-1.40 (4H, m), 1.70-1.83 (2H
, m), 2.75 (2H, t, J=7.6Hz), 3.98 (3H, s), 5.
87 (2H, br s), 6.85 (1H, d, J=8.8Hz), 7.06-
7.12 (1H, m), 7.19-7.34 (3H, m), 7.53 (1H, d
d, J = 2.8, 8.8 Hz), 8.13 (1H, d, J = 2.8 Hz). Example 12 5-[6-amino-8-(3-fluorophenyl)-9-(6-methoxy-3-
pyridyl)-2-pentyl-9H-9-purinyl]-1,2-dihydro-2-pyridyl
Lidinone Hydrochloride 8-(3-fluorophenyl)-9-(6-methoxy-3-
(pyridyl)-2-pentyl-9H-6-purinamine was treated in the same manner as in Example 2,
The compound was converted to a hydrochloride salt to give the title compound. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 0.86 (3H, t
, J=7.2Hz), 1.25-1.37 (4H, m), 1.65-1.77 (
2H, m), 2.80 (2H, t, J = 7.6Hz), 6.47 (1H, d, J
=9.6Hz), 7.36-7.37 (3H, m), 7.51 (1H, dd, J
=2.8, 9.6Hz), 7.53-7.60 (1H, m), 7.76 (1H,
d, J = 2.8 Hz). MS m/e (ESI): 393 (MH ⁺ ). Example 13 N-[8-(3-fluorophenyl)-9-(2-propynyl)-9H-6-propynyl]
Linyl]-N,N-dimethylamine hydrochloride 1) Synthesis of N4-(2-propenyl)-6-chloro-4,5-pyrimidinediamine
A solution of 8 g of 5-amino-4,6-dichloropyrimidine, 5 ml of propargylamine, and 42 ml of diisopropylethylamine in 100 ml of butanol was stirred under a nitrogen atmosphere at 140° C. for 6 hours and 10 minutes. Ethyl acetate and H ₂ O were added to the reaction mixture, and the resulting mixture was stirred for 6 hours and 10 minutes.
The mixture was filtered through Celite, and the residue was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the residue was purified by silica gel column chromatography (ethyl acetate:n
The residue was crystallized from diethyl ether to give the title compound (4.8 g, 54%) as pale brown crystals. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 2.26 (1H, t, J)
=2.4Hz), 3.40 (2H, br s), 4.28 (2H, d, J=2.
4 Hz), 4.98 (1H, br s), 8.10 (1H, s). 2) 6-chloro-8-(3-fluorophenyl)-9-(2-propynyl)-9
3) N-[8-(3-fluorophenyl)-9-(2- propynyl )-9H-6]-purine was reacted with N-[8-(3-fluorophenyl)-9-(2-propynyl)-9H-6]-chloro-4,5-pyrimidinediamine obtained in 1) and 3-fluorobenzoyl chloride in the same manner as in 2) of Example 1 to obtain the title compound.
-purinyl]-N,N-dimethylamine hydrochloride 6-chloro-8-(3-fluorophenyl)-9-(2-propynyl)-9H
A solution of 150 mg of purine and 5 ml of 40% aqueous dimethylamine solution in 5 ml of ethanol was stirred in an autoclave at 70°C for 14 hours. _H2O was added to the reaction mixture, and the resulting suspension was washed with diethyl ether and collected by filtration to obtain N-[8-(3-fluorophenyl)-9-(2-propynyl)-9H-6-purinyl]-N,N-dimethylamine. 1 ml of 5M aqueous hydrochloric acid was added to a methanol suspension of this compound at room temperature, and the solvent was removed from the methanol solution by distillation under reduced pressure. The resulting suspension was washed with diethyl ether and collected by filtration to obtain the title compound (97 mg, 64%). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm; 3.47 (1H, t
, J=2.4Hz), 3.56 (6H, brs), 5.16 (2H, d, J=2
．． 4Hz) 7.45-7.47 (1H, m), 7.63-7.69 (1H, m)
, 7.72-7.78 (2H, m), 8.39 (1H, s). MS m/e (ESI): 296 (MH ⁺ ). Compounds of Examples 14 to 16 were obtained in the same manner.

Example 148-(3-fluorophenyl)-9-(2-propynyl)-6-tetrahydro-
1H-1-pyrrolyl-9H-purine hydrochloride ¹H NMR (400MHz, DMSO-d₆) δppm; 1.93-2.10
(4H, m), 3.51 (1H, t, J=2.4Hz), 3.66-3.81 (
2H, m), 4.15-4.30 (2H, m), 5.20 (2H, d, J=2.
4Hz), 7.42-7.49 (1H, m), 7.63-7.69 (1H, m)
, 7.73-7.78 (2H, m), 8.44 (1H, s). MS m/e (ESI): 322 (MH⁺) Example 15N-cyclopropyl-N-[8-(3-fluorophenyl)-9-(2-propyl
(9H-6-purinyl)amine ¹H NMR (400MHz, DMSO-d₆) δppm; 0.74-0.89
(2H, m), 0.89-0.94 (2H, m), 2.80-2.97 (1H,
m), 3.46 (1H, t, J=2.0Hz), 5.15 (2H, d, J=2.
0Hz), 7.46-7.50 (1H, m), 7.65-7.76 (3H, m)
, 8.54 (1H, s). MS m/e (ESI): 308 (MH⁺) Example 168-(3-fluorophenyl)-9-(2-propynyl)-9H-6-purine
Methylamine Hydrochloride ¹H NMR (400MHz, DMSO-d₆) δppm; 3.52 (1H, t
, J=2.4), 5.16 (2H, d, J=2.4), 7.47-7.51 (1
H, m), 7.66-7.77 (3H, m), 8.45 (1H, s). MS m/e (ESI): 267.92 (MH⁺) Example 179-Allyl-8-(3-fluorophenyl)-9H-6-purinamine hydrochloride
The same procedure as in Example 13 was repeated except that allylamine was used in place of propargylamine.
The title compound was obtained.¹ H NMR (400MHz, DMSO-d₆) δppm; 4.83 (1H, d
d, J=0.91, 17.2), 4.95 (2H, m), 5.16 (1H, dd
, J=0.91, 10.4), 7.45-7.47 (1H, m), 7.61-7
．． 65 (3H, m), 8.48 (1H, s). MS m/e (ESI): 269.91 (MH⁺) Example 189-(2-butynyl)-8-(3-fluorophenyl)-9H-6-purinami
Hydrochloride 1) 2-butynyl methanesulfonate138g of 2-butyn-1-ol and 683ml of triethylamine in methylene chloride
305 ml of methanesulfonyl chloride was added dropwise to 2.7 L of the solution under ice cooling, and the mixture was then heated under nitrogen.
The mixture was stirred under atmospheric pressure at 0°C for 1 hour and 40 minutes. Ice was added to the reaction solution under ice cooling, and
The mixture was extracted with methylene chloride. The organic layer was washed with 1M aqueous hydrochloric acid, saturated sodium bicarbonate, and
Wash with thorium aqueous solution and saturated brine, and dry the organic layer with magnesium sulfate.
After filtering the organic layer, the solvent was evaporated under reduced pressure to give a brown oil (280 g, 96
%) was obtained.2) 1-bromo-2-butyne280 g of 2-butynyl methanesulfonate dissolved in 3.5 L of dimethylformamide
493 g of lithium bromide was added to the solution under ice cooling, and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere.
Ice was added to the reaction mixture under ice cooling, and the mixture was extracted with diethyl ether.
The aqueous layer was extracted again with diethyl ether, and the combined organic layers were washed with water and saturated brine.
The organic layer was washed with water and dried over magnesium sulfate.
The residue was evaporated under reduced pressure to give a brown oil (137 g, 54%).3) N,N-diformyl-2-butyne137 g of 1-bromo-2-butyne in 1.3 L of dimethylformamide, cooled on ice
Then, 117 g of diformylimide sodium salt was added, and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere.
The mixture was stirred for 50 minutes. Tetrahydrofuran was added to the reaction mixture at room temperature, and the resulting suspension was
The suspension was filtered to obtain crystals, which were washed with tetrahydrofuran.
The filtrate was added to a mixture of ethyl acetate and water for extraction. The aqueous layer was extracted again with ethyl acetate.
The combined organic layers were washed with water and saturated brine, and dried over magnesium sulfate.
After filtering the organic layer, the solvent was evaporated under reduced pressure to give a brown oil (77 g, 60%).
Ta.4) 2-butyn-1-amine hydrochloride77g of N,N-diformyl-2-butyne and 390g of 10% hydrochloric acid-methanol solution
The reaction mixture was stirred at 65°C for 15 minutes under a nitrogen atmosphere.
The resulting suspension was washed with diethyl ether and filtered, and 2-butyne-
1-Amine hydrochloride (26 g, 40%) was obtained.¹ H NMR (400MHz, DMSO-d₆) δppm; 1.85 (3H, t
, J=2.6Hz), 3.63 (2H, q, 5Hz), 8.47 (2H, bs)
．5) N1-[4-chloro-6-(2-propynylamino)-5-pyrimidinyl]
-3-fluorobenzamide N4-(2-propynyl)-6-chloro-4,5-pyrimidinediamine 48.
8 mmol of 3-fluorobenzoyl chloride was added to 50 ml of pyridine solution under ice cooling.
The mixture was stirred at 0°C for 15 minutes under a nitrogen atmosphere.
The reaction mixture was stirred at room temperature for another 30 minutes. Water was added to the reaction mixture at room temperature, and the resulting mixture was diluted with vinegar.
The organic layer was washed with water and saturated brine, and the entire aqueous layer was extracted again.
The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was removed.
The crystals were obtained by distillation under reduced pressure. The obtained crystals were washed with diethyl ether and collected by filtration.
Crystal, N1-[4-chloro-6-(2-propynylamino)-5-pyrimidinyl
5.64 g of 4-(4-fluorobenzamide)-3-fluorobenzamide were obtained.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.07 (1H, t
, J=2.4Hz), 4.12-4.14 (2H, m), 7.45-7.50 (
1H, m), 7.58-7.63 (1H, m), 7.80-7.87 (2H, m
), 8.05-8.08 (1H,m), 8.34 (1H,s). Next, N1-[4-chloro-6-(2-propynylamino)-5-pyrimidinyl]
A suspension of 5.64 g of [3-fluorobenzamide] and 56 ml of phosphorus oxychloride
The mixture was stirred at 120° C. for 7 hours. After removing phosphorus oxychloride from the reaction solution by distillation under reduced pressure,
The residue was added to ice water. The mixture was neutralized with sodium bicarbonate.
The aqueous layer was filtered through Celite, and the filtrate was extracted again with ethyl acetate.
The combined organic layer was dried over magnesium sulfate. The residue was filtered through a silica gel short chromatograph.
The crystals were purified by filtration and washed with diethyl ether to give pale brown crystals 6
-chloro-8-(3-fluorophenyl)-9-(2-propynyl)-9H-prop
Phosphorus (2.08 g, 35%) was obtained.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.56 (1H, t
, J=2.6Hz), 3.40 (2H, d, J=2.4Hz), 7.53-7.
58 (1H, m), 7.71-7.76 (1H, m), 7.82-7.87 (1
H, m), 8.89 (1H, s). MS m/e (ESI): 287 (MH⁺) Convert it into hydrochloride by the usual method to 9-(2-butynyl)-8-(3-fluorophenyl
)-9H-6 Plinamine hydrochloride was obtained.¹ H NMR (400MHz, DMSO-d₆) δppm; 1.75 (3H,b
rs). 5.05 (2H, d, J = 2.0Hz), 7.41-7.50 (1H
, m), 7.65-7.91 (5H, m), 8.29 (1H, s). MS m/e (ESI): 282 (MH⁺) Example 195-[6-amino-8-(3-fluorophenyl)-2-(3-hydroxy-3 -methyl-1-butynyl)-9H-9-purinyl]-1,2-dihydro-2-pi
Lidinone Hydrochloride 1) 2-(allyloxy)-5-nitropyridine Allyl alcohol (8.6 g, 148 mmol) in N,N-dimethylformamide
A solution of 60-70% sodium hydride was added to 100 ml of ethanol under a nitrogen atmosphere on ice.
(3.0 g, 75.0 mmol) was added and stirred.
After confirmation, 2-bromo-5-nitropyridine (10.3 g, 50.7 mmol)
The reaction mixture was diluted with saturated aqueous ammonium chloride solution
After dilution, the mixture was extracted with ethyl acetate (x1). The organic layer was washed with saturated ammonium chloride.
After washing with aqueous solution (x3), the mixture was dried over anhydrous sodium sulfate, concentrated, and the title compound was obtained.
A crude product of Compound 24 (9.9 g, quant.) was obtained as a dark brown solid.¹ H NMR (400MHz, DMSO-d₆) δppm; 4.96 (2H, d
t, J = 1.6, 5.6Hz), 5.29 (1H, dq, J = 1.6, 10.4
Hz), 5.41 (1H, dq, J=1.6, 17.2Hz), 6.03-6.
14 (1H, m), 7.08 (1H, d, J = 9.2Hz), 8.50 (1H,
dd, J=2.8, 9.2Hz), 9.08 (1H, d, J=2.8Hz).2) 6-(allyloxy)-3-pyridinamine1) crude product (9.9 g, 50.7 mmol) of ethanol (20
Zinc powder (20 g, 30 ml) was added to a suspension of water (100 ml) and acetic acid (10 ml).
0.06 mmol) was added in small portions and stirred for 30 minutes.
The organic layer was diluted with ethyl acetate and saturated aqueous ammonium chloride solution.
ammonium hydroxide aqueous solution (x1), 1N sodium hydroxide aqueous solution (x1) and saturated
After washing with an aqueous solution of ammonium chloride (x1), it was dried over anhydrous sodium sulfate.
The crude product of the title compound 25 (6.7 g, 88%) was obtained as a dark brown liquid.
I got it.¹ H NMR (400MHz, DMSO-d₆) δppm; 4.64 (2H, d
t, J = 1.6, 5.2Hz), 4.75 (2H, br s), 5.18 (1H
, dq, J = 1.6, 10.4Hz), 5.32 (1H, dq, J = 1.6, 1
7.2Hz), 5.97-6.08 (1H, m), 6.57 (1H, d, J=8
．． 8Hz), 7.01 (1H, dd, J=2.8, 8.8Hz), 7.48 (1
H, d, J = 2.8Hz).3) 5-[6-amino-8-(3-fluorophenyl)-2-(3-hydroxy
-3-methyl-1-butynyl)-9H-9-purinyl]-1,2-dihydro-2
-pyridinone hydrochlorideCompound (90 mg, 0.202 mmol) in ethanol (10 ml) - water (2
ml) solution was added with 10% aqueous palladium on carbon (10 mg) and p-toluene
After adding sulfonic acid monohydrate (12 mg, 0.063 mmol), the mixture was heated under reflux.
After 30 minutes, p-toluenesulfonic acid monohydrate (110 mg, 0.578 mm
After another 1.5 hours, 10% aqueous palladium-carbon (10 mg) and
and p-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) were added.
The mixture was heated under reflux for another 3 days. After filtering off the palladium-carbon, the filtrate was
The mixture was diluted with ethyl acetate and washed with saturated aqueous ammonium chloride solution (x1).
After extraction with 1N aqueous sodium hydroxide solution, the aqueous layer was neutralized with 5N hydrochloric acid.
The aqueous layer was extracted with ethyl acetate (x1), dried over anhydrous sodium sulfate,
The residue was dissolved in methanol-5N hydrochloric acid (3 drops) and concentrated.
The residue was crystallized from methanol-ethyl acetate-diethyl ether, and the solid was
The compound was collected by filtration, washed with diethyl ether, and the title compound 27 (18 mg, 20%) was obtained in a dilute solution.
Obtained as a yellow solid.¹ H NMR (400MHz, DMSO-d₆) δppm; 1.45 (6H,s
), 6.46 (1H, d, J = 9.6Hz), 7.31-7.38 (1H, m)
, 7.40-7.47 (2H, m), 7.47-7.56 (2H, m), 7.7
3 (1H, d, J=2.8Hz). MS m/e (ESI): 405 (MH⁺) Example 201-{2-[9-allyl-6-amino-8-(3-fluorophenyl)-9H-
2-purinyl]-1-ethynyl}-1-cyclobutanol hydrochloride 1) 1-{2-[9-allyl-6-chloro-8-(3-fluorophenyl)-9
H-2-purinyl]-1-ethynyl}-1-cyclobutanol 9-Allyl-6-chloro-8-(3-fluorophenyl)-2-iodo-9H-
Purine (50.0 g, 120.6 mmol), copper(I) iodide (1.1 g, 22
mmol), dichlorobis(triphenylphosphine)palladium(II) (4
.2 g, 22 mmol) and 1-(1-ethynyl)-1-cyclobutanol (
A suspension of 12.7 g (132 mmol) of tetrahydrofuran (500 ml) was added to
Triethylamine (25.2 ml, 343 mmol) was added dropwise at room temperature under nitrogen atmosphere.
The reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate and stirred for 2 hours.
The organic layer was diluted with saturated aqueous ammonium chloride (x1), saturated saline (x
After washing with 1), the mixture was dried over anhydrous sodium sulfate and concentrated.
The solid was suspended in ether, filtered, washed with diethyl ether, and the title compound was obtained.
(45.0 g, 98%) was obtained as a light brown solid.¹ H NMR (400MHz, CDCl₃) δppm; 1.85-2.00 (2
H, m), 2.32-2.42 (2H, m), 2.62-2.70 (2H, m)
, 5.00 (1H, d, J=15.0Hz), 4.95-5.05 (2H, m)
, 5.32 (1H, d, J=10.4Hz), 6.00-6.10 (2H, m)
, 7.24-7.35 (1H, m), 7.50-7.65 (3H, m).2) 1-{2-[9-allyl-6-amino-8-(3-fluorophenyl)-9
H-2-purinyl]-1-ethynyl}-1-cyclobutanol hydrochloride 1-{2-[9-allyl-6-chloro-8-(3-fluorophenyl)-9H
-2-purinyl]-1-ethynyl}-1-cyclobutanol (45 g, 116.
1,2-dimethoxyethane (900 ml) - concentrated aqueous ammonia (4
The suspension (50 ml) was stirred in an autoclave at 70°C for 5 hours.
The reaction mixture was diluted with saturated aqueous ammonium chloride solution and ethyl acetate.
After washing with saturated aqueous ammonium chloride solution (x1),
The residue was suspended in diethyl ether, and the solid matter was collected by filtration.
The mixture was washed with ether to give the free form of the title compound (31.3 g, 98%).
The free form of was suspended in 300 ml of ethanol and dissolved by adding 26 ml of 5N hydrochloric acid.
The residue was washed with diethyl ether and dried to give 30 g of the title compound.
The yield was 64%.¹ H NMR (400MHz, DMSO-d₆) δppm; 1.72-1.83
(2H, m), 2.18-2.24 (2H, m), 2.33-2.40 (2H,
m), 4.76 (1H, d, J = 17.2Hz), 4.86-4.92 (2H,
m), 5.14 (1H, d, J = 10.4Hz), 5.95-6.05 (2H,
m), 7.38-7.42 (1H, m), 7.58-7.65 (3H, m). MS m/e (ESI): 364.01 (MH⁺) Example 215-[6-amino-8-(2-furyl)-9H-9-purinyl]-1-methyl-
1,2-Dihydro-2-pyridinone hydrochloride 5- (2), (3), and (4) were synthesized in the same manner as in Example 1 and Example 2.
[6-amino-8-(2-furyl)-9H-9-purinyl]-1,2-dihydro
-2-pyridinone (400 mg, 1.36 mmol) in methanol (8 ml)
Sodium methoxide (150 mg, 2.78 mmol) was added to the suspension and the mixture was placed under a nitrogen atmosphere.
After 15 minutes, iodomethane (0.26 ml, 4.18 ml) was added.
The reaction mixture was concentrated, and the residue was added to a solution of 1,000 mol of ethanol.
Gel column chromatography (eluent: hexane, hexane-ethyl acetate =
The crude product was suspended in ethanol and then subjected to ethanol-based distillation.
The solid was collected by filtration, washed with ethanol and diethyl ether, and the title compound was obtained.
The resulting free form was extracted with methanol-4N hydrochloric acid/acetic acid.
The residue was dissolved in ethyl acetate (0.4 ml) and concentrated.
After crystallization with ethyl ether, the solid was collected by filtration and washed with diethyl ether.
The title compound (270 mg, 58%) was obtained as a pale brown solid.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.50 (3H, s
), 6.58 (1H, d, J=9.8Hz), 6.68 (1H, dd, J=1.
6, 3.6Hz), 6.74 (1H, d, J=3.6Hz), 7.60 (1H,
dd, J = 3.2, 9.8 Hz), 7.96 (1H, d, J = 1.6 Hz), 8
．． 24 (1H, d, J = 3.2Hz), 8.41 (1H, s); MS m/e (
ESI) 309 (MH⁺) Example 225-[6-amino-8-(2-thienyl)-9H-9-purinyl]-1-methyl
-1,2-Dihydro-2-pyridinone hydrochloride The compounds were synthesized in the same manner as in Examples 1 (2), (3), and (4) and Examples 2 and 21.
Ta.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.51 (3H,s
), 6.61 (1H, d, J=9.6Hz), 7.19 (1H, dd, J=3.
8, 5.0Hz), 7.41 (1H, dd, J=1.4, 3.8Hz), 7.6
2 (1H, dd, J=2.8, 9.6Hz), 7.83 (1H, dd, J=1.
4,5.0Hz), 8.30 (1H, d, J=2.8Hz), 8.45 (1H,
s); MS m/e (ESI) 325 (MH⁺) Example 235-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
,4-Dimethyl-1,2-dihydro-2-pyridinone hydrochloride The synthesis was carried out in the same manner as in Examples 1, 2 and 21.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.42 (3H,s
), 6.46 (1H, s), 7.38-7.60 (4H, m), 8.13 (1H
, s), 8.42 (1H, s); MS m/e (ESI) 351 (MH⁺). Example 245-[6-amino-8-(3-fluorophenyl)-2-methyl-9H-9-propanol
Linyl]-1-methyl-1,2-dihydro-2-pyridinone hydrochloride The synthesis was carried out in the same manner as in Examples 1, 2 and 21.¹ H NMR (400MHz, DMSO-d₆) δppm; 2.54 (3H, s
), 3.43 (3H, s), 6.51 (1H, d, J=10.0Hz), 7.3
5-7.41 (1H, m), 7.44-7.57 (4H, m), 8.11 (1H
, d, J=2.8Hz); MS m/e (ESI) 351 (MH⁺) Example 255-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
-Ethyl-1,2-dihydro-2-pyridinone hydrochloride It was synthesized in the same manner as in Example 21.¹ H NMR (400MHz, DMSO-d₆) δppm; 1.15 (3H, t
, J=7.2Hz), 3.89 (2H, q, J=7.2Hz), 6.53 (1H
, d, J=9.6Hz), 7.38-7.43 (1H, m), 7.45-7.4
9 (2H, m), 7.53 (1H, dd, J=2.8, 9.6Hz), 7.54
-7.60 (1H, m), 8.10 (1H, d, J=2.8Hz), 8.49 (
1H, s); MS m/e (ESI) 351 (MH⁺) Example 265-[6-(cyclopropylamino)-8-(3-fluorophenyl)-9H-
9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone The compounds were synthesized in the same manner as in Example 1 (4), 2, and 21.¹ H NMR (400MHz, DMSO-d₆) δppm; 0.62-0.67
(2H, m), 0.72-0.80 (2H, m), 2.94-3.20 (1H,
br), 3.43 (3H, s), 6.46 (1H, d, J=9.6Hz), 7.
28-7.34 (1H, m), 7.41-7.53 (4H, m), 8.09 (1
H, d, J = 2.8Hz), 8.11-8.28 (1H, br), 8.24 (1
H, br s); MS m/e (ESI) 377 (MH⁺). Example 275-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
-(2-hydroxyethyl)-1,2-dihydro-2-pyridinone It was synthesized in the same manner as in Example 21.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.58 (2H, q
, J=5.2Hz), 3.93 (2H, t, J=5.2Hz), 4.86 (1H
, t, J=5.2Hz), 6.49 (1H, d, J=9.6Hz), 7.29-
7.36 (1H, m), 7.42-7.54 (6H, m), 7.94 (1H, d
, J=2.8Hz), 8.15 (1H, s); MS m/e (ESI) 367 (
MH⁺). Example 285-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
-benzyl-1,2-dihydro-2-pyridinone It was synthesized in the same manner as in Example 21.¹ H NMR (400MHz, DMSO-d₆) δppm; 5.04 (2H,s
), 6.57 (1H, d, J = 9.6Hz), 7.06-7.13 (2H, m)
, 7.26-7.44 (6H, m), 7.45-7.53 (3H, m), 7.6
3 (1H, dd, J = 3.2, 9.6Hz), 8.13 (1H, d, J = 3.2
Hz), 8.16 (1H, s); MS m/e (ESI) 413 (MH⁺). Example 291-allyl-5-[6-amino-8-(3-fluorophenyl)-9H-9-propanol
Linyl]-1,2-dihydro-2-pyridinone It was synthesized in the same manner as in Example 21.¹ H NMR (400MHz, DMSO-d₆) δppm; 4.49 (2H, d
, J = 5.2Hz), 4.90 (1H, d, J = 16.8Hz), 5.10 (1
H, d, J = 10.4Hz), 5.88 (1H, ddd, J = 5.2, 10.4
, 16.8Hz), 6.54 (1H, d, J=9.6Hz), 7.30-7.3
5 (1H, m), 7.41-7.53 (5H, m), 7.45-7.53 (3H
, m), 7.56 (1H, dd, J=3.2, 9.6Hz), 7.93 (1H,
d, J=3.2Hz), 8.16 (1H, s); MS m/e (ESI) 363
(MH⁺) Example 302-[5-[6-amino-8-(2-furyl)-9H-9-purinyl]-2-oxo
so-1,2-dihydro-2-pyridinyl]acetic acid The compound 2-[5-[6-amino-8-(2-amino-
-furyl)-9H-9-purinyl]-2oxo-1,2-dihydro-2-pyridyl
Ethyl]acetate (600 mg, 1.47 mmol) in methanol (6 ml)
A solution of tetrahydrofuran (6 ml) and water (10 ml) was added to 5N aqueous sodium hydroxide.
The reaction mixture was stirred at room temperature for 3 hours.
The concentrate was dissolved in water and neutralized with 5N hydrochloric acid. The resulting crystals were collected by filtration and washed with water.
Purification gave the title compound (252 mg, 57%) as a colorless solid.¹ H NMR (400MHz, DMSO-d₆) δppm; 4.61 (2H,s
), 6.53 (1H, d, J = 9.6Hz), 7.29-7.35 (1H, m)
, 7.45-7.52 (5H, m), 7.55 (1H, dd, J=2.8, 9.
6Hz), 8.05 (1H, d, J=2.8Hz), 8.16 (1H, s); M
S m/e (ESI) 381 (MH⁺) Example 314-[5-[6-amino-8-(2-furyl)-9H-9-purinyl]-2-oxo
so-1,2-dihydro-2-pyridinyl]butyric acid The synthesis was carried out in the same manner as in Examples 21 and 30.¹ H NMR (400MHz, DMSO-d₆) δppm; 1.78 (2H, q
uint, J=7.2Hz), 2.12 (2H, t, J=7.2Hz), 3.8
9 (2H, t, J = 7.2Hz), 6.51 (1H, d, J = 9.6Hz), 7
．． 28-7.34 (1H, m), 7.41-7.54 (6H, m), 7.99 (
1H, d, J = 2.8Hz), 8.16 (1H, s); MS m/e (ESI)
409 (MH⁺) Example 322-[5-[6-amino-8-(2-furyl)-9H-9-purinyl]-2-oxo
so-1,2-dihydro-2-pyridinyl]acetamide 2-[5-[6-amino-8-(2-furyl)-9H-9-purinyl]-2o
1,2-Dihydro-2-pyridinyl] acetic acid (150 mg, 0.394 mm
ol), 1-hydroxybenzotriazole (180 mg, 1.18 mmol)
, ammonium chloride (105 mg, 1.96 mmol), 1-ethyl-3-(3
'-dimethylaminopropyl)carbodiimide (184 mg, 1.19 mmol
) and triethylamine (0.28 ml, 2.00 mmol)
The suspension was stirred in ethylformamide (3 ml) at room temperature for 20 hours.
The residue was purified by silica gel column chromatography (eluent: dichloromethane,
The crude product was subjected to dichloromethane-methanol (dichloromethane-methanol = 20:1, 10:1, 4:1).
The solid was suspended in ethanol, filtered, washed with ethanol, and the title compound was obtained.
(96 mg, 64%) was obtained as a colorless solid.¹ H NMR (400MHz, DMSO-d₆) δppm; 4.51 (2H,s
), 6.48 (1H, d, J=9.6Hz), 7.21 (1H, br s), 7
．． 28-7.34 (1H, m), 7.45-7.54 (6H, m), 7.62 (
1H, br s), 7.98 (1H, d, J=2.8Hz), 8.16 (1H,
s); MS m/e (ESI) 380 (MH⁺) Example 335-[2-(3-fluorophenyl)-7,8-dihydro-3H-imidazo[2
,1-i]purin-3-yl]-1,2-dihydro-2-pyridinone 8-(3-fluorophenyl) synthesized in the same manner as in Example 1 (4) and 2
-6-(2-hydroxyethylamino)-9-(6-methoxy-3-pyridyl
)-9H-6-purine (800 mg, 2.10 mmol) in 1,2-dichloroethane
Thionyl chloride (1.1 ml, 15.1 mmol) was added to the suspension in ethanol (20 ml).
The mixture was stirred at 80° C. for 9.5 hours. After cooling, the reaction mixture was concentrated and diluted with 1N hydrochloric acid and
The mixture was diluted with ethyl acetate, and the aqueous layer was neutralized with a 5N aqueous solution of sodium hydroxide.
The resulting crystals were collected by filtration and washed with water to obtain 620 mg of crude crystals.
The reaction mixture was dissolved in concentrated hydrochloric acid (10 ml) and heated under reflux for 8 hours.
The resulting crystals were collected by filtration, washed with water, and the title compound was obtained.
The compound (210 mg, 29%) was obtained as a light brown solid.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.95 (1H, t
, J = 9.4Hz), 4.13 (1H, t, J = 9.4Hz), 6.43 (1H
, d, J=9.2Hz), 7.23-7.34 (1H, m), 7.33-7.4
0 (2H, m), 7.40-7.52 (2H, m), 7.68 (1H, d, J=
2.8Hz), 8.04 (1H, s); MS m/e (ESI) 349 (MH⁺
). Example 345-[6-amino-8-(3-methylphenyl)-9H-9-purinyl]-1-
Methyl-1,2-dihydro-2-pyridinone hydrochloride In the same manner as in (2), (3), and (4) of Example 1, Example 2, and Example 5
The title compound was synthesized.¹ H NMR (400MHz, DMSO-d₆) δppm; 2.34 (3H,s
), 3.45 (3H, s), 6.49 (1H, d, J=9.2Hz), 7.32
-7.40 (3H, m), 7.47 (1H, dd, J=9.2, 2.8Hz),
7.61 (1H, s), 8.13 (1H, d, J = 2.8Hz), 8.38 (1
H,s); MS m/e (ESI) 333.01 (MH⁺). Example 355-[6-amino-8-(3-nitrophenyl)-9H-9-purinyl]-1-
Methyl-1,2-dihydro-2-pyridinone hydrochloride In the same manner as in (2), (3), and (4) of Example 1, Example 2, and Example 5
The title compound was synthesized.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.44 (3H,s
), 6.51 (1H, d, J=9.6Hz), 7.55 (1H, dd, J=9.
6, 3.0Hz), 7.79 (1H, t, J=8.0Hz), 8.00-8.0
4 (1H, m), 8.16 (1H, d, J = 3.0Hz), 8.34 (1H, d
, J=2.4Hz), 8.36 (1H, s), 8.62 (1H, t, J=1.6
Hz); MS m/e (ESI) 364.00 (MH⁺). Example 365-[6-amino-8-(3-aminophenyl)-9H-9-purinyl]-1-
Methyl-1,2-dihydro-2-pyridinone dihydrochloride The free amine obtained in Example 35 (371 mg) was dissolved in THF (200 ml).
, dissolved in EtOH (200 ml), and 10% Pd-C (aqueous, 0.5 g) was added.
The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
300 mg of the free form of the above compound was obtained.
Dissolved in ethanol (2 ml) and added 4N HCl/EtOAc (0.2 ml).
The precipitated crystals were collected by filtration to obtain 84 mg of the title compound.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.47 (3H,s
), 6.50 (1H, d, J=9.6Hz), 7.21-7.27 (1H, m)
, 7.33-7.38 (1H, m), 7.42-7.53 (2H, m), 7.4
6 (1H, dd, J = 9.6, 2.6Hz), 8.17 (1H, d, J = 2.6
Hz), 8.49 (1H, s); MS m/e (ESI) 334.02 (MH⁺
). Example 37N-[3-[6-amino-9-(1-methyl-6-oxo-1,6-dihydro-
3-pyridinyl)-9H-8-purinyl]phenyl]methanesulfonamide salt
Acid salts The free amine obtained in Example 36 (100 mg) was dissolved in pyridine (2 ml).
After dissolving, methanesulfonyl chloride (28 μl) was added under ice cooling, and the mixture was stirred overnight at 0°C.
The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography.
90 mg of the free form of the title compound was obtained.
1), and 4N HCl/EtOAc (0.6 ml) was added. The precipitated crystals were collected by filtration.
As a result, 55 mg of the title compound was obtained.¹ H NMR (400MHz, DMSO-d₆) δppm; 2.93 (3H,s
), 3.46 (3H, s), 6.48 (1H, d, J=9.6Hz), 7.28
-7.32 (1H, m), 7.42 (1H, dd, J=9.6, 3.0Hz),
7.46-7.50 (2H, m), 7.59 (1H, s), 8.18 (1H, d
, J=3.0Hz), 8.45 (1H, s), 10.04 (1H, s); MS
m/e (ESI) 411.99 (MH⁺). Example 385-[6-amino-8-(3-trifluoromethylphenyl)-9H-9-purine
Nyl]-1-methyl-1,2-dihydro-2-pyridinone hydrochloride In the same manner as in (2), (3), and (4) of Example 1, Example 2, and Example 5
The title compound was synthesized.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.45 (3H,s
), 6.53 (1H, d, J=9.6Hz), 7.54 (1H, dd, J=9.
6, 2.8Hz), 7.75 (1H, t, J=2.8Hz), 7.88-7.9
3 (2H, m), 8.10 (1H, s), 8.17 (1H, d, J = 2.8Hz
), 8.43 (1H, s); MS m/e (ESI) 387.00 (MH⁺).
Example 395-[6-amino-8-(3-chlorophenyl)-9H-9-purinyl]-1-
Methyl-1,2-dihydro-2-pyridinone hydrochloride In the same manner as in (2), (3), and (4) of Example 1, Example 2, and Example 5
The title compound was synthesized.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.43 (3H,s
), 6.50 (1H, d, J=9.6Hz), 7.47-7.61 (4H, m)
, 7.77-7.79 (1H, m), 8.12 (1H, d, J=2.8Hz),
8.34 (1H, s); MS m/e (ESI) 352.96 (MH⁺) Example 405-[6-amino-8-(3-methoxyphenyl)-9H-9-purinyl]-1
-Methyl-1,2-dihydro-2-pyridinone hydrochloride In the same manner as in (2), (3), and (4) of Example 1, Example 2, and Example 5
The title compound was synthesized.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.43 (3H,s
), 3.73 (3H, s), 6.50 (1H, d, J=9.6Hz), 7.06
-7.11 (1H, m), 7.20-7.25 (2H, m), 7.38-7.4
3 (1H, m), 7.49 (1H, dd, J=9.6, 2.8Hz), 8.14
(1H, d, J = 2.8Hz), 8.47 (1H, s); MS m/e (ESI
)349.02(MH⁺) Example 413-[6-amino-9-(1-methyl-6-oxo-1,6-dihydro-3-pyridinyl] Lysinyl)-9H-8-purinyl]benzonitrile hydrochloride In the same manner as in (2), (3), and (4) of Example 1, Example 2, and Example 5
The title compound was synthesized.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.45 (3H,s
), 6.51 (1H, d, J = 10.0Hz), 7.50 (1H, dd, J = 1
0.0, 2.8Hz), 7.72 (1H, t, J=8.0Hz), 7.92-7
．． 96 (1H, m), 7.99-8.03 (1H, m), 8.12-8.15 (
1H, m), 8.14 (1H, d, J=2.8Hz), 8.42 (1H, s);
MS m/e (ESI) 343.99 (MH⁺) Example 422-(3-fluorophenyl)-1-(6-methoxy-3-pyridyl)-1H-
Imidazo[4,5-c]pyridin-4-amine (1) 2,4-dichloro-3-nitropyridine2,4-dihydroxy-3-nitropyridine (2.5 g, 16 mmol)
Phosphorus oxychloride (10 mL) was added, and the mixture was stirred at 110° C. for 4 hours.
The mixture was concentrated under reduced pressure, and ethyl acetate and ice water were added to the residue, followed by filtration through Celite.
Wash with brine, dry over anhydrous magnesium sulfate, filter through silica gel, and concentrate.
The title compound (2.7 g, 87%) was obtained as a brown solid.(2) N4-(6-methoxy-3-pyridyl)-2-chloro-3-nitro-4- Pyridineamine The compound obtained in (1) (10.4 g, 54 mmol), 5-amino-2-methoxy
Cetylpyridine (9.6 g, 77 mmol), triethylamine (5.4 g, 54 mmol),
The reaction mixture was stirred at room temperature for 2 days.
The mixture was concentrated under reduced pressure, and ethyl acetate and water were added to the residue. The organic layer was washed with saturated brine.
The extract was dried over anhydrous magnesium sulfate and concentrated. Silica gel column chromatography
The resulting mixture was purified by HPLC to give the title compound (6.3 g, 42%).¹ H NMR (400MHz, CDCl₃) δppm; 3.98 (3H, s),
6.63 (1H, d, J = 6.4Hz), 6.85 (1H, d, J = 8.8Hz
), 7.46 (1H, dd, J = 8.8, 2.8Hz), 7.92-7.96 (
1H, m), 7.99 (1H, dd, J = 6.4, 0.8Hz), 8.10 (1
H, d, J = 2.8Hz).(3) N4-(6-methoxy-3-pyridyl)-2-chloro-3,4-pyridine
Diamine The compound obtained in (2) (1.0 g) was dissolved in water (10 mL) and ethanol (20 mL).
The mixture was suspended in 100 ml of acetic acid, and zinc powder (1.0 g) and acetic acid (1 mL) were added, followed by stirring at room temperature for 4 hours.
The reaction mixture was filtered through Celite and concentrated under reduced pressure. The residue was diluted with ethyl acetate and saturated aqueous sodium bicarbonate.
The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate,
Silica gel filtration and concentration gave the title compound (0.85 g, 95%).¹ H NMR (400MHz, CDCl₃) δppm; 3.95 (3H, s),
5.79 (1H, s), 6.59 (1H, d, J=5.6Hz), 6.79 (1
H, d, J = 8.8Hz), 7.42 (1H, dd, J = 8.8, 2.8Hz)
, 7.70 (1H, d, J = 5.6Hz), 8.01 (1H, d, J = 2.8H
z).(4) N1-[2-chloro-4-[(6-methoxy-3-pyridyl)amino]-
3-pyridyl]-3-fluorobenzamide Dissolve the compound obtained in (3) (1.0 g, 4.0 mmol) in pyridine (5 mL).
3-Fluorobenzoyl chloride (1.0 g) was added under ice cooling, and the mixture was stirred at room temperature for 5 hours.
The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and added with water and saturated brine.
The extract was washed with HCl, dried over anhydrous magnesium sulfate, and concentrated.
Purification by chromatography gave the title compound (1.2 g, 81%).¹ H NMR (400MHz, CDCl₃) δppm; 3.95 (3H, s),
6.73 (1H, d, J = 5.6Hz), 6.79 (1H, d, J = 8.4Hz
), 6.97 (1H, s), 7.31-7.37 (1H, m), 7.46 (1H
, dd, J=8.4, 2.8Hz), 7.51 (1H, m), 7.69-7.7
9 (2H, m), 7.95 (1H, s), 7.96 (1H, d, J = 5.6Hz
), 8.07 (1H, d, J = 2.8Hz).(5) 4-chloro-2-(3-fluorophenyl)-1-(6-methoxy-3-
pyridyl)-1H-imidazo[4,5-c]pyridine The compound obtained in (4) (980 mg, 2.6 mmol), acetonitrile (20
The mixture of 1 mL of ethanol and phosphorus oxychloride (2 mL) was stirred at 80° C. for 3 hours.
The mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and washed with water and saturated brine.
The extract was dried over magnesium sulfate and concentrated. Silica gel column chromatography
This was purified by HPLC to give the title compound (680 mg, 73%).¹ H NMR (400MHz, CDCl₃) δppm; 4.03 (3H, s),
6.91 (1H, dd, J = 8.8, 0.8Hz), 7.11 (1H, d, J =
5.6Hz), 7.11-7.17 (1H, m), 7.33-7.40 (3H,
m), 7.47 (1H, dd, J=8.8, 2.8Hz), 8.17 (1H, d
d, J = 2.8, 0.8 Hz), 8.23 (1H, d, J = 5.6 Hz).(6) 2-(3-fluorophenyl)-1-(6-methoxy-3-pyridyl)-
1H-imidazo[4,5-c]pyridin-4-amine Mix the compound (1 g) obtained in (5) with ammonia-ethanol solution (20 mL)
The mixture was stirred at 150° C. for 4 days. The reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography.
Purification by chromatography gave the title compound (200 mg, 21%).¹ H NMR (400MHz, CDCl₃) δppm; 4.02 (3H, s),
5.30 (2H, br), 6.55 (1H, dd, J=5.8Hz), 6.88
(1H, d, J=8.8Hz), 7.07-7.13 (1H, m), 7.24-
7.35 (3H, m), 7.46 (1H, dd, J=8.8, 2.8Hz), 7
．． 88 (1H, d, J = 5.8Hz), 8.15 (1H, d, J = 2.8Hz)
; MS m/e (ESI) 336.00 (MH⁺). Example 435-[4-amino-2-(3-fluorophenyl)-1H-imidazo[4,5-
c]pyridin-1-yl]-1,2-dihydro-2-pyridinone 2-(3-fluorophenyl)-1-(6-methoxy-
3-pyridyl)-1H-imidazo[4,5-c]pyridin-4-amine (290
A mixture of 1 mL of ethanol and concentrated hydrochloric acid (10 mL) was stirred at 110° C. for 7.5 hours.
The mixture was concentrated under reduced pressure, and the residue was purified by NH-form silica gel column chromatography.
Purification gave the title compound (120 mg, 43%).¹ H NMR (400MHz, DMSO-d₆) δppm; 6.39 (2H,b
r), 6.45 (1H, d, J=9.6Hz), 6.49 (1H, d, J=5.
8Hz), 7.28-7.34 (1H, m), 7.40-7.54 (4H, m)
, 7.72 (1H, d, J = 5.8Hz), 7.77 (1H, d, J = 2.8H
z); MS m/e (ESI) 321.94 (MH⁺). Example 445-[4-amino-2-(3-fluorophenyl)-1H-imidazo[4,5-
c]pyridin-1-yl]-1-methyl-1,2-dihydro-2-pyridinone
5-[4-amino-2-(3-fluorophenyl)-1-methyl-2-(4-amino-2-(3-fluorophenyl)-1-methyl-2-methyl ...
H-imidazo[4,5-c]pyridin-1-yl]-1,2-dihydro-2-pyridin
Lisinone (100 mg) was suspended in methanol (1 mL) and diluted with 28% sodium hydroxide.
Add 20 mL of methyl iodide in methanol and 20 mL of thiazol-2-one.
The reaction mixture was concentrated under reduced pressure, and the residue was filtered off on an NH-form silica gel column.
The residue was purified by column chromatography to give the title compound (27 mg, 26%).¹ H NMR (400MHz, DMSO-d₆) δppm; 3.45 (3H,s
), 6.40 (2H, br), 6.49 (1H, d, J=9.6Hz), 6.5
6 (1H, d, J = 5.8Hz), 7.29-7.34 (1H, m), 7.44
-7.53 (4H, m), 7.73 (1H, d, J=5.8Hz), 8.17 (
1H, d, J = 2.8Hz); MS m/e (ESI) 335.98 (MH⁺)
. Example 453-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
-Methyl-1,2-dihydro-2-pyridinone hydrochloride The title compound was obtained in the same manner as in Examples 1, 2 and 5.¹ H NMR (400MHz, DMSO-d₆) δppm; 3.46 (3H,s
), 6.45 (1H, t, J=7.0Hz), 7.30-7.53 (4H, m)
, 7.91 (1H, dd, J=7.2, 0.8Hz), 7.97 (1H, dd,
J = 7.2, 0.8Hz), 8.33 (1H, s); MS m/e (ESI) 3
36.97 (MH⁺) Example 465-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
-methyl-1,2-dihydro-2-pyridinone (1) 1-methyl-5-nitro-2(1H)-pyridone A flask was charged with 5-nitro-2-hydroxypyridine (0.55 kg, 3.93
mol), DMSO (2.2L), K₂CO₃(0.88kg, 6.37mol
) was added in this order and stirred until the bubbling subsided.
0.88 kg, 4.71 mol) was added dropwise and the mixture was stirred for 1 hour.

After adding 11 L of water dropwise, the mixture was cooled with ice and the precipitated crystals were collected by filtration and dried in vacuo at 70° C. to obtain 516 g (yield 85%) of the title compound as a yellow powder. (2) 5-amino-1-methyl-2(1H)-pyridone oxalate 1-methyl-5-nitro-2(1H)-pyridone (250 g)
, 1.62 mol), 10% Pd-C (25 g, 0.1 w/w%), EtOH (
Hydrogen was introduced to maintain a pressure of 10 kg/ ^cm² , and the mixture was heated to 30°C.
After 1 minute, the catalyst was filtered off using Celite, and the filter cake was further diluted with EtOH (1
. 25 L).

The filtrate was dissolved in oxalic acid (293 g, 3.2 mol) in EtOH (2.5 L).
The solution was added dropwise, and the mixture was stirred in an ice bath. The resulting crystals were collected by filtration and washed with EtOH (1 L). The crystals were then dried under aeration at 60°C to obtain 182.6 g of the title compound (yield 52.6%).
). ^1H NMR (DMSO- _d6 ) δppm; 3.30 (s, 3H, N-Me),
6.25 (d, 1H, J = 9.3Hz, H-3), 6.91 (d, 1H, J = 2
．． 9Hz, H-6), 7.07 (dd, 1H, J=9.3Hz, 2.9Hz, H
-4); melting point: 224-226°C (3) 5-(5-amino-6-chloropyrimidin-4-yl)amino-1-methyl
1,2-dihydro-2-pyridinone In a flask, 118.6 g of 5-amino-4,6-dichloropyrimidine, 5-
Amino-1-methyl-2(1H)-pyridone oxalate 170.0 g, EtO
360 mL of H and 2.4 L of purified water were added in that order, and the mixture was heated at a bath temperature of 110° C. for 17 hours.

After cooling in an ice bath, 200 mL of aqueous ammonia was poured in and stirred for 1 hour. The crystals were filtered, washed with 750 mL of water, and dried under ventilation at 60°C to obtain the title compound as a crude product in 1% yield.
88.2 g was obtained.

Subsequently, 188 g of this crude product was suspended in 1.9 L (10 vol.) of water, and 100 mL of aqueous ammonia was added and stirred. After 2 hours, the crystals were collected by filtration, washed with 1 L of water, and heated at 60°C.
The residue was dried under aeration at 40°C for 18 hours to obtain 153.8 g of the title compound. ¹ H NMR (DMSO-d ₆ ) δ ppm: 3.42 (s, 3H, NMe-1′
), 5.27 (brs, 2H, NH2-5), 6.40 (d, 1H, J=9.7
Hz, H-3'), 7.49 (dd, 1H, J=9.7Hz, 2.4Hz, H-
4'), 7.77 (s, 1H, H-2), 7.98 (d, 1H, J=2.4Hz
,H-6'), 8.35 (s,1H,NH-4); melting point: 258°C (decom
p.) (4) 5-[6-chloro-5-(3-fluorobenzoyl)aminopyrimidine-
4-yl]amino-1,2-dihydro-2-pyridinone A flask was charged with 5-(5-amino-6-chloropyrimidin-4-yl)amino-
148.9 g of 1-methyl-1,2-dihydro-2-pyridinone and 1490 mL (10 vol.) of pyridine were added and cooled with ice.
1 mL (1.38 eq.) was added dropwise.

After 1 hour, 1490 mL (10 vol) of water was poured into the reaction mixture, and the mixture was evaporated under reduced pressure. 500 mL of DME and then 1490 mL (10 vol) of water were poured into the concentrate.
The mixture was stirred at room temperature. The resulting crystals were collected by filtration and diluted with 1600 mL of DME/H ₂ O (1/5).
The mixture was washed with 5-[6-chloro-5-(3-fluorobenzoyl)aminopyrimidin-4-yl]amino-1,2-dihydro-2-
196.4 g of pyridinone was obtained. ¹ H NMR (DMSO-d ₆ ) δ ppm: 3.41 (s, 3H, NMe-1′
), 6.38 (d, 1H, J=9.71Hz, H-3'), 7.45-7.50
(m, 2H), 7.60 (dd, 1H, J=14.0Hz, 7.0Hz, H-5
”), 7.78-7.90 (m, 3H), 8.30 (s, 1H, H-2), 9.
09 (brs, 1H, NH-4), 10.08 (brs, 1H, NH-5); melting point: 173°C (decomp.) (4-2) 5-[6-chloro-5-(3-fluorobenzoyl)aminopyrimidinyl]
5-[6-chloro-5-(3-fluorobenzoyl) aminopyrimidine-4-yl]amino-1,2-dihydro-2-pyridinone hydrochloride
Acetonitrile (50 mL) was added to [[1,2-yl]amino-1,2-dihydro-2-pyridinone (2.0 g), and the mixture was heated in an oil bath at 85°C, and insoluble matter was filtered off while hot.
The filtrate was diluted with acetonitrile (110 mL), reheated to form a solution, and then added to 4N-
HCl (1.30 mL, 0.97 eq.) was added.
After adding 60 mL of acetonitrile, the crystals were collected by filtration, washed with acetonitrile (20 mL), and
The crystals were dried at 50° C. under forced air to obtain 1.59 g (y. 72.5%) of pale blue-white powder crystals. ¹ H NMR (DMSO-d ₆ ) δ ppm: 3.43 (s, 3H, NMe-1′
), 6.43 (d, 1H, J = 9.5Hz, H-3'), 7.40-7.53 (
m, 2H), 7.60 (dd, 1H, J=14.0Hz, 8.0Hz, H-5"
), 7.77-7.93 (m, 3H), 8.31 (s, 1H, H-2), 9.1
6 (s, 1H, NH-4), 10.17 (s, 1H, NH-5); Melting point: 193
-195°C (decomp.) (5) 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl
]-1-methyl-1,2-dihydro-2-pyridinone Into a flask, 186.0 g of 5-[6-chloro-5-(3-fluorobenzoyl)aminopyrimidin-4-yl]amino-1,2-dihydro-2-pyridinone
, _CH3CN 1.9L, _POCl3 186.0mL (2.0mol, 1vo
1=4 eq.) was added, and the mixture was heated under reflux in an oil bath (bath temperature: 120° C.) for about 6 hours.

The reaction mixture was concentrated, and 372 mL of _CH3CN was added. After dissolution, the mixture was further concentrated under reduced pressure. After concentration, 1.9 L of AcOEt was added for dilution, and 900 mL of 30% _{K2CO3 aqueous} solution was poured into the mixture. 1 L of water and 1.9 L of AcOEt were then added for separation. The organic layer was washed with 1.9 L of water and concentrated under reduced pressure to obtain 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1-methyl-2-methyl-2-methyl-1 ...
161.5 g (undried) of 2-dihydro-2-pyridinone was obtained. ¹ H NMR (DMSO-d ₆ ) δ ppm: 3.44 (s, 3H, NMe-1′
), 6.52 (d, 1H, J = 9.7Hz, H-3'), 7.38-7.47 (
m, 1H), 7.50-7.62 (m, 5H), 8.18 (d, 1H, J=2.
8 Hz, H-6′), 8.80 (d, 1H, J=1.1 Hz, H-2); Melting point:
219°C (5-2) 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purine
5-[6-chloro- 5- (3-fluorobenzoyl)aminopyrimidin-4-yl]amino-1,2-dihydro-2-pyridinone.HCl salt (5 g)
), NMP (25 mL) were added, and the mixture was stirred at 110° C. for 4 hours. Ethyl acetate (100 mL) and a 10% aqueous solution of sodium bicarbonate (50 mL) were added to the reaction mixture for extraction. After separation, the organic layer was washed with saturated brine (50 mL), and one-fifth of the organic layer was used for the following crystallization.

After concentrating the organic layer, DME (10 mL) was added to the concentrate, and the concentrate was dissolved under stirring at 55° C., and water (20 mL) was added to cause crystallization. The crystals were collected by filtration and dried at 50° C. for 16 hours to give a slightly brownish white 5-[6-chloro-8-(3-fluorophenyl)-9H-
9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone 0.64 g (
(5-3) 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purine] was obtained in a yield of 73.8%.
5-[6-chloro-5-(3-fluorobenzoyl)aminopyrimidine-4- (2-methyl-1,2-dihydro-2-pyridinone ] HCl-EtOAc method
[yl]amino-1,2-dihydro-2-pyridinone (1 g, 2.7 mmol) was dissolved in NMP (10 mL) and 4N HCl-EtOAc (0.8 mL, 3.2
The reaction mixture was added with 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-
It was confirmed that 1-methyl-1,2-dihydro-2-pyridinone (90.2%) was produced. (5-4) 5-[6-chloro-8-(3-fluorophenyl)-9H-9-pyridinone
5-[6-chloro-5-(3-fluorobenzoyl)aminopyrimidine-4 -yl]-1-methyl-1,2-dihydro-2-pyridinone *catalyst-free method
[I]ylamino-1,2-dihydro-2-pyridinone (1 g, 2.7 mmol) was dissolved in NMP (2 mL), and the mixture was heated and stirred at 140° C. for 10 hours.
C analysis confirmed that 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone ( 91.3 %) was produced.
One-pot reaction: 5- (5-amino-6-chloropyrimidin-4-yl)amino-1-methyl-
1,2-Dihydro-2-pyridinone → 5-[6-chloro-5-(3-fluorobenzoyl)aminopyrimidin-4-yl]amino-1,2-dihydro-2-pyridinone → 5-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone) A flask was charged with 5-(5-amino-6-chloropyrimidin-4-yl)amino-1
1 g of 1,2-dihydro-2-pyridinone and 10 mL of NMP were added to the suspension, and the mixture was stirred at 40° C. 0.5 mL of 3-fluorobenzoyl chloride was added to the suspension.
3 mL, 1.1 eq.) was added dropwise, and NMP (3.2 mL) was further added, and the mixture was stirred for about 1
After stirring for 5 hours, the reaction temperature was raised to 110°C and stirred for 3 hours. Ethyl acetate (33 mL) and 10% aqueous sodium bicarbonate solution (16.5 mL) were added to the reaction mixture, and the organic layer was washed with saturated brine (16.5 mL) and concentrated. The concentrate was diluted with DME (
The resulting mixture was dissolved under stirring at 55° C., and then water (33 mL) was added to cause crystallization. The crystals were collected by filtration and dried at 50° C. for 4 hours to give a slightly brownish white 5-[6-chloro-
8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-
Dihydro-2-pyridinone 0.94 g (yield over two steps: 66.7%) was obtained. (6) 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl
]-1-methyl-1,2-dihydro-2-pyridinone In an autoclave, 5-[6-chloro-8-(3-fluorophenyl)-9H-
160.0 g of crude crystals (wet) of [9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone (content 96.0%, net weight 155 g), 2600 mL of DME,
1300 mL of concentrated aqueous ammonia (28-30%) was added, and the mixture was heated at an external temperature of 75° C. After one and a half hours, the external temperature was increased to 90° C., and the mixture was stirred for a total of eight and a half hours from the start of heating.

6.5 L of ion-exchanged water was added to the reaction mixture, and after cooling with ice, the precipitated crystals were collected by filtration, washed with 500 mL of water, and dried to obtain 135.0 g of the title compound. (7) 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl
]-1-methyl-1,2-dihydro-2-pyridinone.2H ₂ O Into a flask, 130 g of crude crystals of 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone,
1.3 L of methanol-denatured ethanol (2000 mL of EtOH mixed with 50 g of MeOH) and 1.3 L of water were added, and the mixture was heated in a water bath at 90°C.

The heater was turned off, and the mixture was stirred while gradually lowering the temperature. The precipitated crystals were collected by filtration and washed with 200 mL of methanol-denatured ethanol. The mixture was dried under reduced pressure to give the title compound 119.
1 g was obtained. ¹ H NMR (DMSO-d ₆ ) δ ppm: 3.43 (s, 3H, NMe-1′
), 6.46 (d, 1H, J = 9.7Hz, H-3'), 7.26-7.36 (
m, 1H), 7.36-7.60 (m, 6H), 8.09 (d, 1H, J=2.
8Hz, H-6'), 8.14 (s, 1H, H-2); Melting point: 244°C (dec
omp.) Example 47 6-chloro-9-(2-chloro-4-pyridyl)-8-(3-fluorophenyl
)-9H-purine (1) N-(6-chloro-5-nitro-4-pyrimidinyl)-N-(2-chloro
-4-pyridylamine A suspension of 5-nitro-4,6-dichloropyrimidine (8.0 g, 41.2 mmol) in tetrahydrofuran (160 mL) was added with 4-amino-2-chloropyridine (8.0 g, 62.2 mmol) and triethylamine (8.7 mL) at room temperature.
After adding these in order, the mixture was heated under reflux for 4 hours. After cooling, the mixture was diluted with ethyl acetate (160 ml), washed with 160 ml of water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting solid matter was suspended in diethyl ether. The resulting solid matter was collected by filtration and air-dried to obtain the title compound (2.2 g, 19%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm; 7.39 (1H, dd,
J=1.9, 5.5Hz), 7.79 (1H, d, J=2.0Hz), 8.31
(1H, d, J = 5.6), 8.62 (1H, s), 9.14 (1H, bs) (2) N4-(2-chloro-4-pyridyl)-6-chloro-4,5-pyrimidine
Diamine N-(6-chloro-5-nitro-4-pyrimidinyl)-N-(2-chloro-4-
(pyridyl)amine (2.2 g, 7.6 mmol) was dissolved in 44 ml of ethanol and 4 ml of acetic acid.
The mixture was suspended in 4 ml of HCl, and 2.2 g of zinc powder was slowly added at 0°C. The reaction mixture was allowed to reach room temperature and stirred for 1 hour, after which the insoluble matter was filtered off. The filtrate was concentrated and suspended in water. The resulting solid was filtered and air-dried to obtain 2.5 g of the crude title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm; 7.52 (1H, dd,
J=2.0, 5.9), 7.84 (1H, J=2.0), 8.12 (1H, J=
5.5), 8.13 (1H, s) (3) N1-[4-chloro-6-[(2-chloro-4-pyridyl)amino]-5
-pyrimidinyl]-3-fluorobenzamide To a suspension of N4-(2-chloro-4-pyridyl)-6-chloro-4,5-pyrimidinediamine (2.5 g, 9.8 mmol) in pyridine (50 mL) was added 3-fluorobenzoyl chloride (1.3 mL, 10.7 mmol) at 0-5° C. under a nitrogen atmosphere.
) was added dropwise over 5 minutes, and the mixture was stirred for 12 hours. The reaction mixture was diluted with water and ethyl acetate (100 mL). The organic layer was washed with 1N hydrochloric acid (×1). The 1N hydrochloric acid layer was extracted with ethyl acetate (×2), and the combined organic layer was washed with saturated aqueous sodium bicarbonate solution (×1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (2.3 g, 62%) as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm; 7.38-7.42 (2
H, m), 7.56-7.62 (1H, m), 7.70-7.78 (3H, m)
, 7.99 (1H, bs), 8.27 (1H, d, J=5.7), 8.60 (1
H,s) Next, N1-{4-chloro-6-[(2-chloro-4-pyridyl)amino]-
5-pyrimidinyl}-3-fluorobenzamide (2.3 g, 6.1 mmol)
A suspension of the above in phosphorus oxychloride (75 mL) was heated to reflux under a nitrogen atmosphere for 1.5 hours.
After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 ml), washed with water (×3), saturated aqueous sodium bicarbonate solution (×2), and saturated brine (×1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (1.0, 46%) as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm; 7.21 (1H, d, J
=1.8, 5.3Hz), 7.24-7.30 (2H, m), 7.39-7.4
8 (3H, m), 8.56 (1H, d, J = 5.3Hz), 8.79 (1H, s
Example 48 9-(2-chloro-4-pyridyl)-8-(3-fluorophenyl)-9H-6
- Prinamin A suspension of 6-chloro-9-(2-chloro-4-pyridyl)-8-(3-fluorophenyl)-9H-purine (325 mg, 0.9 mmol) from Example 47 in 1,2-dimethoxyethane (10 mL) and concentrated aqueous ammonia (5 mL) was stirred in an autoclave at 80° C. for 11 hours. After cooling, the reaction mixture was diluted with saturated aqueous ammonium chloride and ethyl acetate. The organic layer was extracted with saturated aqueous ammonium chloride (
The residue was suspended in diethyl ether, and the solid matter was collected by filtration and washed with diethyl ether to obtain the title compound (229 mg, 75%) as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 5.75 (2H, br)
, 7.16-7.24 (2H, m), 7.31-7.41 (2H, m), 7.4
4 (1H, d, J = 1.8Hz), 8.41 (1H, s), 8.51 (1H, d
, J=5.3Hz), 8.14 (1H, s), 8.23 (1H, d, J=2.8
Hz). Example 49 8-(3-fluorophenyl)-9-{2-[(4-methoxybenzyl)oxy]
]-4-pyridyl}-9H-6-purinamine 200 mg of metallic sodium was dissolved in 4-methoxybenzyl alcohol at 80°C, and 9-(2-chloro-4-pyridyl)-8-(3-fluorophenyl)-9H-6-purinamine (596 mg, 1.75 mmol) from Example 48 was added and stirred for 1 hour. After cooling, the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was suspended in a mixture of ethyl acetate and hexane, and the resulting solid was collected by filtration and washed with diethyl ether to obtain the title compound (
690 mg, 89%) was obtained as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 3.80 (3H, s),
5.34 (2H, s), 6.13 (2H, bs), 6.80-6.88 (2H,
m), 6.90 (2H, d, J = 8.1Hz), 7.10-7.16 (1H, m
), 7.23-7.35 (2H, m), 7.37 (2H, d, J = 8.2Hz)
, 8.28 (1H, d, J = 5.3 Hz), 8.36 (1H, s). Example 50 4-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
,2-dihydro-2-pyridinone 8-(3-fluorophenyl)-9-{2-[(4-methoxybenzyl)oxy]-4-pyridyl}-9H-6-purinamine (690 mg, 1
The reaction mixture was diluted with water and the resulting precipitate was collected by filtration, washed with water, and dried to give the title compound (
510 mg, 75%) was obtained as the trifluoroacetate salt. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 6.15 (1H, d, J
= 5.1Hz), 6.43 (1H, d, J = 1.8Hz), 7.32-7.54
(5H,m), 8.22 (1H,s). Example 51 4-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1
-methyl-1,2-dihydro-2-pyridinone Example 50, 4-[6-amino-8-(3-fluorophenyl)-9H-9-
Purinyl]-1,2-dihydro-2-pyridinone (50 mg, 0.16 mmol
) was dissolved in 1 ml of N,N-dimethylformamide, and 64 mg of anhydrous potassium carbonate,
15 μL of methyl iodide was added and the mixture was reacted at 60°C for 2 hours. The reaction mixture was cooled, the insoluble matter was filtered off, and the mixture was concentrated to dryness. The residue was purified on a silica gel column (eluted with ethyl acetate).
After concentration, the title compound (30 mg, 55%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 3.53 (3H, s),
5.89 (2H, bs), 6.20 (1H, dd, J=2.2, 7.1Hz),
6.46 (1H, d, J = 2.3Hz), 7.38 (1H, d, J = 7.1Hz
), 8.32 (1H,s). MS m/e (FAB) 337 (MH ⁺ ). Example 52 8-(3-fluorophenyl)-9-(4-pyridyl)-9H-6-purine
hmm 9-(2-chloro-4-pyridyl)-8-(3-fluorophenyl)-9H-6-purinamine (50 mg, 0.15 mmol) from Example 48 was dissolved in 5 ml of methanol.
The resulting solution was dissolved in 5 ml of tetrahydrofuran, and 8.2 mg of potassium hydroxide and 50 mg of 10% palladium on carbon were added. The mixture was stirred at room temperature under hydrogen for 1 hour. The reaction mixture was diluted with ethyl acetate, the catalyst was filtered off, and then the mixture was concentrated under reduced pressure. The residue was suspended in water, and the resulting precipitate was collected by filtration to give the title compound (35 mg, 77%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 5.82 (2H, br)
, 7.08-7.14 (2H, m), 7.22-7.32 (4H, m), 8.3
3 (1H, s), 8.71 (2H, d, J = 6.0 Hz). MS m/e (FAB) 306 (MH ⁺ ). Example 53 5-[8-3(fluorophenyl)-9H-9-purinyl]-1-methyl-1,
2-Dihydro-2-pyridinone Example 46 5-[6-amino-8-(3-fluorophenyl)-9H-9-
Purinyl]-1-methyl-1,2-dihydro-2-pyridinone (1.0 g, 3.
1.0 mmol) was dissolved in 20 ml of tetrahydrofuran, and 1.2 ml of isoamyl nitrite was added.
The reaction mixture was cooled and then concentrated under reduced pressure, and the residue was purified on a silica gel column. The target product was eluted with ethyl acetate, and the solvent was distilled off to obtain the title compound (
340 mg, 35%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 3.62 (3H, s),
6.68 (1H, d, J=9.7), 7.21 (1H, dd, J=2.9, 9.
7), 7.23-7.27 (1H, m), 7.41-7.49 (2H, m), 7
．． 53-7.57 (1H, m), 7.58 (1H, d, J = 2.8), 9.00
(1H,s), 9.23 (1H,s). MS m/e (ESI) 322 (MH ⁺ ). Example 54 N-[9-(6-chloro-3-pyridazinyl)-8-(3-fluorophenyl)
-9H-9-purinyl]-N,N-dimethylamine (1) 2-[(6-chloro-5-nitro-4-pyrimidinyl)amino]ethylsilyl
Anido A suspension of 5-nitro-4,6-dichloropyrimidine (20.0 g, 0.10 mol) in tetrahydrofuran (400 mL) was added to 2-cyanoethylamine (
15.9 g, 62.2 mmol) and acetic acid (13 mL), methanol 30 ml
After adding the mixed solution at 0°C, the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate (400 ml), washed with 400 ml of water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid matter was suspended in diethyl ether. It was filtered and air-dried to obtain the title compound (18.7 g, 79%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm; 2.80 (2H, t, J
= 6.6Hz), 3.94 (2H, q, J = 6.6Hz), 7.81 (1H, b
s), 8.46 (1H, s) (2) 2-[(5-amino-6-chloro-4-pyrimidinyl)amino]ethylsilyl
Anido 2-[(6-chloro-5-nitro-4-pyrimidinyl)amino]ethyl cyanide (18.7 g, 82.2 mmol) was dissolved in 180 ml of ethanol, 180 ml of water,
The mixture was dissolved in 18 ml of acetic acid, and zinc powder was slowly added at 0°C. The reaction mixture was allowed to cool to room temperature for 3 minutes.
After stirring for 10 minutes, the insoluble matter was filtered off and the mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was suspended in diethyl ether, and the precipitated solid was collected by filtration. The title compound was collected by filtration and washed with diethyl ether to obtain the title compound (44.6 g, 51%). ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm; 2.80 (2H, t, J
= 6.2Hz), 3.80 (2H, q, J = 6.2Hz), 5.30 (1H, b
s), 8.10 (1H, s) (3) N1-{4-chloro-6-[(2-cyanoethyl)amino]-5-pyrimidinyl
{dinyl}-3-fluorobenzamide 2-[(5-amino-6-chloro-4-pyrimidinyl)amino]ethyl cyanide (10.0 g, 45.2 mmol) was dissolved in 63 ml of pyridine, and 4.3 ml of 3-fluorobenzoyl chloride was added at 0°C. The reaction solution was stirred at room temperature for 12 hours. The reaction solution was diluted with ethyl acetate, washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, the mixture was suspended in diethyl ether, and the precipitated solid was collected by filtration and washed with diethyl ether to obtain 8.9 g of the title compound. Yield: 87
% ¹ H NMR (400 MHz, CDCl ₃ ) δppm; 2.73 (2H, t, J
= 6.6Hz), 3.80 (2H, q, J = 6.4Hz), 6.28 (1H, b
s), 7.30-7.54 (1H, m), 7.47-7.53 (1H, m), 7
．． 62-7.70 (2H, m), 7.80 (1H, d, bs), 8.37 (1H
, s). (4) 2-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl
］ethyl cyanide A suspension of N1-{4-chloro-6-[(2-cyanoethyl)amino]-5-pyrimidinyl}-3-fluorobenzamide (8.9 g, 27.9 mmol) in phosphorus oxychloride (140 mL) was heated to reflux under a nitrogen atmosphere for 1.5 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with water (×3), saturated aqueous sodium bicarbonate solution (×2), and saturated brine (×1), dried over anhydrous sodium sulfate, and concentrated. The residue was suspended in diethyl ether, and the solid was collected by filtration and washed with diethyl ether to obtain the title compound (4.1 g).
, 49%) was obtained as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 3.04 (2H, t, J
= 6.8Hz), 4.59 (2H, t, J = 6.8Hz), 7.26-7.32
(1H,m) 7.45-7.57 (3h,m), 8.72 (1H,s). (5) 2-[6-(dimethylamino)-8-(3-fluorophenyl)-9H-
9-purinyl]ethyl cyanide 2-[6-chloro-8-(3-fluorophenyl)-9H-9-purinyl]e
Tetrahydrofuran (30 mL) of tetracyanide (1.5 g, 4.9 mmol)
To the solution was added 40% aqueous dimethylamine solution at 0°C and stirred at room temperature for 1 hour. The reaction mixture was diluted with water and ethyl acetate, washed with water and saturated brine, and then the organic layer was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was suspended in diethyl ether, and the precipitated solid was collected by filtration and washed with ether to obtain the title compound (740 mg, 48%). ^1H NMR (400 MHz, DMSO- _d6 ) δ ppm; 3.07 (2H, t
, J=6.6Hz), 3.32 (6H, s), 4.50 (2H, t, J=6.6
Hz), 7.40-7.46 (1H, m), 7.60-7.66 (3H, m),
8.28 (1H,s). (6) N-[8-(3-fluorophenyl)-9H-6-purinyl]-N,N-
Dimethylamine 2-[6-(dimethylamino)-8-(3-fluorophenyl)-9H-9-
To a solution of [purinyl]ethyl cyanide (100 mg, 0.32 mmol) in N,N-dimethylformamide, 14.1 mg of sodium hydride (60% in mine) was added.
Aqueous ammonium chloride (5 ml) was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature for 1 hour. 5 ml of saturated aqueous ammonium chloride solution was added, and the mixture was diluted with ethyl acetate. After washing with water and saturated brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure, and diethyl ether was added to the residue. The precipitated solid was collected by filtration to obtain the title compound (80 mg, 96%).
^1H NMR (400MHz, DMSO- _d6 ) δppm; 3.30 (6H, s
), 7.28-7.36 (1H, m), 7.54-7.60 (1H, m), 7.
88-8.00 (2H,m), 8.20 (1H,s). Next, N-[8-(3-fluorophenyl)-9H-6-purinyl]-N,N
-Dimethylamine (309 mg, 1.20 mmol) was dissolved in 15 ml of N,N-dimethylformamide, and 2 g of potassium carbonate and 1.5 g of 3,6-dichloropyridazine were added.
1 g of methyl 2,4-dichlorobenzofuran was added and the mixture was stirred at 80°C for 2 hours. After cooling the reaction mixture, it was diluted with 100 ml of ethyl acetate and insoluble matter was filtered off. The filtrate was concentrated to dryness, and the residue was purified on a silica gel column. After elution with ethyl acetate and concentration under reduced pressure, the desired title compound (80 mg, 18%) was obtained. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 3.50 (3H, s),
4.11 (3H, s), 7.01-7.08 (1H, m), 7.36-7.42
(1H, m), 7.83 (1H, d, J = 9.2Hz), 8.00-8.04 (
1H, m), 8.08-8.12 (1H, m), 9.21 (1H, s), 9.3
6 (1H, d, J = 9, 3 Hz). MS m/e (ESI) 370 (MH ⁺ ). Example 55 N-[8-(3-fluorophenyl)-9-(6-methoxy-3-pyridazinyl
)-9H-6-purinyl]-N,N-dimethylamine N-[9-(6-chloro-3-pyridazinyl)-8-(3-fluorophenyl)-9H-9-purinyl]-N,N-dimethylamine (50 mg, Example 54)
0.18 mmol) was dissolved in 5 ml of anhydrous methanol, and sodium methoxide (
To the reaction mixture was added 15 mg of acetic acid (0.28 mmol), and the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, suspended in water, and the precipitated solid was filtered off to obtain the title compound (35 mg, 52%) as a colorless solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 3.40 (3H, s),
4.04 (3H, s), 4.15 (3H, s), 6.92-6.98 (1H, m
), 7.23 (1H, d, J = 9.5Hz), 7.28-7.34 (1H, m)
, 7.93-7.97 (1H, m), 8.0-8.06 (1H, m), 8.91
(1H, d, J = 9.5 Hz), 8.93 (1H, s). Example 56 5-[6-amino-8-(3-fluorophenyl)-2-(3-hydroxy-3
-methyl-1-butynyl)9H-9-purinyl]-1-methyl-1,2-dihydro
rho-2-pyridinone The compound obtained in Example 19 was treated in the same manner as in Example 21 to obtain the title compound. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.63 (6H, s),
3.60 (3H, s), 6.20-6.40 (2H, br), 6.62 (2H,
dd, J=1.6, 9.3Hz), 7.10-7.20 (2H, m), 7.30
-7.44 (3H, m), 7.57 (1H, bs). MS m/e (FAB) 419 (MH ⁺ ). Example 57 5-(6-amino-8-(3-fluorophenyl)-2-[2-(1-hydroxyphenyl)-2-propanol] -4-yl]propanol
[cyclobutyl]-1-ethynyl]-9H-9-purinyl)-1-methyl-1,
2-Dihydro-2-pyridinone hydrochloride The title compound was obtained by treating in the same manner as in Example 21. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm: 1.75-1.83 (2
H, m), 2.21-2.30 (2H, m), 2.50-2.60 (2H, m)
, 3.54 (3H, s), 6.10 (2H, bs), 6.56 (2H, d, J=
9.7Hz), 7.07 (1H, dd, J=2.9, 9.7Hz), 7.08-
7.14 (1H, m), 7.26-7.38 (3H, m), 7.50 (1H, d
, J=2.4 Hz). MS m/e (FAB) 431 (MH ⁺ ). Example 58 9-(6-Methoxy-3-pyridyl)-8-(2-pyridyl)-9H-6-pyridyl
Naminé (1) N4-(6-methoxy-3-pyridyl)-6-chloro-4,5-pyrimidinyl
diamine To 800 mL of a 1:1 mixture of ethanol and water containing 40 g of 5-amino-4,6-dichloropyrimidine and 60.5 g of 5-amino-2-methoxypyridine, 40 mL of concentrated aqueous hydrochloric acid was added dropwise at room temperature. The mixture was stirred at 130°C for 7 hours and 20 minutes, and 800 mL of water was added to the reaction mixture at room temperature. The resulting suspension was filtered to obtain crude crystals, which were then recrystallized from dimethylformamide and water to obtain 32.7 g (53% yield) of greenish-brown crystals of the title compound. (2) 5-(6-chloro-9H-9-purinyl)-2-pyridyl methyl ether
L To a suspension of 32.7 g of N4-(6-methoxy-3-pyridyl)-6-chloro-4,5-pyrimidinediamine in 400 mL of dimethylformamide was added dropwise 10.8 mL of concentrated hydrochloric acid at room temperature, and the mixture was stirred at room temperature for 40 minutes, followed by further stirring at 100°C for 20 minutes. The reaction mixture was allowed to cool to room temperature, and the resulting suspension was filtered to obtain crude crystals. These were recrystallized from dimethylformamide and water to obtain 25 g (74% yield) of gray crystals of the title compound. (3) 9-(6-methoxy-3-pyridyl)-9H-6-purinamine 5-(6-chloro-9H-9-purinyl)-2-pyridyl methyl ether 2
A mixture of 5 g of ammonium hydroxide, 250 mL of concentrated aqueous ammonia, and 500 mL of dimethoxyethane was added to 70
The resulting suspension was filtered to give 21.2 g of white crystals of the title compound.
(91% yield) was obtained. (4) 8-Bromo-9-(6-methoxy-3-pyridyl)-9H-6-pyridyl
hmm 21.2 g of 9-(6-methoxy-3-pyridyl)-9H-6-purinamine was added to a 1:1 mixture of dimethylformamide and water (1.6 L) at room temperature with 9.0 g of bromine.
The mixture was stirred at room temperature for 7 hours and 25 minutes, and the reaction mixture was filtered to obtain yellow crystals.
The 1:1 (600 mL) suspension was stirred overnight at room temperature and the suspension was filtered to give 12.3 g (44% y.) of white crystals of the title compound.

Next, a solution of 500 mg of 8-bromo-9-(6-methoxy-3-pyridyl)-9H-6-purinamine, 1.15 g of tri-n-butyl(2-pyridyl)tin, 180 mg of tetrakis(triphenylphosphine)palladium(0), and 814 uL of N,N-diisopropylethylamine in 15 mL of xylene was heated at 150°C for 24 hours.
The mixture was stirred for 40 minutes. A small amount of methylene chloride and methanol was added to the reaction mixture, and the mixture was filtered through Celite. The filtrate was purified by short column chromatography to obtain 351 mg (71% yield) of the desired compound as brown crystals.

Example 59 5-[6-amino-8-(2-pyridyl)-9H-9-purinyl]-2-pyridyl
Knoll A mixture of 350 mg of 9-(6-methoxy-3-pyridyl)-8-(2-pyridyl)-9H-6-purinamine and 6 mL of concentrated hydrochloric acid was stirred at 105°C for 1 hour and 45 minutes. The solvent was distilled off from the resulting yellow-brown oil to give yellow-brown crystals. The resulting crystals were filtered with ethanol to give 77 mg (23%) of brown crystals of the title compound.
y.) was obtained.

Example 60 5-[6-amino-8-(2-pyridyl)-9H-9-purinyl]-1-methyl
-1,2-dihydro-2-pyridinone 5-[6-amino-8-(2-pyridyl)-9H-9-purinyl]-2-pyridinol 150 mg, sodium methoxide 133 mg, and methyl iodide 306 μg
A 1:120 mL mixed solution of methanol and tetrahydrofuran from L was stirred at room temperature for 2 hours and 35 minutes, and then stirred at 60°C for an additional 45 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted once with ethyl acetate. The organic layer was washed with saturated brine, and the combined aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure from the residue obtained after filtration to obtain 90 mg of brown crystalline product of the title compound.
(58% y.) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.44 (1 H, s
), 6.43 (1H, d, J = 9.2Hz), 7.42-7.47 (2H, m)
, 7.53 (2H, brs), 7.96-8.02 (2H, m), 8.16-8
．． 12 (2H, m), 8.49-8.50 (2H, m); MS m/e (ESI
) (MH ⁺ ). Example 61 2-(3-fluorophenyl)-3-(6-methoxy-3-pyridyl)-3H-
Imidazo[4,5-b]pyridine (1) N-(6-methoxy-3-pyridyl)-N-(3-nitro-2-pyridyl)
) amine A solution of 15 g of 2-chloro-3-nitropyridine, 11.7 g of 5-amino-2-methoxypyridine, and 26.1 g of potassium carbonate in 150 mL of dimethylformamide was stirred at room temperature for 4 hours and 25 minutes, and then stirred at 70°C for an additional 3 hours and 10 minutes. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted once with ethyl acetate. The organic layer was washed three times with saturated aqueous ammonium chloride and once with saturated brine, and then dried over magnesium sulfate. The residue was roughly purified by short column chromatography, and 9.10 g of reddish-brown crystals of the title compound were obtained from the resulting dark brown oil using diethyl ether.
(39% yield) (2) N2-(6-methoxy-3-pyridyl)-2,3-pyridinediamine A solution of 9.10 g of N-(6-methoxy-3-pyridyl)-N-(3-nitro-2-pyridyl)amine and 1 g of 10% palladium-carbon powder in a 1:1 mixture of methanol and ethyl acetate (200 mL) was stirred under hydrogen at room temperature for 12 hours and 20 minutes. The reaction mixture was filtered through Celite, and the residue was purified by short column chromatography to obtain crude crystals. The obtained crude crystals were filtered with diethyl ether to obtain 4.52 g (57% yield) of the title compound as brown crystals.

Next, N2-(6-methoxy-3-pyridyl)-2,3-pyridinediamine 2
A solution of 25 mL of methanol containing 1.5 g of ferric chloride, 1.24 mL of 3-fluorobenzaldehyde, and 3.3 mL of acetic acid was stirred at room temperature for 50 minutes. The solvent was distilled off from the reaction mixture under reduced pressure, and the residue was azeotroped three times with toluene to obtain orange crystals. A suspension of 2.06 g of anhydrous iron(III) chloride in 25 mL of ethanol was added to the obtained crystals at room temperature, and the mixture was heated to 95°C for 1 minute.
The mixture was stirred for 30 minutes. Ethyl acetate and saturated aqueous ammonium chloride were added to the reaction mixture, and the mixture was filtered through Celite. The residue was extracted once with ethyl acetate, and the organic layer was washed successively twice with saturated aqueous ammonium chloride and once with saturated brine. The solvent was evaporated from the residue under reduced pressure to give a brown oil, which was purified by short column chromatography to give 1.80 g (48% y) of the title compound as dark green crystals.

Example 62 5-[2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin -3-yl]-2-pyridinol 2-(3-fluorophenyl)-3-(6-methoxy-3-pyridyl)-3H
A mixture of 1.80 g of 4,5-imidazo[4,5-b]pyridine and 20 mL of 47% hydrobromic acid was stirred at 100°C for 3 hours and 35 minutes. The solvent was distilled off from the reaction mixture under reduced pressure to obtain a brown oil. This oil was azeotroped three times with toluene to obtain a brown oil. Crystals were then filtered off using methanol to obtain 1.07 g (
63% y.) was obtained.

Example 63 5-[2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridine
-3-yl]-1-methyl-1,2-dihydro-2-pyridinone 5-[2-(3-fluorophenyl)-3H-imidazo[4,5-b]pyridin-3-yl]-2-pyridinol 250 mg, sodium methoxide 177 m
g and methyl iodide in a 1:1 mixture of methanol and tetrahydrofuran (10
The resulting mixture was stirred at room temperature for 1 day. Ethyl acetate and saturated aqueous ammonium chloride solution were added, and the mixture was extracted three times with ethyl acetate. The organic layer was washed once with saturated brine and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to obtain crude crystals. The resulting crude crystals were filtered using diethyl ether to obtain 160 ml of brown crystals of the title compound.
g (61% y.) was obtained. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm: 3.46 (1 H, s
), 6.51 (2H, d, J = 9.6Hz), 7.38-7.44 (2H, m)
, 7.55-7.59 (4H, m), 8.18 (1H, s), 8.23 (1H,
d, J = 8.0Hz), 8.39 (1H, d, J = 4.8Hz); MS m/e
(ESI) (MH ⁺ ).

───────────────────────────────────────────────────────── Continued from the front page (51) Int.Cl. ⁷ Identification Symbol FI A61P 3/10 A61P 3/10 43/00 111 43/00 111 C07D 213/73 C07D 213/73 213/75 213/75 235/18 235/18 239/48 239/48 471/04 107 471/04 107A 471/08 471/08 473/16 473/16 473/18 473/18 473/40 473/40 487/04 144 487/04 144 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), AU, BR, CA, CN, HU, IL, JP, KR, MX, NO, NZ, RU, US, ZA (72) Inventor Takashi Inoue 2-2-1 Chateau Higashi 201, Tsukuba City, Ibaraki Prefecture (72) Inventor Tatsuhisa Horizoe 1-14-1-503 Inodai, Toride City, Ibaraki Prefecture (72) Inventor Nobuyuki Yasuda 16-26 Otemachi, Tsuchiura City, Ibaraki Prefecture (72) Inventor Kaya Ohashi 1-35-19 Kannondai, Tsukuba City, Ibaraki Prefecture Lumina 502, Kannondai No. 2 Building (72) Inventor: Hiroe Minami 9-7, Inarimae, Tsukuba City, Ibaraki Prefecture 506, Tsukuba No. 2 Dormitory (72) Inventor: Junsaku Nagaoka 1803-1, Kaneda, Tsukuba City, Ibaraki Prefecture (72) Inventor: Manabu Murakami 1-6-8, Tokodai, Tsukuba City, Ibaraki Prefecture (72) Inventor: Seiichi Kobayashi 165, Oakley Road, Belmont, Massachusetts, USA (72) Inventor: Isao Tanaka 2-5-16, Ninomiya, Tsukuba City, Ibaraki Prefecture (72) Inventor: Chikara Kawada 2-16-19, Kida Yotodai, Tsuchiura City, Ibaraki Prefecture (72) Inventor: Naoyuki Shimomura 3-32-6, Sakuradai, Ushiku City, Ibaraki Prefecture (72) Inventor: Hiroshi Akamatsu 4-14-3, Azuma, Tsukuba City, Ibaraki Prefecture La Terra Su Azuma Building B, No. 1 (72) Inventor: Ozeki Naoki 4331 Miyanaka, Kashima City, Ibaraki Prefecture (72) Inventor: Shimizu Toshikazu 2-9-19 Matsushiro, Tsukuba City, Ibaraki Prefecture (72) Inventor: Hayashi Kenji 4-6-33 Matsushiro, Tsukuba City, Ibaraki Prefecture (72) Inventor: Ushita Toyokazu 6-16-27 Chite Chuo, Kamisu Town, Kashima District, Ibaraki Prefecture Room 526, Kaminoike Sakuraka Dormitory (72) Inventor: Negi Shigeto 2-8-15 Higashi, Tsukuba City, Ibaraki Prefecture (72) Inventor: Naito Toshihiko 616-54 Koshirakama, Tsukuba City, Ibaraki Prefecture (Note) This publication is based on the gazette published internationally by the International Bureau of Patents (WIPO). The effect of the international publication of the Japanese patent application (Japanese utility model registration application) related to this publication arises pursuant to Article 184-10, Paragraph 1 of the Patent Act (Article 48-13, Paragraph 2 of the Utility Model Act), and is unrelated to this publication.

Claims (36)

[Claims] [Claim 1] General formula (I) In the formula, R ¹ is 1) a hydrogen atom, 2) a hydroxyl group, 3) a halogen atom, 4) a C1 to C8 alkyl group which may have a substituent, or 5) a group of the formula -NR ⁴ R ⁵ (in the formula, R ⁴ and R ⁵ are the same or different and each is a hydrogen atom,
It means a C1-C8 alkyl group or a C3-C8 cycloalkyl group, or a C2-C5 saturated cyclic amino group formed together with the nitrogen atom to which it is bonded. This ring may contain oxygen atoms, sulfur atoms, or nitrogen atoms in addition to the nitrogen atom, and may further contain a C1-C4 alkyl group optionally substituted with a halogen atom.
^R2 represents 1) a hydrogen atom, 2) a halogen atom, 3) a ^group of the formula ^-NR6R7 (wherein ^R6 and ^R7 may be the same or different and represent a hydrogen atom,
or ^R6 and ^R7 together with the nitrogen atom to which they are bonded represent a saturated C2-C5 cyclic amino group. This ring may contain oxygen, sulfur or nitrogen atoms in addition to the nitrogen atom, and may further be substituted with a C1-C4 alkyl group optionally substituted with a halogen atom.
4) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group or a C3-C6 cycloalkyl group, 5) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 6) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or 7) a C1-C8 alkoxy group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, ^R3 represents 1) a C3-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 2) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 3) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 4) an aryl group optionally having a substituent, 5) a heteroaryl group optionally having a substituent, 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C3-C6 cycloalkyl group optionally having a substituent, 7) a dihydrooxopyrimidyl group a) optionally substituted with a halogen atom or a C1-C6 alkyl group, and wherein the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group, b-2) an optionally substituted C3-C6 cycloalkyl-C1-C4 alkyl group, or b-3) a C3-C6 cycloalkyl group, or 8) a) optionally substituted with a halogen atom or a C1-C6 alkyl group, and wherein the nitrogen atom is further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group, b-2) an optionally substituted C3-C6 cycloalkyl-C1-C4 alkyl group, or b-3) a C3-C6 cycloalkyl group, 3) an oxopyridyl group optionally substituted with a halogen atom or a C1-C6 alkyl group and further substituted at the nitrogen atom with a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or 4) an oxopyrimidyl group optionally substituted with a halogen atom or a C1-C6 alkyl group and further substituted at the nitrogen atom with a C1-C6 alkyl group or a C3-C6 cycloalkyl group, and Q and W are the same or different and represent N or CH. However, in the above, when ^R2 is 4) a C2-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group, a C1-C4 alkyl group or a C3-C6 cycloalkyl group, 5) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or 6) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, then ^R3 is 3) a halogen atom,
1) a C1-C8 alkyl group optionally substituted with a hydroxyl group or a C1-C4 alkyl group, or 2) an aryl group optionally having a substituent. 2. The fused imidazole compound, pharmacologically acceptable salt or hydrate thereof according to claim 1, wherein R ² is a hydrogen atom. 3. The compound according to claim 1, wherein ^R3 is 1) a heteroaryl group which may have a substituent;
a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-1) a C1-C6 alkyl group optionally having a substituent, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-
3) a 1,2-dihydro-2-oxopyridyl group optionally substituted by a C3 to C6 cycloalkyl group which may have a substituent; 3) a) a halogen atom or C
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, and b-2) a C3-C6 alkyl group optionally having a substituent;
a) a dihydrooxopyrimidyl group substituted with a cycloalkyl-C1-C4 alkyl group, or b-3) a dihydrooxopyrimidyl group substituted with a C3-C6 cycloalkyl group, or 4) a) a dihydrooxopyrimidyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, wherein the nitrogen atom is b-1)
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group; b-2) a C3
a-1) a C1-C6 cycloalkyl-C1-C4 alkyl group, or b-2) a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3-C6 cycloalkyl-C1-C4 alkyl group, or a-3) a C3-C6 cycloalkyl group, or a hydrate thereof. 4. ^R3 is 1) a pyridyl group which may have a substituent, 2) a pyrimidyl group which may have a substituent, 3) a C1-C6 alkyl group which may be substituted with a halogen atom or a C1-C6 alkyl group and further wherein the nitrogen atom is b-1) a halogen atom, a hydroxyl group or a carboxyl group which may have a protecting group
b-1) a C6 alkyl group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group which may have a substituent, or b-3) a C3-C6 cycloalkyl-C1-C4 alkyl group which may have a substituent.
4) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom of which may be further substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group;
A fused imidazole compound or a pharmacologically acceptable salt or hydrate thereof according to claims 1 to 3, which is b-2) a C3 to C6 cycloalkyl-C1 to C4 alkyl group which may have a substituent, or b-3) a dihydrooxopyrimidyl group substituted with a C3 to C6 cycloalkyl group. 5. The compound according to any one of claims 1 to 4, wherein Ar is an aryl group which may have a substituent.
1. The fused imidazole compound, or a pharmacologically acceptable salt thereof, or a hydrate thereof, according to any one of the above. 6. The compound according to claim 1, wherein Ar is a phenyl group substituted with a halogen atom.
6. The fused imidazole compound, or a pharmacologically acceptable salt thereof, or a hydrate thereof according to any one of claims 1 to 5. 7. The compound according to claim 1, wherein R ¹ is a group represented by the formula —NR ⁴ R ⁵ (wherein R ⁴ and R ⁵ may be the same or different and represent a hydrogen atom, a C1-C8 alkyl group, or a C3-C8 cycloalkyl group, or a C2-C8 cycloalkyl group formed together with the nitrogen atom to which R 1 is attached).
7. The fused imidazole compound, or a pharmacologically acceptable salt thereof, or a hydrate thereof according to any one of claims 1 to 6, wherein the ring is a saturated cyclic amino group of formula (I). 5. This ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom in addition to the nitrogen atom, and may be further substituted with a C1-C4 alkyl group optionally substituted with a halogen atom. 8. The fused imidazole compound, a pharmacologically acceptable salt or a hydrate thereof according to any one of claims 1 to 7, wherein R ¹ is an amino group. 9. A compound according to claim 9, wherein R ¹ is an amino group, R ² is a hydrogen atom, and R ³ is 1) a pyridyl group optionally substituted with a hydroxyl group or a C1-C6 alkyl group, or 2) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, and the nitrogen atom thereof may further be substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a C3-C6 cycloalkyl group optionally having a substituent.
9. The fused imidazole compound, or a pharmacologically acceptable salt thereof, or a hydrate thereof according to any one of claims 1 to 8, wherein R is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 2 10. The fused imidazole compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 9, wherein ^R1 is an amino group, ^R2 is a hydrogen atom, and ^R3 is a 1,2-dihydro-2-oxopyridyl group optionally substituted with a C1-C6 alkyl group whose nitrogen atom may be substituted with a halogen atom. 11. The fused imidazole compound or pharmacologically acceptable salt thereof according to any one of claims 1 to 8, or a hydrate thereof, wherein ^R1 is an amino group, ^R2 is a C2 alkynyl group substituted with a hydroxyl group and a ^C4 to C6 cycloalkyl group, R3 is a C3 alkenyl group, and Ar is a phenyl group substituted with a halogen atom. 12. The fused imidazole compound according to claim 1, or a pharmacologically acceptable salt thereof, or a hydrate thereof, selected from the following group: 1) 5-[6-amino-8-(3-fluorophenyl)-9H-9-purinyl]
-1-Methyl-1,2-dihydro-2-pyridinone 2) 1-{2-[6-amino-8-(3-fluorophenyl)-9-(2-propenyl)-9H-2-purinyl]-1-ethynyl}-1-cyclobutanol 13. The fused imidazole compound or a pharmacologically acceptable salt or hydrate thereof according to claim 1, which is a purine compound in which Q and W represent nitrogen atoms. 14. The fused imidazole compound or pharmacologically acceptable salt thereof according to claim 1, which is a benzimidazole compound in which Q and W represent —CH. 15. The fused imidazole compound or pharmacologically acceptable salt thereof according to claim 1, which is an imidazopyridine compound in which one of Q and W is N and the other is —CH. 16. A prophylactic and/or therapeutic agent for diabetes, comprising the fused imidazole compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof, as an active ingredient. 17. A preventive and/or therapeutic agent for diabetic complications, comprising the fused imidazole compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof, as an active ingredient. 18. A preventive or therapeutic agent for a disease for which the fused imidazole compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof is effective. 19. A preventive and/or therapeutic agent for diabetic retinopathy, comprising the fused imidazole compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof, as an active ingredient. 20. An adenosine A2 receptor antagonist comprising the fused imidazole compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof. 21. A pharmaceutical composition comprising the fused imidazole compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof, and a pharmacologically acceptable carrier. Claim 22: A compound of the formula: 5-amino-1-methyl-2(1H)-pyridone oxalate represented by the formula: 23. A compound represented by the following general formula: (wherein ^L1 represents a halogen atom, ^R2 represents 1) a hydrogen atom, 2) a halogen atom, 3) a group of the formula ^-NR6R7 (wherein ^R6 and ^R7 are the same or different and represent a hydrogen atom, a C2- ^C5 acyl group, a C1-C8 alkyl group, or a C3-C8 cycloalkyl group, or ^R6 and ^R7 together with the nitrogen atom to which they are bonded represent a C2-C5 saturated cyclic amino group. This ring may contain an oxygen atom, a sulfur atom, or a nitrogen atom in addition to the nitrogen atom, and may further include a C1-C5 acyl group optionally substituted with a halogen atom).
4) a halogen atom, a hydroxyl group, a C1 alkyl group, or a C2 alkyl group;
C optionally substituted by a C to C alkyl group or a C to C cycloalkyl group
R3 represents 1) a C3-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 2) a C3-C8 alkenyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 3) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, or ⁴ ) a C1-C8 alkynyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group,
1) a C1-C6 alkyl group optionally substituted with an alkyl group, 2) a C1-C8 alkenyl group optionally substituted with an alkyl group, 3) a C1-C8 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a C1-C4 alkyl group, 4) an aryl group optionally having a substituent, 5) a heteroaryl group optionally having a substituent, 6) a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, the nitrogen atom of which is optionally substituted with b-1) a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group,
b-2) a C3 to C6 cycloalkyl-C1 to C4 alkyl group which may have a substituent, or b-3) a 1,2-dihydro-2-oxopyridyl group which may be substituted with a C3 to C6 cycloalkyl group which may have a substituent, 7) a) a group which may be substituted with a halogen atom or a C1 to C6 alkyl group, and in which the nitrogen atom is b
b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent.
6) a dihydrooxopyrimidinyl group substituted with a cycloalkyl group, or 8)
a) a C1-C6 alkyl group optionally substituted with a halogen atom or a C1-C6 alkyl group, wherein the nitrogen atom is b-1) a C1-C6 alkyl group optionally substituted with a halogen atom, a hydroxyl group or a carboxyl group optionally having a protecting group, b-2) a C3-C6 cycloalkyl-C1-C4 alkyl group optionally having a substituent, or b-3) a C
and X represents a halogen atom, and X represents a dihydrooxo or tetrahydrodioxopyrazinyl group substituted with a C3 to C6 cycloalkyl group, and Q and W are the same or different and represent N or CH.
Ar is 1) an aryl group which may have a substituent, 2) a heteroaryl group which may have a substituent, 3) an oxopyridyl group which may be substituted with a halogen atom or a C1-C6 alkyl group and in which the nitrogen atom is substituted with a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or 4) a halogen atom or a C1-C6 alkyl group.
The nitrogen atom may be substituted with a C1 to C6 alkyl group or a C
means an oxopyrimidyl group substituted with a 3-C6 cycloalkyl group.
The method is characterized in that an acyl compound represented by the following general formula: (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), or a salt thereof, or a hydrate thereof. 24. A compound represented by the following general formula: (wherein L ¹ , R ² , R ³ , Q and W are the same as defined above), and an aminopyridine derivative (A2) represented by the general formula ArCOX (wherein X
and Ar are the same as defined above,
The compound represented by the following general formula, which is characterized by reacting in the presence of pyridine: (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), or a salt thereof, or a hydrate thereof. 25. The process for producing the acylaminopyridine derivative (A3), or a salt thereof, or a hydrate thereof according to claim 23 or 24, wherein ^R3 is an N-C1-C8 alkyl-2-oxopyridinyl group. Claim 26: A compound represented by the following general formula: (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), in the presence of POCl ₃ , a ring-closing reaction is carried out to obtain a compound represented by the following general formula: (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), or a salt thereof, or a hydrate thereof. 27. A compound represented by the following general formula: (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same groups as defined above), in the presence of hydrochloric acid or using a hydrochloride of the acylaminopyridine derivative (A3), (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), or a salt thereof, or a hydrate thereof. 28. A compound represented by the following general formula: wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above, are subjected to a ring-closing reaction in NMP (1-methyl-2-pyrrolidone) under heating to produce a compound represented by the following general formula: (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), or a salt thereof, or a hydrate thereof. 29. The process for producing the imidazopyridine derivative (A4), or a salt thereof, or a hydrate thereof according to any one of claims 24 to 28, wherein ^R3 is an N-C1-C8 alkyl-2-oxopyridinyl group. 30. A compound represented by the following general formula: (wherein L ¹ , R ² , R ³ , Q and W are the same as defined above), and an aminopyridine derivative (A2) represented by the general formula ArCOX (wherein X
and Ar are the same groups as defined above, and then subjected to a ring-closure reaction. (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), or a salt thereof, or a hydrate thereof. 31. The method for producing the imidazopyridine derivative (A4) or a salt thereof or a hydrate thereof according to claim 30, characterized in that the aminopyridine derivative (A2) is converted into the imidazopyridine derivative (A4) by a one-pot reaction. 32. A compound represented by the following general formula: wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above, are subjected to amination of an imidazopyridine derivative (A4) represented by the general formula: (wherein L ¹ , R ² , R ³ , Ar, Q and W are the same as defined above), or a salt thereof, or a hydrate thereof. 33. The process for producing the aminoimidazopyridine derivative (A5), or a salt thereof, or a hydrate of the foregoing according to claim 32, wherein ^R3 is an N-C1-C8 alkyl-2-oxopyridinyl group. [Claim 34] The following general formula: (In the formula, R¹is 1) a hydrogen atom, 2) a hydroxyl group, 3) a halogen atom, or 4) a group having a substituent.
or 5) a C1 to C8 alkyl group of the formula -NR⁴R⁵(In the formula, R⁴
and R⁵are the same or different and represent a hydrogen atom, a C1-C8 alkyl group, or
means a C3-C8 cycloalkyl group, or together with the nitrogen atom to which it is attached
This ring is a saturated cyclic amino group of C2 to C5 formed by the nitrogen.
In addition to the hydrogen atoms, the alkyl group may contain oxygen atoms, sulfur atoms, or nitrogen atoms.
and optionally substituted with a C1-C4 alkyl group optionally substituted with a halogen atom.
) means the expression is a dihydrooxopyridinyl or pyrimidyl group, or a dihydro or tetra
means a hydropyrazinyl group, and R²Ar, Q and W are the same groups as defined above.
The imidazopyridine derivative (C2) represented by the formula (C1) is alkylated to
The general formula is(In the formula, R¹³is a halogen atom, a hydroxyl group or a carbo
a C1-C6 alkyl group optionally substituted with an xyl group;
C3-C6 cycloalkyl-C1-C4 alkyl group or
R means a C3-C6 cycloalkyl group which may be optionally substituted;¹, expressionR², Ar, Q and W each represent the same group as defined above.
Method for producing imidazopyridine derivative (C3) or its salt or hydrate thereof
Law. 35. A method for treating diabetes, diabetic complications, diabetic retinopathy or a diabetic complication comprising administering a pharmacologically effective amount of the fused imidazole compound according to any one of claims 1 to 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof, to a patient.
16. A method for preventing or treating a disease for which the fused imidazole compound according to any one of 15, or a pharmacologically acceptable salt thereof, or a hydrate thereof is effective, or a disease for which an adenosine A2 receptor antagonism is effective. 36. Diabetes, diabetic complications, diabetic retinopathy or any of claims 1 to 15.
a condensed imidazole compound according to any one of claims 1 to 4, or a pharmacologically acceptable salt thereof, or a hydrate thereof, for use as a preventive or therapeutic agent for a disease for which the condensed imidazole compound according to any one of claims 1 to 4, or adenosine A
16. Use of the fused imidazole compound, or the pharmacologically acceptable salt thereof, or the hydrate thereof according to any one of claims 1 to 15 for the production of a 2 receptor antagonist.