WO2013089212A1

WO2013089212A1 - Substituted triazine derivative and pharmaceutical composition containing same

Info

Publication number: WO2013089212A1
Application number: PCT/JP2012/082444
Authority: WO
Inventors: 浩幸甲斐; 康彦藤井; 透堀口; 健太郎旭; 中村　健一郎
Original assignee: 塩野義製薬株式会社
Priority date: 2011-12-15
Filing date: 2012-12-14
Publication date: 2013-06-20
Also published as: TW201331188A

Abstract

The present invention provides a novel compound that has P2X₃ and/or P2X_2/3 receptor antagonist activity, for example, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, R^a and R^b as well as R^d and R^e are both hydrogen atoms or the like; R^c represents a hydrogen atom or the like; each of R^4a and R^4b represents a hydrogen atom or the like; n represents 1 or the like; R² represents a cycloalkyl group or the like; each of -X- and -L- represents -O-, -S- or the like; ring D represents a benzene ring or the like; carbon atoms a and b are carbon atoms; ring B represents an aromatic carbon ring or the like; each of s and s' represents 0 or the like; and each of R⁹ and R^9' represents a halogen group or the like.)

Description

Substituted triazine derivatives and pharmaceutical compositions containing them

The present invention relates to compounds useful for treating diseases or conditions involving P2X receptors, particularly P2X ₃ and / or P2X _2/3 receptors, and pharmaceutical compositions containing such compounds.

Adenosine triphosphate (ATP) is known as an intracellular energy source and phosphorylated substrate. On the other hand, it is also known to work as an extracellular information transmission substance. Furthermore, ATP is released to the outside of cells by various stimuli such as cell damage, inflammation, nociceptive stimulation, reduction of blood oxygen concentration, and released from the primary sensory nerve ending together with other neurotransmitters. It is known. ATP released to the outside of the cell performs various extracellular information transmission via the ATP receptor (Non-patent Documents 4 and 5).

ATP receptors are roughly classified into an ion channel type P2X family and a G protein coupled type P2Y family. Seven types of subtypes have been reported in the P2X receptor family, and function as non-selective cation channels by forming homotrimers or heterotrimers with other P2X subtypes (Non-patent Document 6). ).

It is already known that ATP causes pain, and studies using P2X ₃ knockout and knockdown techniques have shown that the P2X ₃ receptor is involved in the transmission of chronic pain. P2X ₃ receptors peripheral sensory nerves specifically expressed to form hetero-complex with homo complex or P2X ₂ a (P2X _2/3). (Non-Patent Document 1)

Subsequently, a compound called A-317491 was reported as an antagonist specific for the P2X ₃ and P2X _2/3 receptors. A-317491 has the following formula:

Is a tri-substituted-N-[(1S) -1,2,3,4-tetrahydro-1-taphthalenyl] benzamide derivative (Patent Document 1), which antagonizes P2X ₃ and P2X _2/3 receptors It has been reported that it showed activity and showed analgesic action in a rat neuropathic pain model and inflammatory pain model (Non-patent Document 7). This indicates that it pain via the P2X ₃ or P2X _2/3 receptor is transmitted, and P2X ₃ or P2X _2/3 compounds with receptor antagonistic activity are useful as analgesics . Patent Documents 2 to 7 also describe compounds exhibiting P2X ₃ or P2X _2/3 receptor antagonism.

In addition, it has recently been reported that P2X ₃ knockout mice show a marked decrease in bladder reflex (Non-patent Document 2), and a compound having a P2X ₃ receptor antagonistic action is used in the treatment of diseases associated with abnormal urination function. It also suggests that it is useful. Patent Documents 2 to 7 describe compounds exhibiting P2X ₃ or P2X _2/3 receptor antagonism.

Furthermore, P2X ₃ that the receptor is expressed in neuroepithelial bodies (NEB) of the lungs (Non-Patent Document 9), and ATP-induced cough (Non-Patent Document 10), etc., P2X ₃ receptors It has been suggested that it is involved in information transmission in the respiratory organs (Non-patent Document 11). These reports, compounds having a P2X ₃ receptor antagonism, suggesting potential utility in the treatment of respiratory diseases.

Thereafter, a compound called A-317491, known as a P2X ₃ and P2X _2/3 receptor antagonist, has been reported to inhibit the activity of vagal afferent A fibers in lung diseases (Patent Document WO2006). / 012639).
In addition, biphenyl and phenyl-pyridine derivatives have been reported as P2X ₃ and / or P2X _2/3 receptor antagonists, suggesting that they have an action to improve respiratory diseases in asthma and lung function models (Patent Document WO2010). / 149578). Patent Documents 2 to 7 describe compounds exhibiting P2X ₃ or P2X _2/3 receptor antagonism.

Patent Documents 8, 9, 10, 11 and 15 and Non-Patent Document 14 describe compounds having a structure similar to that of the compound of the present invention, but analgesic action and P2X ₃ or P2X _2/3 receptor antagonistic action Is not described. Non-Patent Document 8 describes a compound having a structure similar to that of the compound of the present invention and showing analgesic activity, but does not describe P2X ₃ or P2X _2/3 receptor antagonism. Patent Document 12 and Non-Patent Documents 12 and 13 describe compounds having a P2X ₃ receptor antagonistic action, but differ in structure from the compounds of the present invention. Patent Literature 13 and Patent Literature 14 describe compounds having a P2X ₃ or P2X _2/3 receptor antagonistic activity having a triazine skeleton.

International Publication No. 02/094767 Specification International Publication No. 2005/095359 Specification US Patent Application Publication No. 20070037974 US Patent Application Publication No. 20070049758 US Patent Application Publication No. 20070049610 US Patent Application Publication No. 20070049609 US Patent Application Publication No. 20070049534 Japanese Patent Laid-Open No. 12-072757 International Publication No. 2006/104713 Specification International Publication No. 2006/104715 Specification International Publication No. 2006/102112 Specification International Publication No. 2010/051188 International Publication No. 2010/092966 International Publication No. 2012/020749 International Publication No. 2011/017347 Specification

The present invention provides novel P2X ₃ and / or P2X _2/3 receptor antagonistic compounds. Further, to provide a pharmaceutical composition having a P2X ₃ and / or P2X _2/3 receptor antagonism.

As a result of intensive studies in order to solve the above-mentioned problems, the present inventors have found that a novel compound that specifically binds to the P2X ₃ and / or P2X _2/3 receptor and exhibits antagonism, and P2X ₃ and / or Alternatively, a novel compound that specifically binds to the P2X _2/3 receptor was found. Also found a pharmaceutical composition having P2X ₃ and / or P2X _2/3 receptor antagonism.
The pharmaceutical compositions encompassed by the compounds or the present invention included in the present invention, P2X ₃ receptor inhibiting activity, a rat serum albumin (hereinafter, RSA) good results in P2X ₃ receptor inhibitory activity and the like in the presence of Indicated. In addition, the compound included in the present invention or the pharmaceutical composition included in the present invention is a CYP enzyme inhibition confirmation test, FAT test, solubility confirmation test, metabolic stability confirmation test, hERG inhibitory activity confirmation test, bioavailability confirmation. Good results were also shown in tests and / or protein binding confirmation tests.
The present invention relates to the following (1) to (37).

(1)
Formula (I):

(Where
R ^a and R ^b are both a hydrogen atom or together, oxo, thioxo or ═N—R ^x ;
R ^d and R ^e are both hydrogen atoms or together, oxo, thioxo or ═N—R ^y ;
R ^x and R ^y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R ^c is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
Each R ^4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R ^4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R ^4a and R ^4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R ² represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R ⁵ ) — or — (C (R ^5a ) (R ^5b )) —;
—L— represents —O—, —S—, —N (R ^{5 ′} ) — or — (C (R ^{5a ′} ) (R ^{5b ′} )) —;
R ⁵ and R ^{5 ′} are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R ^5a , R ^5b , R ^{5a ′} and R ^{5b ′} each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or Unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy or substituted or unsubstituted alkenyloxy;
Ring D is benzene, pyridine, pyrimidine, pyrazine or pyridazine;
Carbon atom a and carbon atom b are carbon atoms constituting ring D;
Ring B is an aromatic carbocycle, non-aromatic carbocycle, aromatic heterocycle or non-aromatic heterocycle;
s and s ′ are each independently an integer of 0 to 3;
R ⁹ is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxy Carbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfoni Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
R ^{9 ′} is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfo Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
(However, when ring B is cyclopentane, benzene, tetrahydropyran or piperidine, s ′ is an integer of 1 to 3)
Or a pharmaceutically acceptable salt thereof.

(2)
—R ^c is — (C (R ^11c ) (R ^11d )) m′-CN
(Wherein R ^11c each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R ^11d is each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R ^11c and R ^11d bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle;
m ′ is an integer of 1 to 4)
Or a pharmaceutically acceptable salt thereof according to (1) above.
(3)
R ^c is substituted with 3 to 5 hydroxy groups, and substituent group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro and thioxo) An optionally substituted C3-C6 alkyl; a C3-C6 alkenyl optionally substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; or Substituted with 3-5 hydroxy A compound or a pharmaceutically acceptable salt thereof according to above (1) is a further one or more substituents may C3 ~ C6 alkynyl optionally substituted with selected from Substituent group alpha.
(3 ')
R ^c is substituted with 3 to 5 hydroxy groups, and substituent group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo) C3-C6 alkyl optionally substituted with substituents; C3-C6 optionally substituted with 3 to 5 hydroxy and further substituted with one or more substituents selected from substituent group A Alkenyl; or 3-5 hydro The compound or a pharmaceutically acceptable salt thereof according to the above (1), which is C3-C6 alkynyl substituted with cis and further substituted with one or more substituents selected from Substituent Group A .
(4)
s is 1 or 2, and at least one R ⁹ is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Any of (1) to (3) and (3 ′) above, which is substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl Or a pharmaceutically acceptable salt thereof.
(5)
formula:

The group represented by the formula:

(Wherein —X— and —L— are as defined above (1); R ⁹ is halogen or substituted or unsubstituted alkyl; Y ¹ , Y ² and Y ³ are each independently CH or N; provided that Y ¹ , Y ² and Y ³ are not simultaneously N), and the compound according to any one of (1) to (3), (3 ′) and (4) above Or a pharmaceutically acceptable salt thereof.

(6)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) and (5), wherein —L— is —O—.
(7)
The compound according to any one of the above (1) to (3), (3 ′), (4), (5) and (6) or a pharmaceutically acceptable salt thereof, wherein ring B is an aromatic heterocyclic ring salt.
(8)
(1) to (1) above, wherein Ring B is thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, furan, thiophene, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine or benzoxazole. 3) The compound according to any one of (3 ′) and (4) to (7) or a pharmaceutically acceptable salt thereof.
(9)
Ring (B) is thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine or pyridazine, (1) to (3), (3 ′) and (4) to (8) Or a pharmaceutically acceptable salt thereof.
(10)
s ′ is 1 or 2, and at least one R ^{9 ′} is hydroxy, carboxy, cyano, substituted alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′) and (4) to (9), which is substituted sulfinyl.
(11)
any one of (1) to (3), (3 ′) and (4) to (10) above, wherein s ′ is 1 and R ^{9 ′} is carboxy or substituted or unsubstituted carbamoyl A compound or a pharmaceutically acceptable salt thereof.
(12)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′) and (4) to (11), wherein Ring D is benzene.
(13)
Any one of (1) to (3), (3 ′) and (4) to (12) above, wherein the carbon atom a and the carbon atom b on the ring D are in a positional relationship of (1, 4) Or a pharmaceutically acceptable salt thereof.
(14)
—R ^c is — (C (R ^11a ) (R ^11b )) m—OH
(Wherein each R ^11a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R ^11b is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R ^11a and R ^11b bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle;
m is an integer of 2 to 4, and the compound or a pharmaceutically acceptable salt thereof according to any one of (1) or (4) to (13) above.
(15)
—R ^c is — (C (R ^11a ) (R ^11b )) m—OH
[Wherein R ^11a represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R ^11b is — (C (R ^12a ) (R ^12b )) u—OH; wherein R ^12a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Or substituted or unsubstituted alkynyl; each R ^12b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; u is an integer of 0 to 2 );
m is an integer of 2 to 4, and the compound or pharmaceutically acceptable salt thereof according to any one of (1) or (4) to (14) above.

(16)
R ^c is of the formula:

The compound or a pharmaceutically acceptable salt thereof according to any one of (1) or (4) to (15) above, which is a group represented by:
(17)
-R ^c is-(C (R ^14a ) (R ^14b )) tN (R ^15a ) (R ^15b )
(Wherein each R ^14a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R ^14b each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R ^14a and R ^14b bonded to the same carbon atom together Substituted or unsubstituted cycloalkanes, substituted or unsubstituted cycloalkenes, or substituted or unsubstituted non-aromatic heterocycles;
t is an integer from 2 to 4;
R ^15a and R ^15b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, Substituted or unsubstituted acyl, substituted sulfonyl or substituted sulfinyl); or —R ^c is — (C (R ^{14a ′} ) (R ^{14b ′} )) t′—C (═O) N (R ^{15a ′} ) (R ^{15b '} )
(Wherein R ^{14a ′} each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R ^{14b ′} is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R ^{14a ′} and R ^{14b ′} bonded to the same carbon atom. Together, a substituted or unsubstituted cycloalkane, a substituted or unsubstituted cycloalkene, or a substituted or unsubstituted non-aromatic heterocycle;
t ′ is an integer of 1 to 4;
R ^{15a ′} and R ^{15b ′} each independently represent a hydrogen atom, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted (1) or (4) to (13) or a pharmaceutically acceptable salt thereof, which is substituted sulfamoyl, substituted or unsubstituted acyl, substituted sulfonyl or substituted sulfinyl).

(18)
R ^c is of the formula:

(Wherein R ^15a , R ^15b , R ^{15a ′} and R ^{15b ′} have the same meanings as in (17) above)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1), (4) to (13) or (17), which is a group represented by:

(19)
Formula (II):

(Where
R ^a and R ^b are both a hydrogen atom or together, oxo, thioxo or ═N—R ^x ;
R ^d and R ^e are both hydrogen atoms or together, oxo, thioxo or ═N—R ^y ;
R ^x and R ^y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R ^c is substituted with 3 to 5 hydroxy groups, and further substituted group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, and thioxo) C3-C6 alkyl optionally substituted with C3-C6 alkenyl substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; Or substituted with 3-5 hydroxy Are further 1 or more are also may C3 ~ optionally C6 alkynyl substituted with a substituent selected from substituent group alpha;
Each R ^4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R ^4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R ^4a and R ^4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R ² represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R ⁵ ) — or — (C (R ^5a ) (R ^5b )) —;
R ⁵ represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R ^5a and R ^5b each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkynyloxy or substituted or unsubstituted alkenyloxy;
R ³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl )
Or a pharmaceutically acceptable salt thereof.
(19 ')
Formula (II):

(Where
R ^a and R ^b are both a hydrogen atom or together, oxo, thioxo or ═N—R ^x ;
R ^d and R ^e are both hydrogen atoms or together, oxo, thioxo or ═N—R ^y ;
R ^x and R ^y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R ^c is substituted with 3 to 5 hydroxy groups, and further substituted group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo) C3-C6 alkyl optionally substituted with substituents; C3-C6 optionally substituted with 3 to 5 hydroxy and further substituted with one or more substituents selected from substituent group A Alkenyl; or 3-5 hydro Substituted with shea further 1 or more are also may C3 ~ optionally C6 alkynyl substituted with a substituent selected from substituent group A;
Each R ^4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R ^4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R ^4a and R ^4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R ² represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R ⁵ ) — or — (C (R ^5a ) (R ^5b )) —;
R ⁵ represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R ^5a and R ^5b each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkynyloxy or substituted or unsubstituted alkenyloxy;
R ³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl )
Or a pharmaceutically acceptable salt thereof.
(20)
R ^a and R ^b together are oxo,
R ^d and R ^e together are oxo,
R ^c is

(Wherein Alk is alkyl)
A group represented by
n is 1, R ^4a and R ^4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,

And the other symbols have the same meanings as in (1) above, or the pharmaceutically acceptable salt thereof.
(21)
R ^a and R ^b together are oxo,
R ^d and R ^e together are oxo,
R ^c is

Is;
The compound according to the above (1), wherein s ′ is an integer of 1 to 3, and at least one R ^{9 ′} is halogen or haloalkyl, and the other symbols are as defined in the above (1), or a pharmaceutical product thereof Top acceptable salt.
(22)
R ^a and R ^b together are oxo,
R ^d and R ^e together are oxo,
R ^c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group;
n is 1, R ^4a and R ^4b are both hydrogen atoms,
-X- is -N (H)-;
-L- is -O-,
Ring D is benzene,
Ring B is pyridine or thiazole;
s ′ is an integer from 1 to 3; and at least one R ^{9 ′} is carboxy or alkyloxycarbonyl, and the other symbols are as defined in (1) above, or Its pharmaceutically acceptable salt.
(23)
R ^a and R ^b together are oxo,
R ^d and R ^e together are oxo,
R ^c is alkyl;
n is 1, R ^4a and R ^4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,
s is an integer of 1 to 3,

(Wherein s ″ is an integer of 0 to 2 and the other symbols have the same meanings as in (1) above, or a pharmaceutically acceptable salt thereof.
(24)
R ^a and R ^b together are oxo,
R ^d and R ^e together are oxo,
R ^c is

(Wherein Alk is alkyl)
A group represented by
n is 1, R ^4a and R ^4b are both hydrogen atoms,
R ² is substituted or unsubstituted cycloalkyl,
-X- is -N (H)-;
-L- is -O-,
Ring D is benzene,
The other symbols have the same meanings as in (1) above, the compound according to (1) above or a pharmaceutically acceptable salt thereof.
(25)
R ^a and R ^b are together oxo, and R ^d and R ^e are together oxo, (1) to (3), (3 ′), (4) to (19 ), (19 ′) and (20) to (24), or a pharmaceutically acceptable salt thereof.
(26)
The compound according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (25), wherein n is 1, or a pharmaceutical thereof Top acceptable salt.
(27)
Any one of (1) to (3), (3 ′), (4) to (19), (19 ′), and (20) to (26), wherein R ^4a and R ^4b are both hydrogen atoms. The described compound or a pharmaceutically acceptable salt thereof.
(28)
The above (1) to (3), (3 ′), (4) to (19), wherein R ² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. ), (19 ′) and (20) to (22), or a pharmaceutically acceptable salt thereof.
(29)
—X— is —N (R ⁵ ) — (wherein R ⁵ has the same meaning as (1) above), (1) to (3), (3 ′), (4) to (19) , (19 ′) and (20) to (28), or a pharmaceutically acceptable salt thereof.
(30)
Any of (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (29) above, wherein —X— is —NH—. Or a pharmaceutically acceptable salt thereof.
(31)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A pharmaceutical composition containing.
(32)
The pharmaceutical composition according to the above (31), which has a P2X ₃ and / or P2X _2/3 receptor antagonistic action.
(33)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A pharmaceutical composition having an analgesic action and / or an effect of improving dysuria.
(34)
(1) to (3), (3 ′), (4) to (19), (9) above for use in the treatment and / or prevention of diseases involving P2X ₃ and / or P2X _2/3 receptors 19 ′) and the compound according to any one of (20) to (30) or a pharmaceutically acceptable salt thereof.
(35)
Any of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) for use in analgesia and / or dysuria improvement Or a pharmaceutically acceptable salt thereof.
(36)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A method for treating and / or preventing a disease involving a P2X ₃ and / or P2X _2/3 receptor, which comprises administration.
(37)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A method for analgesia and / or a method for improving dysuria, characterized by administration.

The compounds of this invention have an antagonistic effect on P2X ₃ and / or P2X _2/3 receptor and are useful for the disease or condition P2X ₃ and / or P2X _2/3 receptors are involved.

The terms used in this specification are explained below. Each term has the following meaning unless otherwise specified.

“Halogen” means fluorine, chlorine, bromine and iodine.

The halogen part of “haloalkyl”, “haloalkylcarbamoyl” and “haloalkyloxy” has the same meaning as the above “halogen”.

“Alkyl” includes a straight or branched monovalent hydrocarbon group having 1 to 15 carbon atoms, 1 to 10 carbon atoms in one embodiment, and 1 to 6 carbon atoms in another embodiment. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl, n-undecanyl, dodecanyl, tridecanyl and the like.
In the present specification, the number of carbon atoms in “alkyl” may be limited. For example, C3-C6 alkyl means “alkyl” having 3 to 6 carbon atoms.
Examples of the unsubstituted alkyl for R ^c include n-propyl.

“Haloalkyl”, “hydroxyalkyl”, “aminoalkyl”, “alkylaminoalkyl”, “alkylamino”, “alkylimino”, “alkylsulfonyl”, “alkylsulfamoyl”, “alkylcarbamoyl”, “arylalkyl” ”,“ Alkylsilylalkynyl ”,“ alkylsulfonyl ”,“ alkylsulfinyl ”,“ alkylcarbamoyl ”,“ alkylcarbamoylalkyl ”,“ alkylcarbamoylalkyloxy ”,“ alkylsulfamoyl ”,“ alkylsulfamoylalkyl ”, “Haloalkylcarbamoyl”, “hydroxyalkylcarbamoyl”, “alkyloxycarbonylalkyl”, “alkylcarbamoylamino”, “alkyloxycarbonylamino”, “alkylsulfonyl” Rubamoiru "and the alkyl moiety of the" arylalkyl amino "as defined in the above" alkyl ".

“Alkyloxy” includes an alkyloxy group in which the alkyl moiety is the above “alkyl”. Examples thereof include alkyloxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.

“Haloalkyloxy”, “arylalkyloxy”, “alkyloxycarbonyl”, “alkyloxycarbonylalkyl”, “alkyloxyalkyloxy”, “alkylcarbamoylalkyloxy”, “carbamoylalkyloxy”, “carboxyalkyloxy” and The alkyloxy part of “alkyloxyimino” has the same meaning as the above “alkyloxy”.

Examples of “alkylthio” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio and the like.

Examples of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and the like.

Examples of the “alkylcarbamoyl” include mono- or dialkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and dipropylcarbamoyl groups. Can be mentioned.

“Alkenyl” is a straight or branched chain having 2 to 15 carbon atoms having one or more double bonds at any position, one embodiment having 2 to 10 carbon atoms, and another embodiment having 2 to 6 carbon atoms. Of alkenyl. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, dekenyl, undecenyl, dodecenyl, tridecenyl and the like.
In the present specification, the number of carbon atoms in “alkenyl” may be limited. For example, C3-C6 alkenyl means “alkenyl” having 3 to 6 carbon atoms.

The alkenyl part of “alkenyloxy”, “alkenylthio”, “alkenylcarbamoyl”, “alkenylsulfamoyl” and “alkenyloxycarbonyl” has the same meaning as the above “alkenyl”.

“Alkynyl” includes linear or branched alkynyl having 2 to 15 carbon atoms, one embodiment having 2 to 10 carbon atoms, and another embodiment having 2 to 6 carbon atoms. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonyl, decynyl and the like. These have one or more triple bonds at arbitrary positions, and may further have a double bond.
In the present specification, the number of carbon atoms in “alkynyl” may be limited. For example, C3-C6 alkynyl means “alkynyl” having 3 to 6 carbon atoms.

The alkynyl part of “alkynyloxy”, “alkynylthio” and “alkynyloxycarbonyl” has the same meaning as the above “alkynyl”.

“Acyl” means R—C (═O) — (for example, R is “hydrogen”, “alkyl”, “alkenyl”, “alkynyl” or “cycloalkyl”, “cycloalkenyl”, A group represented by “non-aromatic heterocyclic group”, “aryl” or “heteroaryl”.

The “acyl” part of “acylamino” and “acylimino” has the same meaning as the above “acyl”.

“Cycloalkane” includes monocyclic or polycyclic saturated carbocyclic rings having 3 to 10 carbon atoms. Examples of the monocyclic cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane. Examples of the polycyclic cycloalkane include norbornane and tetrahydronaphthalene.

“Cycloalkyl” includes a monovalent group derived from the above “cycloalkane”. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. One embodiment includes C3-C8 cycloalkanes. Other embodiments include C3-C7 cycloalkanes. Examples of the polycyclic cycloalkyl include norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl and the like.
Examples of “cycloalkyl” in R ² include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Examples of “cycloalkyl” in R ³ include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The “cycloalkyl” part of “cycloalkylcarbonyl”, “cycloalkyloxycarbonyl” and “cycloalkyloxy” has the same meaning as the above “cycloalkyl”.

“Cycloalkene” includes a non-aromatic monocyclic or polycyclic ring having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond. One embodiment includes C3-C8 cycloalkene. Other embodiments include C3-C7 cycloalkene. Examples of the monocyclic cycloalkene include cyclopentene and cyclohexene. Examples of the polycyclic cycloalkene include norbornene and indene.

“Cycloalkenyl” includes a monovalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. One embodiment includes C3-C8 cycloalkyl. Other embodiments include C3-C7 cycloalkyl. Examples of polycyclic cycloalkenyl include norbornenyl, inden-1-yl, inden-2-yl, inden-3-yl and the like.

The “cycloalkenyl” part of “cycloalkenyloxycarbonyl” and “cycloalkenyloxy” has the same meaning as the above “cycloalkenyl”.

The “aromatic carbocycle” includes a monocyclic or condensed aromatic hydrocarbon ring. Examples thereof include benzene, naphthalene, anthracene, phenanthrene and the like.

“Aryl” means a monovalent group derived from the above “aromatic carbocycle”. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like.
“Aryl” in R ² includes phenyl.
“Aryl” in R ³ includes phenyl.

The “aryl” part of “aryloxy”, “arylthio” and “aryloxycarbonyl” has the same meaning as the above “aryl”.

“Heterocycle” means a 5- to 7-membered ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring,
A ring in which two or more of them are independently fused, or
A 5- to 7-membered ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the “aromatic carbocycle”, the “cycloalkane” or the “cycloalkene”. An aromatic or non-aromatic fused ring derived from the above ring.
For example, monocyclic non-aromatic heterocycles such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorphone, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, etc. ;
For example, pyrrole, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc. Family heterocycles;
For example, indole, isoindole, indazole, indolizine, indoline, isoindoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzopyran, benzimidazole, benzisoxazole, benzoxazole, benzoxazidi Azole, benzoisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazole, benzodioxane, tetrahydroquinoline, tetrahydrobenzothiophene, etc. And a condensed heterocyclic ring.

The “heterocyclic group” includes a monovalent group derived from the above “heterocycle”.
For example, pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyridyl, dihydropyridinyl, dihydropyridinyl, dihydropyridinyl Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl;
For example, pyrrolyl, pyrazinyl, pyrazolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc. A cyclic group;
For example, indolyl, isoindolyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl Diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazo Examples include condensed heterocyclic groups such as linyl, benzodioxanyl, tetrahydroquinoline, tetrahydrobenzothienyl and the like.

The “non-aromatic carbocycle” includes the above “cycloalkane” and the above “cycloalkene”, and the ring in which the “cycloalkane” or the “cycloalkene” is fused to the “aromatic carbocycle”. . Examples of the condensed ring include indene.

The “non-aromatic carbocyclic group” includes a monovalent group derived from the above “non-aromatic carbocyclic group”. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, norbornenyl, inden-1-yl , Inden-2-yl, inden-3-yl and the like.

The “non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic alkyloxy” and the “non-aromatic carbocyclic” moiety are synonymous with the above “non-aromatic carbocyclic”.

The “aromatic heterocycle” includes those that are aromatic rings among the above “heterocycle”.
A 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
An aromatic ring in which two or more of them are independently fused,
An aromatic ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
For example, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc. ring;
For example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo Examples thereof include condensed aromatic heterocycles such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline and the like.

The “5-membered or 6-membered aromatic heterocycle” includes the 5-membered or 6-membered “aromatic heterocycle” described above. Examples include thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophene, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.

The “5-membered aromatic heterocycle” includes the 6-membered “aromatic heterocycle” described above. Examples thereof include pithiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophene, imidazole, triazole, tetrazole and the like.
The “6-membered aromatic heterocycle” includes the 6-membered “aromatic heterocycle”. For example, pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like can be mentioned.

Examples of the “aromatic heterocycle” in ring B include pyridine, pyrazine, pyridazine, thiazole, isothiazole, oxazole and isoxazole. More specifically, pyridine is mentioned.

“Heteroaryl” includes a monovalent group derived from the above “aromatic heterocycle”. A 5- to 7-membered aromatic cyclic group having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
An aromatic cyclic group in which two or more of them are independently fused,
An aromatic group in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
For example, pyrrolyl, pyrazinyl, pyrazolyl, indolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc. Aryl,
For example, isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazozolyl, benzoxiazozolyl, benzothiazozolyl Condensation such as ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, benzimidazolinyl Heteroaryl.

“Heteroaryl” in R ² includes pyridyl, and “heteroaryl” in R ³ includes pyridyl, pyrimidyl, benzofuryl, benzothienyl, indolyl, benzoisoxazolyl, benzothiazolyl, and the like.
“Heteroaryl” in R ³ includes pyridyl.

The “heteroaryl” part of “heteroaryloxy” and “heteroaryloxycarbonyl” has the same meaning as the above “heteroaryl”.

The “non-aromatic heterocyclic ring” includes those that are non-aromatic rings among the above-mentioned “heterocyclic rings”.
A 4- to 7-membered non-aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
A non-aromatic ring in which two or more of them are independently fused,
A ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “cycloalkane” or “cycloalkene”;
A 5- to 7-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle”. Includes fused rings.
For example, oxetane, thietane, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran (for example, 2-tetrahydropyran, 3-tetrahydropyran, 4- Tetrahydropyran), dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazoline, tetrahydroisothiazoline and the like,
Examples thereof include condensed non-aromatic heteroaromatic rings such as indoline, isoindoline, benzopyran, benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, tetrahydrobenzothiophene and the like.

The “non-aromatic heterocyclic group” includes a monovalent group derived from the above “non-aromatic heterocyclic ring”.
For example, pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyridyl, dihydropyridinyl, dihydropyridinyl, dihydropyridinyl Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl,
Examples thereof include condensed heterocyclic groups such as benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, and tetrahydrobenzothiophene.

The “non-aromatic heterocycle” portion of “non-aromatic heterocycle oxy” and “non-aromatic heterocycle oxycarbonyl” has the same meaning as the above “non-aromatic heterocycle”.

The term “nitrogen-containing non-aromatic heterocyclic group” includes at least one nitrogen atom in the ring, and may further include one or more atoms arbitrarily selected from an oxygen atom and a sulfur atom in the ring. It includes a group derived from a non-aromatic 4- to 7-membered ring or a ring in which two or more thereof are condensed. Examples include pyrrolinyl, pyrrolidino, pyrrolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholino and the like.

The “non-aromatic heterocycle” portion of “non-aromatic heterocycle oxycarbonyl” has the same meaning as the above “non-aromatic heterocycle”.

“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylthio”, “substituted alkenylthio”, “substituted alkynylthio”, Substituents of “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl”, “substituted alkynyloxycarbonyl” and “substituted alkylcarbamoyl” are each one or more selected from the group consisting of the same or different Examples include but are not limited to substituents:
Hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyloxy (eg CF ₃ O), cycloalkyl (eg cyclopropyl), cycloalkenyl (eg cyclopropenyl), alkyloxy (eg methoxy, Ethoxy, propoxy, butoxy, etc.), alkenyloxy (eg, vinyloxy, allyloxy, etc.), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino (eg, methyl) Amino, ethylamino, dimethylamino, etc.), acylamino (eg, acetylamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, alkylsulfonylamino (Eg methanesulfonylamino), alkylsulfinylamino (eg methanesulfinylamino), non-aromatic heterocyclic group amino (eg 4-tetrahydropyranylamino), imino, hydroxyimino, alkylimino (eg methylimino, Ethylimino, dimethylimino, etc.), alkyloxyimino (eg, methoxyimino, ethoxyimino, etc.), acylimino (eg, acetylimino, benzoylimino, etc.), azide, aryl (eg, phenyl, etc.), arylalkyl (eg, benzyl, Phenylethyl, etc.), arylalkyloxy (eg benzyloxy), non-aromatic heterocyclic groups (eg pyrrolinyl, piperidyl, piperazinopyrrolidino, pyrrolidinyl, morpholinyl, morpholino, 2,2-dimethyl) 1,3-dioxolanyl, etc.), heteroaryl (eg, furyl, thienyl, pyridyl, isoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, tetrazolyl, indolyl, benzofuryl, etc.), heteroarylalkyl (pyridylmethyl, pyridylethyl, etc.) , Cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (eg, methylthio, etc.), alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl), carbamoyl, alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, etc.) , Sulfamoyl, alkylsulfamoyl, acyl (eg, formyl, acetyl, etc.), formyloxy, thioformyl Thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, azide, ureido, amidino, guanidino, phthalimide, trialkylsilyl (trimethylsilyl, etc.), hydroxyalkylcarbamoyl (hydroxyethylcarbamoyl), terahydropyranyloxy, carbamoylamino Alkylcarbamoylamino (eg, methylcarbamoylamino, etc.), alkyloxycarbonylamino (eg, methyloxycarbonylamino, etc.), haloalkylcarbamoyl (eg, trifluoroethylcarbamoyl, etc.), alkyloxyalkyloxy (eg, methyloxymethyloxy, etc.) ), Carbamoylcarbamoyl, alkylsulfonylcarbamoyl (eg, methanesulfonylcarbamoyl) And oxo.

The substituent of “substituted acyl” is selected from the group consisting of the substituent of the above “substituted alkyl”, the above “alkyl”, the above “alkenyl”, and the above “alkynyl”. In particular, when R of acyl (R—C (═O) —) is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, “heteroaryl”, Ring substituents include alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF ₃ , CH ₂ CF ₃ , CH ₂ CCl _3, etc.), alkenyl, alkynyl (eg, ethynyl) , Alkyloxy (for example, methoxy, ethoxy, isopropyloxy), halogen (for example, fluorine, chloro and the like) and the like.

Substituents for “substituted carbamoyl” or “substituted sulfamoyl” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of:
Hydroxy, carboxy, carboxyalkyl (eg, carboxymethyl, carboxyethyl, etc.), halogen (F, Cl, Br, I), alkyl (eg, methyl, ethyl), alkenyl (eg, vinyl), alkynyl (eg, ethynyl) , Cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), hydroxyalkyl (eg, hydroxyethyl), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), alkyloxycarbonyl Alkyl (eg, methoxycarbonylmethyl, ethoxycarbonylmethyl, etc.), amino, alkylamino (eg, methylamino, ethylamino, dimethylamino, etc.), acylamino (eg, acetylamino) Benzoylamino etc.), arylalkylamino (eg benzylamino, tritylamino), hydroxyamino, aryl (eg phenyl etc.), non-aromatic heterocyclic group (eg 4-tetrahydropyranyl), heteroaryl (eg Pyridyl), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato and acyl (eg, formyl, acetyl, etc.).

The substituents of “substituted sulfonyl” or “substituted sulfinyl” are the above “substituted or unsubstituted alkyl”, the above “substituted or unsubstituted alkenyl”, the above “substituted or unsubstituted alkynyl”, the following “substituted or unsubstituted cycloalkyl”. Selected from the group consisting of the following "substituted or unsubstituted cycloalkenyl", the following "substituted or unsubstituted non-aromatic heterocyclic group", the following "substituted or unsubstituted aryl", and the following "substituted or unsubstituted heteroaryl" Is done. In particular, R in R—S (═O) ₂ — or R—S (═O) — is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, “heteroaryl” , Etc., each ring substituent may be alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF ₃ , CH ₂ CF ₃ , CH ₂ CCl _3, etc.), Examples include alkenyl, alkynyl (eg, ethynyl), alkyloxy (eg, methoxy, ethoxy, isopropyloxy), halogen (eg, fluorine, chloro and the like) and the like.

Substituents for “substituted amino”, “substituted imino” and “substituted guanidyl” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of:
Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF ₃ , CH ₂ CF ₃ , CH ₂ CCl _3, etc.), hydroxyalkyl (eg, hydroxyethyl, —C (CH ₃ ) ₂ CH ₂ OH, etc.), alkenyl (eg, vinyl), alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy) Etc.), haloalkyloxy (eg CF ₃ O), alkenyloxy (eg vinyloxy, allyloxy etc.), alkyloxycarbonyl (methoxycarbonyl, tert-butyloxycarbonyl etc.), alkyloxycarbonylalkyl, amino, alkylamino (eg , Methylamino, ethi Amino, dimethylamino, etc.), acylamino (eg, acetylamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, imino, hydroxyimino, alkylimino (eg, methylimino, ethylimino, dimethyl) Imino etc.), alkyloxyimino (eg methoxyimino, ethoxyimino etc.), acylimino (eg acetylimino, benzoylimino etc.), aryl (eg phenyl etc.), arylalkyl (eg benzyl etc.), aryloxy ( For example, phenoxy etc.), non-aromatic heterocyclic groups (eg pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino etc.), heteroaryl (eg pi Lysyl, thienyl, thiazolyl, furyl, etc.), heteroarylalkyl (eg, pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl, etc.), non-aromatic heterocyclic oxy (piperazinooxy, piperidinooxy, etc.), heteroaryloxy (pyridyloxy, etc.) , Hydroxy, halogen (F, Cl, Br, I), cyano, acyl (eg, formyl, acetyl, etc.), non-aromatic heterocyclic carbonyl (eg, 4-tetrahydropyranylcarbonyl, etc.), alkylsulfonyl (eg, methane) Sulfonyl etc.), non-aromatic heterocyclic sulfonyl (eg 4-tetrahydropyranylsulfonyl etc.), alkylsulfinyl (eg methanesulfinyl etc.), carbamoyl, alkylcarbamoyl (eg methylcarbamoyl etc.), alkylcarbamo Rualkyl (eg, methylcarbamoylmethyl, etc.), carbamoylalkyl (eg, carbamoylmethyl, etc.), carboxyalkyl (eg, carboxymethyl, etc.), sulfamoyl, alkylsulfamoyl (eg, methylsulfamoyl, etc.), alkylsulfamoyl Alkyl (eg, methylsulfamoylmethyl) and sulfamoylalkyl (eg, sulfamoylmethyl)

“Substituted cycloalkyl”, “Substituted cycloalkenyl”, “Substituted aryl”, “Substituted phenyl”, “Substituted heteroaryl”, “Substituted heteroaryl”, “Substituted non-aromatic carbocyclic” “Substituted non-aromatic Group heterocyclic group "," substituted nitrogen-containing non-aromatic heterocyclic group "," substituted cycloalkyloxy "," substituted cycloalkenyloxy "," substituted aryloxy "," substituted heteroaryloxy "," substituted non-substituted "Aromatic heterocyclic oxy", "substituted cycloalkyloxycarbonyl", "substituted cycloalkenyloxycarbonyl", "substituted non-aromatic heterocyclic oxycarbonyl", "substituted aryloxycarbonyl", "substituted heteroaryloxycarbonyl", " Substituted cyclopropane, substituted cyclopropene, substituted oxetane, substituted thietane and substituted azetidine As the substituents include one or more of the same or different substituents selected from the group consisting of but not limited to:
Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF ₃ , CH ₂ CF ₃ , CH ₂ CCl _3, etc.), haloalkyloxy (eg, CF ₃ O, CHCF ₂ O, etc.), Alkenyl (eg vinyl), alkynyl (eg ethynyl), cycloalkyl (eg cyclopropyl), cycloalkenyl (eg cyclopropenyl), alkyloxy (eg methoxy, ethoxy, propoxy, butoxy etc.), alkenyloxy ( For example, vinyloxy, allyloxy, etc.), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino (eg, methylamino, ethylamino, dimethylamino, etc.), acylamino (For example, AS Ruamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, amino substituted with one or two identical or different substituents selected from the following substituent group Y, imino , Hydroxyimino, alkylimino (eg, methylimino, ethylimino, dimethylimino, etc.), alkyloxyimino (eg, methoxyimino, ethoxyimino, etc.), acylimino (eg, acetylimino, benzoylimino, etc.), azide, aryl (eg, Phenyl, etc.), arylalkyl (eg, benzyl, etc.), unsubstituted non-aromatic carbocyclic oxy (eg, cyclopropyloxy, etc.), one or more selected from the following substituent group Z, or the same or different Non-substituted with substituent Aromatic carbocyclic oxy, unsubstituted non-aromatic carbocyclic alkyloxy (eg, cyclopropylmethyloxy, etc.), substituted with one or more of the same or different substituents selected from the following substituent group Z Non-aromatic carbocyclic alkyloxy, unsubstituted aryloxy (for example, phenoxy and the like), aryloxy substituted with one or more each same or different substituents selected from the following substituent group Z, non- A substituted arylalkyloxy (for example, benzyloxy and the like), an arylalkyloxy substituted with one or more of the same or different substituents selected from the following substituent group Z, a non-aromatic heterocyclic group ( For example, pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, etc. ), Heteroaryl (eg, pyridyl, thienyl, thiazolyl, furyl, etc.), heteroarylalkyl (eg, pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl, etc.), unsubstituted non-aromatic heterocyclic oxy (eg, piperazinooxy, Piperidinooxy, etc.), non-aromatic heterocyclic oxy, unsubstituted heteroaryloxy (eg, pyridyloxy, pyrida) substituted with one or more of the same or different substituents selected from the following substituent group Z Zinyloxy, pyrimidinyloxy, pyrazinyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, furyloxy, thienyloxy, etc.), the following substituent group Z 1 selected from Heteroaryloxy, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (eg, methylthio, etc.), alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl), each substituted with the same or different substituents Substituted or unsubstituted carbamoyl (eg, carbamoyl, N-methyl-N-methoxycarbamoyl, etc.), substituted or unsubstituted alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, hydroxyethylcarbamoyl, trifluoromethylcarbamoyl, Trifluoroethylcarbamoyl, etc.), sulfamoyl, alkylsulfamoyl, hydroxy, carboxy, alkyloxycarbonyl, halogen (F, Cl, Br, I), acyl (eg, formyl, acetyl, etc.), formyloxy, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, azide, ureido, amidino, guanidino, phthalimide and Oxo.

Substituent group Y is hydroxyalkyl (eg, hydroxyethyl, —C (CH ₃ ) ₂ CH ₂ OH, etc.), alkyloxycarbonyl (methoxycarbonyl, tert-butyloxycarbonyl, etc.), alkyloxycarbonylalkyl, alkylsulfonyl (Eg methanesulfonyl etc.), alkylsulfinyl (eg methanesulfinyl etc.), carbamoyl, alkylcarbamoyl (eg methylcarbamoyl etc.), alkylcarbamoylalkyl (eg methylcarbamoylmethyl etc.), carbamoylalkyl (eg carbamoylmethyl etc. ), Carboxyalkyl (eg, carboxymethyl, etc.), sulfamoyl, alkylsulfamoyl (eg, methylsulfamoyl, etc.), alkylsulfamoylalkyl (eg, methyls) Include sulfamoyl, such as methyl) and sulfamoyl alkyl (e.g., a sulfamoyl methyl, etc.).
Substituent group Z includes halogen (for example, F, Cl and the like), hydroxy, carboxy, carboxyalkyloxy (for example, carboxymethyloxy and the like), cyano, nitro, alkyl (for example, methyl and the like), hydroxyalkyl (for example, Hydroxymethyl, etc.), aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, acyl, alkyloxycarbonyl (eg, methyloxycarbonyl, ethyloxycarbonyl, etc.) , Alkenyloxycarbonyl, alkynyloxycarbonyl, carbamoyl, carbamoylalkyloxy (eg, carbamoylmethyloxy, etc.), alkylcarbamoyl (eg, methylcarbamoyl) Tilcarbamoyl etc.), haloalkylcarbamoyl, cycloalkylcarbamoyl (eg cyclopropylcarbamoyl etc.), alkylcarbamoylalkyloxy (eg methylcarbamoylmethyloxy etc.), hydroxyalkylcarbamoyl (eg hydroxyethylcarbamoyl etc.), cyanocarbamoyl, amino , Acylamino, amino, sulfamoyl, methylsulfonyl, methylsulfinyl, cycloalkyl, cycloalkenyl, non-aromatic heterocyclic group substituted with one or two same or different substituents selected from the above substituent group Y , Aryl, heteroaryl (eg, tetrazolyl, etc.), cycloalkyloxy, cycloalkenyloxy, non-aromatic heterocyclic oxy, aryloxy, heteroaryloxy And encompasses oxo.

Examples of the substituent of “substituted aryl” and “substituted heteroaryl” in R ² include halogen, alkyl, alkenyl, alkynyl, alkyloxy, cycloalkyl, alkylsilylalkynyl and the like.

As the substituent of “substituted aryl” and “substituted heteroaryl” in R ² , fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, propenyl, vinyl, ethynyl, methyloxy, cyclopropyl, trimethylsilylethynyl Etc.

As the “heteroaryloxy” which is a substituent of “substituted aryl” and “substituted heteroaryl” in R ³ , for example, pyrrolyloxy, pyrazinyloxy, pyrazolyloxy, indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, Pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, Oxazolyloxy, oxadiazolyloxy and the like can be mentioned.

Substituents for “substituted aryl” and “substituted heteroaryl” in R ³ are unsubstituted heteroaryloxy, substituted with one or more of the same or different substituents selected from the above substituent group Z. Heteroaryloxy and the like. Furthermore, in addition to the above substituents, halogen, hydroxy, carboxy, cyano, nitro, alkyl, haloalkyl, haloalkyloxy, alkyloxy, amino and the like can be mentioned. The heteroaryloxy is a group selected from the following group which is unsubstituted or substituted with one or more of the same or different substituents selected from the substituent group Z: pyrrolyloxy, pyrazinyloxy, pyrazolyloxy , Indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isoxa Examples include zolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, oxazolyloxy, and oxadiazolyloxy.

The substituent of “substituted amino” in R ^{9 ′} includes “carbamoyl, alkylcarbamoyl (eg, methylcarbamoyl etc.), alkylcarbamoylalkyl (eg, methylcarbamoylmethyl etc.), carbamoylalkyl (eg, carbamoylmethyl etc.) or carboxy Alkyl (for example, carboxymethyl and the like) ".

R ^{9 ′} includes halogen, hydroxy, carboxy, cyano, nitro, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, acyl , Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carbamoyl, alkylcarbamoyl, haloalkylcarbamoyl, hydroxyalkylcarbamoyl, cyanocarbamoyl, amino, acylamino, one or two each selected from the above substituent group Y are the same or different Examples include amino, sulfamoyl, methylsulfonyl, and methylsulfinyl substituted with a substituent.

In the general formula (I) or the general formula (II), “R ^4a and R ^4b bonded to the same carbon atom together are oxo or thioxo” includes, for example, the following cases.

^{^(Wherein, n,} ^R ^4a, R ^4b and ^{R 2} are synonymous above (1)), and the like.

In the general formula (I), the positions of carbon atom a, Q ^a atom, Q ^b atom, carbon atom b, Q ^c atom and Q ^d atom constituting benzene, pyridine, pyrimidine, pyrazine or pyridazine, which are D rings, The first, second, third, fourth, fifth and sixth positions, respectively. The position numbers of these atoms are different from the position numbers based on the IUPAC nomenclature. That is, “the positional relationship of carbon atom a and carbon atom b on ring D is (1, 4)” includes the following cases.

(Wherein, Q ^a atom, Q ^b atom, Q ^c atom and Q ^d atom are each independently a carbon atom or a nitrogen atom, and —X—, —L—, ring D, ring B, s, s ′, R ⁹ and R ^{9 ′} are synonymous with the above (1))

In the general formula (I), the positions of carbon atom a, Q ^a atom, Q ^b atom, carbon atom b, Q ^c atom and Q ^d atom constituting benzene, pyridine, pyrimidine, pyrazine or pyridazine, which are D rings, The first, second, third, fourth, fifth and sixth positions, respectively. The position numbers of these atoms are different from the position numbers based on the IUPAC nomenclature. That is, “the positional relationship of carbon atom a and carbon atom b on ring D is (1,3)” includes the following cases.

In general formula (I) or general formula (II), “R ^11c and R ^11d bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted The term “or an unsubstituted non-aromatic heterocyclic ring” includes the following cases.

[Wherein, m ′, R ^11c and R ^11d have the same ^{meaning as} in the above (2);
vd is an integer of 0 to 3 (eg, 0 or 1, for example, 0);
—Wd— represents —O—, —S— or —N (R ^17d ) — (for example, —O—);
R ^17d is a hydrogen atom, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl,] and the like.

In general formula (I) or general formula (II), “R ^11a and R ^11b bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted The term “or an unsubstituted non-aromatic heterocyclic ring” includes the following cases.

[Wherein, m, R ^11a and R ^11b are as defined above (14);
v is an integer of 0 to 3 (for example, 0 or 1, such as 0);
—W— represents —O—, —S— or —N (R ¹⁷ ) — (for example, —O—);
R ¹⁷ represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].

In general formula (I) or general formula (II), “R ^14a and R ^14b bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted The “unsubstituted non-aromatic heterocycle” includes the following cases.

[Wherein, t, R ^14a , R ^14b , R ^15a and R ^15b have the same ^meanings as the above (17);
va is an integer of 0 to 3 (for example, 0 or 1, such as 0);
—Wa— represents —O—, —S— or —N (R ^17a ) — (for example, —O—);
R ^17a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].

In general formula (I) or general formula (II), “R ^{14a ′} and R ^{14b ′} bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, “Substituted or unsubstituted non-aromatic heterocycle” includes the following cases.

[Wherein, t ′, R ^{14a ′} , R ^{14b ′} , R ^{15a ′} and R ^{15b ′} have the same ^meaning as the above (17);
vb is an integer of 0 to 3 (for example, 0 or 1, such as 0);
—Wb— represents —O—, —S— or —N (R ^17b ) — (for example, —O—);
R ^17b is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].

In the general formula (I) or the general formula (II), R ^c is substituted with “3 to 5 hydroxy groups, and further substituted group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl Substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, Substituted or unsubstituted amino, substituted Or unsubstituted imino, substituted or unsubstituted guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cyclo Alkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, And “C3-C6 alkyl optionally substituted with one or more substituents selected from thioxo)” means that C3-C6 alkyl is necessarily substituted with 3-5 hydroxy, The alkyl is selected from substituent group A Means that are 1 or more substituents may C3 ~ C6 alkyl which may be substituted with a group. For example, R ^c includes the following groups.

The general synthesis method of the compound of the present invention is shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds.

The compounds represented by general formula (I), general formula (II), general formula (II ') and general formula (II' ') of the present invention can be produced, for example, by the synthetic route shown below. If necessary, it can be produced with reference to the contents described in WO2010 / 092966.

[Method A]

(Where Lg is

R ¹⁰ is alkyl, R ²⁷ is alkyl, n ′ is an integer of 0 to 3, Lg ¹ is a leaving group, and other symbols are as defined above. )
(First step)
Compound (i) or a hydrochloride or bromate thereof, etc. in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, dimethylsulfoxide, DBU, Reaction with isocyanate (ii) or 1-carbamoylimidazole (ii) ′ in the presence of a base such as triethylamine or pyridine (preferably DBU) at −20 ° C. to 50 ° C., preferably −10 ° C. to ice cooling . Subsequently, the reaction mixture is carbonylated or thiocarbonylated, such as 1,1′-carbonyldiimidazole, 1,1′-thiocarbonyldiimidazole, phosgene, thiophosgene, triphosgene, and DBU, triethylamine, pyridine, etc. Compound (iii) can be produced by reacting with a base (preferably DBU) at −20 ° C. to 50 ° C., preferably −10 ° C. to ice cooling.
(Second step)
Compound (iii) is reacted with compound (iv) in a solvent such as acetonitrile, acetone, DMF or DMSO in the presence of a base such as potassium carbonate or sodium carbonate at 50 ° C. to heating under reflux, preferably under heating to reflux. Thus, compound (v) can be produced.
Examples of the leaving group include halogen and —OSO ₂ (C _t F _{2t + 1} ) (wherein t is an integer of 1 to 4). As the halogen, chlorine, iodine and bromine are preferable. As the —OSO ₂ (C _t F _{2t + 1} ) group, —OTf group (trifluoromethanesulfonic acid ester) is preferable.
(Third step)
Compound (v) may be used in a solvent such as NMP, DMF, DMSO or without solvent, under microwave irradiation at 150 ° C. to 250 ° C., preferably at 200 ° C. to 230 ° C., or in a solvent such as t-butanol, acetic acid, etc. By reacting with the compound (vii) at 60 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C. in the presence of an acid, the compound represented by the general formula (II ′) can be produced.
By using optically active isocyanate (ii), an optically active compound represented by general formula (II ′) can be synthesized.

[Method B]

(First step)
(In the formula, Hal ² and Hal ³ are halogen, and other symbols are as defined above.)
Compound (vii) is reacted with an alkylating agent (viii) such as methyl iodide or ethyl iodide in a solvent such as methanol or ethanol at −40 ° C. to 30 ° C., preferably under ice cooling, to give compound ( ix) can be manufactured.
(Second step)
Compound (ix) is dissolved in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane in the presence of a base such as triethylamine, N, N-diisopropylethylamine, at −20 ° C. to 30 ° C., preferably under ice-cooling. Compound (x) can be produced by reacting with an isocyanate such as (chlorocarbonyl) isocyanate.
(Third step)
Compound (xi) is reacted with compound (vi) under heating and reflux in the presence of an acid such as acetic acid, formic acid or methanesulfonic acid in a solvent such as t-butanol, isopropanol, ethanol or acetonitrile. Can be manufactured.
(4th process)
By reacting compound (xi) with compound (xii) in a solvent such as DMF or NMP in the presence of a base such as potassium t-butoxide or sodium hydride at 40 ° C. to 100 ° C., preferably 50 ° C. to 70 ° C. A compound represented by the general formula (II ″) can be produced.
By using the optically active compound (xii), an optically active compound represented by the general formula (II ″) can be synthesized.

[Method C]

(Wherein Pg ¹ is a suitable protecting group for a hydroxyl group, s is an integer of 1 to 4, and the other symbols are as defined above.)
(First step)
To a mixture of a compound (x) obtained by Method B and an alcohol (xii) in which one hydroxyl group is protected, such as 2- (tetrahydro-2H-pyran-2-yloxy) ethanol, in a solvent such as THF or dioxane, Compound (xiii) can be produced by reacting triphenylphosphine or the like with diethyl azodicarboxylate or the like.
(Second step)
Compound (xiv) can be produced by reacting compound (xiii) with compound (vi) in the presence of an acid such as formic acid or acetic acid under heating and reflux.

[Method D]

Wherein Pg ² is a suitable protecting group for an amino group and R ¹¹ is substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl Or substituted or unsubstituted heteroaryl, R ¹² is hydroxy or halogen, t is an integer of 1 to 4, and other symbols are as defined above.
(First step)
Compound (xvi) can be produced by reacting compound (xv) obtained by Method A or Method B with an acid such as hydrochloric acid-dioxane solution, hydrochloric acid-methanol, hydrochloric acid-ethyl acetate solution, or trifluoroacetic acid. .
(Second step)
Compound (xviii) is produced by reacting compound (xvi) with an acid halide (xvii) (R ¹² is halogen) in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as THF or dioxane. Can do. If necessary, dimethylaminopyridine or the like may be added.
Alternatively, compound (xvi) and carboxylic acid (xvii, R ¹² is hydroxy) such as 1-hydroxybenzotriazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc. in a solvent such as THF and DMF Compound (xviii) can be produced by reacting in the presence of a condensing agent and a base such as triethylamine or diisopropylpropylamine.

[E method]

Wherein R ¹³ is substituted or unsubstituted alkyl, R ^20a and R ^20b are hydrogen, halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted Alternatively, unsubstituted imino, substituted or unsubstituted guanidyl, or R ^20a and R ^{20b taken} together are oxo, or thioxo, u is an integer of 1 to 4, and other symbols are as defined above.
(First step)
Compound (x) obtained by Method B is present in a solvent such as DMF, NMP, or THF in the presence of a base such as DBU, potassium t-butoxide, or sodium hydride at 0 ° C. to 80 ° C., preferably 30 ° C. to 50 ° C. The compound (xx) can be produced by reacting with the compound (xix).
(Second step)
By reacting compound (xx) with compound (vi) in a solvent such as t-butanol, isopropanol, ethanol, acetonitrile, etc. in the presence of an acid such as formic acid, acetic acid, methanesulfonic acid and the like under heating and reflux. Compound (xxi) can be produced.
(Third step)
Compound (xxi) is reacted with a lithium hydroxide aqueous solution, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or the like in a solvent such as methanol or ethanol, or in a mixed solvent of these and a solvent such as THF or dioxane. xxii) can be produced.

[F method]

Wherein R ¹⁴ is substituted or unsubstituted alkyl, R ¹⁵ and R ¹⁶ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, (Substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, u is an integer of 1 to 4, and other symbols are as defined above.)
(First step)
Compound (xxiii) obtained by Method A or Method B in a solvent such as methanol or ethanol or in a mixed solvent of these and a solvent such as dioxane or THF, an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution Compound (xxiv) can be produced by reacting with the above.
(Second step)
Compound (xxiv) in a solvent such as THF, DMF, NMP, 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, a condensing agent such as HATU, PyBOP, and triethylamine, Compound (xxvi) can be produced by reacting with compound (xxv) in the presence of a base such as diisipropylethylamine.

[L method]

(The symbols in the formula are as defined above.)
(First step)
A compound (ixl) is produced by reacting a compound (x) obtained by Method B with an alcohol (xxxviii) and a solvent such as THF or dioxane with triphenylphosphine or the like and diethyl azodicarboxylate. be able to.
(Second step)
Compound (II) can be produced by reacting compound (ixl) with compound (vi) in the presence of an acid such as formic acid or acetic acid under heating and reflux.
By using optically active alcohol (xxxviii), optically active compound (II) can be synthesized.
Alcohol (xxxviii) used as an intermediate can be produced according to a commercially available product or a method described in the literature listed below.
Tetrahedron (1993), 49 (11), 2325-44.
Chemical Communications (2008), (47), 6408-6410.
Tetrahedron (1990), 46 (24), 8207-28.
Synlett (1994), (3), 199-200.
Bulletin of the Chemical Society of Japan (1994), 67 (8), 2244-7
Canadian Journal of Chemistry (1996), 74, 1731-1737
Chemistry--A European Journal (2010), 16 (2), 577-587
Bioorganic & Medicinal Chemistry Letters (2009), 19 (21), 6196-6199.
Chemische Berichte (1985), 118 (10), 3966-79.
Tetrahedron: Asymmetry (1992), 3 (4), 515-16.
Organic Letters (1999), 1 (6), 957-959.
Chimia (1986), 40 (5), 172-3.

[M method]

(Wherein R ²¹ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, etc., R ²² is bromo, or iodine, and R ²³ and R ²⁴ are each independently substituted or unsubstituted. Alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or (Unsubstituted heteroaryl, other symbols are as defined above.)
(First step)
The compound (xxxvii) obtained by the methods A to F or L is mixed with the compound (xxxviii) at 50 ° C. to heating under reflux in a solvent such as THF or dioxane in the presence of a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution or the like. The compound (xxxix) can be produced by reacting at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C., preferably under heating under reflux or under microwave irradiation.

(Second step)
A compound (xxxix) is dissolved in an alcohol solvent such as methanol or ethanol, and a hydrogenation reactor (for example, H-Cube (10% Pt-C, H2 = 1 atm)) or palladium-carbon, platinum oxide, chlorotris (tri) Compound (xl) can be obtained by catalytic reduction using a metal catalyst such as phenylphosphine) rhodium (I).

[N method]

(The symbols in the formula are as defined above.)
(First step)
The compound (xli) obtained by the methods A to F or L is heated with a compound (xxxviii) at 50 ° C. to heating under reflux in a solvent such as THF or dioxane in the presence of a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution or the like. The compound (xlii) can be produced by reacting at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C., preferably under heating under reflux or under microwave irradiation.

(Second step)
A compound (xlii) is dissolved in an alcohol solvent such as methanol or ethanol, and a hydrogenation reactor (eg, H-Cube (10% Pt-C, H2 = 1 atm)) or palladium-carbon, platinum oxide, chlorotris (tri- The compound (xliii) can be obtained by catalytic reduction using a metal catalyst such as phenylphosphine) rhodium (I).

[O method]

(Wherein R ²⁵ is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy, R ²⁶ is bromo or iodine, and other symbols are as defined above.)
(First step)
Compound (xlvi) can be obtained by performing compound (xlib) in the presence of a Lewis acid, trifluoroacetic acid or the like in the absence of a solvent or in a suitable solvent at 0 ° C. to heating under reflux.

(Second step)
Compound (xlvi) is mixed with compound (xlvii) in a solvent such as THF, dioxane and the like in the presence of a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution, etc. at 50 ° C. to heating under reflux, preferably under heating under reflux, or Compound (xlviii) can be produced by reaction at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C. under microwave irradiation.

[P method]

(Wherein the symbols are as defined above.)
Compound (xli) or a hydrochloride or bromate thereof in a solvent such as THF, dioxane or methanol in the presence or absence of a Lewis acid or acid such as titanium tetrachloride, cobalt (II) chloride or methanesulfonic acid Compound (xli) by reacting with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, diborane, lithium borohydride, sodium borohydride and the like at −20 ° C. to heating under reflux, preferably at room temperature Can be manufactured.

As one embodiment of the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof,
R ^c is substituted with 3 to 5 hydroxy groups, and substituent group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, and thioxo) C3-C6 alkyl optionally substituted with C3-C6 alkenyl substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; Or substituted with 3-5 hydroxy In addition, the compound or a pharmaceutically acceptable salt thereof according to the above (1), which is C3-C6 alkynyl optionally substituted with one or more substituents selected from substituent group α .

Preferred embodiments of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
Formula (I):

Formula (I ′):

Formula (I ″):

In either

1) R ^c is

(Wherein Alk is alkyl)
And a group represented by

Or a pharmaceutically acceptable salt thereof.

2) R ^c is

(Wherein Alk is alkyl)
And a group represented by

Or a pharmaceutically acceptable salt thereof.

3) R ^c is

(Wherein Alk is alkyl)
Or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazine, pyridazine, thiazole, isothiazole, oxazole or isoxazole.

4) R ^c is

(Wherein Alk is alkyl)
A group represented by:

Is;
A compound or a pharmaceutically acceptable salt thereof, wherein s ′ is an integer of 1 to 3 and at least one R ^{9 ′} is halogen or haloalkyl.
5) R ^c is

(Wherein Alk is alkyl)
And a group represented by

Is;
A compound or a pharmaceutically acceptable salt thereof, wherein s ′ is an integer of 1 to 3 and at least one R 9 ′ is halogen or haloalkyl.

6) R ^c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group;
Ring B is pyridine or thiazole;
A compound or a pharmaceutically acceptable salt thereof, wherein s ′ is an integer of 1 to 3; and at least one R ^{9 ′} is carboxy or alkyloxycarbonyl.

7) R ^c is substituted or unsubstituted alkyl;
Ring B is pyridine;
s ′ is an integer from 1 to 3; and at least one R ^{9 ′} is aryl, heteroaryl, aryloxy or heteroaryloxy, which are substituted with at least one carboxy, alkyloxycarbonyl or cyano Or a pharmaceutically acceptable salt thereof, which may further have other substituents.

8) R ^c is alkyl; and

(Where s '' is an integer from 0 to 2)
Or a pharmaceutically acceptable salt thereof.
9) R ^c is alkyl; in formula (I ′), s is an integer from 1 to 3;

(Where s '' is an integer from 0 to 2)
Or a pharmaceutically acceptable salt thereof.

10) R ^c is

(Wherein Alk is alkyl)
A group represented by
R ² is substituted or unsubstituted cycloalkyl,
The other symbols have the same meanings as in (1) above, the compound according to (1) above or a pharmaceutically acceptable salt thereof.
(However, in the above 1) to 10), substituents not particularly defined are as defined in (1) above)

In the compound represented by formula (I), formula (I ′) or formula (I ″),
R ^c is

As the absolute configuration of R ^c , the group represented by

Is mentioned.

As the absolute configuration of R ^c , the group represented by

Is mentioned.

The compounds of formula (I), formula (I ′), formula (I ″), formula (II) etc. are not limited to specific isomers, but all possible isomers (eg keto Enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof. For example, the compound in which —X— is —NH— in the formula (I) includes the following tautomers.

In addition, one or more hydrogen, carbon or other atoms of a compound of formula (I), formula (I ′), formula (I ″), formula (II), etc. are hydrogen, carbon or other atom isotopes. Can be replaced by the body. Compounds of formula (I), formula (I ′), formula (I ″), formula (II) and the like are represented by formula (I), formula (I ′), formula (I ″), formula (II) and the like. Includes all radiolabeled forms of the compounds. Such “radiolabeled”, “radiolabeled” and the like of compounds of formula (I), formula (I ′), formula (I ″), formula (II) and the like are each included in the present invention. It is useful as a research and / or diagnostic tool in metabolic pharmacokinetic studies and binding assays. It is also useful as a pharmaceutical product.

One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), formula (I ′), formula (I ″), formula (II) etc. are hydrogen, carbon and / or respectively. It can be substituted with isotopes of other atoms. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II) and the like includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and all radiolabeled compounds of the compounds represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II), etc. Is included. A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

Radiolabeled compounds of the compounds represented by formula (I), formula (I ′), formula (I ″), formula (II) and the like can be prepared by methods well known in the art. For example, a tritium-labeled compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II), or the like can be converted into a compound of the formula (I ), Formula (I ′), formula (I ″), formula (II) and the like, can be prepared by introducing tritium into the specific compound. This method can be used in formula (I), formula (I ′), formula (I ″), formula (II), etc. in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. The compounds shown include reacting appropriately halogen substituted precursors with tritium gas. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ¹⁴ C-labeled compounds can be prepared by using raw materials having ¹⁴ C carbon.

Examples of the pharmaceutically acceptable salt of the compound represented by formula (I), formula (I ′), formula (I ″), formula (II) and the like include, for example, a compound represented by formula (I), an alkali Metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexyl) Amine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphorous) Acids, hydroiodic acid, etc.) and organic acids (eg formic acid, acetic acid, propionic acid) Trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfone Salts with acid, ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
The compound represented by the formula (I), formula (I ′), formula (I ″), formula (II) or the like of the present invention or a pharmaceutically acceptable salt thereof is a solvate (for example, hydrate etc. ) And / or crystalline polymorphs, and the present invention also encompasses such various solvates and crystalline polymorphs. The “solvate” is an arbitrary number of solvent molecules (for example, water molecules) with respect to the compounds represented by formula (I), formula (I ′), formula (I ″), formula (II), etc. And may be coordinated. The compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II) or the like or a pharmaceutically acceptable salt thereof is left in the atmosphere to absorb moisture, Adsorbed water may adhere or a hydrate may be formed. Further, by recrystallizing the compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II) or the like or a pharmaceutically acceptable salt thereof, the crystal polymorphs thereof are obtained. May form.
The compound represented by the formula (I), formula (I ′), formula (I ″), formula (II) or the like of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug. The invention also encompasses such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is represented by the formula (I), formula (I ′), formula (I ″), formula (II), etc. after enzymatically oxidizing, reducing, hydrolyzing and the like under physiological conditions in vivo. Including compounds converted into compounds, compounds that are hydrolyzed by gastric acid, etc., and converted into compounds represented by formula (I), formula (I ′), formula (I ″), formula (II), etc. . Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
When the compound represented by formula (I), formula (I ′), formula (I ″), formula (II) or the like or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group Acyloxy derivatives and sulfonyloxy produced by reacting with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride and a mixed anhydride, or by reacting with a condensing agent. Examples are prodrugs such as derivatives. For example, CH ₃ COO—, C ₂ H ₅ COO—, tert-BuCOO—, C ₁₅ H ₃₁ COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH ₂ CH ₂ COO—, CH ₃ CH (NH ₂ ) COO—, CH ₂ N (CH ₃ ) ₂ COO—, CH ₃ SO ₃ —, CH ₃ CH ₂ SO ₃ —, CF ₃ SO ₃ —, CH ₂ FSO ₃ —, CF ₃ CH ₂ SO ₃ —, p -CH ₃ O-PhSO _3- , PhSO _3- , p-CH ₃ PhSO ₃ -can be mentioned.

The compounds represented by the above general formula (I), formula (I ′), formula (I ″), formula (II) and the like have an antagonistic action on the P2X ₃ and / or P2X _2/3 receptor, It is useful as a therapeutic agent for diseases involving P2X ₃ and / or P2X _2/3 . P2X ₃ and / or P2X _2/3 receptor is believed to be involved in pain, urinary system diseases, and respiratory diseases (Nature 407, 26, 1011-1015 ( 2000), Nature, Vol.407, No.26 , 1015-1017 (2000), Non-Patent Document 1, Non-Patent Document 2, Non-Patent Documents 9 to 11, etc.), and is useful as a pharmaceutical composition having an analgesic action or an urination disorder improving action.
For example, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, headache, migraine, oral and facial pain, toothache, glossodynia, pain associated with temporomandibular disorders, trigeminal neuralgia, shoulder pain, pain associated with disc herniation, Pain associated with degenerative cervical spondylosis, pain associated with spinal stenosis, pain associated with thoracic outlet syndrome, pain associated with brachial plexus withdrawal syndrome, shoulder-hand syndrome, pain associated with whiplash, chest pain, abdominal pain, colic, cholelithiasis Pain associated with pancreatitis, pain associated with urolithiasis, pain associated with irritable bowel syndrome, low back pain, sciatica, pain associated with fracture, pain associated with osteoporosis, joint pain, pain associated with gout, Pain associated with cauda equina syndrome, pain associated with ankylosing spinal inflammation, muscle pain, painful spasm, myofascial pain syndrome, fibromyalgia syndrome, complex local pain syndrome, pain associated with obstructive arteriosclerosis, Buerger disease With pain, Raynaud Pain associated with elephant, pain associated with shingles, causalgia, pain associated with strangulation neuropathy, pain associated with carpal tunnel syndrome, pain associated with diabetes, pain associated with Guillain-Barre syndrome, pain associated with leprosy, associated with drug therapy Pain, pain associated with radiation therapy, pain associated with spinal cord injury, pain associated with spinal cord injury, pain associated with stroke, thalamic pain, afferent blockade pain, sympathetic nerve-dependent pain, pain associated with ABC syndrome, multiple sclerosis Pain, skin pain, cancer pain, postoperative pain, pain associated with trauma, pain associated with gangrene, pain associated with physical expression disorder, pain associated with somatization, pain associated with depression, Parkinson's disease Pain associated with pain, knee joint pain, pain associated with arthritis, menstrual pain, intermediate pain, labor pain and other neuropathic pain, inflammatory pain, nociceptive pain, psychogenic pain and / or pain associated with endometriosis etc;
Overactive bladder, urge incontinence, stress urinary incontinence, reflex urinary incontinence, urgency, neurogenic bladder, unstable bladder, urethritis, urinary tract infection, interstitial cystitis, cystitis, bladder Cancer, urinary tract disorder associated with chemotherapy, urinary tract disorder associated with brain disorder such as stroke, urination disorder and / or pain in prostatic hypertrophy and / or prostatitis, etc .;
And chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, chronic cough, etc .;
It is effective in the treatment, alleviation and / or prevention of symptoms.

The “pharmaceutical composition having an effect of improving urination disorder” includes a pharmaceutical composition used for the treatment, prevention and / or improvement of the above-mentioned urination disorder.

Compound or pharmaceutical composition of the invention of the present invention, ATP receptor, especially high affinity for P2X ₃ receptor, has high selectivity for subtype selectivity and other receptors, side effects (e.g., motion It can be a medicine with reduced functions). In addition, the compound included in the present invention or the pharmaceutical composition included in the present invention has high P2X ₃ receptor inhibitory activity in the presence of RSA, high metabolic stability, high oral absorption, high solubility, It also has advantages such as good bioavailability, low clearance, long half-life, high drug sustainability, low liver enzyme inhibitory activity, high protein non-binding rate, and / or high safety.

When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods. For parenteral administration, any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.

Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.

The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. In addition, each abbreviation has the meaning shown below in this specification.
Me: methyl TMS: tetramethylsilane DMSO: dimethyl sulfoxide DMA: dimethylacetamide DMF: dimethylformamide THF: tetrahydrofuran DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene NMP: N-methyl-2- Pyrrolidone HOAt: 1-hydroxy-7-azabenzotriazole HATU: 2- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium PyBOP hexafluorophosphate: benzotriazole-1 -Yl-oxytrispyrrolidinophosphonium hexafluorophosphate rt: room temperature M: mol / L

(1) Preparation of 3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione

DBU (63.3 mL, 420 mmol) was added to a mixture of 1-amidinopyrazole hydrochloride (58.6 g, 400 mmol), ethyl isocyanate (33.2 mL, 420 mmol) and DMA (240 mL) at −10 ° C. over 15 minutes. The solution was added dropwise and stirred for 30 minutes under ice cooling. 1,1′-Carbonyldiimidazole (97.2 g, 600 mmol) was added to the reaction solution under ice cooling, and then DBU (93 mL, 620 mmol) was added at −5 ° C. over 30 minutes. The reaction solution was stirred for 1 hour under ice-cooling, and further stirred at room temperature for 1 hour. To the reaction solution, 2 mol / L hydrochloric acid (1.16 L) was added at 20 ° C. over 1 hour. The resulting powder was collected by filtration, and 3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (73.0 g, yield: 88%) Obtained as a brown powder.
1H-NMR (δ ppm TMS / CDCl3): 1.30 (6H, t, J = 7.0 Hz), 4.02 (2H, q, J = 7.0 Hz), 6.59 (1H, m), 7.34 (1H, m), 8.48 (1H, m), 9.79 (1H, brs).

(2) Preparation of 1- (4-chlorobenzyl) -3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione

3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (89 g, 480 mmol), 4-chlorobenzyl bromide (108 g, 528 mmol) Diisopropylethylamine (92 mL, 528 mmol) was added dropwise to a mixture of PEG and DMA (400 mL) at room temperature over 10 minutes, and the mixture was stirred at 60 ° C. for 2 hours. Water (800 mL) was added dropwise to the reaction solution under ice-cooling over 40 minutes, and hexane (200 mL) was added. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (156 g Yield: 97.6%) as a slightly brown powder.
1H-NMR (δ ppm TMS / CDCl ₃ ): 1.30 (3H, t, J = 7.1 Hz), 4.04 (2H, q, J = 7.1 Hz), 5.86 (2H, s), 6.48 (1H, m), 7.02 (2H, d, J = 8.6 Hz), 7.20-7.25 (2H, m), 7.84 (1H, m), 8.33 (1H, m).

(3) 1- (4-Chlorobenzyl) -3-ethyl 6- [4- (6-hydroxymethyl-3-pyridazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I- 248)

1- (4-chlorobenzyl) -2-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (1.33 g, 4.00 mmol), 4- ( A mixture of 6-methoxycarbonyl-3-pyridazyloxy) aniline (1.01 g, 4.12 mmol) and t-butanol (15 mL) was stirred with heating under reflux for 2 hours. 50% ethyl acetate / hexane (30 mL) was added to the reaction mixture, and the resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3-ethyl-6- [4- (6-methoxycarbonyl-3 -Pyridazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.8 g, yield: 88%) was obtained as a light brown powder.
1- (4-Chlorobenzyl) -3-ethyl-6- [4- (6-methoxycarbonyl-3-pyridazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.9 g, 3.73 mmol) was dissolved in a mixture of THF (20 mL) and methanol (20 mL). Sodium borohydride (0.42 g, 11.2 mmol) was added in several portions under ice cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, wash the residue with ethyl acetate, 1- (4-chlorobenzyl) -3-ethyl 6- [4- (6-hydroxymethyl-3-pyridazyloxy) phenylimino] -1,3,5-triazinan -2,4-dione (I-248, 1.57 g, yield: 87%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (3H, t, J = 7.1Hz), 3.77 (2H, q, J = 6.6 Hz), 4.68 (2H, d, J = 5.6 Hz), 5.12 (0.5H, s), 5.29 (1.5H, s), 5.60 (1H, t, J = 5.8 Hz), 6.83 (0.3H, s), 7.17-7.24 (2H, m), 7.33-7.50 (7.0H , m), 7.79 (1H, d, J = 9.12 Hz), 9.33 (0.6H, s).

(1) Preparation of 3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione

DBU (31.7 mL, 210 mmol) was added to a mixture of 1-amidinopyrazole hydrochloride (29.3 g, 200 mmol), propyl isocyanate (19.68 mL, 210 mmol) and DMA (120 mL) at −10 ° C. over 5 minutes. The solution was added dropwise and stirred for 30 minutes under ice cooling. 1,1′-Carbonyldiimidazole (48.6 g, 300 mmol) was added to the reaction solution under ice cooling, and then DBU (46.7 mL, 310 mmol) was added at −5 ° C. over 30 minutes. The reaction solution was stirred for 1 hour under ice-cooling, and further stirred at room temperature for 1 hour. To the reaction solution, 2 mol / L hydrochloric acid (1580 mL) was added at 20 ° C. over 35 minutes. The resulting powder was collected by filtration to give 3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (43.18 g, yield: 98%). Obtained as a brown powder.
1H-NMR (δ ppm TMS / CDCl3): 1.07 (3H, t, J = 7.6 Hz), 1.76 (2H, sext, J = 7.6 Hz), 3.92 (2H, m), 5.13 (1H, brs), 6.59 (1H, m), 7.84 (1H, t, J = 0.8 Hz), 8.50 (1H, t, J = 0.7 Hz).

(2) trans-6- [4- (5-Cyano-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) methyl-3-propyl-1,3,5-triazinan-2,4- Preparation of dione (I-298)

3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (0.44 g, 2 mmol), trans- (4-methylcyclohexyl) methanol (0.31 g , 2.4 mmol), di-2-methoxyethyl azodicarboxylate (0.56, 2.4 mmol) was added to a mixture of triphenylphosphine (0.63 g, 2.4 mmol) and THF (6 mL) under ice-cooling. For 2 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (200 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to obtain trans-1- (4-methylcyclohexyl) methyl-3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione as a crude product Obtained.
4- (5-Cyano-2-pyridyloxy) aniline (0.21 g, 1 mmol) and t-butanol (6 mL) were added to the obtained crude product, and the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate / hexane), trans-6- [4- (5-cyano-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl). ) Methyl-3-propyl-1,3,5-triazinan-2,4-dione (I-298, 0,41 g, yield: 86%) was obtained as a white amorphous.
1H-NMR (δ ppm TMS / CDCl3): 0.87 (3H, t, J = 6.5 Hz), 0.95 (3H, t, J = 7.4 Hz), 1.07-1.96 (12H, m), 3.77-3.81 (2H, m), 3.93 (2H, d, J = 7.2 Hz), 6.85-7.15 (5H, m), 7.70 (1H, s), 7.93 (1H, dd, J = 6.4, 2.4 Hz), 8.43 (1H, m ).

trans-6- [4- (5-hydroxycarbonyl-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) methyl-3-propyl-1,3,5-triazinan-2,4-dione ( Preparation of I-318)

trans-6- [4- (5-Cyano-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) methyl-3-propyl-1,3,5-triazinan-2,4-dione (0.38 g, 0.80 mmol) in DMSO (4 mL) was added 1 mol / L sodium hydroxide (4 mL), and the mixture was stirred at 60 ° C. for 4.5 hours. The reaction mixture was poured into water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Concentrate under reduced pressure, add ethyl acetate and hexane to the residue, filter the resulting powder, and trans-6- [4- (5-hydroxycarbonyl-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) ) Methyl-3-propyl-1,3,5-triazinan-2,4-dione (I-318, 0.14 g, yield: 34%) was obtained as a pale green powder.
1H-NMR (δ ppm TMS / d6 DMSO): 0.80-1.80 (18H, m), 3.67 (2H, t, J = 6.9 Hz), 3.85-3.95 (2H, m), 7.14 (1H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 7.2 Hz), 8.30 (1H, dd, J = 2.1, 8.7 Hz), 8.09 (1H, d, J = 1.8 Hz), 9.19 (1H, brs).

(1) Preparation of 3,5-dioxahexylamine

To a mixture of benzyl 2-hydroxyethyl carbamate (25.3 g, 130 mmol), diisopropylethylamine (27.2 ml, 156 mmol) and methylene chloride (200 mL), chloromethyl methyl ether (10.8 mL, 143 mmol) is cooled with ice. The solution was added dropwise over 10 minutes and stirred at room temperature overnight. Water (225 mL) was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane) to give benzyl 3,5-dioxahexyl carbamate (28.2 g, yield: 92%) as a colorless oil.
1H-NMR (δ ppm TMS / DMSO-d6): 3.17 (2H, q, J = 5.9Hz), 3.23 (3H, s), 3.45 (1H, dd, J = 5.8Hz, J = 6.1Hz), 4.54 (2H, s), 5.01 (2H, s), 7.20-7.40 (5H, m).
To a solution of benzyl 3,5-dioxahexyl carbamate (9.75 g, 40.7 mmol) in ethanol (100 mL) was added 10% palladium carbon (0.87 g), and the mixture was stirred under a hydrogen atmosphere for 12 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 3,5-dioxahexylamine (3.87 g, yield: 90%) as a colorless oil.
1H-NMR (δ ppm TMS / DMSO-d6): 2.66 (2H, dd, J = 7.6Hz, J = 8.0Hz), 2.72 (2H, brs), 3.23 (3H, s), 3.40 (2H, dd, J = 6.4Hz, J = 8.0Hz), 4.54 (2H, s).

(2) 1- (4-Chlorobenzyl) -3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione Preparation of

To a solution of 1,1'-carbonyldiimidazole (6.79 g, 41.9 mol) in DMA (20 mL) was added 3,5-dioxahexylamine (4 g, 38 mol) at -10 ° C, and at 0 ° C for 2 hours. Stir. 1-Amidinopyrazole hydrochloride (4.65 g, 31.7 mmol) was added to the reaction solution, and then DBU (4.87 ml, 32.3 mmol) was added at −10 ° C. over 25 minutes. After stirring at room temperature for 1 hour, the mixture was stirred at 45 ° C. for 1.5 hours. 1,1′-carbonyldiimidazole (7.71 g, 47.6 mmol) was added to the reaction solution, and then DBU (7.17 ml, 47.6 mmol) was added at 0 ° C. over 1 hour. After stirring at room temperature for 1 hour, the mixture was stirred at 45 ° C. for 4 hours. To the reaction solution, 2 mol / L hydrochloric acid (200 ml) was added dropwise under ice cooling. The resulting powder was collected by filtration, and 3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (6.13 g, Yield: 72%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 3.20 (3H, s), 3.63 (2H, t, J = 6.3 Hz), 3.95 (2H, dd, J = 6.1 Hz, J = 6.4 Hz), 4.52 (2H, s), 6.70 (1H, m), 8.02 (1H, m), 8.53 (1H, m).
3- (3,5-Dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (5.49 g, 20.5 mmol), 4-chlorobenzyl To a mixture of bromide (4.64 g, 22.6 mmol) and DMA (15 mL), diisopropylethylamine (4 mL, 22.6 mmol) was added dropwise at room temperature over 10 minutes. After stirring at 55 ° C. for 1 hour, water (225 mL) was added under ice cooling. Extraction was performed with ethyl acetate (200 mL × 2), and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, hexane / ethyl acetate was added. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H , 3H) -dione (6.58 g, yield: 82%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 3.20 (3H, s), 3.66 (2H, dd, J = 6.1 Hz, J = 6.3 Hz), 4.00 (2H, dd, J = 5.9 Hz, J = 6.3 Hz), 4.53 (2H, s), 5.44 (2H, s), 6.62 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.5 Hz), 7.93 (1H, m), 8.44 (1H, m).

(3) 1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2, 4-dione (I-204) and
1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-hydroxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione Preparation of (I-241)

1- (4-Chlorobenzyl) -3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (0.8 g , 2.04 mmol), 4- (5-methoxycarbonyl-2-pyrazyloxy) aniline (0.53 g, 2.14 mmol), and t-butanol (16 mL) were stirred with heating under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure to give 1- (4-chlorobenzyl) -3- (3,5-dioxahexyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3 , 5-Triazinan-2,4-dione (1.39 g) was obtained as a crude product.
Water (0.38 mL) and trifluoroacetic acid (8 mL) were added to the obtained crude product, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, methanol (4 mL) and pyridine (4 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, n-hexane and chloroform were added, and the resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2 -Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-204, 1.04 g, yield: 97%) was obtained as a light brown powder.
1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione To a THF (2 mL) solution of (0.25 g, 0.48 mmol) was added 1 mol / L sodium hydroxide (1 mL, 1 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-hydroxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5 -Triazinan-2,4-dione (I-241, 0.21 g, yield: 86%) was obtained as a light brown powder.
1H-NMR (δ ppm TMS / d6 DMSO): 3.83 (H, t, J = 6.0 Hz), 4.77 (1H, brs), 5.26 (2H, bds), 7.25 (2H, d, J = 7.5 Hz), 7.35-7.50 (6H, m), 8.62 (1H, s), 8.77 (1H, s), 9.37 (1H, bds)

1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione ( Preparation of I-205)

1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione To a THF (2 mL) solution of (0.25 g, 0.48 mmol) was added 28% aqueous ammonia solution (4 mL), and the mixture was stirred at room temperature for 2.5 hours. The powder produced in the reaction solution was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1, 3,5-Triazinan-2,4-dione (I-205, 0.15 g, yield: 60%) was obtained as a light brown powder.
1H-NMR (δ ppm TMS / d6 DMSO): 3.77 (H, t, J = 6.6 Hz), 4.65 (1H, brs), 5.16 (2H, s), 7.03 (2H, d, J = 9.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.34-7.44 (4H, m), 7.68 (1H, s), 8.07 (1H, s), 8.48 (1H, s), 8.72 (1H, m).

(1) Preparation of 1- (4-chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione

To a mixture of S-ethylthiourea hydrobromide (1.85 g, 10 mmol) and DMF (9.3 mL), t-butyl isocyanate (1.2 mL, 10.5 mmol) and DBU (1.9 mL, 12.8 mmol) were ice-cooled. Added below and stirred for 6 hours. To the reaction solution, 1,1′-carbonyldiimidazole (1.95 g, 12 mmol) and DBU (1.9 mL, 12.8 mmol) were added under ice cooling, and the mixture was stirred for 2 hours. 2 mol / L hydrochloric acid (80 mL) was added over 50 minutes under ice cooling, and the resulting powder was collected by filtration. The powder was dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 6- (ethylthio) -3-t-butyl-1,3,5-triazine-2,4 (1H, 3H) -dione (1.15 g, yield: 50%) as a light brown powder. It was.
1H-NMR (δ ppm TMS / DMSO-d6): 1.27 (3H, t, J = 7.3 Hz), 1.55 (9H, s), 3.03 (2H, q, J = 7.3), 12.30 (1H, brs)
6- (Ethylthio) -3-t-butyl-1,3,5-triazine-2,4 (1H, 3H) -dione (22.93 g, 100 mmol), 4-chlorobenzyl bromide (22.60 g, 110 mmol) To a mixture of acetonitrile and acetonitrile (200 mL), potassium carbonate (17.97 g, 130 mmol) was added, and the mixture was stirred for 3 hours under heating to reflux. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-t-butyl-1- (4-chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H 39.9 g of crude) -dione was obtained as a light brown oil.
Trifluoroacetic acid (100 mL) was added to the obtained crude product under ice cooling, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and 1- (4-chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (29.03 g, yield: 97%) Was obtained as a fine brown powder.
1H-NMR (δ ppm TMS / d6-DMSO): 1.25 (3H, t, J = 7.3 Hz), 3.08 (2H, q, J = 7.3 Hz), 5.02 (2H, s), 7.30-7.33 (2H, m), 7.39-7.42 (2H, m), 11.61 (1H, s).

(2) 1- (4-Chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4- Preparation of dione

1- (4-Chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (2.98 g, 10 mmol), methyl bromoacetate (1.04 mL, 11 mmol) ) And DMF (30 mL) were added potassium carbonate (1.80 g, 13 mmol), and the mixture was stirred at room temperature for 4 hours. Water (250 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (250 mL) and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and ethyl acetate and hexane were added to the residue. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione ( 3.26 g, yield: 88%) was obtained as a colorless powder.
1H-NMR (δ ppm TMS / CDCl ₃ ): 1.37 (3H, t, J = 7.2 Hz), 3.23 (2H, q, J = 7.2 Hz), 3.78 (3H, s), 4.68 (2H, s), 5.11 (2H, s), 7.27-7.35 (4H, m).
1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (1.0 g, 2.70 mmol), 4 A mixture of-(5-carbamoyl-2-pyrazyloxy) aniline (0.75 g, 3.24 mmol), t-butanol (5.0 mL) and acetic acid (2.3 mL) was stirred with heating under reflux for 7 hours. 50% ethyl acetate / hexane (10 mL) was added to the reaction mixture, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-carbamoyl). -2-Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.35 g, yield: 93%) was obtained as a light brown powder.
1H-NMR (δ ppm TMS / d6-DMSO): 3.68 (3H, s), 4.52 (2H, s), 5.29 (2H, s), 7.25 (2H, m, J = 8.1 Hz), 7.32-7.50 ( 6H, m), 7.71 (1H, s), 8.09 (1H, m), 8.56 (1H, s), 8.73 (1H, m).

(3) 1- (4-Chlorobenzyl) -3- (hydroxylcarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4- Preparation of dione (I-206)

1- (4-Chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.0 g, 1.86 mmol) in pyridine (10 mL) was added trifluoroacetic anhydride (1.31 mL, 9.30 mmol) under ice cooling. The reaction solution was stirred for 1.5 hours under ice-cooling, and then poured into a 5% aqueous citric acid solution (100 mL). The resulting powder was collected by filtration and purified by silica gel column chromatography (ethyl acetate / hexane) to give 1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-cyano- 2-Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (0.93 g, yield: 96%) was obtained as a pale yellow amorphous.
1- (4-Chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (0.9 g, 1.73 mmol) in THF (14 mL) was added 1 mol / L sodium hydroxide (3.5 mL, 3.5 mmol) under ice cooling, and the mixture was stirred for 6 hours. The reaction solution was poured into ice water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chloroform / methanol), and 1- (4-chlorobenzyl) -3- (hydroxylcarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) Phenylimino] -1,3,5-triazinan-2,4-dione (I-206, 97 mg, yield: 11%) was obtained as a light brown amorphous.
1H-NMR (δ ppm TMS / d6-DMSO): 4.52 (2H, s), 5.30 (2H, brs), 7.40-7.50 (8H, m), 8.75 (1H, s), 8.82 (1H, s), 9.56 (1H, brs), 13.05 (1H, brs).

1- (4-Chlorobenzyl) -3- (carbamoylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I- 254)

1- (4-Chlorobenzyl) -3- (hydroxycarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (304 mg, 0.6 mmol) was dissolved in DMF (3 mL). The reaction mixture was ammonium chloride (39 mg, 7.20 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 7.2 mmol), 4-dimethylaminopyridine (7.3 mg, 0.06 mmol), 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide (138 mg, 0.72 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, ethyl acetate was added to the residue, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (carbamoylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) Phenylimino] -1,3,5-triazinan-2,4-dione (I-254, 0.21 g, yield: 69%) was obtained as a pale yellow powder.
1H-NMR (δ ppm TMS / DMSO-d6): 4.28 (2Hm s), 5.30 (2H, s), 6.85-7.62 (10H, m), 8.75 (1H, s), 8.80 (1H, s), 9.42 (1H, s).

(1) 1- (4-Chlorobenzyl) -3- (2-tetrahydropyran-2-yl-2-propenyl) -6- [4- (3-isoxazolyloxy) phenylimino] -1,3 Of 1,5-triazinan-2,4-dione

1- (4-Chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (1090 mg, 3.65 mmol), 2- (tetrahydropyran-2-yloxy) ) Methyl-2-propenol (628 mg, 3.65 mmol) and triphenylphosphine (956 mg, 3.65 mmol) were dissolved in 1,4-dioxane (5.0 mL). Dimethoxyethyl azadicarboxylate (854 mg, 3.65 mmol) was added to the reaction solution at room temperature, and the mixture was stirred for 3 hours. Furthermore, triphenylphosphine (478 mg, 1.82 mmol) and dimethoxyethyl azadicarboxylate (478 mg, 1.82 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and diethyl ether was added to the resulting residue. The resulting powder was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 1- (4-chlorobenzyl) -6- (ethylthio) -3- (2-tetrahydropyran-2-yloxy-2-propenyl)- 1,3,5-triazine-2,4 (1H, 3H) -dione (1589 mg, yield 96%) was obtained as a colorless oil.
1- (4-Chlorobenzyl) -6- (ethylthio) -3- (2-tetrahydropyran-2-yloxy-2-propenyl) -1,3,5-triazine-2,4 (1H, 3H) -dione Add t-butanol (3.0 mL), 4- (3-isoxazolyloxy) aniline (292 mg, 1.66 mmol) and acetic acid (0.949 mL, 16.6 mmol) to (500 mg, 1.11 mmol) and heat for 9 hours Refluxed. To the reaction solution was added 2 mol / L aqueous sodium hydroxide solution (8 mL), and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL), 5% aqueous citric acid solution (50 mL x 2), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (ethyl acetate / hexane) and 1- (4-chlorobenzyl) -3- (2-tetrahydropyran-2-yloxy-2-propenyl) -6- [4- (3-Isoxazolyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (338 mg, 54% yield) was obtained as a white powder.
1H-NMR (CDCl3) δ: 2.55 (br s, 1H), 4.06 (s, 2H), 4.47 (s, 2H), 5.07-5.27 (m, 4H), 6.10-6.16 (m, 1H), 6.84 ( d, 2H, J = 8.6 Hz), 7.25 (d, 2H, J = 9.1 Hz), 7.30 (d, 2H, J = 8.6 Hz), 7.49 (d, 2H, J = 8.1 Hz), 8.07 (s, 1H), 8.24 (d, 1H, J = 1.5 Hz).

(2) 1- (4-Chlorobenzyl) -3- (2-hydroxymethyl-2,3-dihydroxypropyl) -6- [4- (3-isoxazolyloxy) phenylimino] -1,3, Preparation of 5-triazinan-2,4-dione (I-065)

1- (4-Chlorobenzyl) -3- (2-tetrahydropyran-2-yloxy-2-propenyl) -6- [4- (3-isoxazolyloxy) phenylimino] -1,3,5- Triazinan-2,4-dione (247 mg, 0.436 mmol) was dissolved in 95% aqueous THF (2.0 mL). To the reaction solution were added potassium osmium (VI) dihydrate (16.1 mg, 0.044 mmol) and N-methylmorpholine (102 mg, 0.873 mmol), and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution were added 5% aqueous sodium sulfite solution (1.0 mL) and water (20 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with 5% aqueous citric acid solution (20 mL x 2) and saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give 1- (4-chlorobenzyl) -3- (2-hydroxymethyl-2-tetrahydropyran-2-yloxymethyl-3-hydroxypropyl) -6- [4- (3-isoxazoly (Luoxy) phenylimino] -1,3,5-triazinan-2,4-dione was obtained as a crude product.
To the obtained crude product, 2 mol / L hydrochloric acid methanol solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The residue was purified by silica gel chromatography (chloroform / methanol), and 1- (4-chlorobenzyl) -3- (2-hydroxymethyl-2,3-dihydroxypropyl) -6- [4- (3 -Isoxazolyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-065, 164 mg, 73% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 3.25-3.32 (m, 4H), 3.93 (s, 2H), 4.29 (s, 1H), 4.42 (t, 2H, J = 5.9 Hz), 5.27 (s , 2H), 6.46 (s, 1H), 7.15-7.55 (m, 8H), 8.82 (s, 1H), 9.40 (s, 1H).

(1) Preparation of 3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione

3-Aminopropanenitrile (20.0 g, 285 mmol) was dissolved in DMA (80 mL). Under ice cooling, 1,1′-carbonyldiimidazole (48.6 g, 300 mmol) and DBU (64.5 mL, 428 mmol) were slowly added to the reaction solution, followed by stirring at 0 ° C. for 30 minutes. 1-Amidinopyrazole hydrochloride (41.8 g, 235 mmol) and DBU (47.3 mL, 314 mmol) were added to the reaction solution, and the mixture was stirred for 50 minutes under ice cooling. 1,1′-carbonyldiimidazole (48.6 g, 300 mmol) was added to the reaction solution under ice cooling, then DBU (66.7 mL, 442 mmol) was added at 0 ° C., and the mixture was stirred at 80 ° C. for 1 hour. Furthermore, 1,1′-carbonyldiimidazole (27.8 g, 171 mmol) and DBU (25.8 mL, 171 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. 2 mol / L hydrochloric acid (1.57 L) was added to the reaction solution at 20 ° C., and ice (1 kg) was added with stirring. The resulting powder was collected by filtration, and 3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (20.6 g, yield: 31 %) As a flesh-colored powder.
1H-NMR (δ ppm TMS / DMSO-d6): 2.84 (2H, t, J = 5.9 Hz), 4.02 (2H, t, J = 5.9 Hz), 6.70-6.72 (1H, m), 8.04 (1H, m), 8.56-8.57 (1H, m).

(2) 1- (4-Chlorobenzyl) -3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione

3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (10.0 g, 43.1 mmol), 4-chlorobenzyl bromide (10.2 g 49.5 mmol) was dissolved in DMA (50 mL). Diisopropylethylamine (8.65 mL, 49.5 mmol) was added dropwise to the reaction solution at room temperature, and the mixture was stirred at 80 ° C. for 50 minutes. Diisopropylethylamine (0.75 mL, 4.3 mmol) and 4-chlorobenzyl bromide (0.89 g, 4.31 mmol) were added, and the mixture was stirred at 80 ° C. for 20 minutes. Water (70 mL) was slowly added dropwise to the reaction mixture under ice-cooling, hexane (20 mL) was added, and the mixture was stirred for 5 min. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H)- Dione (12.8 g, yield: 83.2%) was obtained as a yellow powder.
1H-NMR (δ ppm TMS / DMSO-d6): 2.87 (2H, t, J = 6.6 Hz), 4.06 (2H, t, J = 6.6 Hz), 5.45 (2H, s), 6.62-6.63 (1H, m), 7.26-7.34 (4H, m), 7.97 (1H, m), 8.45 (1H, m).

(3) 1- (4-Chlorobenzyl) -3- (2-cyanoethyl) -6- [4- (4-hydroxycarbonyl-2-pyridyloxy) phenylimino] -1,3,5-triazinan-2, Preparation of 4-dione (I-227)

3- (2-Cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (0.300 g, 0.841 mmol), 2- (4-aminophenoxy) A mixture of isonicotinic acid (0.194 g, 0.841 mmol) and t-butanol (4 mL) was stirred with heating under reflux for 2 hours. The reaction solution was purified by high performance liquid chromatography (acetonitrile / water containing 0.3% formic acid) to give 1- (4-chlorobenzyl) -3- (2-cyanoethyl) -6- [4- (4-hydroxycarbonyl-2- Pyridyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-227, 0.288 g, yield: 66.0%) was obtained as a colorless powder.
1H-NMR (δ ppm TMS / DMSO-d6): 2.87 (2H, t, J = 6.7 Hz), 4.03 (2H, t, J = 6.7 Hz), 5.32 (2H, s), 7.19-7.57 (10H, m), 8.35-8.37 (1H, m), 9.46 (1H, s).

1- (4-Chlorobenzyl) -6- [4- (6-tetrazol-5-yl-2-pyridyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-350) Preparation of

4- (6-Cyano-2-pyridyloxy) aniline (2.00 g, 9.47 mmol) was dissolved in DMA (20 mL). Sodium azide (6.16 g, 95 mmol) and ammonium chloride (5.07 g, 95 mmol) were added to the reaction mixture, and the mixture was stirred at 100 ° C. for 1 hr. To the reaction solution was added 5% aqueous citric acid solution (100 mL), and the mixture was extracted with ethyl acetate (200 mL x 2). The organic layer was washed with 5% aqueous citric acid solution (100 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 4- (6-tetrazol-5-yl-2-pyridyloxy) aniline (1.53 g, yield 64%) as a brown powder.
1- (4-Chlorobenzyl) -6 (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (150 mg, 0.504 mmol) to t-butanol (3.0 mL), 4- (6-Tetrazol-5-yl-2-pyridyloxy) aniline (192 mg, 0.756 mmol) and acetic acid (0.864 mL, 15.11 mmol) were added, and the mixture was heated to reflux for 14 hours. To the reaction solution was added 5% aqueous citric acid solution (20 mL), and the mixture was extracted with chloroform (50 mL x 3). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by high performance liquid chromatography (acetonitrile / water containing 0.3% formic acid) to give 1- (4-chlorobenzyl) -6- [4- (6-tetrazol-5-yl-2-pyridyloxy). ) Phenylimino] -1,3,5-triazinan-2,4-dione (I-350, 166 mg, 67% yield) was obtained as a white powder.
¹ H-NMR (DMSO-d ₆ ) δ: 5.18 (d, 2H, J = 74.0 Hz), 6.77-7.30 (m, 4H), 7.31-7.54 (m, 5H), 7.89-8.02 (m, 1H) , 8.03-8.15 (m, 1H), 9.30 (s, 0.5H), 10.21 (s, 0.5H), 11.21 (d, 1H, J = 76.5 Hz).

1- (4-Chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione ( I-358)

1- (4-Chlorobenzyl) -6- (ethylthio) -3- (3-tetrahydropyran-2-yloxypropyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (528mg , 1.2 mol), 4- (5-methoxycarbonyl-2-pyrazyloxy) aniline (530 mg, 2.2 mmol), a mixture of acetic acid (1 mL) and t-butanol (3 ml), and stirred under heating overnight. did. 2 mol / L hydrochloric acid aqueous solution (1 ml) and methanol (1 ml) were added to the reaction solution at room temperature, and the mixture was stirred for 3 hours. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (50 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). Hexane / ethyl acetate was added, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenyl. Imino] -1,3,5-triazinan-2,4-dione (451 mg, yield: 70%) was obtained as a colorless powder.
1H-NMR (δ ppm TMS / DMSO-d6): 1.68 (2H, ddd, J = 7.3 Hz, J = 3.6 Hz, J = 1.8 Hz), 3.43 (2H, q, J = 5.9 Hz), 3.79 (2H , t, J = 6.8 Hz), 4.44 (1H, t, J = 5.0 Hz), 5.29 (2H, s), 7.03-7.33 (2H, m), 7.33-7.52 (6H, m), 8.67 (1H, br s), 8.80 (1H, d, J = 1.3 Hz), 9.35 (0.7H, br s), 10.65 (0.3H, br s).
1- (4-Chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione To a methanol (4 ml) solution of (326 mg, 0.61 mmol), 28% aqueous ammonia (3.91 ml, 181 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, methanol was added to the residue, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-carbamoyl-2 -Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-358, 227 mg, yield: 72%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 1.69 (2H, ddd, J = 7.2 Hz, J = 3.6 Hz, J = 1.8 Hz), 3.43 (2H, dd, J = 11.5 Hz, 6.3 Hz), 3.79 (2H, t, J = 6.9 Hz), 4.44 (1H, t, J = 5.1 Hz), 5.01-5.44 (2H, m), 6.72-7.32 (2.5H, m), 7.36-7.49 (5.5H, m), 7.71 (1H, s), 8.08 (1H, s), 8.43-8.65 (1H, m), 8.73 (1H, d, J = 1.5 Hz), 9.34 (0.6H, s), 10.64 (0.4H , s).

(1) Preparation of (S) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione

1-Amidinopyrazole hydrochloride (5.68 g, 38.7 mmol) and (S) -methyl-2-isocyanatopropanoate (5 g, 38.7 mmol) were dissolved in DMA (40 mL). DBU (5.84 ml, 38.7 mmol) was added dropwise to the reaction solution at 0 ° C. over 15 minutes. The mixture was stirred for 30 minutes under ice cooling, and then stirred at 45 ° C. for 3 hours. To the reaction solution, 1,1′-carbonyldiimidazole (6.28 g, 38.7 mmol) was added under ice cooling, and DBU (8.76 ml, 58.1 mmol) was added at −5 ° C. over 30 minutes. After stirring for 2 hours under ice-cooling, the mixture was stirred for 1 hour at room temperature. 2 mol / L hydrochloric acid was added to the reaction solution at 20 ° C. over 1 hour to adjust the pH to 2-3, followed by extraction with ethyl acetate (200 mL × 2). The organic layer was washed with saturated brine (300 ml) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give (S) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (3.59 g, yield) : 35%) as a tan oil.
1H-NMR (δ ppm TMS / DMSO-d6): 1.45 (3H, d, J = 7.0 Hz), 3.61 (3H, s), 5.30 (1H, q, J = 6.9 Hz), 6.73 (1H, m) , 8.07 (1H, m), 8.57 (1H, m).

(2) (S) 1- (4-Chlorobenzyl) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H)- Preparation of dione

(S) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (3.3 g, 12.5 mmol), 4- Chlorobenzyl bromide (2.83 g, 13.8 mmol) was dissolved in DMA (15 mL). Diisopropylethylamine (2.4 mL, 13.8 mmol) was added dropwise to the reaction solution at room temperature over 10 minutes, and the mixture was stirred at 55 ° C. for 1 hour. Water (50 mL) was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, and (S) 1- (4-chlorobenzyl) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -Dione (4.88 g, yield: 100%) was obtained as a tan oil.
1H-NMR (δ ppm TMS / DMSO-d6): 1.48 (3H, d, J = 6.9 Hz), 3.61 (3H, s), 5.35 (1H, q, J = 6.9 Hz), 5.48 (2H, s) , 6.66 (1H, m), 7.23 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.98 (1H, m), 8.49 (1H, m).
(3) (S) -1- (4-Chlorobenzyl) -6- [4- (3-isoxazolyloxy) phenylimino] -3- (1-hydroxy-2-propyl) -1,3, Preparation of 5-triazinan-2-one (I-001)

(S) -1- (4-Chlorobenzyl) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione ( 1.17 g, 3 mmol), a mixture of 4- (3-isoxazolyloxy) aniline (0.529 g, 3 mmol) and t-butanol (6 mL) was stirred at 120 ° C. for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give (S) -1- (4-chlorobenzyl) -6- [4- (isoxazolyloxy) phenylimino. ] -3- (2-methoxycarbonylethyl) -1,3,5-triazinan-2,4-dione (0.669 g, yield: 45%) was obtained as a colorless oil.
1H-NMR (δ ppm TMS / DMSO-d6): 1.43 (3H, d, J = 7.1 Hz), 3.59 (3H, s), 5.18-5.32 (3H, m), 6.46 (1H, s), 7.24 ( 2H, d, J = 8.1 Hz), 7.32-7.40 (4H, m), 7.46 (2H, d, J = 8.1 Hz), 8.82 (2H, d, J = 1.5 Hz).
(S) -1- (4-Chlorobenzyl) -6- [4- (isoxazolyloxy) phenylimino] -3- (2-methoxycarbonylethyl) -1,3,5-triazinan-2,4 -Dione (0.25 g, 0.5 mmol) was dissolved in THF (2.4 mL). Lithium aluminum hydride (26.7 mg, 0.703 mmol) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (1 ml), 2 mol / L aqueous hydrochloric acid solution (1 ml) and ethyl acetate (5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and wash the residue with ethyl acetate (S) -1- (4-chlorobenzyl) -6- [4- (3-isoxazolyloxy) phenylimino] -3- (1-hydroxy-2 -Propyl) -1,3,5-triazinan-2-one was obtained as a white powder (I-001, 21 mg, yield: 9%).
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (3H, d, J = 6.9 Hz), 3.44 (1H, m, J = 5.5 Hz), 4.18 (1H, m, J = 6.7 Hz, J = 6.1 Hz), 4.60 (2H, s), 5.21 (2H, s), 6.49 (1H, s), 7.16-7.57 (8H, m). 8.85 (1H, d, J = 1.5 Hz), 9.9 (0.3H , m), 11.2 (0.7H, m).

The following compounds of the present invention were obtained according to the above general production methods and the methods described in Examples. The structure and physical properties are shown below.
(Compound identification method)
The LC / MS data of the compound of the present invention was measured under any of the following five conditions (Methods 1 to 5), and showed the retention time (minutes) and [M + H] ⁺ .
(Method 1)
Column: Luna C18 (2) (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method 2)
Column: Xbridge C18 (5 μm, id 4.6 × 50 mm) (Waters)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method 3)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method 4)
Column: Develosil RPAq, (50 x 4.6 mm)
Flow rate: 1.5 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid, and the 60% solvent [B] is maintained for 0.5 minutes, and 60% -100% for 4.5 minutes. A linear gradient of solvent [B] was performed and 100% solvent [B] was maintained for 1.0 minute.
(Method 5)
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution, and a linear gradient of 10% -100% solvent [B] is performed for 3.5 minutes. 100% solvent [B] was maintained for minutes.
(Method 6)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: linear gradient of 10% -50% solvent [B] in 3 minutes, 1 minute , 50% solvent [B] was maintained.

Furthermore, the compounds described in the following table were also synthesized.

Hereinafter, biological test examples of the compounds of the present invention will be described.

Test Example Test Example 1-1: 1 stably expressing cell lines by introducing the human P2X ₃ receptor inhibitory activity evaluation human P2X ₃ receptor gene (GenBank Accession sequence Y07683) to C6BU-1 cells in PDL coated 96-well microplate Seeded to 8000 per well, in a medium (DMEM containing 8.3% fetal calf serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C., 5% dioxide Incubated for 1 day under carbon. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 μL of wash buffer. The microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) The DMSO solution of the present invention diluted to have different concentrations was dispensed by 40 μL per well with an automatic dispenser built in the FDSS 3000. After 5 minutes, 50 μL of 50 nM ATP solution diluted with a dilution buffer was dispensed with an automatic dispensing device built in FDSS 3000, and then fluorescence intensity measurement was continued for 3 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC ₅₀ ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics). IC ₅₀ was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
The test results of the compounds of the present invention are shown in the following table.

Test Example 1-2: Human P2X ₃ Evaluation of the receptor inhibitory activity human P2X ₃ receptor gene per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells in PDL coated 96-well microplate Seeded to 8000 cells in medium (7.0% fetal calf serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide Incubate for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide. Wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 μL of wash buffer. The microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) The DMSO solution of the present invention diluted to have different concentrations is dispensed by 40 μL per well with an automatic dispensing device built in the FDSS 3000. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer is dispensed with an automatic dispensing device built in the FDSS 3000, and then fluorescence intensity measurement is continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC ₅₀ ) is calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics). IC ₅₀ is calculated using software of Microsoft Excel (Microsoft) and XLfit (idbs).

Test Example 1-3: Human P2X ₃ Evaluation of the receptor inhibitory activity human P2X ₃ receptor gene per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells PDL coated 384-well microplates 3000 seeds were seeded and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. For 2 days. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, 0.5 % BSA, 0.04% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 20 μL of wash buffer. The microplate was installed in a high throughput screening system FLIPR 384 (Molecular Devices). Measurement of fluorescence intensity by FLIPR 384 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) The present compound DMSO solution diluted to different concentrations was dispensed by 20 μL per well with an automatic dispensing device built in FLIPR 384. After 5 minutes, 25 μL of 150 nM ATP solution diluted with dilution buffer was dispensed with an automatic dispensing device built in FLIPR 384, and then fluorescence intensity measurement was continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC ₅₀ ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity and IC ₅₀ were calculated using software from Spotfire (Science Technology Systems).
The test results of the compounds of the present invention are shown in the following table.

Test Example 2-1: was expressed by introducing the rat P2X ₃ Rating rat P2X ₃ receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution). The cells were cultured at 5 ° C. for 5 days at 5 ° C. The expression plasmid was introduced using a gene introduction reagent FuGENE6 (Roche) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 μL of wash buffer. The microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% pluronic F-127, pH 7.5), and the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FDSS 3000, 40 μL per well. did. After 5 minutes, 50 μL of 50 nM ATP solution diluted with a dilution buffer was dispensed with an automatic dispensing device built in FDSS 3000, and then fluorescence intensity measurement was continued for 3 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC ₅₀ ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics). IC ₅₀ was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
The test results of the compounds of the present invention are shown in the following table.

Test Example 2-2: introducing and expressing rat P2X ₃ Rating rat P2X ₃ receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution). Incubate for 1 day at 5 ° C. and 5% carbon dioxide. An expression plasmid is introduced using a gene introduction reagent FuGENE6 (manufactured by Promega) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide. Wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Filled with 40 μL of wash buffer per minute. The microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) is used to dispense 40 μL of the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FDSS 3000 per well. To do. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer is dispensed with an automatic dispensing device built in the FDSS 3000, and then fluorescence intensity measurement is continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC ₅₀ ) is calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics). IC ₅₀ is calculated using software of Microsoft Excel (Microsoft) and XLfit (idbs).

Test Example 3-1: was expressed by introducing rat serum albumin (RSA) Evaluation rat P2X ₃ receptor gene of the rat P2X3 receptor inhibitory activity in the presence of a (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution). The cells were cultured at 5 ° C. for 5 days at 5 ° C. The expression plasmid was introduced using a gene introduction reagent FuGENE6 (Roche) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 μL of wash buffer. The microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl ₂ , 5.0 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid) 1 solution of DMSO solution of the compound of the present invention diluted to different concentrations using a solution in which rat serum albumin is added to 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% Each 40 μL was dispensed by an automatic dispensing device built in the FDSS 3000. After 5 minutes, 50 μL of 50 nM ATP solution diluted with a dilution buffer was dispensed with an automatic dispensing device built in FDSS 3000, and then fluorescence intensity measurement was continued for 3 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC ₅₀ ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics). IC ₅₀ was calculated using software from Microsoft Excel (Microsoft) and XLfit (idbs).
The test results of the compounds of the present invention are shown in the following table.

Test Example 3-2: introducing and expressing rat serum albumin (RSA) Evaluation rat P2X ₃ receptor gene of the rat P2X3 receptor inhibitory activity in the presence of a (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution). Incubate for 1 day at 5 ° C. and 5% carbon dioxide. An expression plasmid is introduced using a gene introduction reagent FuGENE6 (manufactured by Promega) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-4-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide. Wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 μL of wash buffer. The microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl ₂ , 1.26 mM CaCl ₂ , 5.6 mM D-glucose, 2.5 mM probenecid) 1 solution of DMSO solution of the compound of the present invention diluted to different concentrations using a solution in which rat serum albumin is added to 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% Dispense 40 μL per unit with an automatic dispenser built in FDSS 3000. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer is dispensed with an automatic dispensing device built in the FDSS 3000, and then fluorescence intensity measurement is continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC ₅₀ ) is calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics). IC ₅₀ is calculated using software from Microsoft Excel (Microsoft) and XLfit (idbs).

The compounds described herein exhibit inhibitory activity against P2X ₃ receptor. In addition, since the compound of the present invention acts on the P2X ₃ subtype, it is considered that the compound of the present invention also exhibits inhibitory activity against the P2X _2/3 receptor that is also composed of the P2X ₂ subtype.

Test Example 4: Evaluation of urinary function in rat cystitis model Cystometry operation Rats are anesthetized by inhalation of 2% isoflurane (anesthetic background; laughing gas: oxygen = 7: 3) and then fixed in the supine position. A midline incision is made in the abdomen to expose the bladder. A small incision is made in the top of the bladder, a cannula (produced by processing a polyethylene tube (PE-50: Becton Dickinson)) is inserted and fixed, and a bladder fistula is produced. The other end of the cannula is guided subcutaneously to the back, and the muscle layer and skin are sutured. The cannula led to the back is protected by a stainless steel spring and connected to a sieve.
Acetic acid injection Two days after surgery, 0.3% acetic acid is injected into the bladder at a rate of 4 mL / hr for 30 minutes via a cannula placed in the bladder to induce cystitis. An animal that is not injected with acetic acid is defined as a normal animal.
Cystometry measurement Two to three days after acetic acid injection, connect the other end of the cannula inserted into the bladder to a three-way stopcock, and inject the heated physiological saline from one side at a rate of 3.0 mL / hr, The intravesical pressure is continuously recorded by a pressure amplifier through a pressure transducer. The intravesical pressure is measured for a stable period (about 20 minutes), followed by a pre-dose value (about 40 minutes), and after administration of the test substance, a post-dose value is measured for 120 minutes. The compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared using 0.5% methylcellulose solution to a concentration of 0.1 to 2 mg / mL / kg. Oral administration. Simultaneously with the measurement of intravesical pressure, excreted urine is received on a balance under the cage, and its weight change is measured simultaneously.
Criteria for data adoption Based on the urination interval, those with a urination interval of 10 minutes or more are adopted for normal animals, and those with less than that are excluded. For animals that have been injected with acetic acid, those with a micturition interval of less than half of the mean value for normal animals are adopted as cystitis animals, and those beyond that are excluded.
Collection of residual urine After the measurement is completed, stop injection of physiological saline immediately after urination and collect residual urine under anesthesia with sodium pentobarbital. The collected residual urine is transferred to the excretion receptacle and recorded on the chart.
Analysis items Analyze the intravesical pressure (static pressure and urination pressure), urination interval, and single urination volume 1 hour to 2 hours after the start of measurement. In addition, the amount of residual urine after the measurement is analyzed.

The following values are used as indicators of the effect on the urination interval.
Urinary dysfunction improvement rate = (urination interval after drug treatment for cystitis animals−urination interval before drug treatment for cystitis animals) / (mean value of urination interval before drug treatment for normal animals−urination interval before drug treatment for cystitis animals) ) X 100
The following values are used as indicators of the effect on the amount of urination once.
Improvement rate of 1 urination volume = (1 urination volume after drug treatment in cystitis rats-1 urination volume before drug treatment in cystitis animals) / (Average value of 1 urination volume before drug treatment in normal animals-cystitis) Animal urination once before drug treatment) x 100

Test Example 5: Evaluation of drug efficacy using the Seltzer model Rat Partial sciatic nerve ligation model (rat sciatic nerve partial ligation model)
Model preparation Rats were anesthetized with isoflurane and the hair on the left foot was shaved. The skin at the upper thigh was incised, and the muscle was broken to expose the sciatic nerve. 1/3 to 1/2 of the sciatic nerve was strongly ligated with a thread, and the muscle and skin were sutured. This was the operation side. The right foot was treated in the same manner as sciatic nerve ligation, and the sham operation was performed.
Evaluation (1)
Two weeks after surgery, the effect on tactile allodynia was assessed by von Frey filament. Two weeks after the operation, rats were placed in a plastic cage placed on a wire mesh and habituated. The von Frey filament (0.4-26 g) was pressed against the back of the rat foot from the wire mesh side, and the pressure value of the von Frey fiber at which the rat began to show escape behavior was taken as the pain threshold. The pain threshold was evaluated for the left and right hind limbs and used as the pretreatment pain threshold. Animals with a surgical threshold of 0.6 to 2 g and a sham surgical threshold of 8 to 15 g were used. In order to train the animals, the same operation was performed before measuring the pre-treatment pain threshold. The compound of the present invention was administered to the adopted animals. The compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared using 0.5% methylcellulose solution to a concentration of 0.1 to 2 mg / mL / kg. Orally administered. From 1 to 5 hours after administration, the pain threshold value of the left and right hind limbs was evaluated and used as a post-treatment pain threshold value. The% reversal value was calculated by the following method, and the analgesic action of the compounds was compared.
% reversal value = (logarithm of pain threshold after operation side treatment-logarithm of pain threshold value before operation side treatment) / (logarithm of pain threshold value before surgery side treatment-logarithm of pain threshold value before operation side treatment)
The test results of the compounds of the present invention are shown in the following table. The analgesic action of the compound of the present invention after 3 hours of oral administration at 3 mg / kg is shown in the following table as% reversal.

Evaluation (2)
Analgesiometer is used to evaluate the effect on mechanical hyperalgesia. Two weeks after the operation, the rat's hind limb is compressed by an analgesiometer so as to increase the stimulation pressure by 16 g per second, and the pressure when the rat exhibits escape behavior is set as a pain threshold. Pain thresholds are evaluated for the left and right hind limbs and set as pre-treatment pain thresholds. Animals with a surgical threshold of 60-90 g and a sham surgical threshold of 100-175 g are employed. In order to train the animal, the same operation is performed before measuring the pre-treatment pain threshold. The compound of the present invention is administered to the adopted animal. The compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Orally. 1 to 5 hours after administration, the pain threshold value of the left and right hind limbs is evaluated and set as a post-treatment pain threshold value. The% reversal value is calculated by the following method to compare the analgesic action of the compounds.
% reversal = (Pain threshold after surgical treatment-Pain threshold before surgery) / (Pain threshold before sham surgery-Pain threshold before surgery)

Test Example 6 CYP3A4 Fluorescence MBI Test The CYP3A4 Fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of compounds by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (BFC) is CYP3A4 using E. coli-expressed CYP3A4 as an enzyme. The reaction was debenzylated with an enzyme to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) as an indicator.

The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), pre- 62.5 pmol / mL during reaction, 6.25 pmol / mL during reaction (10-fold dilution); drug concentration of the present invention, 1.56, 3.125, 6.25, 12.5, 25, 50 μmol / L (6 points).

Add the enzyme and the drug solution of the present invention to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the above pre-reaction composition, and add the substrate and K-Pi buffer to the other 96-well plate. A portion thereof was transferred so as to be diluted by 10/10, and a reaction using NADPH as a coenzyme was started as an index (no pre-reaction). After reaction for a predetermined time, acetonitrile: 0.5 mol / L Tris ( The reaction was stopped by adding (trishydroxyaminomethane) = 4: 1. Also, add NADPH to the remaining pre-reaction solution to start the pre-reaction (with pre-reaction), and after the pre-reaction for a predetermined time, make sure that another plate is diluted 1/10 with the substrate and K-Pi buffer. The reaction was started by moving the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile: 0.5 mol / L Tris (trishydroxyaminomethane) = 4: 1. The fluorescence value of 7-HFC, which is a metabolite, was measured using a fluorescent plate reader on the plate on which each index reaction was performed (Ex = 420 nm, Em = 535 nm).

The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the drug solution of the present invention was calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model. The case where the difference in IC ₅₀ value was 5 μmol / L or more was designated as (+), and the case where it was 3 μmol / L or less was designated as (−).
The test results of the compounds of the present invention are shown in the following table.

Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.

The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6) ), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; drug concentration of the present invention, 1.0, 5.0, 10, 20 μmol / L ( 4 points).

As a reaction solution in a 96-well plate, each of 5 types of substrates, human liver microsomes, and the drug of the present invention was added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, was added as an indicator for metabolism. The reaction was started and reacted at 37 ° C. for 15 minutes, and then the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was collected using a fluorescent multilabel counter with tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite). Then, dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

A control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the drug solution of the present invention was calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model.
The test results of the compounds of the present invention are shown in the following table.

Test Example 8-1 FAT test (Fluctuation Ames Test)
Twenty microliters of Salmonella typhimurium TA98 and TA100 were cryopreserved and inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer solution (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g /) L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L), and 110 mL of Exposure Add to medium (BioF: 8 μg / mL, histidine: 0.2 μg / mL, glucose: MicroF buffer solution containing 8 mg / mL), TA100 strain to 3.16 mL bacterial solution added to 120 mL of Exposure medium and test bacterial solution Was prepared. Test substance DMSO solution (maximum dose 50mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, 50μg / mL for TA98 strain under non-metabolic activation conditions as positive control Nitroquinoline-1-oxide in DMSO solution, TA100 strain, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, TA98 strain under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for TA100 strain and 20 μg / mL 2-aminoanthracene DMSO solution for TA100 strain, respectively, and 588 μL of the test bacterial solution (under the metabolic activation conditions, the test bacterial solution 498 μL and S9 mix 90 μL) were mixed and cultured at 37 ° C. for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the test substance is added to Indicator Medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL) 2300 50 μL each was mixed in μL, dispensed into 48 microwells / dose of the microplate, and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutations in the amino acid (histidine) synthase gene turn from purple to yellow due to pH change, count the number of bacterial growth wells that turn yellow in 48 wells per dose. Evaluation was made in comparison with the negative control group.
The test results of the compounds of the present invention are shown in the following table.

Test Example 8-2 FAT test (Fluctuation Ames Test)
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 7. 70 mL of Micro F buffer (K ₂ HPO ₄ : 3.5 g / L, KH ₂ PO ₄ : 1 g / L, (NH ₄ ) ₂ SO ₄ : 1 g / L, trisodium citrate dihydrate: The cells are suspended in 0.25 g / L, MgSO ₄ · 7H ₂ 0: 0.1 g / L), and 110 mL of Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) To the MicroF buffer). TA100 strain is added to 120 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL of the test bacterial solution and S9 under metabolic activation conditions). mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL aliquots into 48 wells / dose of the microplate and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacterial growth wells that changed to yellow in 48 wells per dose was counted. Evaluate compared to negative control group. The negative mutagenicity is indicated as (−) and the positive mutagenicity is indicated as (+).

Test Example 9 Solubility test The solubility of the compound was determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution to pH 6.8 artificial intestinal juice (250 mL of 0.2 mol / L potassium dihydrogen phosphate test solution, add 118 mL of 0.2 mol / L NaOH test solution, add 1000 added to 594 μL). After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water = 1/1, and the concentration in the filtrate was measured by HPLC or LC / MS / MS by the absolute calibration curve method.
The test results of the compounds of the present invention are shown in the following table.

Test Example 10 Metabolic Stability Test Using a commercially available pooled human liver microsome, the target compound is reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.

1 mmol / L NADPH present in 0.2 mL buffer (50 mmol / L tris-HCl pH7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the centrifugal supernatant was quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction was calculated with the amount of the compound at 0 minute reaction as 100%.
The test results of the compounds of the present invention are shown in the following table. The residual ratio at a compound concentration of 0.5 μmol / L is shown as%. The test result of I-362 was 92%.

Test Example 11-1 hERG Test For the purpose of evaluating the risk of extending the electrocardiogram QT interval of the compound of the present invention, HEK293 cells expressing a human ether-a-go-related gene (hERG) channel were used for the ventricular repolarization process. Consider the action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ), which plays an important role.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), the cell was held at a membrane potential of −80 mV by the whole cell patch clamp method, a leak potential of −50 mV was applied, and then a depolarization stimulus of +40 mV was applied. I _Kr elicited when 2 seconds of additional -50 mV repolarization stimulation was applied for 2 seconds was recorded. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH ₂ PO ₄ : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl ₂ · 2H ₂ O: 1.8 mmol / L, MgCl ₂ · 6H ₂ O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2- Hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was applied to the cells for 10 minutes at room temperature. From the obtained I _Kr , the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I _Kr was evaluated.
(Result) The inhibition rate at a compound concentration of 1 μmol / L is shown.

Test Example 11-2 hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, CHO cells expressing human ether-a-go related gene (hERG) channels were used for ventricular repolarization process. Consider the action of the compounds of the present invention on the delayed rectifier K ⁺ current (I _Kr ), which plays an important role.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), the cell was held at a membrane potential of −80 mV by a whole cell patch clamp method, and after applying a leak potential of −50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the _{I Kr} induced repolarization stimulated when given 2 seconds -50 mV. After the generated current is stabilized, an extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl ₂ : 2 mmol / L, MgCl ₂ : 1 mmol) in which the compound of the present invention is dissolved at a desired concentration. / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7 4) is applied to the cells for 10 minutes at room temperature. The absolute value of the maximum tail current is measured from the obtained I _Kr using analysis software (Falster Patch; Sophion Bioscience A / S) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I _Kr is evaluated.

Test Example 12: Metabolic stability test Using prepared rat cryopreserved hepatocytes, the target compound is allowed to react for a certain period of time, the residual rate is calculated by comparing the reaction sample with the unreacted sample, and the degree of metabolism in the liver is evaluated. To do.

Incubate at 37 ° C for 0, 1 or 2 hours in William E medium containing 1.0x10 ⁶ cells / mL of rat frozen hepatocytes. After the reaction, 120 μL of methanol / acetonitrile = 1/1 (v / v) solution is added to 30 μL of the reaction solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the centrifugal supernatant is quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction is calculated with the amount of the compound at 0 minute reaction as 100%.

Test Example 13: Protein binding test The serum protein non-binding rate of the inventive compound was measured using various sera.

Reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 2 μg / mL.

Test solutions were added to various sera and stirred to prepare serum samples having the above compound concentrations. A serum sample was added to one of the equilibrium dialysis cells, and phosphate buffered saline (PBS) was added to the other, followed by equilibrium dialysis at 37 ° C. for 24 hours. The amount of compound in the sample collected from each cell was measured by LC / MS / MS.
The test results of the compounds of the present invention are shown in the following table. The ratio of the amount of compound in PBS to the amount of compound in serum is shown as protein non-binding rate (%).

Test Example 14: Bioavailability (BA) test Examination of oral absorbability Experimental materials and methods (1) Animals used: SD rats were used.
(2) Breeding conditions: SD rats were allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral and intravenous administration at a predetermined dosage. Groups were set up as follows. (Dose may vary for each compound)
Oral administration 1 mg / kg (n = 2)
Intravenous administration 0.5 mg / kg (n = 2)
(4) Preparation of administration solution: Oral administration was administered as a suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was administered intragastrically with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention was calculated from the dose ratio of the group and the AUC ratio.
The test results of the compounds of the present invention are shown in the following table.

Test Example 15: Powder solubility test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution are added to each container. (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and precipitates, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.

Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.

Compound represented by the general formula (I) and formula (II), have an antagonistic effect on P2X ₃ and / or P2X _2/3 receptor, diseases P2X ₃ and / or P2X _2/3 receptor is involved Or it may be useful for conditions such as chronic pain, dysuria, respiratory disease.

Claims

Formula (I):

(Where
R a and R b are both a hydrogen atom or together, oxo, thioxo or ═N—R x ;
R d and R e are both hydrogen atoms or together, oxo, thioxo or ═N—R y ;
R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R c is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
Each R 4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R 4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R 5 ) — or — (C (R 5a ) (R 5b )) —;
—L— represents —O—, —S—, —N (R 5 ′ ) — or — (C (R 5a ′ ) (R 5b ′ )) —;
R 5 and R 5 ′ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R 5a , R 5b , R 5a ′ and R 5b ′ each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or Unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy or substituted or unsubstituted alkenyloxy;
Ring D is benzene, pyridine, pyrimidine, pyrazine or pyridazine;
Carbon atom a and carbon atom b are carbon atoms constituting ring D;
Ring B is an aromatic carbocycle, non-aromatic carbocycle, aromatic heterocycle or non-aromatic heterocycle;
s and s ′ are each independently an integer of 0 to 3;
R 9 is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxy Carbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfoni Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
R 9 ′ is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfo Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
(However, when ring B is cyclopentane, benzene, tetrahydropyran or piperidine, s ′ is an integer of 1 to 3)
Or a pharmaceutically acceptable salt thereof.
—R c is — (C (R 11c ) (R 11d )) m′-CN
(Wherein R 11c each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 11d is each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 11c and R 11d bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle;
m ′ is an integer of 1 to 4)
The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
R c is substituted with 3 to 5 hydroxy groups, and substituent group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro and thioxo) An optionally substituted C3-C6 alkyl; a C3-C6 alkenyl optionally substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; or Substituted with 3-5 hydroxy Further 1 or more substituents may C3 ~ C6 alkynyl optionally substituted with selected from Substituent group alpha, a compound or a pharmaceutically acceptable salt thereof according to claim 1.
s is 1 or 2, and at least one R 9 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, 4. The compound according to claim 1, which is substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl, or a pharmaceutical thereof Acceptable salt.
formula:

The group represented by the formula:

Wherein -X- and -L- are as defined in claim 1; R 9 is halogen or substituted or unsubstituted alkyl; Y 1 , Y 2 and Y 3 are each independently CH or N; wherein Y 1 , Y 2 and Y 3 are not simultaneously N), or a pharmaceutically acceptable salt thereof.
Formula (II):

(Where
R a and R b are both a hydrogen atom or together, oxo, thioxo or ═N—R x ;
R d and R e are both hydrogen atoms or together, oxo, thioxo or ═N—R y ;
R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R c is substituted with 3 to 5 hydroxy groups, and further substituted group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, and thioxo) C3-C6 alkyl optionally substituted with C3-C6 alkenyl substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; Or substituted with 3-5 hydroxy Are further 1 or more are also may C3 ~ optionally C6 alkynyl substituted with a substituent selected from substituent group alpha;
Each R 4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R 4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R 5 ) — or — (C (R 5a ) (R 5b )) —;
R 5 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R 5a and R 5b each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkynyloxy or substituted or unsubstituted alkenyloxy;
R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl )
Or a pharmaceutically acceptable salt thereof.
R a and R b together are oxo,
R d and R e together are oxo,
R c is

(Wherein Alk is alkyl)
A group represented by
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,

Wherein the other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
R a and R b together are oxo,
R d and R e together are oxo,
R c is

(Wherein Alk is alkyl)
A group represented by
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,

Is;
The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein s 'is an integer of 1 to 3, and at least one R 9' is halogen or haloalkyl, and other symbols are as defined in claim 1. Salt.
R a and R b together are oxo,
R d and R e together are oxo,
R c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group;
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
-L- is -O-,
Ring D is benzene,
Ring B is pyridine or thiazole;
The compound according to claim 1, wherein s 'is an integer of 1 to 3; and at least one R 9' is carboxy or alkyloxycarbonyl, and other symbols are as defined in claim 1, or a pharmaceutical thereof Top acceptable salt.
R a and R b together are oxo,
R d and R e together are oxo,
R c is alkyl;
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,
s is an integer of 1 to 3,

(Wherein s ″ is an integer of 0 to 2 and other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof).
R a and R b together are oxo,
R d and R e together are oxo,
R c is

(Wherein Alk is alkyl)
A group represented by
n is 1, R 4a and R 4b are both hydrogen atoms,
R 2 is substituted or unsubstituted cycloalkyl,
-X- is -N (H)-;
-L- is -O-,
Ring D is benzene,
The other symbols have the same meanings as in claim 1, or the compound or pharmaceutically acceptable salt thereof according to claim 1.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.
P2X 3 and / or P2X 2/3 pharmaceutical composition according to claim 12, further comprising a receptor antagonism.
The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving P2X 3 and / or P2X 2/3 receptor.
The treatment and / or prevention of a disease involving P2X 3 and / or P2X 2/3 receptor, which comprises administering the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. Method.