JP2001097979A - Condensed heterocyclic compound, and method of production and application thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a preventive and/or treating agent excellent in activity and safety for kidney diseases, heart diseases, inflammatory diseases, allergic diseases, autoimmune diseases, arteriosclerosis, diabetic retinitis, infectious diseases, malignant tumors, rejection symptoms after organ transplantation, or the like. SOLUTION: An MIF inhibitor containing a compound expressed by formula (I) [wherein, the ring A and the ring B are each a 4-membered or 8-membered heterocycle; and U is a group expressed by formula (III): -Q-(CH2)k-W-R3 (wherein, R1 is a group bound via O; R2 is a hydrocarbon group or the like; and n=1-4) or a group expressed by formula (IV): -CR6R7- (wherein, k=1-6; R3 is an aryl or the like; G is N or the like; and W is formula (VI) (wherein, R6 is a group bound via O; and R7 is H or the like))] or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a MIF (Macrophage
Migration Inhibitory Factor) has an inhibitory effect and is a prophylactic / therapeutic agent against renal disease, heart disease, inflammatory disease, allergic disease, autoimmune disease, arteriosclerosis, infectious disease, malignant tumor, rejection after organ transplantation, etc. The present invention relates to a useful fused heterocyclic compound, a method for producing the compound, and a medicament containing the compound.

[0002]

2. Description of the Related Art MIF is an inflammatory cytokine produced by immunocompetent cells, pituitary gland, and the like in response to biological invasion, and is known to be located upstream of the inflammatory cytokine cascade to control the inflammatory response. [Annual
Reports in Medicinal Chemistry (Annual
Reports in Medicinal Chemistry) Vol. 33, pp. 243-252 (1
998); Advances in Immunology (Advan
ces in Immunology) 66, 197-223 (1997)]. Furthermore, it has been revealed that MIF is involved in the proliferation and differentiation of fat cells and cancer cells, and plays an important role not only in the immune response but also in various biological reactions [International Journal of Molecular Medicine (International Journal of Molecular Medicine) 2
Volume, pp. 17-28 (1998)]. Cells and tissues that express MIF include T cells, monocytes / macrophages, mesangial cells, tubular epithelial cells, corneal epithelial cells, hepatocytes, egg cells,
Sertoli cells, keratinocytes, osteoblasts, synovial cells,
Fat cells, astrocytes, cancer cells, mucous membranes, pituitary glands and the like are known. Examples of the involvement of MIF in human disease include synovial fluid in rheumatic patients, alveolar lavage in patients with acute respiratory distress syndrome, and diabetes, systemic lupus erythematosus,
There have been reports showing that serum MIF levels in patients with atopic dermatitis are significantly elevated compared to healthy individuals,
Further, as an example showing that suppressing the function of MIF leads to improvement of symptoms, an experimental example using an anti-MIF neutralizing antibody can be mentioned. That is, in animal disease models such as nephritis, hepatitis, pneumonia, arthritis and endotoxin shock, a clear improvement effect was observed in the group to which the anti-MIF neutralizing antibody was administered [International Journal of International
Molecular Medicine (International Journal of
Molecular Medicine, Vol. 2, pp. 17-28 (1998)]. On the other hand, it is known that proliferation and interleukin 2 production induced when mouse spleen-derived T cells are stimulated with an anti-CD3 antibody are suppressed by an anti-mouse MIF neutralizing antibody (Proceeding of National).・ Academy ・
Proceeding of National Academy of
Science) 93, 7849-7854 (1996)]. In addition, anti-mouse MIF antiserum improves survival in a mouse endotoxin shock model (Nature 365).
Volume, p. 756 (1993)) and that MIF knockout mice are more resistant to endotoxin shock than normal mice [Journal of Experimental
Medicine (Journal of Experimental Medicine) No. 189
Volume, p. 341 (1999)]. However, M
No low-molecular compound that inhibits the physiological function of IF has been reported at all. Compounds that inhibit dopachrome tautomerase activity exhibited by MIF include several dopachrome analogs (WO97 / 29635, Journal of Biochemistry, Vol. 122, 1040-1).
045 (1997)], but none of them has a weak inhibitory activity, and there is no description as to whether or not they inhibit the physiological function of MIF.

[0003]

SUMMARY OF THE INVENTION Heretofore, steroids have been used to treat renal diseases, heart diseases, inflammatory diseases, allergic diseases, autoimmune diseases, arteriosclerosis, infections, malignancies, and rejection after organ transplantation. Drugs and drugs such as immunosuppressants, including cyclosporin, have been used, but their effectiveness and safety are not sufficient, and in these respects, further improved renal disease, There is a demand for the development of preventive / therapeutic drugs for heart disease, inflammatory disease, allergic disease, autoimmune disease, arteriosclerosis, infectious disease, malignant tumor, and rejection after organ transplantation.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies on low molecular weight compounds that inhibit the physiological function of MIF in order to solve the above-mentioned problems. New formula featuring a unique chemical structure

Embedded image [Wherein, ring A and ring B each represent a 4- to 8-membered heterocyclic ring which may have a substituent (however,

Embedded image (Wherein each symbol has the same meaning as described above), is not a 5H-pyrimido [5,4-b] indole ring. ), U is the formula

Embedded image (Wherein R ¹ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ² represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and m and n are the same or different and each represents an integer of 1 to 4. ) Or a formula

Embedded image (In the formula, k is an integer of 1 to 6, R ³ is an optionally substituted aryl group or an optionally substituted heterocyclic group, Q is an optionally substituted nitrogen atom, a sulfur atom,
W represents an oxygen atom or an optionally substituted carbon atom,

Embedded image (Wherein, R ⁶ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ⁷ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ), A carbonyl group or a thiocarbonyl group. However, if (i) k is 1, the equation

Embedded image (Wherein each symbol has the same meaning as described above).

Embedded image (In the formula, Z represents a nitrogen atom or an optionally substituted carbon atom, and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, or a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom. Represents a group that binds to
When Z is a carbon atom, R ⁵ may be bonded to Z to form a ring C), and when W represents a carbonyl group, Q is substituted; A nitrogen atom, an oxygen atom or an optionally substituted carbon atom, and (ii) when k is an integer of 2 to 6, W
Represents a carbonyl group, and Q represents an optionally substituted nitrogen atom. ). ] Or a salt thereof for the first time, the obtained compound has unexpectedly excellent MIF inhibitory activity based on its specific chemical structure, and has a renal disease, heart disease, inflammatory Disease, allergic diseases, autoimmune diseases, arteriosclerosis, infectious diseases, malignant tumors, rejection after organ transplantation, etc. It was completed. That is, the present invention provides the following equation (1).

Embedded image [Wherein, ring A and ring B each represent a 4- to 8-membered heterocyclic ring which may have a substituent (however,

Embedded image (Wherein each symbol has the same meaning as described above), is not a 5H-pyrimido [5,4-b] indole ring. ), U is the formula

Embedded image (Wherein R ¹ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ² represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and m and n are the same or different and each represents an integer of 1 to 4. ) Or a formula

Embedded image (In the formula, k is an integer of 1 to 6, R ³ is an optionally substituted aryl group or an optionally substituted heterocyclic group, Q is an optionally substituted nitrogen atom, a sulfur atom,
W represents an oxygen atom or an optionally substituted carbon atom,

Embedded image (Wherein, R ⁶ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ⁷ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ), A carbonyl group or a thiocarbonyl group. However, if (i) k is 1, the equation

Embedded image (Wherein each symbol has the same meaning as described above).

Embedded image (In the formula, Z represents a nitrogen atom or an optionally substituted carbon atom, and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, or a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom. Represents a group that binds to
When Z is a carbon atom, R ⁵ may be bonded to Z to form a ring C), and when W represents a carbonyl group, Q is substituted; A nitrogen atom, an oxygen atom or an optionally substituted carbon atom, and (ii) when k is an integer of 2 to 6, W
Represents a carbonyl group, and Q represents an optionally substituted nitrogen atom. ). Or a salt thereof represented by the formula (2):

Embedded image Is a group represented by the formula

Embedded image [In the formula, each of X and Y represents an optionally substituted nitrogen atom, sulfur atom, oxygen atom or optionally substituted carbon atom (provided that X and Y may be both substituted Atom is not shown),

Embedded image Represents a single bond or a double bond, and other symbols have the same meanings as described in the above (1). The compound according to the above (1), which is a condensed ring represented by the formula:

Embedded image Is a group represented by the formula

Embedded image [Wherein each symbol has the same meaning as in the above (2). A compound according to the above (2), which is a condensed ring group represented by the formula:
¹ is a halogen atom, a hydroxyl group which may be substituted, an amino group which may be substituted, a nitro group, a cyano group, an alkylcarbonyl group, an arylcarbonyl group, a hydroxyalkyl group, a carboxyl group which may be esterified, The compound according to the above (1), which is an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group or an optionally substituted mercapto group,
(5) The compound according to the above (1), wherein R ¹ is a halogen atom, a hydroxyl group, a cyano group, a hydroxy C _1-6 alkyl group, a formyl group or a C _1-6 alkylcarbonyl group,
(1) The compound according to the above (1), wherein ¹ is a hydroxyl group, a cyano group or a C _1-6 alkylcarbonyl group, (7) the compound according to the above (1), wherein R ¹ is a hydroxyl group, and (8) R ² is substituted. A compound according to the above (1), which is an optionally substituted aryl group, an optionally substituted heterocyclic group, an optionally substituted alkyl group, or an optionally substituted alkenyl group, wherein (9) R ² is A compound according to the above (1), which is an _optionally substituted C _6-12 aryl group; (10) a compound according to the above (1), wherein R ² is an optionally substituted phenyl group; (11) R ³ is an aryl group which may be substituted (1) compounds described, (12) said R ³ is a phenyl group optionally substituted (1) compounds described, is (13) R ⁴ A thienyl group which may be substituted,
An aryl group which may be substituted, an alkyl group which may be substituted, an alkenyl group which may be substituted, a carboxyl group which may be esterified, an alkylcarbonyl group which may be substituted, An optionally substituted alkylthiocarbonyl group, an optionally substituted arylcarbonyl group, an optionally substituted arylthiocarbonyl group, an optionally substituted carbamoyl group, an optionally substituted cyclic aminocarbonyl group or an optionally substituted (2) which is an alkylthio group which may be
A compound according, (14) R ⁴ is an optionally substituted thienyl group, an optionally substituted phenyl group, an optionally substituted alkyl group, an optionally substituted alkylcarbonyl group, substituted be aryl group, substituted optionally be also a carbamoyl group or a substituted cyclic aminocarbonyl group which may 5 or 6-membered said (2) the compound according, (15) R ⁵ is a hydrogen atom, An alkyl group which may be substituted, a cyano group,
An amino group optionally substituted with an alkylcarbonyl or arylcarbonyl, a cyclic amino group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, or a substituted (16) The compound according to (2), wherein R ⁵ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group. (17) R ⁶ is a halogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, a nitro group,
Cyano group, alkylcarbonyl group, arylcarbonyl group, hydroxyalkyl group, optionally esterified carboxyl group, optionally substituted carbamoyl group, optionally substituted thiocarbamoyl group, or optionally substituted The compound according to the above (1), which is a good mercapto group; (18) the compound according to the above (1), wherein R ⁶ is a hydroxyl group; and (19) the compound according to the above, wherein R ⁷ is a hydrogen atom or an optionally substituted alkyl group. The compound according to (1),
(20) the compound according to the above (1), wherein Q is an optionally substituted nitrogen atom; (21) the compound according to the above (1), wherein W is a carbonyl group; (22) m and n are the same or different (23) The compound according to the above (1), wherein m and n are 2; (24) The compound according to the above (1), wherein k is 1, 2 or 3. (25) a prodrug of the compound according to (1) or a salt thereof;

Embedded image [Wherein, L represents a leaving group, and other symbols have the same meanings as described in the above (1). And a salt thereof, and a compound represented by the formula

Embedded image [Wherein the symbols have the same meanings as described in the above (1). ] The compound represented by these, its salt, or a formula.

Embedded image [In the formula, G represents a hydrogen atom or a metal atom, and other symbols have the same meanings as described in the above (1). However, when Q represents an optionally substituted carbon atom, G represents a metal atom. Wherein the compound or a salt thereof is reacted with a compound represented by the formula (1):

Embedded image [Wherein, ring A and ring B each represent a 4- to 8-membered heterocyclic ring which may have a substituent (however,

Embedded image (Wherein each symbol has the same meaning as described above), is not a 5H-pyrimido [5,4-b] indole ring. ), U is the formula

Embedded image (Wherein R ¹ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ² represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and m and n are the same or different and each represents an integer of 1 to 4. ) Or a formula

Embedded image (In the formula, k is an integer of 1 to 6, R ³ is an optionally substituted aryl group or an optionally substituted heterocyclic group, Q is an optionally substituted nitrogen atom, a sulfur atom,
W represents an oxygen atom or an optionally substituted carbon atom,

Embedded image (Wherein, R ⁶ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ⁷ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ), A carbonyl group or a thiocarbonyl group. However, if (i) k is 1, the equation

Embedded image (Wherein each symbol has the same meaning as described above).

Embedded image (In the formula, Z represents a nitrogen atom or an optionally substituted carbon atom, and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, or a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom. Represents a group that binds to
When Z is a carbon atom, R ⁵ may be bonded to Z to form a ring C), and when W represents a carbonyl group, Q is substituted; A nitrogen atom, an oxygen atom or an optionally substituted carbon atom, and (ii) when k is an integer of 2 to 6, W
Represents a carbonyl group, and Q represents an optionally substituted nitrogen atom. ). A pharmaceutical composition comprising a compound represented by the formula:
The pharmaceutical composition according to the above (27), which is an F inhibitor, (2)
9) The above-mentioned (27) which is a prophylactic / therapeutic agent against renal disease, heart disease, inflammatory disease, allergic disease, autoimmune disease, arteriosclerosis, infection, malignant tumor, and rejection after organ transplantation.
And the like.

In the above formula, as the halogen atoms represented by R ¹ and R ⁶ , for example, fluorine, chlorine, bromine, iodine and the like are used.

Examples of the group bonded through the carbon atoms represented by R ¹ , R ⁴ , R ⁵ and R ⁶ include, for example, an optionally substituted hydrocarbon group and an optionally substituted heterocyclic group ( heterocyclic group is attached via a carbon atom on the ring), a cyano group, the ^{formula, -COOR a, -CO-R a} , -CO-NR
^{a R b, -CS-NR a} R b, -CO-SR a, -CS-S
^{R a, -CO-NR a -CO} -NR b or -C (= N
H) —NR ^a R ^b [wherein, R ^a and R ^b are the same or different and represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group. Also, ^Ra
And R ^b together with the adjacent nitrogen atom have the formula

Embedded image May form a ring represented by And the like are used. Examples of the group bonded via the nitrogen atom represented by R ¹ , R ⁴ , R ⁵ , and R ⁶ include, for example, a nitrogen-containing heterocyclic group which may be substituted (the heterocyclic group is a nitrogen atom on the ring ), A nitro group, a formula —NR ^a R ^b , —NR ^{a
-CO-R b, -NR a -CS} -R b, -NR c -CO-N
R ^a R ^b , -NR ^a -CS-NR ^b R ^c , -NR ^a -CO-O
^{R b, -NR a -CS-OR} b, -NR a -CO-SR b,
^{-NR a -CS-SR b, -NR} c -C (= NH) -NR a
_{^{R b, -NR a -SO 2 -R}} b or -NR ^c -NR ^a R
^b [wherein, R ^a , R ^b and R ^c are the same or different and each represent a hydrogen atom, an optionally substituted hydrocarbon group, or an optionally substituted heterocyclic group. Also, ^Ra and ^Rb
Is, together with the adjacent nitrogen atom, the formula

Embedded image May form a ring represented by And the like are used. Examples of the group bonded via an oxygen atom represented by R ¹ , R ⁴ , R ⁵ , and R ⁶ include, for example, a group represented by the formula —OR ^a , —O
^{-CO-R a, -O-CS} -R a, -O-CO-OR a,
-O-CO-NR ^a R ^b, or -O-C (= NH) -NR
^a R ^b wherein each symbol is as defined above. And the like are used. Examples of the group bonded via a sulfur atom represented by R ¹ , R ⁴ , R ⁵ , and R ⁶ include, for example, a group represented by the formula -S
^{R a, -SO-R a,} -SO 2 -R a, -SO 2 -NR
^{a R b, -S-CO-} R a, -S-CS-R a, -S-CO
^{-NR a R b, -S-CS} -NR a R b, -S-C (= N
H) in -NR ^a R ^b or -SCN [wherein each symbol is as defined above. And the like are used.

As the "hydrocarbon group" of the "optionally substituted hydrocarbon group", for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, a bridged cyclic hydrocarbon group and the like are used. Can be

The "alkyl group" is preferably, for example, a linear or branched alkyl group having 1 to 24 carbon atoms (C _1-24 chain alkyl group). Specific examples include methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl, isoamyl, tert-amyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-
Nonyl, n-decyl, n-undecyl, n-dodecyl,
n-Tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl, n-eicosyl, n-docosyl, n-tetracosyl and the like are used. Here, as the alkyl group, a straight-chain or branched alkyl group having 1 to 19 carbon atoms (C _1-19 alkyl group) is preferable, and a straight-chain or branched alkyl group having 1 to 12 carbon atoms is particularly preferable. (C _1-12 alkyl group) is preferable, and particularly, for example, a linear or branched alkyl group having 1 to 6 carbon atoms (C _1-6 alkyl group) is preferable.

The “alkenyl group” includes, for example,
A linear or branched alkenyl group having 2 to 24 carbon atoms (C _2-24 alkenyl group) is preferred, and specific examples thereof include vinyl, propenyl (1-, 2-) and butenyl (1).
-, 2-, 3-), pentenyl, octenyl, butadienyl (1, 3-) and the like are used. Here, as the alkenyl group, for example, a straight-chain or branched alkenyl group having 2 to 19 carbon atoms (C _2-19 alkenyl group) is preferable. Alkenyl groups (C _2-12 alkenyl groups) are preferred,
Particularly, a linear or branched alkenyl group having 2 to 6 carbon atoms (C _2-6 alkenyl group) and the like are preferable.

The “alkynyl group” includes, for example,
A linear or branched alkynyl group having 2 to 24 carbon atoms (C _2-24 alkynyl group) is preferred, and specific examples thereof include ethynyl, propynyl (1-, 2-), butynyl (1-, 2-, 3-), pentynyl, octynyl, decynyl and the like are used. Here, as the alkynyl group,
For example, a linear or branched alkynyl group having 2 to 19 carbon atoms (C _2-19 alkynyl group) is preferable, and a linear or branched alkynyl group having 2 to 12 carbon atoms (C _2-12 ) is particularly preferable. Alkynyl group) is preferable, and particularly, it has 2 carbon atoms.
To 6 linear or branched alkynyl groups (C _2-6
Alkynyl group) and the like are more preferred.

The "cycloalkyl group" is preferably, for example, one having 3 to 10 carbon atoms (C _3-10 cycloalkyl group), and specific examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclooctyl is used. Here, as the cyclic alkyl, for example, those having 3 to 8 carbon atoms (C
_3-8 cycloalkyl groups) are preferred, and among them, 3 carbon atoms
To 6 (C _3-6 cycloalkyl group) are more preferred.

The "aryl group" of the "aryl group" and the "optionally substituted aryl group" for R ³
For example, a monocyclic or condensed polycyclic group is used, and a group having 6 to 18 carbon atoms (C _6-18 aryl group) is preferable, and examples thereof include phenyl, biphenylyl, naphthyl, and the like. Anthryl, phenanthryl, acenaphthylenyl and the like can be mentioned. Here, as the aryl group, for example, those having 6 to 14 carbon atoms (C _6-14 aryl group) such as phenyl and naphthyl are preferable, and those having 6 to 12 carbon atoms (C _6-12 aryl group) are more preferable. .

The "bridged cyclic hydrocarbon group" includes, for example, a bridged cyclic hydrocarbon group having 4 to 19 carbon atoms (C _4-19).
(Crosslinked cyclic hydrocarbon group) and the like are more preferable, and among them, a C4 to C12 crosslinked cyclic hydrocarbon group ( _C4-12 crosslinked cyclic hydrocarbon group) is more preferable. Specific examples of such a bridged cyclic hydrocarbon group include 1-adamantyl, 2-adamantyl, 2-norbornanyl, 5-norbornene-2
-Yl and the like.

The "heterocyclic group" of the "optionally substituted heterocyclic group" includes, for example, an oxygen atom,
One selected from the group consisting of a sulfur atom and a nitrogen atom
A 5- to 8-membered heterocyclic group containing from 4 to 4 heteroatoms or a condensed heterocyclic group thereof (for example, a condensed ring group with a 6- to 8-membered carbocyclic or heterocyclic ring) and the like are used. Specifically, for example, 2- or 3-thienyl, 2
-Or 3-furyl, 2- or 3-pyrrolyl, 2-,
3- or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, 2-, 4- or 5-oxazolyl, 2-,
4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 3-, 4
-Or 5-isoxazolyl, 3-, 4- or 5-
Isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5- (1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- Or 5- (1,2,3-thiadiazolyl), 1,2,5-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl, N-oxide-2- , 3- or 4-pyridyl, N-oxide-2-, 4- or 5-pyrimidinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl, benzofuryl,
Benzothiazolyl, benzoxazolyl, triazinyl, oxotriazinyl, tetrazolo [1,5-b] pyridazinyl, triazolo [1,5-b] pyridazinyl,
Oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4
-Oxazinyl, morpholinyl, 1,4-thiazinyl,
1,3-thiazinyl, piperazinyl, benzimidazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolizinyl, 1,8-naphthyridinyl, purinyl, pteridinyl, dibenzofuranyl, carbazolyl,
Acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, thienopyrimidinyl and the like are used. Examples of the “nitrogen-containing heterocyclic group” of the “optionally substituted nitrogen-containing heterocyclic group” bonded via a nitrogen atom include, for example, a carbon atom, an oxygen atom and a sulfur atom other than 1 to 5 nitrogen atoms And a 5- to 8-membered heterocyclic group containing 1 to 7 atoms selected from the group consisting of: and a condensed heterocyclic group thereof (for example, a condensed ring group with a 6- to 8-membered carbon ring or a heterocyclic ring) and the like. Used. Specifically, for example, pyrrolyl, imidazolyl,
Pyrazolyl, triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, benzimidazolyl, indolyl, isoindolyl, indolinyl, isoindolinyl and the like are used.

"Optionally substituted hydrocarbon group",
As the substituent in the `` optionally substituted heterocyclic group '' and the `` optionally substituted nitrogen-containing heterocyclic group '',
For example, a C _1-12 alkyl group (eg, methyl, ethyl,
Propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc., preferably C _1-6 alkyl, more preferably C _1-4 alkyl), C _3-8 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl) , Cyclohexyl, cycloheptyl and the like, preferably C _3-6 cycloalkyl), a halogen atom (for example, fluorine, chlorine, bromine, iodine and the like), a cyano group, a hydroxyl group which may be acylated (for example,
_1-12 alkanoyl, C _6-14 arylcarbonyl, C _7-13
Hydroxyl which may be acylated with aralkylcarbonyl or the like, specifically, for example, C _1-12 alkanoyloxy (eg, acetyloxy), C _6-14 arylcarbonyloxy (eg, benzoyloxy), C
_7-13 aralkylcarbonyloxy (e.g., benzylcarbonyloxy etc.), etc.), C _1-12 alkoxy group (e.g., methoxy, ethoxy, propoxy, C _1-6 alkoxy such as butoxy), C _{6 -14} aryloxy group (E.g., phenyloxy, naphthyloxy, etc.), carboxyl group, _C1-12 alkoxy-carbonyl group (e.g.,
C _1-6 alkoxy-carbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), nitro group, carbamoyl group optionally substituted by C _1-12 alkyl (eg, butylcarbamoyl etc.), formyl, C _2-12 alkanoyl groups (for example, acetyl, propionyl, butyryl, etc.
_2-6 alkanoyl, etc.), C _6-14 aryl group (for example,
Phenyl, naphthyl, etc.), C _6-14 arylcarbonyl (eg, benzoyl, naphthoyl, etc.), C _7-13 aralkylcarbonyl (eg, benzylcarbonyl, naphthylmethylcarbonyl, etc.), heterocyclic group [eg, nitrogen other than carbon atom 3 to 8 containing 1 to 4 heteroatoms selected from atoms, oxygen atoms or sulfur atoms
Membered heterocyclic group or a condensed heterocyclic group thereof (eg, a condensed ring group with a 6- to 8-membered carbon ring or a heterocyclic ring), specifically, for example, furyl (2-, 3-), thienyl (2- ,
3-), pyridyl (2-, 3-, 4-), thiazolyl,
Imidazolyl, benzothiazolyl, benzimidazolyl, oxazolyl (2-, 4-, 5-) etc.], -NR
^d R ^e [R ^d and R ^e are the same or different and are each a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or —SO ₂ R ^f (R ^f is R ^d and R ^e are the groups represented by
May form a ring with an adjacent nitrogen atom), C _1-12 alkylthio, C _1-12 alkylsulfinyl, C _1-12 alkylsulfonyl, C _6-14 arylthio,
C _6-14 arylsulfinyl, C _6-14 arylsulfonyl and the like are used. These substituents may be substituted at a substitutable site by a substitutable number.

Among the "substituents" in the "optionally substituted hydrocarbon group" and the "optionally substituted heterocyclic group", C _1-12 alkyl, C _3-8 cycloalkyl and C _3-8 An alkyl group of _1-12 alkylthio, C _1-12 alkylsulfinyl or C _1-12 alkylsulfonyl is
For example, C _3-8 cycloalkyl (eg, cyclopentyl,
Such as cyclohexyl, preferably a C _3-6 cycloalkyl group), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), cyano, hydroxyl, C _1-12 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.) Preferably C _1-6 alkoxy), carboxyl, C
_1-12 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc., preferably C _1-6 alkoxy-carbonyl), nitro, amino, carbamoyl, formyl, C _2-12 alkanoyl (eg, acetyl , Propionyl, butyryl and the like, preferably C _2-6 alkanoyl) and the like. These substituents may be substituted at a substitutable site by a substitutable number.

Among the "substituents" in the " _optionally substituted hydrocarbon group" and the "optionally substituted heterocyclic group", C _6-14 aryl group, C _6-14 arylcarbonyl group, _6-14 arylthio, C _6-14 aryl C _6-14 arylsulfinyl or C _6-14 arylsulfonyl, for example, C _1-6 alkyl (e.g. methyl, ethyl, propyl, butyl, etc., preferably C _1-4 Alkyl), C _3-8
Cycloalkyl (eg, cyclopentyl, cyclohexyl, etc., preferably C _3-6 cycloalkyl), halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), cyano,
Hydroxyl, C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc., preferably C _1-4 alkoxy), carboxyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl,
Such as propoxycarbonyl and butoxycarbonyl, preferably C1-4 alkoxy-carbonyl), nitro, amino, carbamoyl, formyl, _C2-6 alkanoyl (eg, acetyl, propionyl, butyryl and the like, preferably _C1-4 alkanoyl); It may be further substituted. These substituents may be substituted at a substitutable site by a substitutable number.

Among the “substituents” in the “optionally substituted hydrocarbon group” and the “optionally substituted heterocyclic group”, the heterocyclic group is, for example, C _1-6 alkyl (eg, methyl , Ethyl, propyl, butyl, etc., preferably C _1-4 alkyl), C _3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, etc., preferably C _3-6 cycloalkyl), a halogen atom (eg, fluorine, chlorine, Bromine, iodine, etc.), cyano, hydroxyl, C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc., C _1-4 alkoxy), carboxyl, C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxy) carbonyl, propoxycarbonyl, and butoxycarbonyl, preferably C _1-4 alkoxy - carbonyl), nitro, amino, Karubamoi , Formyl, C
These substituents which may be further substituted with _2-6 alkanoyl (eg, acetyl, propionyl, butyryl, etc., preferably C _1-4 alkanoyl) may be substituted at the substitutable site by the number of substituents. Good.

[0019] Among the "substituent" in the "optionally substituted hydrocarbon group" and "optionally substituted heterocyclic group", the group represented by -NR ^d R ^e, or -SO ₂ -R ^f In the above, the “hydrocarbon group” of the “optionally substituted hydrocarbon group” represented by R ^d , R ^e and R ^f may be the same as the “hydrocarbon group” described above.
As the “heterocycle” of the “optionally substituted heterocyclic group” represented by R ^d and R ^e , the same as the above “heterocyclic group” can be used. When R ^d and R ^e form a ring together with an adjacent nitrogen atom, the nitrogen-containing ring is selected, for example, from the group consisting of a carbon atom, a nitrogen atom, an oxygen atom and a sulfur atom other than the adjacent nitrogen atom A 5- to 8-membered nitrogen-containing ring which may contain 1 to 4 atoms is used, and the nitrogen-containing ring may be further condensed with a 6 to 8-membered carbocyclic or heterocyclic group. Good. When R ^d and R ^e form a nitrogen-containing ring together with a nitrogen atom as described above, specific examples of the cyclic amino group (—NR ^{d Re} ) constituted by the group —NR ^{d Re} itself include, for example, 1
-Pyrrolidyl, 1-imidazolyl, piperidino (1-piperidyl), 1-piperazinyl, 3-oxazolidinyl, hexamethyleneimino, heptamethyleneimino, morpholino (4-morpholinyl), 1-indolinyl, phthalimide and the like are used. These cyclic amino groups are
It may have a substituent.

As the substituent for the cyclic amino group, for example,
C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.), C _3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, etc., preferably C _1-6 cycloalkyl group), halogen atom (eg, fluorine, Chlorine, bromine, iodine, etc.), cyano, hydroxyl, C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl) , Butoxycarbonyl, etc.), nitro, amino, di-C _1-4 alkylamino, carbamoyl, formyl, C _2-4 alkanoyl (eg, acetyl, propionyl, butyryl, etc.), C _6-12 aryl (eg, phenyl, naphthyl) And 2-pyridyl. These substituents may be substituted at a substitutable site by a substitutable number. The C _1-4 alkyl and C _3-8 cycloalkyl are, for example, C _3-8 cycloalkyl (eg,
Cyclopentyl, cyclohexyl and the like, preferably C
_3-6 cycloalkyl), halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), cyano, hydroxyl, C
_1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl, C _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), nitro, amino, carbamoyl, formyl , C
_It may be further substituted with _2-4 alkanoyl (eg, acetyl, propionyl, butyryl, etc.). Also,
The C _6-12 aryl includes, for example, C _1-4 alkyl (eg, methyl, ethyl, propyl, butyl, etc.), C _3-8 cycloalkyl (eg, cyclopentyl, cyclohexyl, etc.)
Preferably C _3-6 cycloalkyl), a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), cyano, hydroxyl, C _1-4 alkoxy (eg, methoxy, ethoxy, propoxy, butoxy, etc.), carboxyl, C
Further substituted with _1-4 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), nitro, amino, carbamoyl, C _1-4 alkanoyl (eg, formyl, acetyl, propionyl, butyryl, etc.) It may be. As the ring formed by R ^a and R ^b together with the adjacent nitrogen atom, those similar to the above-mentioned ring formed by R ^d and R ^e together with the adjacent nitrogen atom are used.

In the present invention, R ¹ represents a halogen atom or a group bonded through an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom. Specifically, R ¹ represents a halogen atom or an optionally substituted hydroxyl group. An optionally substituted amino group, nitro group, cyano group, alkylcarbonyl group, arylcarbonyl group, hydroxyalkyl group, optionally esterified carboxyl group, optionally substituted carbamoyl group, A thiocarbamoyl group which may be substituted or a mercapto group which may be substituted is preferably used. R ¹ is, among others, a halogen atom, an optionally substituted hydroxyl group, a cyano group, a hydroxyalkyl group (eg, a hydroxy C _1-6 alkyl group), a formyl group, an optionally substituted alkylcarbonyl group or a substituted An alkylthiocarbonyl group which may be used is preferably used. More preferably, an optionally substituted hydroxyl group, a cyano group or an optionally substituted alkylcarbonyl group is used, and among them, a hydroxyl group, a cyano group or a C _1-3 alkylcarbonyl group is preferable, and further, a hydroxyl group, a cyano group, Groups or acetyl groups are more preferred, and hydroxyl groups are particularly preferred.

In the present invention, R ² represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. Specifically, R ² represents an optionally substituted aryl group or an optionally substituted aryl group. An optionally substituted heterocyclic group, an optionally substituted aralkyl group (eg, an optionally substituted C _6-12 aryl-C _1-3 alkyl group), an optionally substituted alkyl group, or a substituted An alkenyl group which may be substituted is preferably used, and an aryl group which may be substituted (eg, a C _6-12 aryl group) is preferably used. More preferably, R ² is a phenyl group which may be substituted, particularly preferably a phenyl group which may be substituted with halogen (eg, a phenyl group substituted with 1 to 3 fluorine atoms). .

In the present invention, R^ThreeIs replaced
A good aryl group or an optionally substituted heterocyclic group
Although shown, specifically, an aryl group which may be substituted
(C _6-12Aryl group) is preferably used, and more preferably
Preferably, an optionally substituted phenyl group is used,
Particularly preferably, a halogen atom-substituted
Phenyl group (eg, a phenyl group substituted with 1 to 3 fluorine atoms)
Nyl group) is used.

In the present invention, R ⁴ and R ⁵ may be the same or different and are each a hydrogen atom, a halogen atom (eg, fluorine, chlorine,
Bromine, iodine, etc.), or a group bonded via a carbon, oxygen, nitrogen or sulfur atom.

R ⁴ is a thienyl group which may be substituted, an aryl group which may be substituted, a benzyl group which may be substituted, an alkyl group which may be substituted, a cyclo group which may be substituted. Alkyl group, alkenyl group which may be substituted, carboxyl group which may be esterified, alkylcarbonyl group which may be substituted, alkylthiocarbonyl group which may be substituted, arylcarbonyl which may be substituted A group, an optionally substituted arylthiocarbonyl group, an optionally substituted carbamoyl group, an optionally substituted cyclic aminocarbonyl group, an optionally substituted alkylthio group, and the like are used. As R ⁴ , a thienyl group which may be substituted, a phenyl group which may be substituted, a benzyl group which may be substituted,
An alkyl group which may be substituted, a cycloalkyl group which may be substituted, an alkylcarbonyl group which may be substituted, an arylcarbonyl group which may be substituted, a carbamoyl group which may be substituted with alkyl or An optionally substituted 5- or 6-membered cyclic aminocarbonyl group is preferably used. Particularly preferably,
Thienyl group, a phenyl group which may be substituted with a hydroxyl group, a halogen atom or alkoxy, a benzyl group, a C _1-6 alkyl group which may be substituted with a hydroxyl group or a halogen atom, a C _3-6 cycloalkyl group, C _1-4 alkylcarbonyl group, a benzoyl group, C _1-6 alkyl or C _3-6 cyclic amino group of the cycloalkyl in the optionally substituted carbamoyl group or a 5 or 6 membered are used.

R ⁵ is a hydrogen atom, an alkyl group which may be substituted, a cycloalkyl group which may be substituted, a cyano group, an amino group which may be acylated,
A cyclic amino group, an optionally substituted alkoxy group, an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, or an optionally substituted alkylsulfonyl group are preferably used. More preferably, R ⁵ is a hydrogen atom, an optionally substituted alkyl group, or an optionally substituted cycloalkyl group (especially an optionally substituted cyclopropyl group). In particular, a hydrogen atom, an alkyl group which may be substituted with an amino group which may have a substituent, or a cyclopropyl group is used.

In the present invention, U is a formula

Embedded image [Wherein the symbols have the same meanings as described above. Or a group represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. ] Is shown.

M and n are the same or different and each represents an integer of 1 to 4, and preferably the same or different and an integer of 1 to 3 is preferable, and particularly preferably, m and n are 2; In the formula

Embedded image As the ring represented by the formula [wherein each symbol has the same meaning as described above], a 4- to 10-membered ring, preferably a 5- to 7-membered ring is used. Also, the formula-(CH ₂ ) _m- or-(C
H ₂ ) The carbon atom of the group represented by _n − may have a substituent. Examples of such a substituent include an oxo group,
A halogen atom, a group bonded via a carbon atom, a group bonded via an oxygen atom, a group bonded via a nitrogen atom, a group bonded via a sulfur atom, and the like are used. Among these substituents, a halogen atom, a group bonded via a carbon atom, a group bonded via an oxygen atom, a group bonded via a nitrogen atom, and a group bonded via a sulfur atom include the aforementioned R. ^{The same} ones as those represented by ¹ can be used, and the replaceable site may be replaced by a replaceable number.

Equation

Embedded image [Wherein the symbols have the same meanings as described above. In the group represented by the formula, k represents an integer of 1 to 6, preferably 1, 2, or 3. Q represents an optionally substituted nitrogen atom, sulfur atom, oxygen atom or optionally substituted carbon atom, and preferably an optionally substituted nitrogen atom. As the substituent for the nitrogen atom and the carbon atom, the groups bonded via the above-described carbon atoms and the like are used. As the group bonded through a carbon atom, those similar to the aforementioned “group bonded through a carbon atom” and the like are used. W is a carbonyl group, a thiocarbonyl group or a formula

Embedded image [Wherein the symbols have the same meanings as described above. A carbonyl group or a group represented by the formula (VI) is preferred.

R ⁶ is a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a carbon atom, an oxygen atom,
A group linked via a nitrogen atom or a sulfur atom.
Among them, as R ⁶ , a halogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, a nitro group, a cyano group, an alkylcarbonyl group, an arylcarbonyl group, a hydroxyalkyl group, and an esterified A good carboxyl group, a carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted, or a mercapto group which may be substituted are preferably used. More preferably, a hydroxyl group, a halogen atom and an amino group which may be substituted are used, and a hydroxyl group is particularly preferably used.

R ⁷ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and a hydrogen atom or an optionally substituted alkyl group is preferably used. In particular, a hydrogen atom or a C _1-3 alkyl group is preferably _used.The carbon atom of the group represented by the formula — (CH ₂ ) _k may have a substituent. As such a substituent, For example, an oxo group, a halogen atom, a group bonded via a carbon atom, a group bonded via an oxygen atom, a group bonded via a nitrogen atom, a group bonded via a sulfur atom, and the like are used. Among the substituents of these substituents, a halogen atom, a group bonded via a carbon atom, a group bonded via an oxygen atom, a group bonded via a nitrogen atom, and a group bonded via a sulfur atom include the same as those represented by R ¹ are used.

In the present invention, the formula

Embedded image The ring (ring A) represents a 4- to 8-membered heterocyclic ring which may have a substituent, and examples of the ring-constituting atoms (ring-constituting atoms) include an oxygen atom, a sulfur atom, An aromatic heterocyclic ring containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from an atom and a nitrogen atom; Alternatively, an unsaturated non-aromatic heterocycle (aliphatic heterocycle) or the like is used. Such heterocyclic groups include, for example,

Embedded image Are preferably used, among which the formula

Embedded image And the like are preferably used. formula

Embedded image In particular, the ring represented by the formula

Embedded image Those represented by are preferably used.

The substitutable site on the ring A may be substituted with a substitutable number of substituents. Examples of such a substituent include a hydrogen atom and a halogen atom represented by R ⁴ (for example, , Fluorine, chlorine, bromine, iodine, etc.), or a group bonded through a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom.

Expression

Embedded image Represents a 4- to 8-membered heterocyclic ring which may have a substituent, and examples of the ring-constituting atom (ring-constituting atom) include an oxygen atom, a sulfur atom, An aromatic heterocyclic ring containing at least one (preferably 1 to 4, more preferably 1 to 2) of 1 to 3 (preferably 1 to 2) heteroatoms selected from atoms and nitrogen atoms, etc .; Alternatively, an unsaturated non-aromatic heterocycle (aliphatic heterocycle) or the like is used. As such a heterocyclic group, for example,

Embedded image Is used, among which the expression

Embedded image Those represented by are preferably used. formula

Embedded image In particular, the ring represented by the formula

Embedded image Those represented by are preferably used.

The substitutable site on the ring B may be substituted with a substitutable number of substituents. Examples of such a substituent include a hydrogen atom and a halogen atom represented by R ⁵ (for example, , Fluorine, chlorine, bromine, iodine, etc.), or a group bonded via a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom.

Further, the ring B may form a condensed ring together with its substituents, for example, a carbon ring such as a benzene ring or a naphthalene ring, a pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an imidazole ring, a pyrazole ring. A heterocyclic ring such as a ring may be condensed. formula

Embedded image Preferred examples of the condensed ring represented by “wherein each symbol is as defined above” include, for example,

Embedded image And the like are used.

In the above formula,

Embedded image As the fused ring group represented by the formula:

Embedded image [Wherein each symbol has the same meaning as described above. And the like are preferably used, and among them, a group represented by the formula

Embedded image And the like are preferably used.

When Z is a carbon atom, the carbon atom may have a substituent. Examples of the substituent include, for example,
A halogen atom, a group bonded via a carbon atom, a group bonded via an oxygen atom, a group bonded via a nitrogen atom, a group bonded via a sulfur atom, and the like are used. As these substituents, those similar to those represented by R ⁴ and R ⁵ are used.

Next, a method for producing the compound (I) of the present invention or a salt thereof will be described. The following description of the production method applies not only to the compound (I) of the present invention but also to a salt thereof, but may be simply abbreviated as the compound (I) in the following description. Further, each compound used in the production of compound (I), for example, even when abbreviated as compound (XII), includes salts thereof. Compound (I) of the present invention is, for example, a compound represented by the formula

Embedded image [Wherein, L represents a leaving group, and other symbols have the same meanings as described above. A compound represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described above. ] Or

Embedded image [Wherein, G represents a hydrogen atom or a metal atom, and other symbols have the same meanings as described above. However, when Q represents an optionally substituted carbon atom, G represents a metal atom. ]
Or a salt thereof, or a salt thereof. When Q is a nitrogen atom, a sulfur atom or an oxygen atom, G is mainly a hydrogen atom,
Alkali metals such as lithium, sodium, potassium and cesium may be used. When Q is a carbon atom, G is preferably a metal such as lithium, magnesium halide, or copper.

This method is a method for producing the compound (I) of the present invention by reacting the compound (IX) with the compound (X) or (XI) or a salt thereof, and is preferably carried out in a solvent. (X) or (XI) or a salt thereof is used in 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to compound (IX). The base may be used in an amount of about 1 to 10 equivalents, preferably 1 to 2 equivalents. In the above formula, the leaving group represented by L may be a halogen atom such as chlorine, bromine or iodine, or a formula -S (O) _p R ⁸ [where p represents 0, 1 or 2; ⁸ is a lower (C _{1 -6} ) alkyl group such as methyl, ethyl and propyl; and C _6-10 such as phenyl and tolyl.
An aryl group or the like is used. ] Is used. As the solvent in the reaction, for example, dichloromethane, chloroform, carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, ethanol, isopropanol, t -Use alcohols such as butanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoramide, water or a mixed solvent thereof. Can be As the base in the reaction, an inorganic base or an organic base or the like is used. Specifically, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine , N, N, -dimethylaminopyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodium amide, diazabicycloundecene (DBU) and the like. The reaction is
The reaction can be carried out under cooling, at room temperature or under heating (about 40 to 150 ° C, preferably about 40 to 100 ° C), and the reaction time is usually about 1 to 20 hours, preferably about 1 to 1 hour.
0 hours. The obtained compound (I) of the present invention can be further subjected to introduction of a substituent or conversion of a functional group by applying means known per se to produce a compound falling within the scope of the present invention. When introducing this substituent or converting the functional group,
If there is a reactive substituent that causes a reaction other than the intended reaction, a protecting group is introduced into the reactive substituent in advance by a method known per se, if necessary, and the protective group is removed after the desired reaction. The compound included in the scope of the present invention can also be produced by removal by a method known per se. Compound (I) which is a product in this reaction may be produced as a single compound or as a mixture. The compound (I) of the present invention thus obtained can be obtained from the reaction mixture by a means known per se, for example, solvent extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, high performance liquid chromatography, The target product can be isolated and purified from the reaction solution with high purity by crystallization or the like.

The prodrug of the compound (I) of the present invention is a compound which is converted into the compound (I) by a reaction with an enzyme or stomach acid under physiological conditions in a living body, that is, causes enzymatic oxidation, reduction, hydrolysis and the like. A compound which is converted to a compound (I) by hydrolysis with gastric acid or the like. Examples of the prodrug of compound (I) include compounds in which the amino group of compound (I) is acylated, alkylated, and phosphorylated (eg, the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated). , (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation,
A compound in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (eg, the hydroxyl group of compound (I) is acetylated) , Palmitoylation, propanoylation, pivaloylation, succinylation, fumarylation,
Alanylated, dimethylaminomethylcarbonylated compounds, etc.); compounds in which the carboxyl group of compound (I) is esterified and amidated (eg, the carboxyl group of compound (I) is ethylesterified, phenylesterified,
Carboxymethyl esterification, dimethylaminomethyl esterification, pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) Methyl esterification, cyclohexyloxycarbonylethyl esterification, methyl amidated compound, and the like). These compounds can be produced from compound (I) by a means known per se. The prodrug of compound (I) is described in “Development of Pharmaceuticals”, Hirokawa Shoten, 1990, Vol.
Compounds which change to compound (I) under physiological conditions as described on pages 3 to 198 may be used.

The compound (I) of the present invention can form a salt with an appropriate acid. When the compound (I) has an acidic group as a substituent, it can form a salt with an appropriate base. Specifically, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, or the like can be used. Examples of the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt and ammonium salt. Is, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine,
A salt with N, N'-dibenzylethylenediamine or the like is used. As salts with inorganic acids, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc. are used.As salts with organic acids, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, Salts with oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like are used. As a salt with a basic amino acid, for example, a salt with arginine, lysine, ornithine and the like are used,
As a salt with an acidic amino acid, for example, a salt with aspartic acid, glutamic acid, or the like is used. Furthermore, a prodrug of the compound (I) of the present invention can be converted into a similar salt.

The compound (I) of the present invention may be a hydrate or an anhydrate, and the prodrug of the compound (I) of the present invention may be a hydrate or an anhydrate. Good. Examples of the hydrate include monohydrate, 0.5 hydrate, and dihydrate. The compound (I) of the present invention may be labeled with an isotope (eg, ³ H, ¹⁴ C, ³⁵ S, ¹²⁵ I, etc.), and the prodrug of the compound (I) of the present invention may be labeled in the same manner. It may be. When the compound (I) of the present invention or a salt thereof has an asymmetric carbon, the obtained mixture of optically active substances (racemic form) can be obtained by a conventional optical resolution means, for example, an optically active acid (eg, camphorsulfonic acid, etc.) Alternatively, a method of forming a salt with an optically active base (eg, 1-methylbenzylamine, etc.), various types of chromatography (eg, liquid chromatography using an optically active column, etc.),
Each optically active substance can be divided by separation means such as fractional recrystallization.

As the starting compound (IX) for this production method, any commercially available one may be used, but if it is not, it can be produced, for example, by the method shown by the following formula.

Embedded image [In the formula, L ¹ and L ² represent a halogen atom, and R ⁵ has the same meaning as described above, but a lower alkyl (eg, C _1-6 alkyl) group, a benzyl group and the like are particularly preferably used. q represents 1 or 2. ]

That is, as method A, compound (VIIIa) can be produced by reacting compound (XII) with a halogenating agent. Further, as a method B, the compound (XII) is reacted with a sulfurizing agent to give a compound (XIII), and then R ⁵ is added in the presence of a base.
It is reacted with a compound represented by L ² to give compound (VIIIb), can be prepared further compound subjected to oxidation reaction (VIIIc). As the halogenating agent in the method A,
For example, about 1 to 5 equivalents of phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, sulfuryl chloride, phosphorus tribromide and the like are used. At this time, the reaction may be carried out in the presence of a base such as diethylaniline, dimethylaniline or pyridine. Solvent-free, but as a reaction solvent, for example, dichloromethane, chloroform, carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, benzene, toluene, aromatic hydrocarbons such as xylene, diethyl ether, tetrahydrofuran, Ethers such as dioxane, acetonitrile, ethyl acetate and the like may be used.
The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is generally about 1 to 20 hours, preferably about 1 to 1 hour.
0 hours.

As the sulfurizing agent in the step of producing compound (XIII) from compound (XII) in Method B, for example, about 1
From 5 to 5 equivalents of Lawesson's reagent, diphosphorus pentasulfide and the like are used. As a reaction solvent, for example, dichloromethane,
Halogenated hydrocarbons such as chloroform, carbon tetrachloride, and 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, and xylene, and ethers such as diethyl ether, tetrahydrofuran, and dioxane are used. The reaction is carried out at room temperature or under heating, and the reaction time is usually about 1 to 20 hours, preferably about 1 to 10 hours. As R ⁵ L ² in the step of producing compound (VIIIb) from compound (XIII) in Method B, for example, about 1 to 5 equivalents of methyl iodide, benzyl chloride, benzyl bromide and the like,
Examples of the base include sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine,
N, N, -dimethylaminopyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodium amide, diazabicycloundecene (DBU) and the like are used. As the reaction solvent,
For example, dichloromethane, chloroform, carbon tetrachloride,
Halogenated hydrocarbons such as 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene and xylene, alcohols such as methanol, ethanol, isopropanol and t-butanol, ethers such as diethyl ether, tetrahydrofuran and dioxane For example, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, water or a mixed solvent thereof is used. The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is generally about 1 to 20 hours, preferably about 1 to 10 hours. As the oxidizing agent in the step of producing the compound (VIIIc) from the compound (VIIIb) in Method B, for example, metachloroperbenzoic acid, hydrogen peroxide, peracetic acid, t-butyl hydroperoxide, potassium peroxysulfate, potassium permanganate, Sodium perborate, sodium periodate, sodium hypochlorite, halogen and the like are used. In the case of producing the compound (VIIIc) where q = 1, the oxidizing agent is used in an amount of about 1 to 1.5 equivalents relative to the compound (VIIIb). In the case of producing the compound (VIIIc) where q = 2, about 2 to 3 equivalents use. The reaction solvent is not particularly limited as long as it does not react with the oxidizing agent.Examples include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, and 1,2-dichloroethane, and aromatic hydrocarbons such as benzene, toluene, and xylene. Hydrogens, methanol, ethanol, isopropanol, alcohols such as t-butanol, ethers such as diethyl ether, tetrahydrofuran, dioxane, carboxylic acids such as acetic acid, trifluoroacetic acid, acetonitrile, ethyl acetate, N, N-dimethylformamide,
Dimethyl sulfoxide, water or a mixed solvent thereof is used. The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is generally about 1 to 20 hours, preferably about 1 to 10 hours.

In the compound (I), a compound represented by the formula

Embedded image Is a ring represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. Is a fused ring represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described above. Similarly, the compound (Ia) which is a group represented by the formula (Ia) can be produced by the following method.

Embedded image [Wherein each symbol has the same meaning as described above. ]

In the compound (I), a compound represented by the formula

Embedded image Is a ring represented by the formula

Embedded image [Wherein the symbols have the same meanings as described above. Is a fused ring represented by the formula:

Embedded image [Wherein the symbols have the same meanings as described above. Similarly, the compound (Ib) which is a group represented by the formula (1) can be produced by the following method.

Embedded image [Wherein each symbol has the same meaning as described above. ]

As the starting compound (VIIId) for this production method, any commercially available one may be used, but if it is not, it can be produced by the same method as described above.
For example, of the compound (VIIId), a compound (IIIe) in which X and Z are a nitrogen atom, Y is an oxygen atom, and L is SR ⁸
Can be produced, for example, by the method shown in the following formula.

Embedded image [Wherein each symbol has the same meaning as described above. That is, compound (XIII) is reacted in the presence of about 1 to 1.5 equivalents of a base,
The compound (XIV) is reacted with about 1 equivalent of a compound represented by the formula R ⁸ SH, and then reacted with about 1 to 5 equivalents of an acylating agent to give a compound (XV). The compound (VIIIe) can be produced by cyclization in the presence of an equivalent amount of a base.

Compound (XIV) from compound (XIII) of the present method
In the step of producing a compound represented by the formula R ⁸ SH, for example, methanethiol, ethanethiol,
Thiophenol, benzyl mercaptan and the like, as a base, for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine, pyridine, N, N,-
Dimethylaminopyridine, sodium methoxide, sodium ethoxide, potassium t-butoxide, sodium hydride, sodium amide, diazabicycloundecene
(DBU) is used. When R ⁸ is a methyl group, sodium thiomethoxide may be used. As the reaction solvent, for example, dichloromethane, chloroform, carbon tetrachloride, halogenated hydrocarbons such as 1,2-dichloroethane, benzene, toluene, aromatic hydrocarbons such as xylene, methanol, ethanol, isopropanol, t-
Alcohols such as butanol, ethers such as diethyl ether, tetrahydrofuran and dioxane, acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide, water or a mixed solvent thereof are used. . The reaction is carried out under cooling, at room temperature or under heating, and the reaction time is usually about 1 to 20 hours, preferably about 1 to 10 hours.
Time. As the acylating agent in the step of producing a compound (XV) from the compound (XIV) of the present method, for example, a compound represented by the formula
An acid chloride represented by R ³ COCl, an acid anhydride represented by the formula (R ³ CO) ₂ O, and the like are used, and an acid chloride is particularly preferable. The reaction may be carried out in the presence of a base, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine,
Pyridine, N, N, -dimethylaminopyridine, diazabicycloundecene (DBU) and the like are used. As the reaction solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane , Acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and the like. The reaction is carried out at room temperature or under heating, and the reaction time is usually about 1 to 20 hours, preferably about 1 to 10 hours. In the step of producing compound (VIIIe) from compound (XV) of the present method, examples of the base include sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, triethylamine, pyridine, N, N, -dimethylaminopyridine And diazabicycloundecene (DBU). As the reaction solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane , Acetone, acetonitrile, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and the like. The reaction is performed at room temperature or under heating, and the reaction time is generally about 1 to 20 hours, preferably about 1 to 10 hours.

In the compound (VIIId), X and Z
Is a nitrogen atom, Y is a sulfur atom, and L is a methylthio group (IIIf), for example, can be produced by the method shown in the following formula.

Embedded image [Wherein each symbol has the same meaning as described above. That is, the compound (XIII) is reacted with about 2 to 3 equivalents of methylthiosodium to give a compound (XVI), and then reacted with about 1 to 5 equivalents of an acylating agent to give a compound (XVII). Compound (IIIf) can be produced by reacting 5 equivalents of a sulfurizing agent. Where the compound (XV
The step of producing compound (XVII) via I) can be carried out in the same manner as described above. From compound (XVII) to compound (III
As the sulfurizing agent in the step of producing f), for example, Lawesson's reagent, diphosphorus pentasulfide and the like are used. As the reaction solvent, for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethers such as diethyl ether, tetrahydrofuran, dioxane And the like are used. The reaction is carried out at room temperature or under heating, and the reaction time is usually about
It is 1 to 20 hours, preferably about 1 to 10 hours.

The starting compound or the synthetic intermediate obtained by the above-mentioned method can be obtained from the reaction mixture by a means known per se, for example, extraction, concentration, neutralization, filtration, crystallization, recrystallization, column chromatography, thin layer chromatography, etc. By using the above-mentioned means, they can be isolated and purified respectively. Further, the reaction mixture may be used as it is as a raw material in the next step without isolation.

The compound (I) of the present invention or a salt thereof has an excellent MIF inhibitory activity and low toxicity, and is useful in humans and mammals (eg, mouse, rat, guinea pig, rabbit, dog, cat, cow, Pigs, sheep, monkeys, chimpanzees, etc.). Further, the compound (I) of the present invention or a salt thereof may be used for renal disease, heart disease, inflammatory disease, allergic disease,
As a prophylactic / therapeutic agent for autoimmune disease, arteriosclerosis, infection, malignancy, rejection after organ transplantation, more specifically, acute and chronic glomerulonephritis, lupus nephritis, acute and chronic renal failure, nephrosis Syndrome, IgA nephropathy, rapidly progressive glomerulonephritis, diabetic nephropathy, diabetic retinopathy,
Obesity, myocarditis, cardiomyopathy, myocardial infarction, sepsis, systemic inflammatory response syndrome, acute respiratory distress syndrome, hepatitis, pneumonia, pancreatitis, peritonitis, peritonitis, encephalitis, colitis, arteriosclerosis, PT
Restenosis prevention after CA, rheumatoid arthritis, knee osteoarthritis, systemic lupus erythematosus, multiple sclerosis, pernicious anemia, idiopathic thrombocytopenic purpura, myasthenia gravis, scleroderma, uveitis, Hashimoto Disease, Sjögren's disease, Addison's disease,
Basedow's disease, granulocytopenia, atopic dermatitis, bronchial asthma, allergic rhinitis, hay fever, contact dermatitis, various diseases associated with infectious diseases, solid cancer, lymphoma, cachexia, rejection after organ transplantation It can be safely used for humans and mammals as a prophylactic / therapeutic agent for such as

When the compound (I) or a salt thereof is used as a medicament, it may be used alone or mixed with an appropriate pharmacologically acceptable carrier, excipient, diluent, or the like to give an orally administered drug (eg, powder) , Granules, tablets, capsules, etc.), parenteral preparations (eg, injections, external preparations (eg, transnasal preparations, transdermal preparations, etc.), suppositories (eg, rectal suppositories, vaginal suppositories) ) Can be safely administered orally or parenterally as a pharmaceutical composition.

These preparations can be produced, for example, by applying a method known per se which is generally used in the production of preparations. Compound (I) in preparation
The mixing ratio varies depending on the form, but for example, it is preferably about 10 to 95% by weight in the above-mentioned oral administration preparation, and for example, about 0.00 in the above-mentioned parenteral administration preparation.
1-95% by weight is preferred.

For example, injections can be prepared by solubilizing compound (I) with a solubilizer (eg, β-cyclodextrins), a dispersant (eg,
Tween 80 (manufactured by Atlas Powder, USA), HCO60 (manufactured by Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc., preservatives (eg, methylparaben, propylparaben, benzyl alcohol, chlorobutanol, etc.), isotonic Aqueous injections can be prepared according to a conventional method together with preparations (eg, sodium chloride, glycerin, sorbitol, glucose, etc.), or vegetable oils (eg, olive oil, sesame oil, peanut oil, cottonseed oil, corn oil, etc.), propylene glycol, etc. And then appropriately dissolved, suspended or emulsified to form an oily injection. For oral administration, the compound (I) may contain, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxy Methylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.) are added as appropriate, compression-molded, and, if necessary, taste masking, enteric coating Alternatively, it can be produced by applying a coating by a method known per se for the purpose of sustainability. As the coating agent, for example, hydroxypropyl methylcellulose,
Ethyl cellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragg (Rohm, West Germany, methacrylic acid, acrylic acid Polymerization), dyes (eg,
Titanium oxide, red iron oxide, etc.) are appropriately used.

Compound (I) of the present invention The compound (I) can be used as a solid, semi-solid or liquid external preparation.
For example, as a solid external preparation, compound (I) may be used as it is, or an excipient (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivatives, acrylic acid) (A polymer or the like), and the like, and mixed to form a powdery composition. The semi-solid external preparation is preferably produced according to a conventional method and used as an aqueous or oily gel or ointment. Liquid external preparations can also be prepared by preparing them as oily or aqueous suspensions by the means used for the production of injections or the equivalent. In addition, the pH of solid, semi-solid or liquid external preparations
A regulator (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), a preservative (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.) may be appropriately added. Specifically, for example, an ointment containing the compound (I) of the present invention generally in an amount of about 0.1 to about 100 mg per 1 g can be used based on petrolatum, lanolin and the like. Compound (I)
Can be oily or aqueous solid, semi-solid or liquid suppositories. As an oily base for producing a suppository, for example, glyceride of a higher fatty acid (eg, cacao butter, witepsol (manufactured by Dynamite Nobel))
Etc.), intermediate fatty acids (eg, miglyolic acid (manufactured by Dynamite Nobel), etc.), and vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) are used as appropriate. As the aqueous base, for example, polyethylene glycols,
Propylene glycol or the like is used, and as the aqueous gel base, for example, natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like are appropriately used.

The dose of the compound (I) or a salt thereof varies depending on the target disease, the target human or mammal, symptoms, age, body weight, symptoms, dosage form, administration method, administration period, and the like. In the case of oral administration in the treatment of the compound (I), the compound (I) or a salt thereof or a prodrug thereof is usually administered in an amount of about 1 kg body weight of a human or mammal.
It is 0.1 to 100 mg, preferably about 0.1 to 50 mg, more preferably about 1 to 50 mg, especially about 2.5 to 50 mg, which is administered once to three times a day. of course,
As described above, the dose varies under various conditions, so that a dose smaller than the above dose may be sufficient, or the dose may be out of the range in some cases.

Hereinafter, the present invention will be described in more detail by reference examples, examples, and test examples, but these are merely examples, and do not limit the present invention. The compounds obtained in Reference Examples and Examples are shown in Tables 1 to 18 below.

[0060]

[Table 1]

[0061]

[Table 2]

[0062]

[Table 3]

[0063]

[Table 4]

[0064]

[Table 5]

[0065]

[Table 6]

[0066]

[Table 7]

[0067]

[Table 8]

[0068]

[Table 9]

[0069]

[Table 10]

[0070]

[Table 11]

[0071]

[Table 12]

[0072]

[Table 13]

[0073]

[Table 14]

[0074]

[Table 15]

[0075]

[Table 16]

[0076]

[Table 17]

[0077]

[Table 18]

[Table 19]

[Table 20]

[0078]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited thereto. ^{The 1} H NMR spectrum was measured with a Varian Gemini 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and all δ values were shown in ppm. The numerical values shown in parentheses in the mixed solvents are volume mixing ratios of the respective solvents.
% Means percent by weight unless otherwise specified. The ratio of the solvent in the silica gel chromatography indicates the volume ratio of the mixed solvents. Each symbol in the examples has the following meaning. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, t
t: triple triplet, m: multiplet, b
r: Wide, J: Coupling constant

[0079]

EXAMPLES Reference Example 1 2-methyl-7- (methylsulfanyl) [1,3] thiazolo [5,4-
d] pyrimidine 5-amino-4,6-dichloropyrimidine 1.00 g in methanol 30
Then, 8.57 g of a 15% aqueous solution of sodium thiomethoxide was added under ice-cooling, and the mixture was further stirred at room temperature for 4 days. After concentrating the reaction solution, it was dissolved in 70 ml of ethyl acetate, filtered, and the solid obtained by concentrating the filtrate was recrystallized from ethyl acetate / n-hexane to obtain 1.04 g of needles. The needle crystals (0.22 g) were dissolved in ethyl acetate (5 ml), acetyl chloride (0.37 g) and N, N-diisopropylethylamine (0.18 g) were added, and the mixture was heated at 70 ° C. for 15 hours. The reaction solution was washed with 5% aqueous sodium hydrogen carbonate, dried and concentrated. The obtained residue was dissolved in ethanol (20 ml), sodium ethoxide (0.07 g) was added, and the mixture was stirred at room temperature for 30 minutes. After concentrating the reaction mixture, add 20 ml of ethyl acetate, wash with 5% aqueous sodium bicarbonate, dry and concentrate, and purify the residue by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 3/2). Thus, 0.23 g of needle crystals was obtained. 0.17 g of this needle crystal was dissolved in 20 ml of toluene, and 0.18 g of Lawesson's reagent was added, followed by heating at 110 ° C. for 12 hours. The reaction solution was washed with 5% aqueous sodium hydrogen carbonate, dried and concentrated, and the residue was subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane =
Purification by 1/3) and recrystallization from ethyl acetate / n-hexane gave 0.11 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.71 (3H, s), 2.88 (3H, s), 8.80 (1
. H, s) IR (KBr ): 1540, 1515, 1430, 1335 cm -1 Elemental analysis (%) Calculated _{(C 7 H 7 N 3 S} 2): C, 42.62; H, 3.58; N, 21.30 Found: C, 42.48; H, 3.56; N, 21.09 Melting point: 139-141 ° C.

Reference Example 2 7- (methylsulfanyl) -2- (3-thienyl) [1,3] thiazolo
[5,4-d] pyrimidine 5-amino-4,6-dichloropyrimidine 1.00 g in methanol 30
Then, 8.57 g of a 15% aqueous solution of sodium thiomethoxide was added under ice-cooling, and the mixture was further stirred at room temperature for 4 days. After concentrating the reaction solution, it was dissolved in 70 ml of ethyl acetate and filtered. The solid obtained by concentrating the filtrate was recrystallized from ethyl acetate / n-hexane to give 5-amino-4,6-dimethylsulfanylpyrimidine 1.04 g was obtained as needles. Dissolve 0.26 g of the needles in 20 ml of ethyl acetate and add 3-thiophenecarbonyl chloride 0.32 g
g was added and the mixture was heated under reflux for 19 hours. The reaction solution was concentrated to dryness, and the obtained residue was washed three times with 5 ml of diethyl ether / n-hexane (1/2) to obtain 0.36 g of needle crystals. The needle crystals were dissolved in 50 ml of toluene, and 0.59 g of Lawson's reagent was added, followed by heating at 110 ° C. for 3 hours. The reaction solution is concentrated, and the residue is subjected to column chromatography (silica gel, eluent: ethyl acetate / n-hexane / chloroform = 15/1/1).
Purification according to 5) gave 0.31 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.72 (3H, s), 7.40-8.15 (3H, m),
8.80 (1H, s).

Reference Example 3 Methyl 7- (methylsulfanyl) [1,3] thiazolo [5,4-d] pyrimidine-2-carboxylate In the same manner as in Reference Example 2, 5-amino-4,6-dimethylsulfanyl 43.9 g of pyrimidine and methyl chloroglyoxylate 3
57.7 g of needles obtained from 4.5 g and 94.8 g of Lawson's reagent
And 42.3 g of the title compound was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.78 (3H, s), 4.09 (3H, s), 8.91
(1H, s).

Reference Example 4 Methyl 2-cyclopropyl 7- (methylsulfanyl) [1,3] thiazolo [5,4-d] pyrimidine-2-carboxylate In the same manner as in Reference Example 2, 5-amino-2- Cyclopropyl-4,
Needle crystals 3.00 g obtained from 6-dimethylsulfanylpyrimidine 2.41 g and methyl chloroglyoxylate 1.65 g,
Reaction with 3.87 g of Lawson's reagent gave 2.24 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.78 (3H, s), 4.09 (3H, s),
8.91 (1H, s).

Reference Example 5 tert-butyl N- (1-hydroxy-1-phenyl-3-propyl) carbamate 2.5 g of N-butoxycarbonyl-β-alanine and 2.0 g of 1-hydroxybenzotriazole hydrate (HOBt) Was dissolved in 20 ml of N, N-dimethylformamide / chloroform (1: 1), and N, N-diisopropylethylamine was added thereto under ice-cooling.
1.9 g and 2.8 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC) were added, and the mixture was stirred for 5 minutes. Furthermore, N, O-dimethylhydroxylamine hydrochloride 1.42 g and N, N-
1.9 g of diisopropylethylamine was added, and the mixture was stirred at room temperature for 4 hours. Add 50 ml of chloroform to the reaction solution and add 0.125M
The extract was washed with citric acid, 5% aqueous sodium bicarbonate and saturated saline three times each, and the organic layer was dried and concentrated, and the residue was subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane =
The product was purified by 1/1) to obtain 2.9 g of an oily substance. 2.0 g of this oil
Was dissolved in 20 ml of tetrahydrofuran, and 3M
7.2 ml of a phenylmagnesium bromide ether solution was added dropwise. The reaction mixture was stirred at room temperature for 2 days, poured into a 5% aqueous ammonium chloride solution (80 ml), and extracted three times with ethyl acetate. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 5/17) to obtain 1.46 g of an oil. 1.0 g of this oil was dissolved in 20 ml of ethanol, and 0.076 g of sodium borohydride was added under ice cooling, followed by stirring at room temperature for 3 hours. The reaction solution was poured into water and extracted three times with ethyl acetate. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/3) to obtain 0.88 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.75-1.95 (2H, m), 3.
05-3.30 (2H, m), 3.35-3.60 (1H, m), 4.75 (1H, t, J = 6.7H
z), 4.89 (1H, br), 7.25-7.45 (5H, m).

Reference Example 6 3-amino-1-phenylpropanone ethylene acetal 5.0 g of β-chloropropiophenone and ethylene glycol
A mixture consisting of 2.8 g, 0.056 g of p-toluenesulfonic acid monohydrate and 100 ml of toluene was refluxed for 10 hours. 5% of this
The solid obtained by washing with sodium bicarbonate water, drying and concentration was dissolved in 100 ml of N, N-dimethylformamide, and sodium azide 2.3
g and potassium iodide 4.9 g were added and stirred at 150 ° C. for 2 hours. The reaction solution was poured into water and extracted three times with chloroform.
The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/15) to obtain 1.8 g of an oil. This was dissolved in 40 ml of ethanol, and palladium-activated carbon (10%) 0.01
8 g was added, and the mixture was stirred under a hydrogen atmosphere for 12 hours. The reaction solution was filtered and the filtrate was concentrated to give the title compound 0.73.
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.07 (2H, t, J = 6.7 Hz), 2.76 (2H, t, J
= 6.7Hz), 3.65-4.15 (4H, m), 7.20-7.55 (5H, m).

Reference Example 7 3- (3,5-difluorophenyl) -3-hydroxypropanenitrile 3.36 g of potassium tert-butoxy in 50 ml of tetrahydrofuran
Acetonitrile (1.48 g) was added dropwise to the suspension at 0 ° C., and after 10 minutes, 4.26 g of 3,5-difluorobenzaldehyde was added dropwise.
After stirring at the same temperature for 3 hours, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated, and the obtained residue was subjected to column chromatography (silica gel, developing solvent: n-hexane / ethyl acetate =
9/1) to give 2.19 g of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 2.76 (2H, d, J = 6.2 Hz), 2.85 (1H, b
s), 5.04 (1H, bd, J = 6.2Hz), 6.72-6.85 (1H, m), 6.87-7.00
(2H, m).

Reference Example 8 tert-butyl 2- (3,5-difluorophenyl) -2-hydroxyethylcarbamate N-tert-butoxycarbonylglycine 20.5 g and 1-hydroxybenzotriazole 17.4 g of chloroform / N,
N-dimethylformamide (1: 1) mixed solution 200 ml, 1-ethyl-3- (3-dimethylaminopropyl) -carboxamide hydrochloride 24.7 g and N, N-diisopropylethylamine 22.5 ml
After stirring for 10 minutes, the mixture was added to 40 ml of a chloroform / N, N-dimethylformamide (1: 1) mixture of 12.6 g of N, O-dimethylhydroxylamine hydrochloride and 22.5 ml of N, N-diisopropylethylamine under ice cooling. Stirred for 2.5 days. The reaction solution was diluted with chloroform, washed with a 0.25 M aqueous citric acid solution, 5% aqueous sodium bicarbonate and saturated saline, dried and concentrated to give a colorless powder 1
9.2 g were obtained. 10.9 g of the obtained powder was dissolved in 50 ml of tetrahydrofuran, and 80 ml of a 3,5-difluoromagnesium bromide / tetrahydrofuran solution prepared from 24.1 g of 1-bromo-3,5-difluorobenzene and 3.04 g of magnesium.
Was added dropwise under ice cooling. After stirring at room temperature for 17 hours, 100 ml of a saturated aqueous ammonium chloride solution and 100 ml of water were added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated,
The obtained residue was purified by column chromatography (silica gel, developing solvent: n-hexane / ethyl acetate = 8/1) to obtain 2.69 g of a pale orange oil. Obtained oil 1
5.0 g was dissolved in 150 ml of ethanol, and 1.05 g of sodium borohydride was added under ice cooling, followed by stirring at room temperature for 1 hour. The reaction solution was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated to obtain 13.4 g of the title compound. ¹ H-NM
R (CDCl ₃ ) δ: 1.45 (9H, s), 3.10-3.60 (2H, m), 3.60 (1
H, bs), 4.75-4.95 (1H, m), 4.90 (1H, bs), 6.60-7.00 (3H,
m).

Example 1 1- (7-Methylthieno [3,2-d] pyrimidin-4-yl) -4-phenyl-4-piperidinol 4-chloro-7-methylthieno [3,2-d] pyrimidine 0.40 g To N, N
-Dimethylformamide dissolved in 15 ml, 4-hydroxy-4-
Add 0.50 g of phenylpiperidine and 0.60 g of potassium carbonate,
Stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted three times with chloroform. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, eluent: ethyl acetate / n-hexane = 1/1) and then recrystallized from chloroform / n-hexane to give the title compound (compound 1) 0.68 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.70 (1H, s), 1.94 (2H, dm, J = 13 Hz),
2.19 (2H, dt, J = 13, 4.6Hz), 2.47 (3H, s), 3.70 (2H, dt, J
= 13,2.4Hz), 4.80 (2H, md, J = 13Hz), 7.25-7.53 (6H, m),
8.66 (IH, s) Elemental analysis (%) Calculated _{(C 18 H 19 N 3 OS} ):. C, 66.43; H, 5.88; N, 12.91 Found: C, 66.18; H, 5.83 N,
12.84 Compounds 1-1 to 1-16 were produced in the same manner.

Example 2 0.25 g of 4- (4-fluorophenyl) -1- (7-methylthieno [3,2-d] pyrimidin-4-yl) -4-piperidinol compound 1-3 was dissolved in 5 ml of dry tetrahydrofuran. Then, the mixture was cooled on ice under a nitrogen stream, and 2.5 ml of 1.0 M 4-fluorophenylmagnesium bromide was added dropwise. After stirring at 0 ° C. for 2 hours, the reaction solution was poured into water and extracted three times with chloroform. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate), and then recrystallized from chloroform / ethyl ether / n-hexane to give 0.10 g of the title compound (compound 2). Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.92 (2H, md, J = 13 Hz), 2.15 (2H, dt,
J = 14, 4.3Hz), 2.47 (3H, s), 3.68 (2H, dt, J = 14,3.0Hz),
4.80 (2H, md, J = 14Hz), 7.05 (2H, t, J = 8.8Hz), 7.35-7.50
. (3H, m), 8.66 (1H, s) Elemental analysis (%) Calculated _{(C 18 H 18 N 3 OSF} ): C, 62.95; H, 5.28; N, 12.24 Found: C, 63.00; H , 5.28; N, 12.23 Compounds 2-1 to 2-13 were prepared in the same manner.

Example 3 4- (4-Fluoro-4-phenyl-1-piperidinyl) -7-methylthieno [3,2-d] pyrimidine 0.20 g of the compound prepared in Example 1 was dissolved in 25 ml of dichloromethane, and iced. Under cooling, diethylaminosulfur trifluoride (DAST)
0.40 g was added dropwise. After stirring at room temperature overnight, the reaction solution was poured into aqueous sodium hydrogen carbonate and extracted twice with chloroform. The extract is dried and concentrated, and the residue is subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/2).
And then recrystallized from chloroform / n-hexane to obtain 0.11 g of the title compound (Compound 3). ¹ H-NMR (CDCl ₃ ) δ: 2.16 (4H, mq), 2.48 (3H, s), 3.61 (2
H, mt), 4.87 (2H, md, J = 12Hz), 7.25-7.40 (6H, m), 8.68 (1
. H, s) Elemental analysis (%) Calculated _{(C 18 H 18 N 3 SF} ): C, 66.03; H, 5.54; N, 12.83 Found: C, 65.77; H, 5.56 ; N, 12.98 Similar By the method, compound 3-1 was prepared.

Example 4 1- [1- (7-Methylthieno [3,2-d] pyrimidin-4-yl) -4-phenyl-4-piperidinyl] -1-ethanol 0.36 g of the compound 1-6 was added to 20 ml of ethanol. , 0.036 g of sodium borohydride was added, and the mixture was heated at 60 ° C. for 30 minutes.
The reaction solution was poured into water and extracted three times with ethyl acetate. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate).
0.33 g of the title compound (compound 4) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 0.97 (3H, d, J = 6.4 Hz), 1.93 (2H, m),
2.42 (1H, md), 2.44 (3H, s), 2.65 (1H, md, J = 13Hz), 3.19
(2H, mq, J = 9.3Hz), 3.69 (1H, q, J = 6.6Hz), 4.67 (2H, md, J =
13Hz), 7.25-7.50 (6H, m), 8.61 (1H, s). Compound 4-1 was produced in the same manner.

Example 5 1- (2-methyl [1,3] thiazolo [5,4-d] pyrimidin-7-yl)-
4-Phenyl-4-piperidinol 0.070 g of the compound produced in Reference Example 1 was dissolved in 10 ml of chloroform, 0.073 g of m-chloroperbenzoic acid was added, and the mixture was stirred under ice cooling for 2 hours. The reaction solution is 5m aqueous 5% sodium thiosulfate
l, 5% aqueous sodium bicarbonate 10ml, washed with saturated saline 10ml, respectively
Dried and concentrated. The residue was dissolved in chloroform (20 ml), 4-hydroxy-4-phenylpiperidine (0.118 g) and tetrahydrofuran (2 ml) were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted three times with chloroform. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane / chloroform = 1/1/1), and then recrystallized from methanol to give the title compound (compound 5) 0.090 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.74 (1H, s), 1.85-2.00 (2H, m), 2.
10-2.30 (2H, m), 2.77 (3H, s), 3.55-3.75 (2H, m), 5.40-
5.60 (2H, m), 7.25-7.55 (5H, m), 8.40 (1H, s) IR (KBr):. 3285, 1560, 1340, 1175 cm -1 Elemental analysis (%) Calculated (C ₁₇ H _{18 N 4 OS): C,} 62.55; H, 5.56; N, 17.16 Found: C, 62.58; H, 5.61 ; in N, 17.04 a similar manner was prepared compounds 5-1 to 5-53.

Example 6 1- [2- (Hydroxymethyl) [1,3] thiazolo [5,4-d] pyrimidin-7-yl] -4-phenyl-4-piperidinol Compound 5-4 0.42 g was dissolved in methanol. Dissolve in 15 ml, under ice cooling,
0.75 ml of a 10% aqueous potassium hydroxide solution was added, and the mixture was stirred for 10 minutes. After concentrating the reaction solution, a saturated saline solution was added, and ethyl acetate was added.
Extracted three times. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, eluent: ethyl acetate / n-hexane / chloroform = 5/1/5) and then recrystallized from methanol to give the title compound (compound 6) 0.11 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.60-2.15 (4H, m), 3.45-3.70 (2H,
m), 4.82 (2H, d, J = 5.5Hz), 5.20-5.50 (2H, m), 5.26 (1H,
s), 6.33 (1H, t, J = 5.7Hz), 7.15-7.55 (5H, m), 8.38 (1H,
. s) IR (KBr): 3300, 1560, 1450, 1370, 1160 cm -1 Elemental analysis (%) Calculated _{(C 17 H 18 N 4 O} 2 S · 0.5H 2 O): C, 58.10; H , 5.45; N, 15.94 Found: C, 58.57; H, 5.36; N, 15.43

Example 7 4-phenyl-1- {2-[(propylamino) methyl] [1,3] thiazolo [5,4-d] pyrimidin-7-yl} -4-piperidinol compound 5-52 0.10 g and propylamine (0.020 g) in the same manner as in Example 1 to give the title compound (compound 7) (0.068 g).
g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 0.95 (3H, t, J = 7.4 Hz), 1.40-1.60 (2
H, m), 1.80-2.30 (4H, m), 2.71 (2H, t, J = 7.1Hz), 3.50-3.8
0 (2H, m), 4.14 (2H, s), 5.35-5.65 (2H, m), 7.20-7.60 (5
. H, m), 8.41 ( 1H, s) Elemental analysis (%) Calculated _{(C 20 H 25 N 5 OS} · 0.5H 2 O): C, 62.64; H, 6.57; N, 18.26 Found: C H, 6.55; N, 18.06 Compounds 7-1 and 7-2 were prepared in a similar manner.

Example 8 1- [2- (2-hydroxyphenyl) [1,3] thiazolo [5,4-d] pyrimidin-7-yl] -4-phenyl-4-piperidinol compound 5-9 0.32 g Was dissolved in N, N-dimethylformamide (17 ml), sodium thiomethoxide (0.42 g) was added, and the mixture was stirred under heating and reflux for 10 minutes. The reaction solution was extracted by adding 1N-sodium hydroxide and ethyl acetate, and the ethyl acetate layer was dried, concentrated and dried, and the residue was recrystallized from ethyl acetate to obtain 0.17 g of the title compound (compound 8). ¹ H-NMR (CDCl ₃ ) δ: 1.94 (2H, m), 2.22 (2H, dt), 3.78
(2H, dt), 5.14 (2H, md), 6.98-7.67 (9H, m), 8.45 (1H, s).
11.58 (IH, s) Elemental analysis (%) Calculated _{(C 22 H 20 N 4 OS} ): C, 65.33; H, 4.98; N, 13.85 Found: C, 65.22; H, 4.84 ; N, 13.82 Similar Compounds 8-1 to 8-3 were produced by the method described above.

Example 9 1- [2-methyl-5- (methylsulfanyl) [1,3] thiazolo [5,
4-d] pyrimidin-7-yl] -4-phenyl-4-piperidinol 5-amino-4,6-dichloro-2-methylmercaptopyrimidine
2.3 g was dissolved in 100 ml of methanol, and 1.86 g of sodium mercapto monohydrate was added, followed by heating under reflux for 1 hour. After the solvent was distilled off, 100 ml of ethyl acetate and acetic chloride were added to the residue, and the mixture was heated under reflux for 6 hours. After evaporating the solvent, chloroform 60 was added to the residue.
ml and 4-hydroxy-4-phenylpiperidine 2.67 g,
At 0 ° C., 30 ml of tetrahydrofuran was added dropwise. 1 at room temperature
After stirring for 5 hours, the solvent was distilled off, and the residue obtained was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane / chloroform = 1/2/2) to give the title compound (compound 9) 0.207. g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.70 (1H, s), 2.17 (2H, ddd, J = 13.5,
13.2,4.6Hz), 2.56 (3H, s), 2.71 (3H, s), 3.61 (2H, br d
d, J = 12.4,12.4Hz), 5.35-5.57 (2H, m), 7.26-7.32 (1H,
. m), 7.34-7.41 (2H, m), 7.47-7.52 (2H, m) Elemental analysis (%) Calculated _{(C 18 H 20 N 4 OS} 2): C, 58.04; H, 5.41; N, 15.04 found: C, 57.67; H, 5.27; N, 15.11. Compounds 9-1 and 9-2 were prepared in the same manner.

Example 10 1- {2- [hydroxy (phenyl) methyl] [1,3] thiazolo [5,
0.15 g of 4-d] pyrimidin-7-yl} -4-phenyl-4-piperidinol compound 5-28 was suspended in 45 ml of methanol, 0.1 g of sodium borohydride was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was extracted with 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with water, concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel, developing solvent:
Purification by ethyl acetate / n-hexane = 1/1) gave 61 mg of the title compound (Compound 10). ¹ H-NMR (CDCl ₃ ) δ: 1.94 (2H, dm), 2.19 (2H, dt), 3.61
(2H, dt), 4.27 (1H, s), 4.80 (2H, m), 6.04 (1H, s), 7.25-
7.53 (5H, m), 8.31 (1H, s) Elemental analysis (%) Calculated _{(C 23 H 22 N 4 O} 2 S, 0.5H 2 O):. C, 64.61; H, 5.42; N, 13.10 Obtained: C, 64.91; H, 5.20;
N, 12.35

Example 11 7- (4-hydroxy-4-phenyl-1-piperidinyl)
[1,3] Thiazolo [5,4-d] pyrimidine-2-carboxylic acid Compound 6-20 0.10 g was dissolved in methanol 50 ml and tetrahydrofuran 20 ml, 1N-sodium hydroxide 0.5 ml was added and the mixture was stirred at room temperature overnight. . The reaction solution was evaporated to dryness under reduced pressure, and water and 0.5 ml of 2N-hydrochloric acid were added to the residue. The precipitated pale yellowish white crude crystals were collected by filtration and recrystallized from ethyl acetate / n-hexane to obtain 40 mg of the title compound (Compound 11). ¹ H-NMR (CDCl ₃ ) δ: 1.99 (2H, dm), 2.19 (2H, dt), 3.70
(2H, dt), 5.5 ( 1H, br), 7.27-7.54 (5H, m), 8.45 (1H, s). Elemental analysis (%) Calculated _{(C 17 H 16 N 4 O} 3 S, 0.5H ₂ O): C, 55.88; H, 4.69; N, 15.33 Found: C, 56.57; H, 4.57; N, 15.66 Compound 11-1 was prepared in the same manner.

Example 12 N-hydroxy-7- (4-hydroxy-4-phenyl-1-piperidinyl) [1,3] thiazolo [5,4-d] pyrimidine-2-carboxamide Compound 5-20 0.22 g was obtained. It was dissolved in 50 ml of methanol, and 1.2 g of a 50% hydroxyamine solution was added. After stirring at room temperature for 2 hours, the mixture was dried under reduced pressure. The residue was recrystallized from methanol to obtain 0.20 g of the title compound (Compound 12). ¹ H-NMR (CDCl ₃ ) δ: 1.82 (2H, dm), 2.03 (2H, dt), 2.52
(2H, s), 5.7 (2H, br), 7.25-7.53 (5H, m), 8.42 (1H, s).
. 9.66 (1H, br) 11.89 (1H, br) Elemental analysis (%) Calculated _{(C 17 H 17 N 5 O} 3 S):. C, 54.97; H, 4.61; N, 18.86 Found: C, 55.02; H, 4.69; N, 18.82 In a similar manner, compounds 12-1 to 12-35 were prepared.

Example 13 1- [2-methyl-5- (methylsulfonyl) [1,3] thiazolo [5,4-
0.204 g of d] pyrimidin-7-yl] -4-phenyl-4-piperidinol compound 9 was dissolved in 6 ml of chloroform, 0.293 g of m-chloroperbenzoic acid was added, and the mixture was stirred under ice cooling for 0.5 hour.
To the reaction mixture was added 10 ml of a saturated aqueous solution of sodium thiosulfate, and the mixture was extracted with chloroform. The residue was recrystallized from chloroform / toluene to obtain 0.207 g of the title compound (Compound 13). ¹ H-NMR (CDCl ₃ ) δ: 1.74 (1H, s), 1.91-2.01 (2H, m), 2.
18 (2H, ddd, J = 13.6,13.6,4.6Hz), 2.81 (3H, s), 3.32 (3H,
s), 3.52-3.85 (2H, m), 5.10-6.10 (2H, m), 7.26-7.32 (1
. H, m), 7.34-7.41 ( 2H, m), 7.47-7.52 (2H, m) Elemental analysis (%) Calculated _{(C 18 H 20 N 4 O} 3 S 2): C, 53.45; H, 4.98; N, 13.85 Found: C, 53.14; H, 4.79; N, 13.68 Compound 13-1 was prepared in the same manner.

Example 14 4-{[7-hydroxy-4-phenyl-1-piperidinyl) [1,3]
Thiazolo [5,4-d] pyrimidin-2-yl] carbonyl} -1-λ-
0.10 g of 4,4-thiazin-1-one compound 12-24 was dissolved in 10 ml of chloroform, and m-
45 mg of chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 1 hour.
The reaction solution was extracted by adding a 5% aqueous sodium hydrogen carbonate solution and ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated to dryness. The crystals were washed by adding a small amount of methanol to the residue to obtain 76 mg of the title compound (Compound 14). ¹ H-NMR (CDCl ₃ ) δ: 1.94 (2H, dm), 2.19 (2H, dt), 2.85
(4H, m), 3.70 (2H, dt), 4.02 (1H, m), 4.37 (1H, m), 4.62
(1H, m), 5.24 (1H, m), 5.35 (2H, m), 7.25-7.50 (5H, m),
8.49 (IH, s) Elemental analysis (%) Calculated _{(C 21 H 23 N 5 O} 3 S 2):. C, 55.12; H, 5.07; N, 15.31 Found: C, 54.98; H, 5.29; N,
15.02 Compound 14-1 was produced in the same manner.

Example 15 1- [2-Methyl-5-amino [1,3] thiazolo [5,4-d] pyrimidine
[7-yl] -4-phenyl-4-piperidinol Compound 14 0.239 g was dissolved in N, N-dimethylformamide (5 ml), sodium azide (0.077 g) was added, and the mixture was stirred at 70 ° C. for one day. After adding 20 ml of water to the reaction solution and extracting with ethyl acetate,
The extract was washed with 20 ml of a saturated saline solution, and the extract was dried and concentrated. The residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 1/2) to obtain 0.131 g of an azide compound. To a mixed solution of the obtained azide compound and 0.014 g of sodium borohydride in 1 ml of dry tetrahydrofuran was added dropwise 0.07 ml of methanol at 60 ° C., followed by stirring at the same temperature for 3 hours. After cooling to room temperature, 1N hydrochloric acid (1 ml) was added, the mixture was stirred for 10 minutes, and then adjusted to pH 10 with 11N aqueous sodium hydroxide solution. After the mixture was extracted four times with chloroform, the extract was dried and concentrated. The obtained residue was recrystallized from chloroform-hexane to obtain 0.069 g of the title compound (Compound 15). ¹ H-NMR (CDCl ₃ ) δ: 1.65 (1H, s), 1.83-1.91 (2H, m), 2.
16 (2H, ddd, J = 13.0,13.0,4.6Hz), 2.66 (3H, s), 3.55 (2H,
ddd, J = 13.0,13.0,2.1Hz), 4.66 (1H, brs), 5.35-5.48 (2
H, m), 7.24-7.31 (1H, m), 7.33-7.41 (2H, m), 7.45-7.53
(2H, m).

Example 16 1- [2-Methyl-5- (4-morpholinyl) [1,3] thiazolo [5,4-d]
Pyrimidin-7-yl] -4-phenyl-4-piperidinol Compound 13 0.160 g was dissolved in N, N-dimethylformamide 4 ml, and morpholine 0.11 ml and potassium carbonate 0.071 g were added.
The mixture was stirred at 100 ° C for 25 hours. After cooling to room temperature, add 2
0 ml was added and extracted with ethyl acetate. The extract was washed with saturated saline, dried and concentrated. The residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 2/1), and the obtained powder was purified with ethyl acetate
Recrystallize from hexane to give the title compound (Compound 16) 0.02
6 g were obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.67 (1H, s), 1.82-1.90 (2H, m), 2.
17 (2H, ddd, J = 13.1,13.1,4.5Hz), 2.66 (3H, s), 3.51-3.6
1 (2H, m), 3.74-3.77 (8H, m), 5.20-5.55 (2H, m), 7.24-7.
40 (3H, m), 7.47-7.52 (2H, m) Elemental analysis (%) Calculated _{(C 21 H 25 N 5 O} 2 S):. C, 61.29; H, 6.12; N, 17.02 Found: C, 61.03; H, 6.09; N, 17.08 In a similar manner, compound 16-1 was prepared.

Example 17 N- [7- (4-hydroxy-4-phenyl-1-piperidinyl) -2-methyl [1,3] thiazolo [5,4-d] pyrimidin-5-yl] acetamide Compound 15 0.127 g and N, N-dimethylaminopyridine 0.00
5 g was dissolved in 2 ml of pyridine, 0.047 ml of acetic chloride was added, and the mixture was stirred at 40 ° C. for 16 hours. After evaporating the solvent, the residue was dissolved in ethyl acetate, washed with 20 ml of water and 20 ml of saturated saline, and the extract was dried and concentrated. The residue was subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane /
The resulting powder was recrystallized from methanol-hexane to obtain 0.065 g of the title compound (compound 17). ¹ H-NMR (CDCl ₃ ) δ: 1.68 (1H, brs), 1.87-1.96 (2H, m),
2.16 (2H, ddd, J = 13.8,12.8,4.6Hz), 2.52 (3H, s), 2.72 (3
H, s), 3.57-3.70 (2H, m), 5.33-5.52 (2H, m), 7.27-7.32
. (1H, m), 7.34-7.41 (2H, m), 7.48-7.53 (2H, m) Elemental analysis (%) Calculated _{(C 19 H 21 N 5 O} 2 S): C, 59.51; H, 5.52; N, 18.26 Found: C, 59.20; H, 5.52; N, 18.35

Example 18 1- [2- (1-hydroxy-1-methylethyl) [1,3] thiazolo
[5,4-d] pyrimidin-7-yl] -4-phenyl-4-piperidinol hydrochloride Dissolve 0.74 g of compound 5-20 in 50 ml of tetrahydrofuran, and add 7 ml of 1.4 M methylmagnesium bromide (toluene / tetrahydrofuran solution). The mixture was stirred at room temperature for 1 hour. A 5% aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried and concentrated to dryness. The residue was subjected to column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 4)
/ 1) and concentrate the target fractions to dryness, then add 4N-HCl
(Ethyl acetate solution) 10 ml was added and the mixture was stirred at room temperature for 1 hour.
The filtrate was concentrated to dryness under reduced pressure to obtain 0.39 g of the title compound (compound 18). ¹ H-NMR (CDCl ₃ ) δ: 1.70 (6H, s), 1.94 (2H, dm), 2.19
(2H, dt), 3.65 (2H, dt), 4.80 (2H, m), 5.50 (2H, d), 7.2
5-7.53 (5H, m), 8.42 (1H, s) Elemental analysis (%) Calculated _{(C 19 H 22 N 4 O} 2 S, HCl):. C, 56.08; H, 5.70; N, 13.77 Found Value: C, 55.79; H, 5.46; N, 13.58 Compound 18-1 was prepared in the same manner.

Example 19a 1- {2-[(acetylamino) carbonyl] [1,3] thiazolo [5,
4-d] pyrimidin-7-yl} -4-phenyl-4-piperidinyl acetate Example 19b N-acetyl-7- (4-hydroxy-4-phenyl-1-piperidinyl) [1,3] thiazolo [ Dissolve 0.10 g of 5,4-d] pyrimidine-2-carboxamide compound 12-26 in 10 ml of pyridine and add acetic anhydride
5 ml and a catalytic amount of N, N-dimethylaminopyridine were added, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure, and the residue was separated and purified by column chromatography (silica gel, developing solvent: ethyl acetate / chloroform / n-hexane = 2/1/1) to give 33 mg of the title compound (compound 19a) and (compound 19a). 19b) 43 mg were obtained. Compound 19a ¹ H-NMR (CDCl ₃ ) δ: 2.13 (3H, s), 2.20 (2H, dt), 2.64
(3H, s), 2.7 (2H, m), 3.66 (2H, m), 5.4 (2H, m), 7.3-7.4
. (5H, m), 8.50 (1H, s) 9.25 (1H, s) Elemental analysis (%) Calculated _{(C 21 H 21 N 5 O} 4 S):. C, 57.39; H, 4.82; N, 15.94 Found: C, 57.50; H, 4.91; N, 15.31 Compound 19b ¹ H-NMR (CDCl ₃ ) δ: 1.70 (1H, s), 1.94 (2H, dmz), 2.19
(2H, dtz), 2.64 (3H, s), 3.77 (3H, m), 5.38 (2H, m), 7.305
. -7.52 (5H, m), 8.49 (1H, s) 9.26 (1H, s) Elemental analysis (%) Calculated _{(C 19 H 19 N 5 O} 3 S, 0.3H 2 O): C, 56.65; H, 4.90; N, 17.38 Found: C, 56.82; H, 4.75; N, 16.86

Example 20 1- [2- (Aminocarbonyl) [1,3] thiazolo [5,4-d] pyrimidin-7-yl] -4-phenyl-4-piperidinyl acetate compound 5-20 0.10 g in 5 ml of pyridine and 2.
5 ml and a catalytic amount of N, N-dimethylaminopyridine were added, and the mixture was stirred at room temperature overnight. The reaction solution was dried under reduced pressure, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / chloroform / n-hexane = 1/2/2). After the target fraction was concentrated to dryness, 6 ml of methanol was added and dissolved. After adding 4 ml of a 2M ammonia / methanol solution and heating under reflux for 1 hour, the mixture was concentrated to dryness, a small amount of methanol was added, and the crystals were washed to obtain 46 mg of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.94 (2H, m), 2.13 (3H, s), 2.19 (2
H, dt), 2.7 (2H, d), 3.56-3.70 (2H, dt), 4.80 (2H, m), 5.
8 (2H, m), 5.4 (1H, s), 6.9 (1H, s), 7.28-7.40 (5H, m), 8.
49 (IH, s) Elemental analysis (%) Calculated _{(C 19 H 19 N 5 O} 3 S, 0.3H 2 O):. C, 56.65; H, 4.90; N, 17.38 Found: C, 56.71; H, 4.83; N, 17.45

Example 21 3-[(7-Methylthieno [3,2-d] pyrimidin-4-yl) amino]
1-Phenyl-1-propanol 0.41 g of the compound of Reference Example 5 was dissolved in 5 ml of ethyl acetate, and 2 ml of a 4N hydrochloric acid / ethyl acetate solution was added under ice-cooling, followed by stirring for 14 hours. The residue obtained by concentrating the reaction solution was dissolved in N, N-dimethylformamide (5 ml), and triethylamine (0.18 g) was added thereto.
Was added and stirred at room temperature for 30 minutes. To this reaction solution, a solution of 0.20 g of 4-chloro-7-methylthieno [3,2-d] pyrimidine in 15 ml of N, N-dimethylformamide was added dropwise, and potassium carbonate was added at 0.
30 g was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was poured into water and extracted three times with chloroform. The extract was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 4/1), and then recrystallized from chloroform / n-hexane to give the title compound (compound 21) 0.28 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.95-2.15 (2H, m), 2.47 (3H, s), 3.
50-3.70 (1H, m), 4.05-4.30 (1H, m), 4.66 (1H, s), 4.70-
4.85 (1H, m), 5.38 (1H, bt, J = 5.7Hz), 7.25-7.45 (6H, m),
8.66 (IH, m) Elemental analysis (%) Calculated _{(C 16 H 17 N 3 OS} · 0.25CHCl 3):. C, 59.28; H, 5.28; N, 12.76 Found: C, 59.85; H, 5.28 ; N, 13.08

Example 22 3-[(7-Methylthieno [3,2-d] pyrimidin-4-yl) amino]
1-phenyl-1-propanone In the same manner as in Example 21, 4-chloro-7-methylthieno
N- [2- (2-phenyl-1,3-dioxolan-2-yl) ethyl] -7-methylthieno [3, prepared from 0.15 g of [3,2-d] pyrimidine and 0.42 g of the compound of Reference Example 6. 0.26 g of [, 2-d] pyrimidin-4-amine was dissolved in 20 ml of chloroform, 2 ml of a 4N hydrochloric acid / ethyl acetate solution and 0.5 ml of water were added, and the mixture was stirred at room temperature for 10 minutes.
The reaction solution was washed with 5% sodium bicarbonate solution, the organic layer was dried and concentrated, and the residue was purified by column chromatography (silica gel, developing solvent: chloroform / n-hexane = 1/2), and then chloroform / n-hexane. Recrystallization from hexane gave 0.16 g of the title compound (Compound 22). ¹ H-NMR (CDCl ₃ ) δ: 2.45 (3H, d, J = 1.1 Hz), 3.43 (2H, t, J
= 5.6Hz), 4.13 (2H, q, J = 5.8Hz), 5.60 (1H, br), 7.40-7.6
5 (3H, m), 7.90-8.05 (2H, m), 8.68 (1H, s). IR (KBr): 3230, 1675, 1585, 1510, 1295 cm ^-1 Elemental analysis value (%) Calculated value (C ₁₆ H ₁₅ N ₃ OS): C, 64.62; H, 5.08; N,
14.13 Found: C, 64.13; H, 5.15; N, 14.18

Example 23 1-phenyl-2-{[2- (3-thienyl) [1,3] thiazolo [5,4-d]
Pyrimidin-7-yl] sulfanyl} -1-ethanol 0.25 g of 2-bromoacetophenone was dissolved in 5 ml of ethanol, and 0.03 g of sodium borohydride was added.
Stir for 5 minutes. The reaction solution was poured into water, and the extract extracted with ethyl acetate was dried and concentrated to obtain 0.21 g of an oil. 2.71 g of the compound of Reference Example 2 was dissolved in 100 ml of chloroform, and 2.20 g of m-chloroperbenzoic acid was added under ice cooling, followed by stirring for 2 hours. The reaction solution was poured into a 5% aqueous solution of sodium thiosulfate, and the organic layer was further washed with aqueous sodium bicarbonate.The organic layer was dried and concentrated.
The residue is subjected to column chromatography (silica gel, developing solvent: ethyl acetate / chloroform / n-hexane = 2/2)
/ 1) to give 2.5 g of 7- (methylsulfinyl) -2- (3-thienyl) [1,3] thiazolo [5,4-d] pyrimidine as needles. Dissolve 0.10 g of the needle crystals in 20 ml of N, N-dimethylformamide, and add
5 g of a 7 g aqueous solution was added dropwise, and the mixture was stirred at room temperature for 5 minutes. To this reaction solution, 5 ml of an N, N-dimethylformamide solution of 0.21 g of an oil produced from 0.25 g of 2-bromoacetophenone and 0.06 g of potassium iodide were added, and the mixture was stirred at 60 ° C. for 14 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate, extracted three times with ethyl acetate, and the extract was dried and concentrated. The residue was subjected to column chromatography (silica gel, eluent: ethyl acetate / chloroform / n-hexane = 1/3 / Purified by 3).
Then, recrystallization from ethyl acetate / n-hexane gave 0.04 g of the title compound (Compound 23). ¹ H-NMR (CDCl ₃ ) δ: 3.50-3.90 (2H, m), 4.37 (1H, br),
5.10-5.25 (1H, m), 7.25-7.55 (6H, m), 7.70-7.75 (1H, m),
8.05-8.15 (1H, m), 8.81 (1H, s) IR (KBr):. 3220, 1555, 1520, 1420, 1340, 1240 cm -1 Elemental analysis (%) Calculated (C ₁₇ H ₁₃ N ₃ OS ₃ ): C, 54.96; H, 3.53; N, 11.31 Found: C, 54.77; H, 3.69; N, 11.28 Compounds 23-1 and 23-2 were produced in the same manner.

Example 24 1-phenyl-2-{[2- (3-thienyl) [1,3] thiazolo [5,4-d]
Pyrimidin-7-yl] amino} -1-ethanone 0.31 g of the compound of Reference Example 2 was dissolved in 30 ml of chloroform.
Under ice cooling, 0.26 g of m-chloroperbenzoic acid was added, and the mixture was stirred for 30 minutes. The reaction solution was poured into a 5% aqueous sodium thiosulfate solution, and the organic layer was further washed with aqueous sodium bicarbonate. The organic layer was dried and concentrated to obtain 0.30 g of needle crystals. The needles were dissolved in N, N-dimethylformamide (20 ml), and thereto was added 2-aminoacetophenone (0.37 g) and triethylamine (0.22 g).
Stirred for hours. The reaction solution was poured into water and extracted three times with chloroform. The extract was dried and concentrated, and the residue was subjected to column chromatography (silica gel, eluent: ethyl acetate / chloroform / n-hexane = 1/2/2). And purified. Then, recrystallization from ethyl acetate / n-hexane gave 0.31 g of the title compound (Compound 24). ¹ H-NMR (CDCl ₃ ) δ: 5.15 (2H, d, J = 4.4 Hz), 7.16 (1H, b
r), 7.40-7.80 (5H, m), 7.95-8.20 (3H, m), 8.50 (1H, s) .IR (KBr): 3410, 1685, 1600, 1540, 1290, 1240 cm ^-1 Elemental analysis (%) calculated _{(C 17 H 12 N 4 OS} 2): C, 57.93; H, 3.43; N, 15.90 Found: C, 57.84; H, 3.49 ; N, at 15.76 a similar manner, compound 24-1 ~ 24-5 were produced.

Example 25 1-phenyl-3-{[2- (3-thienyl) [1,3] thiazolo [5,4-d]
Pyrimidin-7-yl] amino} -1-propanone 7- (methylsulfinyl) -2- (3-
0.15 g of (thienyl) [1,3] thiazolo [5,4-d] pyrimidine was dissolved in 20 ml of chloroform, and 0.12 g of the compound of Reference Example 6 was added thereto.
Was added and stirred at room temperature for 5 hours. The reaction solution is concentrated, and the residue is subjected to column chromatography (silica gel, developing solvent: ethyl acetate / chloroform / n-hexane = 1/2 /
Purification according to 2) and recrystallization from ethyl acetate / n-hexane gave 0.20 g of needles. 0.12 g of the needles was dissolved in 30 ml of chloroform, 2 ml of 2N hydrochloric acid was added, and the mixture was heated at 60 ° C. for 30 minutes. The reaction solution was washed with water, dried and concentrated, and the residue was recrystallized from ethyl acetate / n-hexane to obtain 0.11 g of the title compound (Compound 25). ¹ H-NMR (CDCl ₃ ) δ: 3.45 (2H, t, J = 5.8Hz), 4.14 (2H, q, J
= 5.9Hz), 6.72 (1H, bt, J = 5.6Hz), 7.40-7.70 (5H, m), 7.9
0-8.05 (3H, m), 8.47 (1H, s) IR (KBr):. 3330, 1675, 1285, 840, 775 cm -1 Elemental analysis (%) Calculated _{(C 18 H 14 N 4 OS} 2 ): C, 58.99; H, 3.85; N, 15.29 Found: C, 58.83; H, 3.86; N, 15.06 Compound 25-1 was prepared in the same manner.

Example 26 1-phenyl-2-{[2- (3-thienyl) [1,3] thiazolo [5,4-d]
Pyrimidin-7-yl] amino} -1-ethanol Compound 24 0.11 g was dissolved in ethanol 8 ml, sodium borohydride 0.02 g was added, and the mixture was stirred for 10 minutes. The reaction solution is poured into water, extracted with chloroform, the extract is dried and concentrated, and the residue is purified by column chromatography (silica gel, developing solvent: ethyl acetate / chloroform / n-hexane = 1/1/1). did. Then recrystallized from ethyl acetate / n-hexane to give the title compound (Compound 26)
0.05 g was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.70-4.20 (2H, m), 5.00-5.15 (1H,
m), 6.55 (1H, br), 7.25-7.55 (6H, m), 7.60-7.70 (1H, m),
7.90-8.00 (1H, m), 8.47 (1H, s) IR (KBr):. 3235, 1610, 1540, 1330, 1305 cm -1 Elemental analysis (%) Calculated _{(C 17 H 14 N 4 OS} 2 ): C, 57.61; H, 3.98; N, 15.81 Found: C, 57.04; H, 3.97; N, 15.87 Compounds 26-1 to 26-5 were prepared in the same manner.

Example 27 2- {methyl [2- (3-thienyl) [1,3] thiazolo [5,4-d] pyrimidin-7-yl] amino} -1-phenyl-1-ethanol DL-mandel 1.0 g of ethyl acetate was dissolved in 30 ml of chloroform, and 0.7 g of 3,4-dihydro-2H-pyran and 0.005 g of p-toluenesulfonic acid monohydrate were added thereto, followed by stirring at room temperature for 1 hour. The reaction solution was washed with 5% aqueous sodium hydrogen carbonate, dried and concentrated to obtain 1.52 g of an oil. 0.27 g of this oil was dissolved in 4 ml of methanol, and 0.5 ml of a 40% methylamine / methanol solution was added, followed by stirring at room temperature for 14 hours. The reaction solution was poured into water and extracted with chloroform. After washing the extract three times with water, drying and concentration,
The obtained oil was dissolved in 10 ml of ether, and 0.1 g of lithium aluminum hydride was added thereto, followed by heating under reflux for 3 hours. To the reaction solution, water 0.1 ml, 15% sodium hydroxide aqueous solution 0.
1 ml was added, 0.3 ml of water was added again, the precipitate was removed by filtration, and the filtrate was concentrated to obtain 0.2 g of an oily substance. This oil is 0.
12 g was dissolved in 10 ml of chloroform.
7- (methylsulfinyl) -2- (3-thienyl) prepared in Step 3
0.10 g of [1,3] thiazolo [5,4-d] pyrimidine in chloroform 1
A solution dissolved in 0 ml was added. After stirring the reaction solution at room temperature for 14 hours, it was washed with 0.5N hydrochloric acid, and the organic layer was dried and concentrated. The obtained residue was dissolved in 2 ml of tetrahydrofuran,
1 ml of water and 4 ml of acetic acid were added thereto, and the mixture was stirred at 50 ° C. for 18 hours. The reaction solution was poured into water, extracted with ethyl acetate, the extract was dried and concentrated, and the residue was subjected to column chromatography (silica gel, eluent: ethyl acetate / chloroform / n-hexane = 1/1/1). Purification gave 0.08 g of the title compound (compound 27) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.51 (3H, br), 3.95-4.50 (2H, m),
5.15-5.25 (1H, m), 7.25-7.50 (6H, m), 7.55-7.65 (1H, m),
7.85-8.00 (1H, m), 8.44 (1H, s) Elemental analysis (%) Calculated _{(C 18 H 16 N 4 OS} 2 · 0.5H 2 O):. C, 57.27; H, 4.54; N, 14.84 found: C, 57.38; H, 4.53; N, 14.49

Example 28 5-Cyclopropyl 7-[(3-hydroxy-3-phenylpropyl) amino] [1,3] thiazolo [5,4-d] pyrimidine-2-carboxamide In the same manner as in Example 24 Prepared from the compound of Reference Example 4.
Dissolve 0.090 g of methyl 5-cyclopropyl 7-[(3-hydroxy-3-phenylpropyl) amino] [1,3] thiazolo [5,4-d] pyrimidine-2-carboxylate in 10 ml of methanol and add 7.3M 3 ml of an ammonia / methanol solution were added. After heating under reflux for 1 hour, the mixture was concentrated to dryness, a small amount of methanol was added, and the crystals were collected by filtration. The resulting crystals were added at room temperature with 2 ml of a 4N hydrochloric acid / ethyl acetate solution and stirred for 2 hours. The reaction solution was concentrated to dryness, a small amount of ethanol was added, and the crystals were collected by filtration to obtain 0.055 g of the title compound (compound 28). Elemental analysis value (%) Calculated value (C ₁₈ H ₁₉ N ₅ O ₂ S · HCl) : C, 53.26; H, 4.97; N, 17.25 Found: C, 53.25; H, 5.04; N, 17.03 Compounds 28-1 to 28-12 were produced in the same manner.

Example 29 7- [Methyl (3-oxo-3-phenylpropyl) amino] [1,
3] Thiazolo [5,4-d] pyrimidine-2-carboxamide Prepared from the compound of Reference Example 3 in the same manner as in Example 24.
Dissolve 0.30 g of methyl 7- [methyl (3-hydroxy-3-phenylpropyl) amino] [1,3] thiazolo [5,4-d] pyrimidine-2-carboxylate in 60 ml of acetonitrile and manganese dioxide
0.40 g was added, and the mixture was heated under reflux for 3 hours. After filtration through Celite, the filtrate was concentrated to dryness, a small amount of methanol was added, and the crystals were collected by filtration to obtain 0.14 g. The crystals were dissolved in 5 ml of methanol, and 5 ml of a 2 M ammonia / methanol solution was added to the solution.
After heating and refluxing for an hour, the precipitated crystals were collected by filtration to obtain 0.12 g. The crystals were suspended in 40 ml of methanol, and 5 ml of a 4N hydrochloric acid / ethyl acetate solution was added at room temperature, followed by stirring for 1 hour. The title compound The reaction solution was concentrated to dryness (Compound 29) Elemental analysis value was obtained 0.12 g (%) Calculated _{(C 16 H 15 N 5 O} 2 S · HCl · H 2 O): C, 48.54; H , 4.58; N, 17.69 Found: C, 48.96; H, 4.51; N, 17.67 In a similar manner, compound 29-1 was prepared.

Example 30 7-[(4-Oxo-4-phenylbutyl) amino] [1,3] thiazolo
[5,4-d] pyrimidine-2-carboxamide 1.30 g of the compound of Reference Example 3 was dissolved in 35 ml of chloroform.
1.40 g of -chloroperbenzoic acid was added, and the mixture was stirred for 20 minutes. The residue obtained by distilling off the solvent is subjected to N, N-dimethylformamide
Dissolved in 20 ml, and prepared by the same method as in Reference Example 6 2.23 g of 4-amino-1-phenylbutanone ethylene acetal N, N-
15 ml of a dimethylformamide solution was added dropwise. After stirring for 3 hours, the reaction solution was diluted with ethyl acetate, and the solvent was washed with saturated sodium bicarbonate and brine, and dried. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane = 3/2) to obtain 1.45 g of a colorless powder. 0.3 of the obtained powder
41 g was dissolved in 4 ml of methanol, 4 ml of a 2N ammonia-methanol solution was added, and the mixture was stirred at 60 ° C. for 2 hours. The residue obtained by distilling off the solvent was washed with a mixed solution of ether and hexane, dissolved in 6 ml of tetrahydrofuran, 2 ml of 1N hydrochloric acid was added, and the mixture was stirred for 20 hours. Potassium carbonate was added, the organic solvent was distilled off, and the residue was washed with water and ethyl acetate, and then dried.
0.196 g of a colorless solid was obtained. 0.0913 g of this was ethanol 5
Then, 0.3 ml of a 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was stirred for 30 minutes. The powder obtained by distilling off the solvent was washed with ethyl acetate to obtain 0.0971 g of the title compound (Compound 30). ¹ H-NMR (CD ₃ OD) δ: 2.21 (2H, tt, J = 7.0, 6.8), 3.22 (2
(H, t, J = 6.8), 3.87 (2H, t, J = 7.0), 7.44-7.51 (2H, m), 7.5
6-7.63 (1H, m), 7.94-8.00 (2H, m), 8.63 (1H, s). Elemental analysis (%) Calculated _{(C 16 H 20 N 5 O} 2 S 2 Cl, HCl, 0.25H ₂ O): C, 50.26; H, 4.35; N, 18.32 Found: C, 50.02; H, 4.22; N, 18.59

Example 31 3-{[2- (aminocarbonyl) [1,3] thiazolo [5,4-d] pyrimidin-7-yl] amino} -1-phenylpropyl acetate In the same manner as in Example 24 Prepared from the compound of Reference Example 3.
7- [3-hydroxy-3-phenylpropyl) amino] [1,3]
Methyl thiazolo [5,4-d] pyrimidine-2-carboxylate 0.092 g
Was dissolved in 5 ml of pyridine, 2.5 ml of acetic anhydride and 0.005 g of 4-dimethylaminopyridine were added, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate / n-hexane / chloroform = 2/1/1) to obtain crystals. The crystals were dissolved in 10 ml of methanol, 5 ml of a 2M ammonia / methanol solution was added, and the mixture was heated under reflux for 1 hour. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography (silica gel, eluent: ethyl acetate / n-hexane / chloroform = 3/1/1) to obtain 0.032 g of the title compound (Compound 31). ¹ H-NMR (CDCl ₃ ) δ: 2.14 (3H, s), 2.29 (2H, mt), 3.6
8 (2H, dt), 3.90 (2H, dt), 5.67 to 7.10 (2H, m), 5.96 (2
H, tt) 6.35 (2H, mt) 7.30-7.40 (5H, m), useful as 8.51 (1H, s).

Example 32 7-{[3- (3,5-Difluorophenyl) -3-hydroxypropyl] amino} [1,3] thiazolo [5,4-d] pyrimidine-2-carboxamide Reference Example 7 20 ml of a solution of 2.19 g of compound in tetrahydrofuran
1.56 ml of 10M borane-dimethyl sulfide complex was added dropwise thereto, and the mixture was stirred at 80 ° C. for 4 hours. After the reaction solution was cooled to room temperature, 10 ml of methanol was added, and the mixture was stirred at room temperature for 30 minutes. The residue obtained by concentrating the reaction solution was dissolved in tetrahydrofuran (20 ml). Under ice-cooling, 2.05 g of m-chloroperbenzoic acid was added to this solution at 0 ° C. in 50 ml of a chloroform solution containing 1.92 g of the compound of Reference Example 3 at 0 ° C. In addition, a reaction solution stirred at room temperature for 30 minutes was added dropwise. The mixture was stirred at room temperature for 17 hours, diluted with chloroform, washed with 5% sodium thiosulfate and 5% sodium hydrogen carbonate, dried and concentrated, and the residue was subjected to column chromatography (silica gel,
Developing solvent: n-hexane / chloroform / ethyl acetate = 3
/ 10/10) to give 2.54 g of a pale yellow oil. The obtained oil was dissolved in 4 ml of methanol, and 7.2N
4 ml of an ammonia / methanol solution was added, and the mixture was stirred at 70 ° C. for 1 hour. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the precipitated powder was washed with ethyl acetate and then recrystallized from hot methanol to give the title compound (Compound 32) 1.89.
g. ¹ H-NMR (DMSO-d ₆ ) δ: 1.80-2.25 (2H, m), 3.63 (2H, q, J =
6.2Hz), 4.74 (1H, q, J = 4.5Hz), 5.64 (1H, d, J = 4.5Hz), 6.
95-7.15 (3H, m), 7.85 (1H, bs), 8.02 (1H, bt, J = 5.3Hz),
8.20 (1H, bs), 8.45 (1H, s) Elemental analysis (%) Calculated _{(C 15 H 13 N 5 O} 2 SF 2 · 0.5H 2 O):. C, 48.12; H, 3.77; N, 18.71. Found: C, 48.01; H, 3.75; N, 19.01. Compounds 32-1 to 32-9 were prepared in a similar manner.

Example 33 7-[(4-Hydroxy-4-phenylbutyl) amino] -N-methyl [1,3] thiazolo [5,4-d] pyrimidine-2-carboxamide hydrochloride 4-phenyl-4 To a solution of 9.80 g of -hydroxybutanenitrile in 100 ml of tetrahydrofuran was added dropwise 8 ml of 10M borane-dimethylsulfide complex, and the mixture was heated under reflux for 1 hour. After cooling the reaction solution to room temperature, 30 ml of methanol was added to
Stirred for minutes. The reaction solution was mixed with 7.23 g of the compound of Reference Example 3.
M-chloroperbenzoic acid in 180 ml of chloroform solution of 10.3 g
Was added dropwise to the reaction solution stirred for 30 minutes, and the mixture was stirred for 1 hour. Ethyl acetate was added to the residue obtained by concentrating the reaction solution, washed with saturated aqueous sodium hydrogen carbonate, dried and concentrated, and the residue was subjected to column chromatography (silica gel, developing solvent:
n-hexane / chloroform / ethyl acetate = 1/1/2)
And purified by 7-[(4-hydroxy-4-phenylbutyl)
7.7 g of methyl amino] [1,3] thiazolo [5,4-d] pyrimidine-2-carboxylate was obtained as a pale yellow powder. Of this powder
20 ml of a 40% methylamine / methanol solution was added to 0.20 g, and the mixture was heated under reflux for 1 hour. After concentrating the reaction solution, the obtained residue was purified by column chromatography (silica gel, developing solvent: ethyl acetate) to obtain 0.11 g of a pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.05 (4H, m),
2.80 (2H, d, J = 4.8 Hz), 3.06
(3H, d, J = 5.1 Hz), 3.65-3.80
(2H, m), 4.75-4.85 (1H, m),
6.20-6.85 (1H, m), 7.20-7.5
0 (6H, m), 8.51 (1H, s). The obtained powder was dissolved in 11 ml of methanol, 5 ml of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred for 30 minutes. The powder obtained by distilling off the solvent was washed with ethyl acetate to obtain 0.12 g of the title compound (Compound 33). Elemental analysis (%) Calculated _{(C 17 H 19 N 5 O} 2 S · HCl · H 2 O):. C, 49.57; H, 5.38; N, 17.00 Found: C, 49.27; H, 5.70 ; N , 17.03. Compounds 33-1 to 33-4 were prepared in the same manner.

Example 34 N-methyl-7-[(4-oxo-4-phenylbutyl) amino] [1,
3] thiazolo [5,4-d] pyrimidine-2-carboxamide hydrochloride 7-[(4-hydroxy-4-phenylbutyl) amino] [1,3] thiazolo [5,4-d prepared in Example 33 3.90 g of methyl pyrimidine-2-carboxylate was dissolved in 390 ml of acetonitrile, 11.7 g of manganese dioxide was added, and the mixture was heated under reflux for 5 hours. The precipitate was removed by filtration through Celite, and the residue obtained by concentrating the filtrate was washed with methanol to give a pale yellow powder (3.0 g).
I got 0.20 g of the obtained powder was added to 10 ml of methanol.
And a 40% methylamine / methanol solution 1
0 ml was added and stirred for 10 minutes. The residue obtained by concentrating the reaction solution was purified by column chromatography (silica gel, developing solvent: ethyl acetate), and to the target fraction was added 5 ml of a 4N hydrochloric acid / ethyl acetate solution, followed by stirring for 30 minutes. The powder obtained by evaporating the solvent was washed with ethyl acetate to obtain 0.17 g of the title compound (compound 34). Elemental analysis (%) Calculated _{(C 17 H 17 N 5 O} 2 S · HCl):. C, 52.10; H, 4.63; N, 17.87 Found:. C, 51.91; H, 4.81; N, 17.78 Similar Compounds 34-1 to 34-4 were produced by the method described above.

Example 35 1-phenyl-3-{[2- (2-thienyl) [1,3] thiazolo [5,4-d]
Pyrimidin-7-yl] amino} -1-propanol hydrochloride Compound 24-5 0.411 g was added to N, N-dimethylformamide 4m
Then, 0.97 g of manganese dioxide was added, and the mixture was stirred at 60 ° C for 6 hours. Further, 20 ml of acetonitrile and 0.19 g of manganese dioxide were added, and the mixture was stirred at 60 ° C. for 4.5 hours. The precipitate was removed by celite filtration, and the residue obtained by concentrating the filtrate was subjected to column chromatography (silica gel, developing solvent: n-
Hexane / chloroform / ethyl acetate = 1/1/1) to give 0.10 g of pale yellow powder. ¹ H-NMR (CDCl ₃ ) δ: 3.45 (2H, t, J = 5.9 Hz), 4.12 (2H, dt, J =
5.1Hz, 5.9Hz), 6.63 (1H, bt, J = 5.1Hz), 7.05-7.20 (1H,
m), 7.40-7.65 (5H, m), 7.90-8.10 (2H, m), 8.45 (1H, s). 0.10 g of the obtained powder was dissolved in 5 ml of methanol, and 4N
5 ml of hydrochloric acid / ethyl acetate solution was added and stirred for 30 minutes. The powder obtained by distilling off the solvent was washed with ethyl acetate to obtain 0.10 g of the title compound (compound 35). Elemental analysis (%) Calculated _{(C 18 H 14 N 4 OS} 2 · HCl):. C, 53.66; H, 3.75; N, 13.91 Found: C, 53.74; H, 3.82 ; N, 14.03.

Example 36 1- {7-[(3-hydroxy-3-phenylpropyl) amino] [1,
3] Thiazolo [5,4-d] pyrimidin-2-yl} ethanone hydrochloride To a suspension of 6.13 g of N, O-dimethylhydroxylamine hydrochloride in 120 ml of dichloromethane was added 8.13 g of N, N-diisopropylethylamine. At 0 ° C., 40 ml of a 1.5 M diisobutylaluminum hydride / toluene solution was added dropwise to this mixture, and then 43 ml of a dichloromethane solution of 4.60 g of the compound of Reference Example 3 was added dropwise. After stirring at room temperature for 48 hours, the reaction solution was poured into saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the extract was washed with saturated aqueous sodium bicarbonate solution, dried, concentrated, and the resulting residue was recrystallized from methanol to give a pale yellow needle. 2.82 g of crystals were obtained. 1.35 g of the obtained powder was dissolved in 135 ml of tetrahydrofuran, and 7.1 ml of a 1.4 M methylmagnesium bromide / tetrahydrofuran solution was added dropwise, followed by stirring for 10 minutes. After adding 5% aqueous sodium bicarbonate to the reaction mixture and extracting with ethyl acetate, the extract was washed with water and dried. The residue obtained by distilling off the solvent was washed with methanol to obtain 0.86 g of a colorless powder. Of this powder
0.450 g was dissolved in 10 ml of chloroform, 0.690 g of m-chloroperbenzoic acid was added, and the mixture was stirred for 30 minutes. 1.32 g of 3-hydroxy-3-phenylpropanenitrile was added to the reaction solution.
To a solution of the above in 13 ml of tetrahydrofuran was added dropwise 1.35 ml of a 10M borane-dimethylsulfide complex, and the mixture was heated under reflux for 30 minutes, and the mixture was stirred for 17 hours. The residue obtained by concentrating the reaction solution was purified by column chromatography (silica gel, developing solvent: n-hexane / chloroform / ethyl acetate = 2/1/1) to obtain a colorless solid. ¹ H-NMR (CDCl ₃ ) δ: 2.00-2.18 (2H, m), 2.76 (3H, s),
3.60-3.80 (1H, m), 4.05-4.25 (1H, m), 4.75-4.87 (1H, m
m), 6.68-6.82 (1H, m), 7.25-7.45 (5H, m), 7.50-7.75 (3
H, m), 8.40-8.50 (2H, m), 8.54 (1H, s). The obtained solid was dissolved in 10 ml of methanol, and 5 ml of a 4N hydrochloric acid / ethyl acetate solution was added. The reaction solution was concentrated to obtain 0.386 g of the title compound. Elemental analysis (%) Calculated _{(C 16 H 16 N 4 O} 2 S · HCl · H 2 O):. C, 52.67; H, 4.70; N, 15.36 Found: C, 53.16; H, 5.19 ; N Compound 36-1 was produced in the same manner.

Example 37 {7-[(3-Hydroxy-3-phenylpropyl) amino] [1,3]
Dissolve 0.30 g of thiazolo [5,4-d] pyrimidin-2-yl} (2-thienyl) ethanone hydrochloride in 15 ml of tetrahydrofuran, and at -78 ° C, 0.8 ml of a 1.0 M 2-thienyllithium / tetrahydrofuran solution. Was added dropwise. After heating to -20 ° C, 1.0 more
1.6 ml of M2-thienyllithium / tetrahydrofuran solution
Was added and stirred for 30 minutes. After water was added to the reaction solution, the temperature was raised to room temperature, and the mixture was extracted with ethyl acetate. The residue obtained by concentrating the extract was subjected to column chromatography (silica gel,
Developing solvent: n-hexane / chloroform / ethyl acetate = 1
/ 1/3) to give 0.042 g of a colorless solid. The obtained solid was dissolved in 5 ml of chloroform, and 5 ml of a 4N hydrochloric acid / ethyl acetate solution and then 5 ml of methanol were added. The solvent was distilled off to obtain 0.043 g of the title compound. Elemental analysis (%) Calculated _{(C 19 H 16 N 4 O} 2 S 2 · HCl):. C, 52.71; H, 3.96; N, 12.94 Found: C, 52.64; H, 4.03 ; N, 12.98.

Example 38 4-({2-[(4-methyl-1-piperazinyl) carbonyl] [1,3] thiazolo [5,4-d] pyrimidin-7-yl} amino) -1-phenyl-
1-butanone dihydrochloride 1.30 g of the compound of Reference Example 3 was dissolved in 35 ml of chloroform.
1.40 g of -chloroperbenzoic acid was added, and the mixture was stirred at room temperature for 50 minutes. The residue obtained by concentrating the reaction mixture was dissolved in 20 ml of N, N-dimethylformamide, and 2.23 g of 4-amino-1-phenylbutanone ethylene acetal of 2.23 g of N, N- produced in the same manner as in Reference Example 6. 15 ml of a dimethylformamide solution was added dropwise and stirred for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline, dried, and concentrated. The obtained residue was purified by column chromatography (silica gel, developing solvent: n-hexane / ethyl acetate = 2/3) to obtain 1.45 g of a colorless powder. 0.215 g of the obtained powder
To the mixture was added 0.36 ml of N-methylpiperazine, and the mixture was heated with stirring at 100 ° C. for 2 hours. The solvent was distilled off to obtain a brown oil. The oil was dissolved in 2 ml of tetrahydrofuran, 2 ml of 1N hydrochloric acid was added, and the mixture was stirred for 28 hours. 0.414 g of potassium carbonate was added, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated saline, dried, and concentrated. The obtained residue was recrystallized from n-hexane / ethyl acetate to obtain 0.164 g of pale brown needles. 0.10 g of the obtained needles was dissolved in 2 ml of ethyl acetate,
0.29 ml of a 4N hydrochloric acid / ethyl acetate solution was added, and the mixture was stirred for 2 hours. The powder obtained by distilling off the solvent was washed with ethyl acetate / n-hexane to obtain 0.109 g of the title compound (compound 38). ¹ H-NMR (DMSO-d ₆ ) δ: 2.02 (2H, tt, J =
6.9 Hz, 7.2 Hz), 2.81 (1.5 H,
s), 2.82 (1.5H, s), 3.15-3.
80 (10H, m), 4.53-4.64 (1H,
m), 5.74-5.86 (1H, m), 7.47
−7.55 (2H, m), 7.59-7.66 (1H,
m), 7.92-7.98 (2H, m), 8.41
(1H, s), 8.66-8.74 (1H, m). Elemental analysis (%) Calculated _{(C 21 H 24 N 6 O} 2 S · 2HCl · 0.25H 2 O): C, 50.25;
H, 5.32; N, 16.74. Found: C, 50.05; H, 5.11; N, 16.51. Compounds 38-1 to 38-2 were produced in the same manner.

Example 39 7-{[(2- (3,5-Difluorophenyl) -2-hydroxyethyl] amino} [1,3] thiazolo [5,4-d] pyrimidine-2-carboxamide Reference Example 8 Was dissolved in 10 ml of ethyl acetate, and
3 ml of N hydrochloric acid / ethyl acetate solution and 0.5 ml of trifluoroacetic acid
Was added and stirred at 60 ° C. for 15 minutes. The residue obtained by evaporating the solvent was dissolved in 10 ml of chloroform, and triethylamine was dissolved.
0.202 g was added and stirred for 30 minutes. The residue obtained by evaporating the solvent was dissolved in 10 ml of tetrahydrofuran. This solution was prepared by adding 0.241 g of the compound of Reference Example 3 and m-chloroperbenzoic acid to 0.1 g.
A reaction solution obtained by stirring 20 ml of a chloroform solution with 259 g for 15 minutes was added at 0 ° C., and the mixture was stirred at room temperature for 14 hours. A solution of 0.15 g of triethylamine in 10 ml of chloroform was added at 0 ° C., stirred at room temperature for 1 hour, diluted with chloroform, and added
Washed with 5% sodium thiosulfate and 5% sodium bicarbonate, dried and concentrated. The obtained residue was purified by column chromatography (silica gel, developing solvent: n-hexane / chloroform / ethyl acetate = 1/1/1) to obtain 0.235 g of a colorless powder. 0.164 g of the obtained powder was dissolved in 2 ml of methanol, 2 ml of a 7.2N ammonia / methanol solution was added, and the mixture was heated at 70 ° C. for 1.5 hours. The residue obtained by distilling off the solvent was washed with ether / ethyl acetate to obtain 0.115 g of the title compound (compound 39). ¹ H-NMR (DMSO-d ₆ ) δ: 3.58-3.72 (1H, m), 3.77-3.93 (1
H, m), 4.88-5.00 (1H, m), 5.98 (1H, d, J = 4.4Hz), 7.03-7.5
. 5 (1H, m), 8.10-8.35 (2H, m), 8.47 (1H, s) Elemental analysis (%) Calculated _{(C 14 H 11 N 5 O} 2 SF 2): C, 47.86; H, 3.16; N, 19.93. Found: C, 47.71; H, 3.07; N, 20.13.

Test Example 1 The inhibitory effect of compound (I) on this MIF-dependent T cell response was measured. The results are shown in Table 21. T cells were purified from splenocytes derived from BALB / c mice (male, 9 weeks old; Charles River Japan) using a T cell accumulation column (R & D Systems, USA). The T cells were cultured in an RPMI-1640 medium containing 50 mM 2-mercaptoethanol (Gibco, USA), 2 mM glutamine, 20 mg / ml gentamicin, and 10% fetal bovine serum (BioWicker, USA) (Japan). Suspended in 1 × 10 ⁶ / ml
This was added to a plate previously coated with 1.25 mg / ml anti-mouse CD3 antibody (Pharmingen, USA) together with an appropriate concentration of compound (I), and the mixture was added at 37 ° C under 5% carbon dioxide gas.
After culturing for days, the MTT reduction method (Tada et al., Journal of Immunological Methods (Jounal of Immunologic Methods)
al Methods) 93, 157 (1986)].

Table 21 T cell proliferation response suppressing action

Test Example 2 The inhibitory effect of compound (I) on interleukin 2 (IL-2) production of T cells is shown. The results are shown in Table 22. T cells were cultured with compound (I) for 24 hours under the same conditions as in Test Example 1, except that the concentration of the anti-CD3 antibody to be coated was 0.63 mg / ml. The amount of IL-2 in the culture supernatant was determined by ELISA (commercial kit;
(Perceptive Biosystems, USA).

Table 22 Interleukin 2 production inhibitory action

Test Example 3 Compound (I) in Mouse Endotoxin Shock Model
Was measured. The results are shown in Tables 23 and 24.
BALB / c mouse (male, 9 weeks old; Charles River Japan)
Compound (I) suspended in 0.5% methylcellulose (Shin-Etsu Chemical Co., Japan) solution was intraperitoneally administered (30 mg / kg, 0.05 ml / 10
g), and 30 minutes later, lipopolysaccharide (manufactured by Sigma, USA) dissolved in physiological saline was intravenously administered (17.5 mg / kg,
0.1 ml / 10 g) to determine the survival or death of the mice over time.

Table 23 Endotoxin shock death inhibitory action Significant difference between compound administration group and control group: p <0.05 (log rank test) Table 24 Endotoxin shock death inhibitory effect Significant difference between compound administration group and control group: p <0.01 (log rank test)

[0132]

The compound (I) of the present invention has a MIF inhibitory effect, and is effective for kidney disease, heart disease, inflammatory disease, allergic disease, autoimmune disease, arteriosclerosis, diabetic retinopathy, infectious disease, It is useful as a prophylactic and / or therapeutic agent for malignant tumors and rejection after organ transplantation.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/541 A61K 31/541 31/542 31/542 31/554 31/554 A61P 9/00 A61P 9 / 00 9/10 101 9/10 101 13/12 13/12 27/14 27/14 29/00 29/00 31/00 31/00 35/00 35/00 37/06 37/06 43/00 111 43 / 00 111 C07D 487/04 145 C07D 487/04 145 498/04 105 498/04 105 513/04 351 513/04 351 381 381 381 391 391 (72) Inventor Kimura Unhide 1029 Odaijima Island, Tsukuba, Ibaraki, Japan 1

Claims (29)

[Claims] (1) Formula (1) [In the formula, each of ring A and ring B is a 4- to 8-membered heterocyclic ring which may have a substituent (provided that a compound represented by the formula: (Wherein each symbol has the same meaning as described above), is not a 5H-pyrimido [5,4-b] indole ring. ) And U is of the formula (Wherein R ¹ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ² represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and m and n are the same or different and each represents an integer of 1 to 4. Or a group represented by the formula: (In the formula, k is an integer of 1 to 6, R ³ is an optionally substituted aryl group or an optionally substituted heterocyclic group, Q is an optionally substituted nitrogen atom, a sulfur atom,
W represents an oxygen atom or an optionally substituted carbon atom, and has the formula: (Wherein, R ⁶ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ⁷ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ), A carbonyl group or a thiocarbonyl group. However, when (i) k is 1, the formula (Wherein each symbol has the same meaning as described above), the fused ring group represented by the formula: (In the formula, Z represents a nitrogen atom or an optionally substituted carbon atom, and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, or a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom. Represents a group that binds to
When Z is a carbon atom, R ⁵ may be bonded to Z to form a ring C), and when W represents a carbonyl group, Q is substituted; A nitrogen atom, an oxygen atom or an optionally substituted carbon atom, and (ii) when k is an integer of 2 to 6, W
Represents a carbonyl group, and Q represents an optionally substituted nitrogen atom. ). Or a salt thereof. 2. A compound of the formula Is a group represented by the formula: [In the formula, each of X and Y represents an optionally substituted nitrogen atom, sulfur atom, oxygen atom or optionally substituted carbon atom (provided that X and Y are both optionally substituted carbon atoms) Atom is not shown), Is a single bond or a double bond, and each of the other symbols is claim 1.
The meaning is as described. The compound according to claim 1, which is a condensed ring represented by the formula: 3. A compound of the formula Is a group represented by the formula: Wherein each symbol is as defined in claim 2. The compound according to claim 2, which is a fused ring group represented by the formula: (4) R ¹ is a halogen atom, an optionally substituted hydroxyl group, an optionally substituted amino group, a nitro group,
A cyano group, an alkylcarbonyl group, an arylcarbonyl group, a hydroxyalkyl group, an optionally esterified carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, or an optionally substituted The compound according to claim 1, which is a mercapto group. 5. R ¹ is a halogen atom, a hydroxyl group, a cyano group,
The compound according to claim 1, which is a hydroxy C _1-6 alkyl group, a formyl group or a C _1-6 alkylcarbonyl group. 6. The compound according to claim 1, wherein R ¹ is a hydroxyl group, a cyano group or a C _1-6 alkylcarbonyl group. 7. The compound according to claim 1, wherein R ¹ is a hydroxyl group. 8. An aryl group wherein R ² may be substituted,
The compound according to claim 1, which is an optionally substituted heterocyclic group, an optionally substituted alkyl group, or an optionally substituted alkenyl group. 9. The compound according to claim 1, wherein R ² is an optionally substituted C _6-12 aryl group. 10. The compound according to claim 1, wherein R ² is a phenyl group which may be substituted. 11. The compound according to claim 1, wherein R ³ is an optionally substituted aryl group. 12. The compound according to claim 1, wherein R ³ is a phenyl group which may be substituted. (13) R ⁴ is a thienyl group which may be substituted, an aryl group which may be substituted, an alkyl group which may be substituted, an alkenyl group which may be substituted, Good carboxyl group, optionally substituted alkylcarbonyl group, optionally substituted alkylthiocarbonyl group, optionally substituted arylcarbonyl group, optionally substituted arylthiocarbonyl group, optionally substituted The compound according to claim 2, which is a good carbamoyl group, an optionally substituted cyclic aminocarbonyl group or an optionally substituted alkylthio group. 14. R ⁴ is a thienyl group which may be substituted, a phenyl group which may be substituted, an alkyl group which may be substituted, an alkylcarbonyl group which may be substituted, The compound according to claim 2, which is a good arylcarbonyl group, a carbamoyl group which may be substituted or a 5- or 6-membered cyclic aminocarbonyl group which may be substituted. 15. R ⁵ is a hydrogen atom, an optionally substituted alkyl group, a cyano group, an alkylcarbonyl or optionally substituted amino group with an aryl carbonyl, cyclic amino group, an alkoxy group which may be substituted 3. The compound according to claim 2, which is an optionally substituted alkylthio group, an optionally substituted alkylsulfinyl group, or an optionally substituted alkylsulfonyl group. 16. The compound according to claim 2, wherein R ⁵ is a hydrogen atom, an optionally substituted alkyl group or an optionally substituted cycloalkyl group. 17. R ⁶ is a halogen atom, a hydroxy group which may be substituted, an optionally substituted amino group, a nitro group, a cyano group, an alkylcarbonyl group, an arylcarbonyl group, a hydroxyalkyl group, are esterified An optionally substituted carboxyl group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, or an optionally substituted mercapto group.
A compound as described. 18. The compound according to claim 1, wherein R ⁶ is a hydroxyl group. 19. The compound according to claim 1, wherein R ⁷ is a hydrogen atom or an optionally substituted alkyl group. 20. The compound according to claim 1, wherein Q is an optionally substituted nitrogen atom. 21. The compound according to claim 1, wherein W is a carbonyl group. 22. The compound according to claim 1, wherein m and n are the same or different and each is an integer of 1 to 3. 23. The compound according to claim 1, wherein m and n are 2. 24. The compound according to claim 1, wherein k is 1, 2 or 3. (25) a prodrug of the compound of (1) or a salt thereof; 26. A compound of the formula [Wherein, L represents a leaving group, and other symbols have the same meanings as in claim 1]. And a salt thereof, and a compound represented by the formula: [Wherein each symbol has the same meaning as in claim 1]. Or a salt thereof, or a compound represented by the formula: [In the formula, G represents a hydrogen atom or a metal atom, and other symbols have the same meaning as in claim 1. However, when Q represents an optionally substituted carbon atom, G represents a metal atom. The method for producing a compound or a salt thereof according to claim 1, wherein the compound or a salt thereof is reacted with the compound or a salt thereof. 27. The formula [In the formula, each of ring A and ring B is a 4- to 8-membered heterocyclic ring which may have a substituent (provided that a compound represented by the formula: (Wherein each symbol has the same meaning as described above), is not a 5H-pyrimido [5,4-b] indole ring. ) And U is of the formula (Wherein R ¹ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ² represents an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and m and n are the same or different and each represents an integer of 1 to 4. Or a group represented by the formula: (In the formula, k is an integer of 1 to 6, R ³ is an optionally substituted aryl group or an optionally substituted heterocyclic group, Q is an optionally substituted nitrogen atom, a sulfur atom,
W represents an oxygen atom or an optionally substituted carbon atom, and has the formula: (Wherein, R ⁶ represents a halogen atom or a group bonded via an oxygen atom, a nitrogen atom, a carbon atom or a sulfur atom,
R ⁷ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group. ), A carbonyl group or a thiocarbonyl group. However, when (i) k is 1, the formula (Wherein each symbol has the same meaning as described above), the fused ring group represented by the formula: (In the formula, Z represents a nitrogen atom or an optionally substituted carbon atom, and R ⁴ and R ⁵ are the same or different and each represents a hydrogen atom, a halogen atom, or a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom. Represents a group that binds to
When Z is a carbon atom, R ⁵ may be bonded to Z to form a ring C), and when W represents a carbonyl group, Q is substituted; A nitrogen atom, an oxygen atom or an optionally substituted carbon atom, and (ii) when k is an integer of 2 to 6, W
Represents a carbonyl group, and Q represents an optionally substituted nitrogen atom. ). And a salt thereof. 28. The pharmaceutical composition according to claim 27, which is a MIF inhibitor. 29. The preventive or therapeutic agent according to claim 27, which is a remedy for renal disease, heart disease, inflammatory disease, allergic disease, autoimmune disease, arteriosclerosis, infectious disease, malignant tumor, and rejection after organ transplantation. Pharmaceutical composition.