TRIAZINE DERIVATIVE AND PHARMACEUTICAL COMPOSITION HAVING AN ANALGESIC ACTIVITY COMPRISING THE SAME

Abstract

The present invention provides novel compounds having a P2X3 and/or P2X2/3 receptor antagonistic effect.

Description

TECHNICAL FIELD

The invention relates to a compound useful for the treatment of diseases or conditions associated with P2X receptor, specifically to P2X₃ and/or P2X_2/3 receptor, and a pharmaceutical composition having an analgesic effect, an improving effect of urination disorder comprising such compound.

BACKGROUND ART

Adenosine triphosphate (ATP) is known to serve as a source of energy in cells and a substrate of phosphorylation, as well as an extracellular messenger. It is known that ATP is released from a cell by various stimulation such as cellular injury, inflammation, nociceptive stimulus, reduced blood oxygen level, and also known to be released together with another messenger from a primary sensory nerve terminal, ATP thus released mediates various extracellular signal transductions through an ATP receptor (Non-Patent Document 4, Non-Patent Document 5).

ATP receptor is categorized into ionotropic P2X family and G protein-coupled P2) family. For P2X family, seven subtypes have been reported, and a member of this family forms a homo-trimeric structure or a hetero-trimeric structure together with another member of this subtype and functions as a non-specific cation channel (Non-Patent Document 6).

ATP is known to cause pain, and studies with P2X₃ knockout and knockdown methodologies have shown that P2X₃ receptor mediates transmission of chronic pain. P2X₃ receptors are expressed in a specific manner on peripheral sensory nerve to form a homo-complex or hetero-complex with P2X₂ (P2X_2/3) (Non-Patent Document 1).

Later, the compound A-317491 was reported as a specific antagonist to P2X₃ and P2X_2/3 receptors. A-317491 is tri-substituted-N-[(1S)-1,2,3,4-tetrahydro-1-naplithalenyl]benzamide derivative represented by the formula:

(Patent Document 1). It was reported to exhibit an antagonist activity to P2X₃ and P2X_2/3 receptors and analgesic action in neuropathic pain model and inflammatory pain model (Non-Patent Document 7). This indicates that pain sensation is transmitted via P2X₃ or P2X_2/3 receptor and that a compound having a P2X₃ or P2X_2/3 receptor antagonistic effect is useful as an analgesic. Also, compounds that exhibit P2X₃ or P2X_2/3 receptor antagonistic effect are described in Patent Documents 2-7.

Additionally, it was recently reported that vesical reflex was strongly reduced in P2X₃ knockout mouse (Non-Patent Document 2), suggesting that a compound having P2X₃ antagonistic effect is useful in the treatment of diseases caused by overactive bladder.

Patent Documents 8, 9, 10 and 11 disclose compounds having similar structure to the compounds of the present invention but they do not disclose analgesic effect and P2X₃ or P2X_2/3 receptor antagonistic effect. Non-Patent Document 8 discloses compounds having similar structure to the compounds of the present invention and having analgesic effect, but it does not discloses P2X₃ or P2X_2/3 is receptor antagonistic effect. Patent Document 12 discloses compounds having P2X₃ receptor antagonistic effect but the structures are different with those of the compounds of the present invention. Patent Document 13 discloses compounds having P2X₃ or P2X_2/3 receptor antagonistic effect with a triazine structure but in case that a ring corresponding to ring B of the present application is a cyclopentane ring, a benzene ring, a tetrahydropyrane ring or a piperizine ring, then the ring is unsubstituted, and therefore, the structures are different with those of the present invention.

Patent Document 14 discloses compounds having a pyrazolyl-substituted triazine ring but the structures are different with those of the compound of the formula (XII) of the present invention. Patent Document 14 does not disclose a process for converting a pyrazolyl group on a triazine ring into an anilino group by using a pyrazolyl group as a leaving group.

Non-Patent Documents 9, 10, 11 and 12 disclose a process for converting a pyrazolyl group to an anilino group by using a pyrazolyl group as a leaving group, but do not disclose a process for converting a pyrazolyl group on a triazine ring into an aniline group.

PRIOR ART

Patent Document

• [Patent Document 1] WO02/094707
• [Patent Document 2] WO2005/095359
• [Patent Document 3] US20070037974
• [Patent Document 4] US20070049758
• [Patent Document 5] US20070049610
• [Patent Document 6] US20070049609
• [Patent Document 7] US20070049534
• [Patent Document 8] JP12-072757A
• [Patent Document 9] WO20061104713
• [Patent Document 10] WO2006/104715
• [Patent Document 11] WO2006/102112
• [Patent Document 12] WO2010/051188
• [Patent Document 13] WO2010/092966
• [Patent Document 14] EP547461A

Non-Patent Document

• [Non-Patent Document 1] Neuroscientist 11 (2005) pp. 345-356
• [Non-Patent Document 2] J. Physiol. 567.2 (2005) pp. 621-639
• [Non-Patent Document 3] Expert Opin. Ther. Patens (2006) 16(8), p. 113-1127
• [Non-Patent Document 4] J. Physiology (2003), 554(2), p. 301-308
• [Non-Patent Document 5] J. Physiology (2003), 553(3), p. 683-694
• [Non-Patent Document 6] Pflungers Arch Eur physiol (2006), p. 452, 513-537
• [Non-Patent Document 7] PNAS (2002), 99(26), p. 17179-17184
• [Non-Patent Document 8] Journal of Medicinal Chemistry (2008), 51(23), p. 7635-7639
• [Non-Patent Document 9] J. Org. Chem., (1992), 57, p. 2497-2502
• [Non-Patent Document 10] Tetrahedron Lett. (2007), 48, p. 2357-2359
• [Non-Patent Document 11] Tetrahedron Lett. (2002), 43, p. 1401-1403
• [Non-Patent Document 12] Bioorganic & Medicinal Chemistry Letters (2010), 20(23), p. 6895-6898

SUMMARY OF THE INVENTION

Problems to be Solved by the Invention

The present invention provides a novel compound having a P2X₃ and/or P2X_2/3 receptor antagonistic effect. It also provides a pharmaceutical composition having a P2X₃ and/or P2X_2/3 receptor antagonistic effect and having an analgesic effect or an improving effect of urination disorder. Furthermore, it provides methods of producing the above-mentioned compound or pharmaceutical composition and important intermediates for the producing methods.

Means for Solving the Problem

Through their extensive research to solve the aforementioned problems, the inventors have found novel compounds that bind specifically to P2X₃ and/or P2X_2/3 receptor and exhibit an antagonistic effect, and novel compounds that hind specifically to P2X₃ and/or P2X_2/3 receptor. Additionally, they have discovered pharmaceutical compositions that have P2X₃ and/or P2X_2/3 antagonistic effect and having an analgesic effect or an improving effect of urination disorder. Furthermore, they have found methods for producing the above-mentioned compound or pharmaceutical composition and important intermediates for the producing methods.

The compounds and pharmaceutical compositions encompassed by the present invention produced excellent results of P2X₃ receptor inhibitory effect, P2X₃ receptor inhibitory effect in the presence of rat serum albumin (hereinafter referred to as RSA) and the like. The compounds encompassed by the present invention or the pharmaceutical compositions encompassed by the present invention also produced excellent results in CYP enzyme inhibition assay, FAT assay, solubility assay, metabolic stability assay, hERG inhibitory activity assay, bioavailability assay and/or protein binding assay and the like. The compounds encompassed by the present invention or the pharmaceutical composition encompassed by the present invention showed potent analgesic effect or improving effect of urination disorder.

This invention relates to

(1) A compound of the formula (VIII):

whereinZ¹ and Z² are each independently an oxygen atom, a sulfur atom or ═N—R^x;R^x is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^4a and R^4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic, heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

—X— is —O—, —S—, —N(R⁵)— or —(CR^5aR^5b)—;

-L- is —O—, —S—, —N(R^5′)— or —(CR^5a′R^5b′)—;

R⁵ 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′ are each independently 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 a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;

carbon atom a and carbon atom b are carbon atoms which constitute ring D;ring B is an aromatic carbocyclic ring, a non-aromatic carbocyclic ring, an aromatic heterocyclic ring or a non-aromatic heterocyclic ring;s and s′ are each independently an integer of 0 to 3; andR⁹ and R^9′ are each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;provided that s′ is an integer of 1 to 3 when ring B is a cyclopentane ring, a benzene ring, a tetrahydropyran ring or a piperidine ring,or its pharmaceutically acceptable salt or a solvate thereof.

(2) The compound according to the above (1), wherein -L- is —O—, or its pharmaceutically acceptable salt or a solvate thereof.

(3) The compound according to the above (1) or (2), wherein ring B is an aromatic heterocyclic ring, or its pharmaceutically acceptable salt or a solvate thereof.

(4) The compound according to any one of the above (1) to (3), wherein ring B thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a pyrazole ring, an imidazole ring, a triazole ring, a furan ring, a thiophene ring, a thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring or a benzoxazole ring, or its pharmaceutically acceptable salt or a solvate thereof.

(5) The compound according to any one of the above (1) to (4), wherein ring B is a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, or its pharmaceutically acceptable salt or a solvate thereof.

(6) The compound according to any one of the above (1) to (5), wherein s′ is an integer of 1 to 2, and at least one of R^9′ is hydroxy, carboxy, cyano, substituted alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt or a solvate thereof.

(7) The compound according to any one of the above (1) to (6), wherein s′ is 1, and R^9′ is carboxy or substituted or unsubstituted carbamoyl, or its pharmaceutically acceptable salt or a solvate thereof.

(8) A compound of the formula (IX):

whereinZ¹ and Z² are each independently an oxygen atom, a sulfur atom or ═N—R^x;R^x is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^4a and R^4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

—X— is —O—, —S—, —N(R⁵)— or —(CR^5aR^5b)—;

R⁵ is 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 are each independently 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 a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;carbon atom a and carbon atom b are carbon atoms which constitute ring D;R^13a and R^13b are each independently 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, or R^13a and R^13b attached to the same carbon atom are taken together to form oxo or thioxo;ring E is a cycloalkane ring or a cycloalkene ring;s and s′ are each independently an integer of 0 to 3; andR⁹ and R^9′ are each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy,or its pharmaceutically acceptable salt or a solvate thereof.

(9) The compound according to the above (8), wherein R^13a and R^13b are both hydrogen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(10) The compound according to the above (8) or (9), wherein ring E is a cyclopropane ring, or its pharmaceutically acceptable salt or a solvate thereof.

(11) The compound according to any one of the above (1) to (10), wherein ring D is a benzene ring, or its pharmaceutically acceptable salt or a solvate thereof.

(12) The compound according to any one of the above (1) to (11), wherein carbon atom a is positioned on ring D in a 1,4 relationship with respect to carbon atom b, or its pharmaceutically acceptable salt or a solvate thereof.

(13) The compound according to any one of the above (1) to (12), wherein s and s′ are each independently an integer of 0 to 2; and R⁹ and R^9′ are each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt or a solvate thereof.

(14) A compound of the formula (VII):

whereinZ¹ and Z² are each independently an oxygen atom, a sulfur atom or ═N—R^x;R^x is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

R^4a and R^4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo;

n is an integer of 1 to 4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

—X— is —O—, —S—, —N(R⁵)— or —(CR^5aR^5b)—;

R⁵ is 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 are each independently 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;s is an integer of 0 to 3; and

R⁹ is each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof.

(15) The compound according to the above (14), wherein s is an integer of 0 to 2; and R⁹ is each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt or a solvate thereof.

(16) The compound according to any one of the above (1) to (15), wherein Z¹ and Z² are both oxygen atoms or both sulfur atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(17) The compound according to any one of the above (1) to (16), wherein Z¹ and Z² are both oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(18) The compound according to any one of the above (1) to (17), wherein R^c is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group A, unsubstituted alkynyl or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

(19) The compound according to any one of the above (1) to (18), wherein R^c is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group B″ (Substituent Group B″: hydroxy, carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group B″, unsubstituted alkynyl or alkynyl substituted with one or more substituents selected from Substituent Group B″, or its pharmaceutically acceptable salt or a solvate thereof.

(20) The compound according to any one of the above (1) to (19), wherein R^c is unsubstituted alkyl, or its pharmaceutically acceptable salt or a solvate thereof.

(21) The compound according to any one of the above (1) to (19), wherein R^c is —(CR^11aR^11b)m-OH; R^11a and R^11b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R^11a and R^11b together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; and m is an integer of 2 to 4, or its pharmaceutically acceptable salt or a solvate thereof.

(22) The compound according to any one of the above (1) to (19) and (21), wherein R^c is —(CR^11aR^11b)m-OH; R^11a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R^11b is —(CR^12aR^12b)_u—OH: R^12a and R^12b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; u is an integer of 0 to 2; and m is an integer of 2 to 4, or its pharmaceutically acceptable salt or a solvate thereof.

(23) The compound according to any one of the above (1) to (19), (21) and (22), wherein R^c is a group of the formula:

or its pharmaceutically acceptable salt or a solvate thereof.

(24) The compound according to any one of the above (1) to (19), wherein R^c is —(CR^14aR^14b)t-N(R^15a)(R^15b); R^14a and R^14b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R^14a and R^14b together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; t is an integer of 2 to 4; and 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 —(CR^14a′R^14b′)t′-C(═O)N(R^15a′)(R^15b′); R^14s′ and R^14b′ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl or R^14a′ and R^14b′ together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; t′ is an integer of 1 to 4; and R^15a′ and R^15b′ are each independently a hydrogen atom, cyano, 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 its pharmaceutically acceptable salt or a solvate thereof.

(25) The compound according to any one of the above (1) to (19), and (24), wherein R^c is a group of the formula:

wherein R^15a, R^15b, R^15a′ and R^15b′ are as defined in the above (24), or its pharmaceutically acceptable salt or a solvate thereof.

(26) The compound according to any one of the above (1) to (25), wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof.

(27) The compound according to any one of the above (1) to (26), wherein R^4a and R^4b are both hydrogen atoms, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof.

(28) The compound according to any one of the above (1) to (27), wherein n is 1, and R^4a and R^4b are both hydrogen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(29) The compound according to any one of the above (1) to (28), wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(30) The compound according to any one of the above (1) to (29), wherein R² is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(31) The compound according to any one of the above (1) to (30), wherein —X— is —N(R⁵)—, and R⁵ is as defined in the above (1), or its pharmaceutically acceptable salt or a solvate thereof.

(32) The compound according to any one of the above (1) to (31), wherein —X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof.

(33) A compound of the formula (IV):

whereinZ¹, Z² and Z³ are each independently an oxygen atom or a sulfur atom;R^c1 is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B (Substituent Group B: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl substituted with one or more substituents selected from Substituent Group B, alkynyl substituted with one or more substituents selected from Substituent Group B;R^4a is a hydrogen atom or substituted or unsubstituted alkyl;R^4b is a hydrogen atom:R⁶ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^4a′ is a hydrogen atom or substituted or unsubstituted alkyl;R^4b′ is a hydrogen atom; and

R^6′ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; provided that

1) a compound wherein R^c1 is ethyl substituted with substituted or unsubstituted amino, or propyl substituted with substituted or unsubstituted amino, and R⁶ and R^6′ are both substituted or unsubstituted phenyl, and

2) a compound wherein R^c1 is unsubstituted oxirane, substituted or unsubstituted phenyl, or alkyl substituted with unsubstituted acetyl, are excluded,

or its pharmaceutically acceptable salt or a solvate thereof.

(34) The compound according to the above (33), wherein Z¹, Z² and Z³ are oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(35) The compound according to the above (33) or (34), wherein R⁶ is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(36) The compound according to any one of the above (33) to (35), wherein R^6′ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl: alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

(37) A pharmaceutical composition comprising the compound according to any one of the above (1) to (36), or its pharmaceutically acceptable salt, or a solvate thereof.

(38) The pharmaceutical composition according to the above (37), wherein the composition has a P2X₃ and/or P2X_2/3 receptor antagonistic effect.

(39) A compound according to any one of the above (1) to (36), or its pharmaceutically acceptable salt, or a solvate thereof for use in a method for treating and/or preventing a disease related to P2X₃ and/or P2X_2/3 receptor.

(40) A method for treating and/or preventing a disease related to P2X₃ and/or P2X_2/3 receptor comprising administering the compound according to any one of the above (1) to (36), or its pharmaceutically acceptable salt, or a solvate thereof.

(41) A pharmaceutical composition having an analgesic effect or an improving effect of urination disorder comprising a compound of the formula (I):

wherein(i)R^h and R^j are taken together to form a bond;

R^a and R^b and/or R^d and R^e are taken together to form oxo, thioxo or ═N—R^x;

R^x is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

—R^f is —(CR^4aR^4b)n-R²;R^4a and R^4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

—R^g is —X—R³;

—X— is —O—, —S—, —N(R⁵)— or —(CR^5aR^5b)—;

R³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl; and

R^5a and R^5b are each independently 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; or

(ii)R^h and R^j are taken together to form a bond;R^a is a group of —Y—R^1a;R^1a 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

—Y— is —O—, —S—, —N(R⁷)— or —C(R^8aR^8b)—;

R⁷ is a hydrogen atom, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl;R^8a and R^8b are each independently a hydrogen atom, halogen or substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^b and R^c are taken together to form a bond;R^d and R^e are taken together to form oxo or thioxo; andR^f and R^g are as defined in the above (i); or(iii)R^a and R^b, R^d and R^e, and/or R^g and R^h are taken together to form oxo or thioxo:R^c is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B (Substituent Group B: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl substituted with one or more substituents selected from Substituent Group B, or alkynyl substituted with one or more substituents selected from Substituent Group B;

R^f is —(CR^4aR^4b)—R⁶;

R^j is —(CR^4a′R^4b′)—R^6′;

R⁶ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^6′ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

R^4a, R^4b, R^4a′ and R^4b′ are each independently a hydrogen atom, or substituted or unsubstituted alkyl; or(iv) R^j and R^b are taken together to form a bond;R^a is a group of —Y—R^1a;

—Y— is —O—, —S—, —N(R⁷)— or —C(R^8aR^8b)—;

R^1a 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, a 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^d and R^e are taken together to form oxo, thioxo or ═N—R═;R^x is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;—R^f is —(CR^4aR^4b)n-R²;R^4a and R^4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^g and R^h are taken together to form ═N—R³; andR³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, provided that1) a compound wherein, in (i), —X— is —NH—, and R³ is cyclohexyl substituted with guanidyl, and2) a compound wherein, in (ii), R^a is substituted phenyl, R^d and R^a are taken together to form thioxo, R^4a and R^4b are taken together to form oxo, and R³ is unsubstituted cyclohexyl,are excluded,or its pharmaceutically acceptable salt or a solvate thereof.

(42) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to the above (41), comprising the compound of the formula (II):

whereinZ¹ and Z² are each independently an oxygen atom, a sulfur atom or ═N—R^x;R^x, R^4a, R^4b, n, R², X, and R³ are as defined in the above (41); andR^c1 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(43) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to the above (42), comprising the compound wherein Z¹ and Z² are both oxygen atoms or both sulfur atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(44) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder, according to the above (42) or (43), comprising the compound wherein Z¹ and Z² are both oxygen atoms or its pharmaceutically acceptable salt or a solvate thereof.

(45) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (44), comprising the compound wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

(46) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (45), comprising the compound wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof.

(47) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to the above (41), comprising the compound of the formula (III):

wherein Z² is an oxygen atom, a sulfur atom or ═N—R^x; and R^x, —Y—, R^1a, R^4a, R^4b, n, R², —X— and R³ are as defined in the above (41), or its pharmaceutically acceptable salt or a solvate thereof.

(48) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to the above (47), comprising the compound wherein Z² is an oxygen atom or a sulfur atom, or its pharmaceutically acceptable salt or a solvate thereof.

(49) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to the above (47) or (48), comprising the compound wherein —Y— is —O—, or its pharmaceutically acceptable salt or a solvate thereof.

(50) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (47) to (49), comprising the compound wherein R^1a is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocycyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

(51) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (47) to (50), comprising the compound wherein R^1a is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof.

(52) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (51), comprising the compound wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof.

(53) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (52), comprising the compound wherein R^4a and R^4b are both hydrogen atoms, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof.

(54) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (53), comprising the compound wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(55) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (54), comprising the compound wherein R² is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(56) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (55), comprising the compound wherein —X— is —N(R⁵)—, and R⁵ is as defined in the above (41), or its pharmaceutically acceptable salt or a solvate thereof.

(57) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (56), comprising the compound wherein —X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof.

(58) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (57), comprising the compound wherein R³ is a group of the formula:

wherein ring A is an aromatic carbocyclic ring or an aromatic heterocyclic ring;s is an integer of 0 to 3; andR⁹ is each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof.

(59) The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to any one of the above (42) to (58), comprising the compound wherein R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

(60) A method of producing a compound of the formula (XI):

wherein Z¹ and Z² are each independently an oxygen atom or a sulfur atom, R^f1 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^c1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;

X is —N(R⁵)—;

R⁵ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl, or its pharmaceutically acceptable salt or a solvate thereof, characterized by reacting a compound of the formula (X):

wherein Z¹, Z², R^f1 and R^c1 are as defined above;R²⁷ is substituted or unsubstituted alkyl; andn′ is an integer of 0 to 3 or its salt,with a compound of the formula: R³—X′wherein R⁸ is as defined above;

—X′ is —NH(R⁵); and

R⁵ is as defined above.In the above (60), the following compound of the formula (XII), its pharmaceutically acceptable salt or a solvate thereof can be used instead of the compound of the formula (X), its pharmaceutically acceptable salt or a solvate thereof.

(60′) A method of producing a compound of the formula (XVII):

wherein Z¹, Z², R^c1, R^4a, R^4b, n, R², X and R³ are as defined in the (62) mentioned below, or its pharmaceutically acceptable salt or a solvate thereof comprising the steps ofi) reacting a compound of the formula (XIII);

wherein R²⁷ and n′ are as defined in the above (60) or its salt with a compound of the formula:

wherein R^c is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl or its salt in the presence of a base to give a compound of the formula (XIV):

wherein Z¹, R^c1, R²⁷ and n′ are as defined in the above (60) or its salt,ii) reacting the compound of the formula (XIV) or its salt with a carbonylating agent or a thiocarbonylating agent in the presence of a base to give a compound of the formula (XV):

wherein Z¹, Z², R^c1, R²⁷ and n′ are as defined in the above (60) or its salt,

iii) reacting the compound of the formula (XV) with a compound of the formula:

R²—(CR^4aR^4b)n-Y

wherein R², R^4a, R^4b and n are as defined in the (62) mentioned below and Y is a leaving group or its salt in the presence of a base to give a compound of the formula (XVI):

wherein Z¹, Z², R^c1, R^4a, R^4b, n, R², R²⁷ and n′ are as defined in the (62) mentioned below or its salt,andiv) reacting the compound of the formula (XVI) or its salt with a compound of the formula:

R³—X′

wherein R³ and —X′ are as defined in the above (60) or its salt.In the above (60′), “to give a compound or its salt” includes a case that the compound or its salt are presence in a reaction system and a case that the compound or its salt are isolated.In the above (60′), a compound of the following formula (XII):

wherein R^f1 is —(CR^4aR^4b)n-R² wherein R^4a, R^4b, n and R² are as defined in the (68) mentioned below; Z¹, Z², R^c1, R²⁷ and n′ are as defined in the (66) mentioned below, or its pharmaceutically acceptable salt or a solvate thereof can be used instead of the compound of the formula (XVI) or its pharmaceutically acceptable salt or a solvate thereof.

(61) The method according to the above (60) or (60′), wherein Z¹ and Z² are oxygen atoms.

(62) The method according to any one of the above (60), (60′) and (61), wherein R^f1 is a group of —(CR^4aR^4b)n-R²;

wherein R^4a and R^4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4; andR² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

(63) The method according to any one of the above (60), (60′), (61) and (62), wherein R^c1 is substituted or unsubstituted alkyl.

(64) The method according to any one of the above (60), (60′), and (61) to (63), wherein R⁵ is a hydrogen atom.

(65) The method according to any one of the above (60), (61′), and (61) to (64), wherein R³ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

(66) A compound of the formula (XII):

wherein Z¹ and Z² are each independently an oxygen atom or a sulfur atom; R^f1 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^c1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;provided that R^c1 is not unsubstituted alkyl, unsubstituted alkenyl or unsubstituted cycloalkyl when R^f1 is a hydrogen atom:R²⁷ is substituted or unsubstituted alkyl; andn′ is an integer of 0 to 3, or its pharmaceutically acceptable salt or a solvate thereof.

(67) The compound according to the above (66), wherein Z¹ and Z² are oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(68) The compound according to the above (66) or (67), wherein R^f1 is a group of —(CR^4aR^4b)n-R²;

wherein R^4a and R^4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4; andR² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(69) The compound according to any one of the above (66) to (68), wherein R^c1 is substituted or unsubstituted alkyl, or its pharmaceutically acceptable salt or a solvate thereof.

(70) The compound according to any one of the above (66) to (69), wherein R⁵ is a hydrogen atom, or its pharmaceutically acceptable salt or a solvate thereof.

Furthermore, the present invention relates to the followings:

(1B) A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising a compound of the formula (I):

wherein(i)R^h and R^j are taken together to form a bond;R^a and R^b and/or R^d and R^e are taken together to form oxo, thioxo, or ═N—R^x;R^x is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;—R^f is —(CR^4aR^4b)n-R²;R^4a and R^4b are each independently hydrogen, substituted or unsubstituted alkyl, orR^4a and R^4b are taken together to form oxo or thioxo;n is an integer of 1-4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

R^g is —X—R³;

—X— is —O—, —S—, —N(R⁵)—, or —(CR^5aR^5b)—;

R³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R⁵ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl;R^5a and R^5b are each independently hydrogen, 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;(ii)R^h and R^j are taken together to form a bond;R^a is a group of —Y—R^1a;R^1a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl:

—Y— is —O—, —S—, —N(R⁷)—, or —C(R^8aR^8b)—;

R⁷ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl;R^8a and R^8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^b and R^c are taken together to form a bond;R^d and R^e are taken together to form oxo or thioxo;R^f and R^g are as defined in the above (i);(iii)R^a and R^b, R^d and R^e, and/or R^g and R^h are taken together to form oxo or thioxo;R^c is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B (Substituent Group B: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl substituted with one or more substituents selected from Substituent Group B, or alkynyl substituted with one or more substituents selected from Substituent Group B;

R^f is —(CR^4aR^4b)—R⁶;

R^j is —(CR^4a′R^4b′)—R^6′;

R⁶ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^6′ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^4a, R^4b, R^4a′, and R^4b′ are each independently hydrogen or substituted or unsubstituted alkyl;(iv)R^j and R^b are taken together to form a bond;R^a is a group of —Y—R^1a;

Y— is —O—, —S—, —N(R⁷)—, or —C(R^8aR^8b)—;

R^1a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl:R^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^d and R^e are taken together to form oxo, thioxo, or ═N—R^x;R^x is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;—R^f is —(CR^4aR^4b)n-R²;R^4a and R^4b are each independently hydrogen, substituted or unsubstituted alkyl, orR^4a and R^4b are taken together to form oxo or thioxo;n is an integer of 1 to 4:R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^g and R^h are taken together to form ═N—R³;R³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, provided that1) a compound wherein, in (i), —X— is —NH—, and R³ is cyclohexyl substituted with guanidyl, and2) a compound wherein, in (ii), R^a is substituted phenyl, R^d and R^e are taken together to form thioxo, R^4a and R^4b are taken together to form oxo, and R³ is unsubstituted cyclohexyl,are excluded,or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

Furthermore, the present invention relates to the mentioned below.

(2) A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound of the formula (II):

whereinZ¹ and/or Z² is an oxygen atom, a sulfur atom, or (═)N—R^x;R^x, R^4a, R^4b, n, R², X and R³ are as defined in the above (1B);R^c1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(3B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (2B) wherein Z¹ and/or Z² is an oxygen atom or a sulfur atom or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(4B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (2B) or (3B) wherein Z¹ and Z² are both oxygen atoms, its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(5B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (4B) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(6B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (5B) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(7B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder according to the above (1B) comprising the compound of the formula (III):

wherein Z² is an oxygen atom, a sulfur atom or (═)N—R^x; R¹, —Y—, R^1a, R^4a, R^4b, n, R², —X—, and R³ are as defined in the above (1B) or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(8B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (7B) wherein Z² is an oxygen atom or a sulfur atom or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(9B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (7B) or (8B) wherein —Y— is —O—, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(10B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (7B) to (9B) wherein R^1a is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(11B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (7B) to (10B) wherein R^1a is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′; carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(12B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (11B) wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredients.

(13B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (12B) wherein R^4a and R^4b are both hydrogen atoms or R^4a and R^4b are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(14B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (13B) wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(15B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (14B) wherein R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C, its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(16B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (15B) wherein —X— is —N(R⁵)— wherein R⁵ is as defined in the above (1B), its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(17B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (16B) wherein —X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(18B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (17B) wherein R³ is a group of the formula:

wherein ring A is aryl or heteroaryl;s is an integer of 0 to 3;R⁹ are each 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(19B) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2B) to (18B) wherein R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(20B) A compound of the formula (IV):

whereinZ¹, Z², and/or Z³ is an oxygen atom or a sulfur atom;R^c1 is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B (Substituent Group B: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, and nitro), alkenyl substituted with one or more substituents selected from Substituent Group B, or alkynyl substituted with one or more substituents selected from Substituent Group B;R^4a is hydrogen or substituted or unsubstituted alkyl;R^4b is hydrogen;R⁶ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^4a′ is hydrogen or substituted or unsubstituted alkyl;R^4b′ is hydrogen;R^6′ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or solvate thereof.

(21B) The compound according to the above (20B) wherein Z¹, Z² and Z³ are oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(22B) The compound according to the above (20B) or (21B) wherein R⁶ is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(23B) The compound according to any one of the above (20B) to (22B) wherein R^6′ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

(24B) A compound of the formula (II):

whereinZ¹ and/or Z² is an oxygen atom, a sulfur atom, or (═N)—R^x;R^x is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.R^c1 is hydrogen, alkyl substituted with one or more substituents selected from Substituent Group E (Substituent Group E: sulfo; substituted or unsubstituted sulfamoyl; substituted or unsubstituted imino; substituted or unsubstituted guanidyl; a substituted or unsubstituted non-aromatic heterocyclic group provided that morpholinyl, imidazolidinyl, tetrahydropyranyl and piperidinyl are excluded; substituted or unsubstituted heteroaryl provided that pyridyl is excluded), alkenyl substituted with one or more substituents selected from Substituent Group E, or alkynyl substituted with one or more substituents selected from Substituent Group E;R^4a and R^4b are each independently hydrogen, substituted or unsubstituted alkyl, orR^4a and R^4b are taken together to form oxo or thioxo;n is an integer of 1 to 4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

—X— is —O—, —S—, —N(R⁵)—, or —(CR^5aR^5b)—;

R⁵ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;R^5a and R^5b are each independently hydrogen, 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;R³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(25B) The compound according to the above (24B) wherein Z¹ and/or Z² is an oxygen atom or a sulfur atom, or its pharmaceutically acceptable salt or a solvate thereof.

(26B) The compound according to the above (24B) wherein Z¹ and Z² are both oxygen atoms, its pharmaceutically acceptable salt or a solvate thereof.

(27B) The compound according to any one of the above (24B) to (26B) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

(28B) The compound according to any one of the above (24B) to (27B) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof.

(29B) The compound according to any one of the above (24B) to (28B) wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof.

(30B) The compound according to any one of the above (24B) to (29B) wherein R^4a and R^4b are both hydrogen atoms or R^4a and R^4b are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof.

(31B) The compound according to any one of the above (24B) to (30B) wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(32B) The compound according to any one of the above (24B) to (31B) wherein R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(33B) The compound according to any one of the above (24B) to (33B) wherein —X— is —N(R⁵)— (wherein R⁵ is as defined in the above (1B)), or its pharmaceutically acceptable salt or a solvate thereof.

(34B) The compound according to any one of the above (24B) to (33B) wherein X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof.

(35B) The compound according to any one of the above (24B) to (34B) wherein R³ is a group of the formula:

wherein ring A is aryl or heteroaryl;s is an integer of 0 to 3; andR⁹ are each 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaryloxy, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy), or its pharmaceutically acceptable salt or a solvate thereof.

(36B) The compound according to any one of the above (24B) to (35B) wherein R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino) (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl: alkylthio; cycloalkyl; cycloalkenyl; aryloxy; heteroaryloxy: a non-aromatic heterocyclic group; and alkylamino) or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

(37B) A compound of the formula (VII):

whereinZ¹ and/or Z² is oxo, thioxo, or ═N—R^x;R^x is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^4a and R^4b are each independently hydrogen, substituted or unsubstituted alkyl, orR^4a and R^4b are taken together to form oxo or thioxo;n is an integer of 1 to 4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

—X— is —O—, —S—, —N(R⁵)—, or —(CR^5aR^5b)—;

R⁵ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;R^5a and R^5b are each independently hydrogen, 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;s is an integer of 0 to 3;R⁹ are each 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof.

(38B) The compound according to the above (37B) wherein Z¹ and Z² are both oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(39B) The compound according to the above (37B) or (38B) wherein R^c is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group A, unsubstituted alkynyl, alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

(40B) The compound according to any one of the above (37B) to (39B) wherein R^c is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group B″ (Substituent Group B″: hydroxy, carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group B″, unsubstituted alkynyl, alkynyl substituted with one or more substituents selected from Substituent Group B″, or its pharmaceutically acceptable salt or a solvate thereof.

(41B) The compound according to any one of the above (37B) to (40B) wherein n is 1 and R^4a and R^4b are both hydrogen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(42B) The compound according to any one of the above (37B) to (41B) wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(43B) The compound according to any one of the above (37B) to (42B) wherein R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof given in either of the statements to either of the above (37B)-(42B).

(44B) The compound according to any one of the above (37B) to (43B) wherein —X— is —N(R⁵)— wherein R⁵ is as defined in the above (37B), or its pharmaceutically acceptable salt or a solvate thereof.

(45B) The compound according to any one of the above (37B) to (44B) wherein X— is —NH—, its pharmaceutically acceptable salt or a solvate thereof.

(46B) The compound according to any one of the above (37B) to (45B) wherein s is an integer of 0 to 2, and R⁹ are each 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, and substituted or unsubstituted sulfamoyl), or its pharmaceutically acceptable salt or a solvate thereof.

In (46B), a compound wherein s is 0 or 1, or its pharmaceutically acceptable salt or a solvate thereof is preferable.

(47B) A compound of the formula (VIII):

whereinZ¹ and/or Z² is oxo, thioxo, or ═N—R^x;R^x is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^4a and R^4b are each independently hydrogen, substituted or unsubstituted alkyl, orR^4a and R^4b are taken together to form oxo or thioxo;n is an integer of 1-4;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;—X— is —O—, —S—, —N(R⁵)—, or —(CR^5aR^5b)—; ring B is heteroaryl;s and s′ are each independently is an integer of 0 to 3;R⁹ and R^9′ are each 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof.

(48B) The compound according to the above (47B) wherein Z¹ and Z² are both oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(49B) The compound according to the above (47B) or (48B) wherein R^c is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group A, unsubstituted alkynyl, alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

(50B) The compound according to any one of the above (47B) to (49B) wherein R^c is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group B″ (Substituent Group B″: hydroxy, carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group B″, unsubstituted alkynyl, alkynyl substituted with one or more substituents selected from Substituent Group B″, or its pharmaceutically acceptable salt or a solvate thereof.

(51B) The compound according to any one of the above (47B) to (50B) wherein n is 1 and R^4a and R^4b are both hydrogen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(52B) The compound according to any one of the above (47B) to (51B) wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof

(53B) The compound according to any one of the above (47B) to (52B) wherein R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(54B) The compound according to any one of the above (47B) to (53B) wherein X— is —N(R⁵)— wherein R⁵ is as defined in the above (47B), or its pharmaceutically acceptable salt or a solvate thereof.

(55B) The compound according to any one of the above (47B) to (54B) wherein X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof.

(56B) The compound according to any one of the above (47B) to (55B) wherein ring B is thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, furan, thiophene, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, pyridazine, triazine, or benzoxazole, or its pharmaceutically acceptable salt or a solvate thereof.

(57B) The compound according to any one of the above (47B) to (56B) wherein s and s′ are each independently an integer of 0 to 2, and R⁹ and R^9′ are each 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, or substituted or unsubstituted sulfamoyl, or its pharmaceutically acceptable salt or a solvate thereof.

In (57B), a compound wherein s is 0, s′ is 0 or 1, and R^9′ is 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, or substituted or unsubstituted sulfamoyl, or its pharmaceutically acceptable salt or solvate thereof is preferable.

(58B) A pharmaceutical composition comprising a compound according to any one of the above (20B) to (57B), or its pharmaceutically acceptable salt or a solvate thereof.

(59B) The pharmaceutical composition according to (58B) wherein the composition has a P2X₃ and/or P2X_2/3 receptor antagonistic effect.

(60B) A compound according to any one of the above (20B) to (57B) for use in a method for treating and/or preventing a disease related to P2X₃ and/or P2X_2/3 receptor, or its pharmaceutically acceptable salt or a solvate thereof.

(61B) A compound according to any one of the above (20B) to (57B) for use in a method for treating and/or preventing a disease related to P2X₃ and/or P2X_2/3 receptor, or its pharmaceutically acceptable salt or a solvate thereof.

(62B) A method for treating or preventing a disease related to P2X₃ and/or P2X_2/3 receptor, comprising administering the compound according to any one of the above (20B) to (57B), or its pharmaceutically acceptable salt or a solvate thereof.

(1A) A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound of the formula (I):

wherein(i)R^h and R^j are taken together to form a bond;R^a, and R^b, and/or R^d and R^e are taken together to form oxo, thioxo, or ═N—R^x;R^x is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R^c is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;—R^f is —(CR^4aR^4b)n-R²;R^4a and R^4b are each independently substituted or unsubstituted alkyl, or R^4a and R^4b are taken together to form oxo or thioxo;R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

—R^g is —X—R³;

—X— is —O—, —S—, —N(R⁵)—, or —(CR^5aR^5b)—;

R³ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;R⁵ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;R^5a and R^5b are each independently hydrogen, 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;(ii)

R^h and R^j are taken together to form a bond;

R^a is a group of —Y—R^1a;R^1a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

—Y— is —O—, —S—, —N(R⁷)—, or —C(R^8aR^8b)—;

R⁷ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl;R^8a and R^8b are each independently hydrogen, halogen or substituted or unsubstituted alkyl; hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^b and R^c are taken together to form a bond;R^d and R^e are taken together to form oxo or thioxo;R^f and R^g are as defined in the above (i);(iii)R^a and R^b, R^d and R^e, and/or R^g and R^h are taken together to form oxo or thioxo;R^c is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B (Substituent Group B: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl and nitro), alkenyl substituted with one or more substituents selected from Substituent Group B, or alkynyl substituted with one or more substituents selected from Substituent Group B;

R^f is —(CR^4aR^4b)—R⁶;

R^j is —(CR^4a′R^4b′)—R^6′;

R⁶ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;R^6′ is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R^4a, R^4b, R^4a′, and R^4b′ are each independently hydrogen or substituted or unsubstituted alkyl,

provided that1) a compound wherein, in (i), —X— is —NH—, and R³ is cyclohexyl substituted with guanidyl, and2) a compound wherein, in (ii), R^a is substituted phenyl, R^d and R^e are taken together to form thioxo, R^4a and R^4b are taken together to form oxo, and R³ is unsubstituted cyclohexyl,are excluded.or its pharmaceutically acceptable salt or solvate thereof as an active ingredient.

(2A) A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound of the formula (II):

whereinZ¹ and/or Z² is oxo, thioxo, or ═N—R^x;R^x. R^4a, R^4b, n, R², X, and R³ are as defined in the above (1A);R^c1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(3A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (2A) wherein Z¹ and/or Z² is oxo or thioxo, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(4A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (2A) or (3A) wherein Z¹ and Z² are both oxo, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(5A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (4A) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(6A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (5A) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(7A) A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound of the formula (III):

wherein Z² is oxo, thioxo, or ═N—R^x; R^x, —Y—, R^1a, R^4a, R^4b, n, R², —X—, and R³ are as defined in the above (1A); or its pharmaceutically acceptable salt or solvate thereof as an active ingredient.

(8A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (7A) wherein Z² is oxo or thioxo or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(9A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (7A) or (8A) wherein —Y— is —O—, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(10A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (7A) to (9A) wherein R^1a is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(11A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (7A) to (10A) wherein R^1a is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(12A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (16A) wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(13A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (12A) wherein R^4a and R^4b are both hydrogen, or R^4a and R^4b are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(14A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (13A) wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(15A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (2A) to (14A) wherein R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(16A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to the above (2A) to (15A) wherein —X— is —N(R⁵)— wherein R⁵is as defined in the above (1A), or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(17A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (16A) wherein —X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(18A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (17A) wherein R³ is a group of the formula:

wherein ring A is aryl or heteroaryl;s is an integer of 0 to 3;R⁹ are each independently halogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(18A′) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (18A) wherein R³ is a group of the formula:

wherein R^9a is hydrogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted non-aromatic heteroaryl, substituted or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy;R^9b is halogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(18A″) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (18A) and (18A′) wherein R³ is a group of the formula:

wherein R^9a is as defined in the above (18A′); R¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(19A) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (18A) and (18A′) wherein R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alky; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(19A′) The pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound according to any one of the above (2A) to (18A) wherein R³ is a group of the formula (A):

wherein ═W¹—W²═W³—W⁴═W⁵— is any one selected from the following (a) to (h):

(a): ═C(H)—C(R^10a)═C(R^10b)—C(R^10c)═C(H)—;

(b): ═N—C(R^10a)═C(R^10b)—C(R^10c)═C(H)—;

(c): ═C(H)—N═C(R^10b)—C(R^10c)═C(H)—;

(d): ═C(H)—C(R^10a)═N—C(R^10c)═C(H)—;

(e): ═C(H)—C(R^10a)═C(R^10b)—N═C(H)—;

(f): ═N—C(R^10a)═C(R^10b)—C(R^10c)═N—;

(g): ═C(H)—C(R^10a)═N—C(R^10c)═C(H)—; and

(h): ═C(H)—N═C(R^10b)—N═C(H)—;

R^10a, R^10b, and R^10c are each independently hydrogen, halogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or heteroaryloxy; or R^10a and R^10b or R^10b and R^10C together with the ring atom to which they are attached form a non-aromatic carbocyclic ring, a non-aromatic heterocyclic ring, an aromatic carbocyclic ring or an aromatic heterocyclic ring, or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(19A″) A compound described in any one of the above (1A) to (19A), (18A′), (18A″) and (19A′) for use in a method for treating, preventing and/or improving pain and/or urination disorder, or its pharmaceutically acceptable salt or a solvate thereof.

(19A′″) A method for treating, preventing and/or improving pain and/or urination disorder comprising administering the compound described in any one of the above (1A) to (19A), (18A′), (18A″) and (19A′), or its pharmaceutically acceptable salt or a solvate thereof.

(20A) A compound of the formula (IV):

whereinZ¹, Z², and/or Z³ is an oxygen atom or a sulfur atom;R^c1 is unsubstituted alkyl, unsubstituted alkynyl, alkyl substituted with one or more substituents selected from Substituent Group B, alkenyl substituted with one or more substituents selected from Substituent Group B, or alkynyl substituted with one or more substituents selected from Substituent Group B;R^4a is hydrogen or substituted or unsubstituted alkyl;R^4b is hydrogen;R⁶ is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;R^4a′ is hydrogen or substituted or unsubstituted alkyl;

R^4b′ is hydrogen;

R^6′ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(21A) The compound according to the above (20A) wherein Z¹, Z², and Z³ are oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

(22A) The compound according to the above (20A) or (22A) wherein R⁶ is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C, aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(23A) The compound according to any one of the above (20A) to (22A) wherein R^6′ is aryl optionally substituted with one or more substituents selected from Substituent Group D, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

(24A) A compound of the formula (II):

whereinZ¹ and/or Z² is oxo, thioxo, or ═N—R^x;R^x, R^4a, R^4b, n, R², X and R³ are as defined in the above (1A);R^c1 is hydrogen, alkyl substituted with one or more substituents selected from Substituent Group E (Substituent Group E: sulfo: substituted or unsubstituted sulfamoyl; substituted or unsubstituted, imino; substituted or unsubstituted guanidyl; a substituted or unsubstituted non-aromatic heterocyclic group provided that morpholinyl, imidazolidinyl, tetrahydropyranyl and piperidinyl are excluded; and substituted or unsubstituted heteroaryl provided that pyridyl are excluded), alkenyl substituted with one or more substituents selected from Substituent Group E, or alkynyl substituted with one or more substituents selected from Substituent Group E, or its pharmaceutically acceptable salt or a solvate thereof.

(25A) The compound according to the above (24A) wherein Z¹ and/or Z² is oxo or thioxo, or its pharmaceutically acceptable salt or a solvate thereof.

(26A) The compound according to the above (24A) or (25A) wherein Z¹ and Z² are both oxo, or its pharmaceutically acceptable salt or a solvate thereof.

(27A) The compound according to any one of the above (24A) to (26A) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof.

(28A) The compound according to any one of the above (24A) to (27A) wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof.

(29A) The compound according to any one of the above (24A) to (28A) wherein R^4a and R^4b are both hydrogen atoms or R^4a and R^4b are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof.

(30A) The compound according to any one of the above (24A) to (29A) wherein R² is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(31A) The compound according to any one of the above (24A) to (30A) wherein R² is aryl substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

(32A) The compound according to any one of the above (24A) to (31A) wherein —X— is —N(R⁵)— wherein R⁵ is as defined in the above (1A), or its pharmaceutically acceptable salt or a solvate thereof.

(33A) The compound according to any one of the above (24A) to (32A) wherein X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof.

(34A) The compound according to any one of the above (24A) to (33A) wherein R³ is a group of the formula:

wherein ring A is aryl or heteroaryl;s is an integer of 0 to 3;R⁹ are each independently halogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof according to any one of the above (24A) to (33A).

(34A′) The compound according to any one of the above (24A) to (34A) wherein R³ is a group of the formula:

wherein R^9a is hydrogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy, or substituted or unsubstituted heteroaryloxy;R^9b is halogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a 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 heterocyclyloxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy, or its pharmaceutically acceptable salt or a solvate thereof.

(34A″) The compound according to any one of the above (24A) to (34A) and (34A′) wherein R³ is a group of the formula:

whereinR⁹ is as defined in the above (7A); R¹⁰ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

(35A) The compound according to any one of the above (24A) to (34A), (34A′) and (34A″) wherein R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

(36A) A compound of the following formula:

or its pharmaceutically acceptable salt or a solvate thereof.

(36A′) A compound of the following formula:

or its pharmaceutically acceptable salt or a solvate thereof.

(36A″) A compound of the following formula:

its pharmaceutically acceptable salt or a solvate thereof.

(36A′″) A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound of the following formula:

or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(37A) A pharmaceutical composition comprising the compound according to any one of the above (20A) to (36A), (35A′), (36A′), (35A″) and (36A″), or its pharmaceutically acceptable salt or a solvate thereof.

(37A′) A pharmaceutical composition comprising the compound according to any one of the above (20A) to (36A), (35A′), (36A′), (35A″) and (36A″) or its pharmaceutically acceptable salt or a solvate thereof wherein the composition has a P2X₃ and/or P2X_2/3 receptor antagonistic effect.

(38A) The pharmaceutical composition according to (37A) which has a P2X₃ and/or P2X_2/3 receptor antagonistic effect.

(39A) A compound according to any one of the above (20A) to (36A), (35A′), (36A′), (35A″) and (36A″), or its pharmaceutically acceptable salt or a solvate thereof for use in a method for treating and/or preventing a disease related to P2X₃ and/or P2X_2/3 receptor.

(40A) A method for treating and/or preventing a disease related to P2X₃ and/or P2X_2/3 receptor comprising administering the compound according to (20A) to (36A), (35A′), (36A′), (35A″), (36A″) and (36A′″), or its pharmaceutically acceptable salt or a solvate thereof.

(41A) A compound according to any one of the above (20A) to (36A), (35A′), (36A′), (35A″), (36A″) and (36A′″), or its pharmaceutically acceptable salt or a solvate thereof for use in a method for treating pain and/or urination disorder.

(42A) A method for relieving pain and/or treating urination disorder comprising administering the compound according to (20A) to (36A), (35A′), (36A′), (35A″), (36A″) and (36A′″) or its pharmaceutically acceptable salt or a solvate thereof.

Effect of the Invention

The compound of the invention has an antagonistic effect on P2X₃ and/or P2X_2/3 receptor and is useful in the treatment of diseases or conditions associated with a P2X₃ and/or P2X_2/3 receptor, especially chronic pain, overactive bladder, etc.

MODE FOR CARRYING OUT THE INVENTION

As used throughout the specification, the following terms have the following meaning unless specifically indicated.

The term “halogen” means fluoro, chloro, bromo and iodo.

The halogen moiety in said “haloalkyl”, “haloalkylcarbamoyl” and “haloalkyloxy” is as defined above for “halogen”.

The term “alkyl” includes a straight or branched chain monovalent hydrocarbon group of a carbon number of 1 to 15, as one embodiment a carbon number of 1 to 10, and as another embodiment a carbon number of 1 to 6. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl, n-nonyl, n-decyl, n-undecanyl, dodecanyl, tridecanyl, and the like.

The alkyl moiety in said “haloalkyl”, “hydroxyalkyl”, “aminoalkyl”, “alkylaminoalkyl”, “alkylamino”, “alkylimino”, “alkylsulfonyl”, “alkylsulfamoyl”, “alkylcarbamoyl”, “arylalkyl”, “alkylsilylalkynyl”, “alkylsulfonyl”, “alkylsulfinyl”, “alkylcarbamoyl”, “alkylcarbamoylalkyl”, “alkylsulfamoyl”, “alkylsulfamoylalkyl”, “haloalkylcarbamoyl”, “hydroxyalkylcarbamoyl”, “alkyloxycarbonylalkyl” and “arylalkylamino” is as defined above for “alkyl”.

The term “alkyloxy” includes an alkyloxy group of which alkyl moiety is as defined above for “alkyl”. For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc are exemplified as alkyloxy.

The alkyloxy moiety in said “haloalkyloxy”, “arylalkyloxy”, “alkyloxycarbonyl”, “alkyloxycarbonylalkyl”, and “alkyloxyimino” is as defined above for “alkyloxy”.

For example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio, and the like are exemplified as “alkylthio”.

For example, methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl, and the like are exemplified as “alkyloxycarbonyl”.

For example, mono- or di-alkylcarbamoyl, such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, and the like are exemplified as “alkylcarbamoyl”.

The term “alkenyl” includes linear or branched alkenyl of a carbon number of 2 to 15, as one embodiment a carbon number of 2 to 10, and as another embodiment a carbon number of 2 to 6 having one or more double bonds at any available position. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl and the like.

The alkenyl moiety in said “alkenyloxy”, “alkenylthio”, “alkenylcarbamoyl”, “alkenylsulfamoyl” and “alkenyloxycarbonyl” is as defined above for “alkenyl”.

The term “alkynyl” includes a linear or branched alkynyl of a carbon number of 2 to 15, as one embodiment a carbon number of 2 to 10, as another embodiment a carbon number 2 to 6. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl and decynyl. These have one or more triple bonds at any available position and may further a double bond.

The alkynyl moiety in said “alkynyloxy”, “alkynylthio” and “alkynyloxycarbonyl” is as defined above for “alkynyl”.

The term “acyl” includes a group of the formula R—C(═O)—, wherein R is, for example, “hydrogen”, “alkyl”, “alkenyl” or “alkynyl” as defined above and “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl” or “heteroaryl” as defined below.

The acyl moiety in “acylamino” and “acylimino” is as defined above for “acyl”

The term “cycloalkane” includes a monocyclic or polycyclic saturated cyclic carbocyclic ring containing from 3 to 10 carbons. Monocyclic cycloalkane includes, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, etc. Polycyclic cycloalkane includes norbornanane, tetrahydronaphthalene, etc.

The term “cycloalkyl” includes a monovalent group derived from “cycloalkane” as defined above. Monocyclic cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, etc. As one embodiment, C3 to C8 cycloalkane is exemplified. As another embodiment, C3 to C7 cycloalkane is exemplified. Polycyclic cycloalkyl includes norbornyl, tetrahydronaphthalene 5-yl, tetrahydronaphthalene-6-yl, etc.

Examples of “cycloalkyl” for R² are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

Examples of “cycloalkyl” for R³ are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

The cycloalkyl moiety in said “cycloalkyloxycarbonyl” and “cycloalkyloxy” is as defined above for “cycloalkyl”.

The term “cycloalkene” includes a non-aromatic monocyclic or polycyclic ring of 3 to 10 carbons containing at least one carbon-carbon double bond. As one embodiment C3 to C8 cycloalkene is exemplified. As another embodiment C3 to C7 cycloalkene is exemplified. Monocyclic cycloalkene includes, for example, cyclopentene, cyclohexene, etc. Polycyclic cycloalkene includes norbornene, indene, etc.

The term “cycloalkenyl” includes a monovalent group derived from “cycloalkene” as defined above. Monocyclic cycloalkenyl includes cyclopentenyl, cyclohexenyl, etc. As one embodiment, C3 to C8 cycloalkane is exemplified. As another embodiment, C3 to C7 cycloalkane is exemplified. Polycyclic cycloalkenyl includes norbornenyl, indene-1-yl, indene-2-yl, indene-3-yl, etc.

The cycloalkenyl moiety in said “cycloalkenyloxycarbonyl” and “cyclolalkenyloxy” is as defined above for “cycloalkenyl”.

The term “aromatic carbocyclic ring” includes an aromatic hydrocarbocyclic ring which is monocyclic or fused-cyclic, such as benzene ring, naphthalene ring, anthracene ring, phenanthrene ring, etc.

The term “aryl” includes a monovalent group derived from “aromatic carbocyclic ring” as defined above. For example, phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, etc. are exemplified.

Preferable “aryl” for R³ is phenyl.

The aryl moiety in said “aryloxy”, “arylthio” and “aryloxycarbonyl” is as defined above for “aryl”.

The term “heterocyclic ring” includes an aromatic or a non-aromatic monocyclic or fused-cyclic ring, which includes a five- to seven-membered ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring;

a fused ring consisting of two or more said five- to seven-membered rings; ora fused ring consisting of said five- to seven-membered ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring fused to one or more “aromatic carbocyclic ring”, “cycloalkane” or “cycloalkene” as defined above.

For example, a monocyclic non-aromatic heterocyclic ring such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, tetrahydropyrane, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, etc.;

a monocyclic aromatic heterocyclic ring such as pyrrole, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc; and

a fused heterocyclic ring such as indole, isoindole, indazole, indolizine, indoline, isoindoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzopyrane, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazole, benzodioxane, tetrahydroquinoline, tetrahydrobenzothiophene, etc. are exemplified.

The term “heterocyclic group” includes a monovalent group derived from “heterocyclic ring” as defined above.

For example, monocyclic non-aromatic heterocyclic groups such as pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyranyl, dihydropyridyl, dihydropyridazinyl, dihydropyrazinyl, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl, etc.;

monocyclic aromatic heterocyclic groups such as pyrrolyl, pyrazinyl, pyrazolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc; and

fused heterocyclic groups such as indolyl, isoindolyl, indazolyl, indolizinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazolinyl, benzodioxanyl, tetrahydroquinoline, tetrahydrobenzothienyl, etc. are exemplified.

The term “non-aromatic carbocyclic ring” includes “cycloalkane” as defined above, “cycloalkene” as defined above, a fused ring consisting of “aromatic carbocyclic ring” as defined above fused to “cycloalkane” or “cycloalkene” as defined above. As a fused ring, indene and the like are exemplified.

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

The non-aromatic carbocyclyl moiety in said “non-aromatic carbocyclyloxy” and “non-aromatic carbocyclylalkyloxy” is as defined above for “non-aromatic carbocyclic ring”.

The term “aromatic heterocyclic ring” includes aromatic rings of “heterocyclic ring” as defined above.

“Aromatic heterocyclic ring” includes a five- to seven-membered aromatic ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring;

a fused aromatic ring consisting of two or more said rings; anda fused ring consisting of a five- to seven-membered aromatic ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring fused to one or more “aromatic carbocyclic ring” as defined above.

For example, a monocyclic aromatic heterocyclic ring such as pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc; and

a fused aromatic heterocyclic ring such as indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline, etc. are exemplified.

“Five- or six-membered aromatic heterocyclic ring” includes five- or six-membered rings of “aromatic heterocyclic ring” as defined above. Examples are thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophene, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine, etc.

“Five membered-aromatic heterocyclic ring” includes 6-membered rings of “aromatic heterocyclic ring” as defined above. Examples are thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophen, imidazole, triazole, tetrazole etc.

“Six-membered aromatic heterocyclic ring” includes six-membered rings of “aromatic heterocyclic ring” as defined above. Examples are pyridine, pyrimidine, pyrazine, pyridazine, triazine, etc.

The term “heteroaryl” includes a monovalent group derived from “aromatic heterocyclic ring” as defined above. “Heteroaryl” includes a five- to seven-membered aromatic group having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring;

a fused aromatic group consisting of two or more said rings; anda fused ring consisting of a five- to seven-membered aromatic group having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring fused to one or more “aromatic carbocyclic ring” as defined above.

For example, monocyclic heteroaryl such as pyrrolyl, pyrazinyl, pyrazolyl, indolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc; and

fused heteroaryl such as isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazolinyl, etc. are exemplified.

One of examples of “heteroaryl” for R² is pyridyl.

Examples of “heteroaryl” for R³ are pyridyl, pyrimidyl, benzofuryl, benzothienyl, indolyl, benzisoxazolyl etc.

One of examples of “heteroaryl” for R³ is pyridyl.

The heteroaryl moiety in said “heteroaryloxy” and “heteroaryloxycarbonyl” is as defined above for “heteroaryl”.

The term “non-aromatic heterocyclic ring” includes non-aromatic rings of “heterocyclic ring” as defined above.

“Non-aromatic heterocyclic ring” includes, a four- to seven-membered non-aromatic ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring;

a fused non-aromatic ring consisting of two or more said rings:a fused ring consisting of a five- to seven-membered aromatic ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring fused to one or more “cycloalkane” or “cycloalkene” as defined above; anda fused ring consisting of a five- to seven-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom, and/or sulfur atom in the ring fused to one or more “aromatic carbocyclic ring” or “non-aromatic carbocyclic ring” as defined above.

For example, monocyclic non-aromatic heterocyclic ring such as oxetane, thietane, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran, dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazoline, tetrahydroisothiazoline etc.;

a fused non-aromatic heterocyclic ring such as indoline, isoindoline, benzopyrane, benzodioxane, tetrahydroquinoline, benzo[d]oxazole-2(3H)-one, tetrahydrobenzothiophene etc. are exemplified.

“Non-aromatic heterocyclic group” includes a monovalent group derived from “non-aromatic heterocyclic ring” as defined above.

Examples are monocyclic non-aromatic heterocyclic group such as pyrrolinyl, pyrrolidine, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazine, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyranyl, dihydropyridyl, dihydropyridazinyl, dihydropyrazinyl, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydrlisothiazolinyl etc. and

a fused heterocyclic group such as benzodioxane, tetrahydroquinoline, benzo[d]oxazole-2(3H)-one, tetrahydrobenzothiophene etc.

The non-aromatic heterocyclyl moiety in said “non-aromatic heterocyclyloxy” and “non-aromatic heterocyclyloxycarbonyl” is as defined above for “non-aromatic heterocyclic ring”.

The term “nitrogen-containing non-aromatic heterocyclic group” includes a group derived from a four- to seven-membered non-aromatic ring which contains at least one nitrogen atom in the ring and may contain one or more atoms arbitrarily selected from an oxygen atom and an sulfur atom in the ring and a fused ring consisting of two or more said rings. Examples are pyrrolinyl, pyrrolidino, pyrrolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholino etc.

The non-aromatic heterocyclyl moiety in said “non-aromatic heterocyclyloxycarbonyl” is as defined above for “non-aromatic heterocyclic ring”.

Substituents for “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylthio”, “substituted alkenylthio”, “substituted alkynylthio”, “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl” and “substituted alkynyloxycarbonyl” include but are not limited to one or more same or different substituents selected from the group consisting of:

hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyloxy (e.g., CF₃O), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), lower alkyloxy (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), alkenyloxy (e.g., vinyloxy, allyloxy, etc.), alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino (e.g., methylamino, ethylamino, dimethylamino, etc.), acylamino (e.g., acetylamino, benzoylamino, etc.), arylalkylamino (e.g., benzylamino, tritylamino), hydroxyamino, alkylsulfonylamino (e.g., methanesulfonylamino), alkylsulfinylamino (e.g. methanesulfinylamino), imino, hydroxyimino, alkylimino (e.g., methylimino, ethylimino, dimethylimino, etc.), alkyloxyimino (e.g., methoxyimino, ethoxyimino, etc.), acylimino (e.g., acetylimino, benzoylimino, etc.), azido, aryl (e.g., phenyl, etc.), arylalkyl (e.g., benzyl, phenylethyl etc.), arylalkyloxy (e.g., benzyloxy), a non-aromatic heterocyclic group (e.g., pyrrolinyl, piperidyl, piperazinopyrrolidino, pyrrolidinyl, morpholinyl, morpholino etc.), heteroaryl (e.g., furyl, thienyl, pyridyl, isoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, tetrazolyl, indolyl, benzofuryl etc.) heteroarylalkyl (e.g., pyridylmethyl, pyridylethyl etc.), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (e.g., methylthio, etc.), alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl), carbamoyl, alkylcarbamoyl (e.g. methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, etc.), sulfamoyl, alkylsulfamoyl, acyl (e.g., formyl, acetyl, etc.), formyloxy, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, azido, ureido, amidino, guanidino, phthalimido, tri-alkylsilyl (e.g., trimethylsilyl, etc.), and oxo.

As a substituent for “substituted alkyl”, “substituted alkenyl”, and “substituted alkynyl” for R^c and R^c1, the followings are exemplified.

carboxy; hydroxy; oxo; thioxo; halogen; alkyloxy; alkenyloxy; alkynyloxy; alkyloxyalkyloxy; carbamoyl optionally substituted with hydroxy, cyano, alkyl, alkenyl, alkynyl, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, non-aromatic heterocyclylalkyl, a non-aromatic heterocyclic group, aryl or heteroaryl; sulfamoyl optionally substituted with hydroxy, cyano, alkyl, alkenyl, alkynyl, hydroxyalkyl, haloalkyl, haloalkenyl, haloalkynyl, cycloalkylalkyl, cycloalkenylalkyl, non-aromatic heterocyclylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl, cycloalkenyl, heteroaryl, aryl, or heteroaryl; amino optionally substituted with hydroxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl; imino optionally substituted with hydroxy, alkyloxy, alkenyloxy, or alkynyloxy; guanidyl optionally substituted with cyanoalkyl;cycloalkyl optionally substituted with carboxy, alkyl, hydroxyalkyl, carboxyalkyl, arylalkyl, heteroarylalkyl, alkyloxyarylmethyl, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkyloxyalkyl, cycloalkenyloxyalkyl, non-aromatic heterocyclyloxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, oxo or thioxo;a non-aromatic heterocyclic group optionally substituted with carboxy, alkyl, hydroxyalkyl, carboxyalkyl, alkyloxycarbonyl, arylalkyl, alkyloxyarylmethyl, non-aromatic heterocyclyloxyalkyl, or oxo;aryl optionally substituted with halogen or alkyloxycarbonyl;heteroaryl optionally substituted with carboxy, alkyloxy, alkyloxycarbonyl, non-aromatic heterocyclyloxyalkyloxy;alkyloxycarbonyl; alkenyloxycarbonyl; alkynyloxycarbonyl; cycloalkyloxycarbonyl; cycloalkenyloxycarbonyl; non-aromatic heterocyclyloxycarbonyl; aryloxycarbonyl; or heteroaryloxycarbonyl etc.

As a substituent for “substituted alkyl”, “substituted alkenyl”, and “substituted alkynyl” for R^c and R^c1, the followings are exemplified.

halogen; hydroxy; carboxy; alkyloxy; alkyloxyalkyloxy; sulfo;cycloalkyl optionally substituted with carboxy, alkyl, hydroxyalkyl, carboxyalkyl, alkyloxycarbonyl, arylalkyl, alkyloxyarylmethyl, non-aromatic heterocyclyloxyalkyl, or oxo;a non-aromatic heterocyclic group optionally substituted with carboxy, alkyl, hydroxyalkyl, carboxyalkyl, alkyloxycarbonyl, arylalkyl, alkyloxyarylmethyl, non-aromatic heterocyclyloxyalkyl, or oxo;aryl optionally substituted with halogen or alkyloxycarbonyl;heteroaryl optionally substituted with carboxy, alkyloxy, alkyloxycarbonyl, or non-aromatic heterocyclyloxyalkyloxy;alkyloxycarbonyl; alkenyloxycarbonyl; alkynyloxycarbonyl; cycloalkyloxycarbonyl; cycloalkenyloxycarbonyl; non-aromatic heterocyclyloxycarbonyl; aryloxycarbonyl; heteroaryloxycarbonyl;carbamoyl optionally substituted with hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, non-aromatic heterocyclylalkyl or a non-aromatic heterocyclic group;sulfamoyl optionally substituted with hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, non-aromatic heterocyclylalkyl or a non-aromatic heterocyclic group;amino optionally substituted with hydroxy, alkyloxycarbonyl, alkenyloxycarbonyl, or alkynyloxycarbonyl;imino optionally substituted with hydroxy, alkyloxy, alkenyloxy, or alkynyloxy; guanidyl optionally substituted with cyanoalkyl; oxo; thioxo etc.

As a substituent for “substituted alkyl”, “substituted alkenyl”, and “substituted alkynyl” for R^c and R^C1, the followings are exemplified.

halogen; hydroxy; carboxy; alkyloxy; alkyloxyalkyloxy; sulfo; cycloalkyl;a non-aromatic heterocyclic group optionally substituted with carboxy, alkyl, hydroxyalkyl, carboxyalkyl, alkyloxycarbonyl, arylalkyl, alkyloxyarylmethyl, non-aromatic heterocyclyloxyalkyl, or oxo;aryl optionally substituted with halogen, or alkyloxycarbonyl:heteroaryl optionally substituted with carboxy, alkyloxy, alkyloxycarbonyl, or non-aromatic heterocyclyloxyalkyloxy;alkyloxycarbonyl; alkenyloxycarbonyl; alkynyloxycarbonyl; cycloalkyloxycarbonyl; cycloalkenyloxycarbonyl; non-aromatic heterocyclyloxycarbonyl; aryloxycarbonyl; heteroaryloxycarbonyl;carbamoyl optionally substituted with hydroxy, cyano, alkyl, hydroxyalkyl, haloalkyl, non-aromatic heterocyclylalkyl or a non-aromatic heterocyclic group;sulfamoyl;amino optionally substituted with hydroxy, or alkyloxycarbonyl;imino optionally substituted with hydroxy, or alkyloxy;guanidyl optionally substituted with cyanoalkyl;oxo; thioxo etc.

As a substituent for “substituted alkyl”, “substituted alkenyl”, and “substituted alkynyl” for R^C and R^C1, the followings are exemplified:

fluoro, hydroxy, carboxy, methyloxy, methyloxymethyloxy, sulfo, methyloxycarbonyl, ethyloxycarbonyl, t-butyloxycarbonyl, tetrahydropyranylmethyloxycarbonyl, methylcarbamoyl, hydroxycarbamoyl, dihydroxyisopropylcarbamoyl, aminocarbamoyl, cyanocarbamoyl, trifluoromethylcarbamoyl, hydroxyethylcarbamoyl, tetrahydropyranylcarbamoyl, tetrahydropyranylethylcarbamoyl, sulfamoyl, hydroxyamino, methyloxycarbonylamino, t-butyloxycarbonylamino, hydroxyimino, methyloxyimino, guanidyl, cyanomethylguanidyl, cyclopropyl, carboxypyrrolidinyl, oxetanyl, oxodihydrooxadiazolyl, dimethyldioxaranyl, oxopyrrolidinyl, methyloxopyrrolidinyl, hydroxyethyloxopyrrolidinyl, carboxymethyloxopyrrolidinyl, oxodihydropyrrolidinyl, methyloxycarbonylmethyloxopyrrolidinyl, morpholinyl, piperazinyl, t-butyloxycarbonylpiperazinyl, oxo(phenylmethyl)(methyl)piperazinyl, oxo(methyloxyphenylmethyl)(methyl)piperazinyl, tetrahydropyranyloxyethyloxopiperazinyl, phenyl, chlorophenyl, ethyloxycarbonylphenyl, triazolyl, tetrazolyl, carboxyisoxazolyl, methyloxycarbonylisoxazolyl, ethyloxycarbonylisoxazolyl, oxazolyl, carboxyfuranyl, methyloxycarbonylfuryl, methyloxypyridyl, carboxypyridyl, methyloxycarbonylpyridyl, hydroxyethyloxypyridyl, ethyloxycarbonylthiazoly, tetrahydropyranyloxyethyloxypyridinyl, oxo etc.

Substituents for “substituted acyl” are selected from the substituents as defined above for “substituted alkyl”, the above “alkyl”, the above “alkenyl” and the above “alkynyl”. If R in acyl (R—C(═O)—) is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, or “heteroaryl”, then each ring may be substituted with alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (e.g., CF₃, CH₂CF₈, CH₂CCl₃, etc.), alkenyl, alkynyl (e.g., ethynyl), alkyloxy (e.g., methoxy, ethoxy, isopropyloxy), halogen (e.g., fluoro, chloro etc.) or the like.

Substituents for “substituted carbamoyl”, “substituted thiocarbamoyl” and “substituted sulfamoyl” are one or more same or different groups selected from, but are not limited to, the group consisting of:

hydroxy, carboxy, halogen (F, Cl, Br, I), alkyl (e.g., methyl, ethyl), alkenyl (e.g., vinyl), alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), amino, alkylamino (e.g., methylamino, ethylamino, dimethylamino, etc.), acylamino (e.g., acetylamino, benzoylamino, etc.), arylalkylamino (e.g., benzylamino, tritylamino), hydroxyamino, aryl (e.g. phenyl, etc.), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato and acyl (e.g. formyl, acetyl, etc.).

Substituents for “substituted sulfonyl” or “substituted sulfinyl” are selected from the above “substituted or unsubstituted alkyl”, the above “substituted or unsubstituted alkenyl”, the above “substituted or unsubstituted alkynyl”, the after-mentioned “substituted or unsubstituted cycloalkyl”, the after-mentioned “substituted or unsubstituted cycloalkenyl”, the after-mentioned “a substituted or unsubstituted non-aromatic heterocyclic group”, the after-mentioned “substituted or unsubstituted aryl”, and the after-mentioned “substituted or unsubstituted heteroaryl”. If R in R—S(═O)₂— or R—S(═O)— is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, “heteroaryl” or the like, then each ring may be substituted with alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃, etc.), alkenyl, alkynyl (e.g. ethynyl), alkyloxy (e.g., methoxy, ethoxy, isopropyloxy), halogen (e.g., fluoro, chloro etc.) or the like.

Substituents for “substituted amino”, “substituted imino” and “substituted guanidyl” are one or more same or different groups selected from, but are not limited to, the group consisting of:

alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl etc.), haloalkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃, etc.), hydroxyalkyl (e.g., hydroxyethyl, —C(CH₃)₂CH₂OH, etc.), alkenyl (e.g., vinyl), alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl, cycloalkenyl (e.g., cyclopropenyl), alkyloxy (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), haloalkyloxy (e.g., CF₃O), alkenyloxy (e.g., vinyloxy, allyloxy, etc.), alkyloxycarbonyl (methoxycarbonyl, tert-butyloxycarbonyl, etc.), alkyloxycarbonylalkyl, amino, alkylamino (e.g., methylamino, ethylamino, dimethylamino, etc.), acylamino (e.g., acetylamino, benzoylamino, etc.), arylalkylamino (e.g., benzylamino, tritylamino), hydroxyamino, imino, hydroxyimino, alkylimino (e.g., methylimino, ethylimino, dimethylimino, etc.), alkyloxyimino (e.g., methoxyimino, ethoxyimino, etc.), acylimino (e.g. acetylimino, benzoylimino, etc.), aryl (e.g., phenyl, etc.), arylalkyl (e.g. benzyl, etc.), aryloxy (e.g., phenoxy etc.), a non-aromatic heterocyclic group (e.g. pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino etc.), heteroaryl (e.g., pyridyl, thienyl, thiazolyl, furyl etc.), heteroarylalkyl (e.g., pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl etc.), non-aromatic heterocyclyloxy (pipiperazinooxy, piperidinooxy etc.), heteroaryloxy (pyridyloxy etc.), hydroxy, halogen, (F, Cl, Br, I), cyano, acyl (e.g., formyl, acetyl, etc.), alkylsulfonyl (e.g., methanesulfonyl etc.), alkylsulfinyl (e.g., methansulfinyl), carbamoyl, alkylcarbamoyl (e.g., methylcarbamoyl etc.), alkylcarbamoylalkyl (e.g., methylcarbamoylmethyl etc.), carbamoylalkyl (e.g., carbamoylmethyl etc.), carboxyalkyl (e.g., carboxymethyl etc.), sulfamoyl, alkylsulfamoyl (e.g., methylsulfamoyl etc.), alkylsulfamoylalkyl (e.g., methylsulfamoylmethyl etc.), and sulfamoylalkyl (e.g, sulfamoylmethyl etc.).

Substituents for “substituted cycloalkyl”, “substituted cycloalkenyl”, “substituted aryl”, “substituted phenyl”, “substituted heterocyclic group”, “substituted heteroaryl”, “a substituted non-aromatic carbocyclic group”, “a substituted non-aromatic heterocyclic group”, “a substituted nitrogen-containing non-aromatic heterocyclic group”, “substituted cycloalkyloxycarbonyl”, “substituted cycloalkyenyloxycarbonyl”, “substituted non-aromatic heterocyclyloxycarbonyl”, “substituted aryloxycarbonyl”, “substituted heteroaryloxycarbonyl”, “a substituted cyclopropane ring”, “a substituted cyclopropene ring”, “a substituted oxetane ring”, “a substituted thietane ring” and “a substituted azetizine ring” are one or more same or different groups selected from, but are not limited to, the group consisting of:

alkyl (e.g., methyl, ethyl, isopropyl, tert-butyl etc.), haloalkyl (e.g., CF₃, CH₂CF₃, CH₂CCl₃, etc.), haloalkyloxy (e.g., CF₃O, CHCF₂O etc.), alkenyl (e.g., vinyl), alkynyl (e.g., ethynyl), cycloalkyl (e.g., cyclopropyl), cycloalkenyl (e.g., cyclopropenyl), alkyloxy (e.g., methoxy, ethoxy, propoxy, butoxy, etc.), alkenyloxy (e.g., vinyloxy, allyloxy, etc.), alkyloxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino (e.g., methylamino, ethylamino, dimethylamino, etc.), acylamino (e.g., acetylamino, benzoylamino, etc.), arylalkylamino (e.g., benzylamino, tritylamino), hydroxyamino, amino substituted with one or two same or different substituent selected from the after-mentioned substituent Group Y, imino, hydroxy imino, alkylimino (e.g., methylimino, ethylimino, dimethylimino etc.), alkyloxyimino (e.g., methoxyimino, ethoxyimino etc.), acylimino (e.g., acetylimino, benzoylimino etc.), azido, aryl (e.g., phenyl etc.), arylalkyl (e.g. benzyl etc.), unsubstituted non-aromatic carbocyclyloxy (e.g., cyclopropyloxy etc.), non-aromatic carbocyclyloxy substituted with one or more same or different substituents selected from the after-mentioned Substituent Group Z, unsubstituted non-aromatic carbocyclylalkyloxy (e.g., cyclopropylmethyloxy etc.), non-aromatic carbocyclylalkyloxy substituted with one or more same or different substituents selected from the after-mentioned Substituent Group Z, unsubstituted aryloxy (e.g., phenoxy etc.), aryloxy substituted with one or more same or different substituents selected from the after-mentioned Substituent Group Z, unsubstituted arylalkyloxy (e.g., benzyloxy etc.), arylalkyloxy substituted with one or more same or different substituents selected from the after-mentioned Substituent Group Z, a non-aromatic heterocyclic group (e.g., pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino etc.), heteroaryl (e.g., pyridyl, thienyl, thiazolyl, furyl etc.), heteroarylalkyl (e.g., pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl etc.), unsubstituted non-aromatic heterocyclyloxy (e.g. piperazinooxy, piperizinooxy etc.), non-aromatic heterocyclyloxy substituted with one or more same or different substituents selected from the after-mentioned Substituent Group Z, unsubstituted heteroaryloxy (e.g., pyridyloxy etc.), heteroaryloxy substituted with one or more same or different substituents selected from the after-mentioned Substituent Group Z, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (e.g., methylthio etc.), alkylsulfonyl (e.g., methanesulfonyl, ethanesulfonyl), substituted or unsubstituted carbamoyl (e.g., carbamoyl. N-methyl-N-methoxycarbamoyl etc.), substituted or unsubstituted alkylcarbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, hydroxyethylcarbamoyl, trifluoromethylcarbamoyl, trifluoroethylcarbamoyl etc.), sulfamoyl, alkylsulfamoyl, hydroxy, carboxy, halogen (F, Cl, Br, I), acyl (e.g., formyl, acetyl etc.), formyloxy, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, azido, ureido, amidino, guanidino, phthalimido and oxo.

A substituent Group Y includes hydroxy alkyl (e.g., hydroxyethyl, —C(CH₃)₂CH₂OH etc.), alkyloxycarbonyl (methoxycarbonyl, tert-butyloxycarbonyl etc.), alkyloxycarbonylalkyl, alkylsulfonyl (e.g., methanesulfonyl etc.), alkylsulfinyl (e.g., methanesulfinyl etc.), carbamoyl, alkylcarbamoyl (e.g., methylcarbamoyl etc.), alkylcarbamoylalkyl (e.g., methylcarbamoylmethyl etc.), carbamoylalkyl (e.g. carbamoylmethyl etc.), carboxyalkyl (e.g., carboxymethyl etc.), sulfamoyl, alkylsulfamoyl (e.g., methylsulfamoyl etc.), alkylsulfamoylalkyl (e.g., methylsulfamoylmethyl etc.) and sulfamoylalkyl (e.g., sulfamoylmethyl etc.).

A substituent Group Z 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, amino substituted with one or two same or different substituent selected from the above substituent Group Y, sulfamoyl, methylsulfonyl, methylsulfinyl, cycloalkyl, cycloalkenyl, a non-aromatic heterocyclic group, aryl, heteroaryl, cycloalkyloxy, cycloalkenyloxy, non-aromatic heterocyclyloxy, aryloxy and heteroaryloxy.

As substituents for “substituted aryl” and “substituted heteroaryl” for R², halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, a non-aromatic heterocyclic group, alkylsilylalkynyl and the like are exemplified.

As substituents for “substituted aryl” and “substituted heteroaryl” for R², halogen, alkyl, alkenyl, alkynyl, alkyloxy, cycloalkyl, alkylsilylalkynyl and the like are exemplified.

As substituents for “substituted aryl” and “substituted heteroaryl” for R², fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, propenyl, vinyl, ethynyl, methyl oxy, cyclopropyl, trimethylsilylethynyl and the like are exemplified.

As substituents for “substituted aryl” and “substituted heteroaryl” for R³, halogen; hydroxy;

alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, dialkylamino, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl;alkenyl optionally substituted with cycloalkyl, cycloalkenyl or a non-aromatic heterocyclic group;alkynyl optionally substituted with cycloalkyl, cycloalkenyl or a non-aromatic heterocyclic group;unsubstituted alkyloxy;alkyloxy substituted with a non-aromatic heterocyclic group optionally substituted with halogen, alkyloxy, alkenyloxy, alkynyloxy, aryl, alkyl, alkenyl or alkynyl;alkylthio; alkenylthio; alkynylthio; cycloalkyl; cycloalkenyl; a non-aromatic heterocyclic group; alkylamino; alkenyl amino; alkynylamino and the like are exemplified.

As substituents for “substituted aryl” and “substituted heteroaryl” for R³ are halogen; hydroxy;

alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroarylalkyl:alkenyl optionally substituted with cycloalkyl;alkynyl optionally substituted with cycloalkyl;alkyloxy optionally substituted with a non-aromatic heterocyclic group optionally substituted with halogen, alkyloxy, aryl, or alkyl;alkylthio; cycloalkyl; cycloalkenyl; a non-aromatic heterocyclic group; alkylamino and the like are exemplified.

As substituents for “substituted aryl” and “substituted heteroaryl” for R³, chloro, bromo, fluoro, hydroxy, methyl, trifluoromethyl, methyloxymethyl, cyanomethyl, difluoroethyl, methyloxyiminomethyl, isopropyl, propyl, trifluoroisopropyl, dimethylaminomethyl, butyl, isobutyl, isopropyloxymethyl, pentyl, cyclopropylethyl, cyclopentylmethyl, pyridylmethyl, methylisopropenyl, vinyl, cyclopropylvinyl, methyl propenyl, cyclopentylidenemethyl, cyclopropylethynyl, hydroxyethyl, methyloxy, difluoromethyloxy, trifluoromethyloxy, ethyloxy, propyloxy, methyloxy ethyloxy, oxetanyloxy, cyclobutyloxy, cyclopentyloxy, s-butyloxy, isobutyloxy, cyclopropylmethyloxy, tetrahydropyranyloxy, 2-methylbutyloxy, dimethylbutyloxy, pentanyloxy, pentane-3-yloxy, dimethylpyridyloxy, methylpyridyloxy, pyridyloxy, phenyloxy, methylthio, ethylthio, cyclopentyl, cyclopentenyl, cyclohexyl, piperazinyl, piperidinyl, azepanyl and the like are exemplified.

Examples of “heteroaryloxy” as substituents for “substituted aryl” and “substituted heteroaryl” for R³ include pyrrolyloxy, pyrazinyloxy, pyrazolyloxy, indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isooxazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, oxazolyloxy, oxadiazolyloxy and the like.

As substituents for “substituted aryl” and “substituted heteroaryl” for R³, unsubstituted heteroaryloxyl, heteroaryloxyl substituted with one or more same or different substituents selected from the above Substituent Group Z and the like are exemplified. Further, halogen, hydroxy, carboxy, cyano, nitro, alkyl, haloalkyl, haloalkyloxy, alkyloxy, amino and the like are exemplified. The above heteroaryloxyl includes the following groups which are unsubstituted or substituted with one or more same or different substituents selected from the above Substituent Group Z:

pyrrolyloxy, pyrazinyloxy, pyrazolyloxy, indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isooxazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, oxazolyloxy, and oxadiazolyloxy and the like.

As substituents for “substituted heteroaryl” for R³, halogen; alkyl; alkenyl; alkynyl; alkyloxy; alkenyloxy; alkynyloxy; cycloalkyloxy, cycloalkenyloxy; aryloxyl; heteroaryloxyl and the like are exemplified.

As substituents for “substituted heteroaryl” for R³, halogen: alkyl; alkyloxy; cycloalkyloxy and the like are exemplified.

As substituents for “substituted non-aromatic heterocyclic group” for R³, arylalkyl, heteroarylalkyl, aryl, heteroaryl and the like are exemplified.

As substituents for “substituted non-aromatic heterocyclic group” for R³, arylalkyl, aryl and the like are exemplified.

As substituents for “substituted non-aromatic heterocyclic group” for R³, phenylmethyl, phenyl and the like are exemplified.

As substituents for “substituted amino” for R^9′, carbamoyl, alkylcarbamoyl (e.g., methylcarbamoyl etc.), alkylcarbamoylalkyl (e.g., methylcarbamoylmethyl etc.), carbamoylalkyl (e.g., carbamoylmethyl etc.), carboxyalkyl (e.g., carboxymethyl etc.) and the like are exemplified.

Examples of “substituted or unsubstituted alkyl” for R³⁰ and R³¹ are methyl, monofluoromethyl, difluoromethyl, trifluoromethyl, ethyl and the like.

Examples of R^9′ are 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, amino substituted with one or two same or different substituents selected from the above Substituent Group Y, sulfamoyl, methylsulfonyl, methylsulfinyl and the like.

In general formula (VIII), general formula (IX), general formula (VII), general formula (IV), general formula (I), general formula (II) or general formula (III), “R^4a and R^4b attached to the same carbon atom are taken together to form oxo or thioxo” includes the followings:

wherein n, R^4a, R^4b, and R² are as defined in the above (1)and the like.

In general formula (VIII), the positions of carbon atom a, Q^a atom, Q^b atom, carbon atom b, Q^c atom and Q^d atom which constitute a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring as ring D is defined as 1-position, 2-position, 3-position, 4-position, 5-position and 6-position, respectively. Each of the position numbers of these atoms is different from position number based on IUPAC nomenclature. That is, “carbon atom a is positioned on ring D in a 1,4 relationship with respect to carbon atom b” includes the followings:

[Chemical Formula 50]

wherein Q^a atom, Q^b atom, Q^c atom and Q^d atom are each independently a carbon atom or a nitrogen atom, —X—, -L-, ring D, ring B, s, s′, R⁹ and R^9′ are as defined in the above (1).

In general formula (VIII), the positions of carbon atom a, Q^a atom, Q^b atom, carbon atom b, Q^c atom and Q^d atom which constitute a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring as ring D is defined as 1-position, 2-position, 3-position, 4-position, 5-position and 6-position, respectively. Each of the position numbers of these atoms is different from position number based on IUPAC nomenclature. That is, “carbon atom a is positioned on ring D in a 1,3 relationship with respect to carbon atom b” includes the followings:

[Chemical Formula 51]

wherein Q^a atom, Q^b atom, Q^c atom and Q^d atom are each independently a carbon atom or a nitrogen atom, —X—, -L-, ring D, ring B, s, s′, R⁹ and R^9′ are as defined in the above (1).

In general formula (IX), the positions of carbon atom a, Q^a atom, Q^b atom, carbon atom b, Q^c atom and Q^d atom which constitute a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring as ring D is defined as 1-position, 2-position, 3-position, 4-position, 5-position and 6-position, respectively. Each of the position numbers of these atoms is different from position number based on IUPAC nomenclature. That is, “carbon atom a is positioned on ring D in a 1,4 relationship with respect to carbon atom b” includes the followings:

[Chemical Formula 52]

wherein Q^a atom, Q^b atom, Q^c atom and Q^d atom are each independently a carbon atom or a nitrogen atom, —X—, -L-, ring D, R^13a, R^13b, ring E, s, s′, R⁹ and R^9′ are as defined in the above (8).

In general formula (IX), each of the position of carbon atom a, Q^a atom, Q^b atom, carbon atom b, Q^c atom and Q^d atom which constitute a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring as ring D is defined as 1-position, 2-position, 3-position, 4-position, 5-position and 6-position, respectively. Each of the position numbers of these atoms is different from position number based on IUPAC nomenclature. That is, “carbon atom a is positioned on ring D in a 1,3 relationship with respect to carbon atom b” includes the followings:

[Chemical Formula 53]

wherein Q^a atom, Q^b atom, Q^c atom and Q^d atom are each independently a carbon atom or a nitrogen atom, —X—, -L-, ring D, R^13a, R^13b, ring E, s, s′, R⁹ and R^9′ are as defined in the above (8).

In general formula (VIII), general formula (IX), and general formula (VII), “R^11a and R^11b together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring” includes the followings:

wherein m, R^11a and R^11b are as defined in the above (21);v is an integer of 0 to 3 (e.g., 0 or 1, and e.g., 0);

—W— is —O—, —S— or —N(R¹⁷)— (e.g., —O—);

R¹⁷ is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyland the like.

In general formula (VIII), general formula (IX), and general formula (VII), “R^14a and R^14b together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring” includes the followings:

wherein t, R^14a and R^14b are as defined in the above (24);va is an integer of 0 to 3 (e.g., 0 or 1, and e.g., 0)

-Wa- is —O—, —S— or —N(R^17a)— (e.g., —O—):

R^17a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl and the like.

In general formula (VIII), general formula (IX), and general formula (VII), “R^14a′ and R^14b′ together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring” includes the followings:

wherein t, R^14a and R^14b are as defined in the above (24);va is an integer of 0 to 3 (e.g., 0 or 1, and e.g., 0);

-Wa- is —O—, —S— or —N(R^17a)— (e.g., —O—);

R^17a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyland the like.

One embodiment of the compound of the present invention or the composition of the present invention is mentioned below.

The following (II″-A) to (II″-C) are embodiments of a pharmaceutical composition having an analgesic effect or and/or an improving effect of urination disorder comprising the compound of the formula (II″):

or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(II″-A)

A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A:R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C;R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen: hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl cycloalkyloxy: aryloxyl; heteroaryloxyl optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), heteroaryl optionally substituted with one or more substituents selected from Substituent Group D;R^4a and R^4b are both hydrogen;R⁵ is hydrogen,or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(II″-B)

A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound wherein R^c1 is a group of the formula:

wherein t is an integer of 1 to 4;R^c2 is 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, a 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 cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxylcarbonyl, substituted or unsubstituted heteroaryloxylcarbonyl, 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxylcarbonyl, substituted or unsubstituted heteroaryloxylcarbonyl, or nitro;R^c3 and R^c4 are each independently hydrogen, hydroxy, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl,or(i) R^c3 and R^c4 are taken together to form oxo or thioxo, or,(ii) R^c3 and R^c4 attached to the same carbon atom, are taken together to form —(CR^c5R^c6)x-;R^c5 and R^c6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R² is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C;x is an integer of 1 to 4;R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D:R^4a and R^4b are both hydrogen;

R⁵ is hydrogen.

its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(II″-C)

A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound of the above (II″-A) wherein R^c1 is alkyl substituted with one or more substituents selected from Substituent Group E (Substituent Group E: sulfo; substituted or unsubstituted sulfamoyl; substituted or unsubstituted imino; substituted or unsubstituted guanidyl; a substituted or unsubstituted non-aromatic heterocyclic group (provided that the heterocyclic group is morpholino, imidazolidine, tetrahydropyranyl and piperizino) and substituted or unsubstituted heteroaryl (provided that the heteroaryl is pyridino)), alkenyl optionally substituted with one or more substituents selected from Substituent Group E, or alkynyl substituted with one or more substituents selected from Substituent Group E,or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

One embodiment of the compound of the present invention or the composition of the present invention is mentioned below.

The following (III″-A) to (III″-C) are embodiments of a pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound of the formula (III″):

or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(III′-A)

A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound wherein R^a1 is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 alkynyloxy carbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group A, alkynyl substituted with one or more substituents selected from Substituent Group A, alkyloxy substituted with one or more substituents selected from Substituent Group A, alkenyloxy substituted with one or more substituents selected from Substituent Group A, alkynyloxy substituted with one or more substituents selected from Substituent Group A, alkylthio substituted with one or more substituents selected from Substituent Group A, alkenylthio substituted with one or more substituents selected from Substituent Group A, alkynylthio substituted with one or more substituents selected from Substituent Group A, alkylamino substituted with one or more substituents selected from Substituent Group A, alkenylamino substituted with one or more substituents selected from Substituent Group A or alknynylamino substituted with one or more substituents selected from Substituent Group A,

R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl) or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C;R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl: alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxyl; heteroaryloxyl optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D:R^4a and R^4b are both hydrogen:R⁵ is hydrogen,or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

(III′-B)

A pharmaceutical composition having an analgesic effect and/or an improving effect of urination disorder comprising the compound wherein R^a1 is

wherein —Y— is —O—, —S— or —NR^Y—:R^Y is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl; and other symbols are as defined in the above II′-B;R^c5 and R^c6 are each independently, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R² is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;x is an integer of 1 to 4;R³ is aryl optionally substituted with one or more substituents selected from Substituent Group D, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D;R^4a and R^4b are both hydrogen:R⁵ is hydrogen,or its pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

One embodiment of the compound of the present invention is mentioned below. A compound of the formula (VII′):

whereinR^c1 is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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, and substituted or unsubstituted guanidyl), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group A, unsubstituted alkynyl or alkynyl substituted with one or more substituents selected from Substituent Group A;R^4a and R^4b are both hydrogen;R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyl oxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C;R⁵ is hydrogen;R⁹ is halogen, hydroxy, carboxy, cyano, alkyloxy, unsubstituted alkyl, alkyl optionally substituted with one or more substituents selected from Substituent Group F (Substituent Group F: halogen, hydroxy, carboxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, and heteroaryl), unsubstituted alkenyl, alkenyl optionally substituted with one or more substituents selected from Substituent Group F, unsubstituted alkynyl, or alkynyl optionally substituted with one or more substituents selected from Substituent Group F; and s is an integer of o to 2,its pharmaceutically acceptable salt or a solvate thereof.

One embodiment of the compound of the present invention is mentioned below. A compound of the formula (VIII′):

whereinR^c1 is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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, and substituted or unsubstituted guanidyl), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group A, unsubstituted alkynyl or alkynyl substituted with one or more substituents selected from Substituent Group A;R^4a and R^4b are both hydrogen;R² is aryl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C;R⁵ is hydrogen;

R⁹ is 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

s is an integer of 0 to 2;ring B is thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, furan, thiophen, oxadiazole, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine or benzoxazole:R^9′ is 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, carboxy, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxy carbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryls′ is an integer of 0 to 2;or its pharmaceutically acceptable salt or a solvate thereof.

The following embodiments are examples of the compound (VIII) of the present invention.

A compound of the formula (VIII-a):

whereinR^c is selected from the following (a1) to (a32):

wherein R^15a, R^15b, R^15a′ and R^15b′ are each independently selected from the following (b1) and (b2):(b1) a hydrogen atom, cyano, 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, and(b2) a hydrogen atom, methyl, ethyl, acetyl or trifluoroacetyl.(a31) ethyl; and(a32) methyl;ring F is selected from the following (c1) to (c3)(c1) a benzene ring;(c2) a pyridine ring; and(c3) a cyclohexane ring;R³⁰ is selected from the following (d1) and (d2):(d1) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and(d2) fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or ethyl;R³¹ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;n″ is 0 or 1;ring D is selected from the following (e1) and (e2):(e1) a benzene ring; and(e2) a pyridine ring;relationship of carbon atom a and carbon atom b on the ring D are selected from the following (f1) and (f2):(f1) 1,4 relationship; and(f2) 1,3 relationship;ring B is selected from the following (g1) to (g12):(g1) a thiazole ring;(g2) an isothiazole ring;(g3) an oxazole ring;(g4) an isoxazole ring;(g5) a thiadiazole ring;(g6) an oxadiazole ring;(g7) a pyridine ring;(g8) a pyrimidine ring;(g9) a pyrazine ring;(g10) a pyridazine ring;(g11) a triazine ring; and(g12) a pyrazole ring;s′ is selected from the following (h1) and (h2):(h1) 0; and(h2) 1;when s′ is 1, then R^9′ is selected from the following (i1) to (i14):(i1) hydroxy;(i2) carboxy;(i3) cyano;(i4) alkyl substituted with hydroxy, carboxy, cyano, carbamoyl, amino, sulfamoyl, methanesulfonyl or methanesulfinyl;(i5) substituted or unsubstituted carbamoyl;(i6) alkylcarbamoyl or alkenylcarbamoyl;(i7) substituted or unsubstituted amino;(i8) amino substituted with carbamoyl, alkylcarbamoyl, alkylcarbamoylalkyl, carbamoylalkyl or carboxyalkyl;(i9) substituted or unsubstituted sulfamoyl;(i10) alkylsulfamoyl or alkenylsulfamoyl;(i11) substituted sulfonyl;(i12) substituted sulfinyl;(i13) unsubstituted alkyl, or alkyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; and(i14) unsubstituted alkyl.

The compound of the formula (VIII-a) of the present invention includes the compounds comprising the combination of some or all of options of the above (a1) to (a32), (b1) and (b2), (c1) to (c3), (d1) and (d2), (e1) and (e2), (f1) and (f2), (g1) to (g12), (h1) and (h2), and (i1) to (i14).

The following embodiments are examples of the compound (VIII) of the present invention.

A compound of the formula (VIII-b):

[Chemical Formula 67]

whereinR^c is a group selected from the following (ba1) to (ba16):(ba1) a group of the formula: —(CR^11aR^11b)m-OHwherein R^11a and R^11b are each independently, a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R^11a and R^11b together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropane ring, a substituted or unsubstituted cyclopropene ring, a substituted or unsubstituted oxetane ring, a substituted or unsubstituted thietane ring, or a substituted or unsubstituted azetizine ring; m is an integer of 2 to 4;(ba2) a group of the formula: —(CR^11aR^11b)m-OH]wherein R^11a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;R^11b is a group of the formula: —(CR^12aR^12b)u-OHwherein R^12a and R^12b are each independently 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;(ba3) a group of the formula:

(ba4) a group of the formula:

(ba5) a group of the formula:

(ba6) a group of the formula: —(CR^14aR^14b)t-N(R^15a)(R^15b)wherein R^14a and R^14b are each independently hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or

R^14a and R^14b together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropane ring, a substituted or unsubstituted cyclopropene ring, a substituted or unsubstituted oxetane ring, a substituted or unsubstituted thietane ring, or a substituted or unsubstituted azetizine ring; t is an integer of 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;

(ba7) a group of the formula:

wherein R^15a and R^15b are as defined in the above (ba6);(ba8) a group of the formula:

wherein R^15a and R^15b are as defined in the above (ba6);(ba9) a group of the formula: —(CR^14a′R^14b′)t′-C(═O)N(R^15a′)(R^15b′)wherein R^14a′ and R^14b′ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R^14a′ and R^14b′ together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropane ring, a substituted or unsubstituted cyclopropene ring, a substituted or unsubstituted oxetane ring, a substituted or unsubstituted thietane ring, or a substituted or unsubstituted azetizine ring; t′ is an integer of 1 to 4; R^14a′ and R^15b′ are each independently a hydrogen atom, cyano, 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:(ba10) a group of the formula:

wherein R^15a′ and R^15b′ are as defined in the above (ba9);(ba11) a group of the formula:

wherein R^15a′ and R^15b′ are as defined in the above (ba9);(ba12) a group of the formula:

wherein R^15′ and R^15b′ are as defined in the above (ba9):(ba13) unsubstituted alkyl; or alkyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy;(ba14) unsubstituted alkyl;(ba15) methyl; ethyl; methyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy: or ethyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; and(ba16) methyl or ethyl;ring F is a group selected from the following (bc1) and (bc2):(bc1) a benzene ring, a pyridine ring or a cyclohexane ring; and(bc2) a benzene ring;R³⁰ is a group selected from the following (bd1) and (bd2):(bd1) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and(bd2) fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or ethyl;R³¹ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;n″ is 0 or 1;ring D a group selected from the following (be1) to (be4):(be1) a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;(be2) a benzene ring or a pyridine ring;(be3) a benzene ring; and(be4) a pyridine ring;relationship of carbon atom a and carbon atom b on ring D is selected from the following (bf1) to (bf3):(bf1) 1, 4 relationship or 1, 3 relationship;(bf2) 1, 4 relationship; and(bf3) 1, 3 relationship;ring B is a group selected from the following (bg1) to (bg9):(bg1) an aromatic heterocyclic ring;(bg2) a five- or six-membered aromatic heterocyclic ring;(bg3) a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, or a pyrazole ring;(bg4) a thiazole ring, an isoxazole ring, a thiadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;(bg5) a six-membered aromatic heterocyclic ring;(bg6) a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a triazine ring;(bg7) a five-membered aromatic heterocyclic ring;(bg8) a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, an oxadiazole ring or a pyrazole ring; and(bg9) a thiazole ring, an isoxazole ring or a thiadiazole ring;s′ is a group selected from the following (bh1) to (bh3):(bh1) 0 or 1;(bh2) 0; and(bh3) 1;when s′ is 1, then R^9′ is a group selected from the following (bi1) to (bi7):(bi1) hydroxy; carboxy; cyano; alkyl substituted with hydroxy, carboxy, cyano, carbamoyl, amino, sulfamoyl, methanesulfonyl or methanesulfinyl; substituted or unsubstituted carbamoyl; substituted or unsubstituted amino; substituted or unsubstituted sulfamoyl; substituted sulfonyl; or substituted sulfinyl;(bi2) hydroxy; carboxy; cyano; alkyl substituted with hydroxy, carboxy, cyano, carbamoyl, amino, sulfamoyl, methanesulfonyl or methansulfinyl; carbamoyl; alkylcarbamoyl; amino substituted with alkyl, haloalkyl, hydroxy alkyl, alkyloxy, haloalkyloxy, carbamoyl, alkylcarbamoyl, alkylcarbamoylalkyl, carbamoylalkyl or carboxyalkyl; sulfamoyl; alkylsulfamoyl; alkylsulfonyl; or alkylsulfinyl;(bi3) carboxy; carbamoyl; alkylcarbamoyl; sulfamoyl; alkylsulfamoyl or alkylsulfonyl;(bi4) alkyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or unsubstituted alkyl;(bi5) unsubstituted alkyl;(bi6) methyl; ethyl; methyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or ethyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; and(bi7) methyl or ethyl,or its pharmaceutically acceptable salt or a solvate thereof.The compound of the formula (VIII-b) of the present invention includes the compounds comprising the combination of some or all of options of the above (ba1) to (ba16), (bc1) and (bc2), (bd1) and (bd2), (be1) to (be4), (bf1) to (bf3), (bg1) to (bg9), (bh1) to (bh3) and (bi1) to (bi7).

The following embodiments are examples of the compound (IX) of the present invention.

A compound of the formula (IX-a):

whereinRc is a group selected from the following (ca1) to (ca5):(ca1) a group of the formula: —(CR^11aR^11b)m-OHwherein R^11a and R^11b are each independently, a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R^11a and R^11b together with the carbon atom to which they are attached form a substituted or unsubstituted cyclopropane ring, a substituted or unsubstituted cyclopropene ring, a substituted or unsubstituted oxetane ring, a substituted or unsubstituted thietane ring, or a substituted or unsubstituted azetizine ring: m is an integer or 2 to 4:(ca2) Rc is a group of the formula: —(CR^11aR^11b)m-OHwherein R^11a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;

R^11b is a group of the formula; —(CR^12aR^12b)u-OH;

wherein R^12a and R^12b are each independently, 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;(ca3) a group of the formula:

(ca4) a group of the formula:

and(ca5) a group of the formula:

ring F is a group selected from the following (cc1) and (cc2):(cc1) a benzene ring, a pyridine ring or a cyclohexane ring; and(cc2) a benzene ring;R³⁰ is a group selected from the following (cd1) and (cd2):(cd1) halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl; and(cd2) fluoro, chloro, methyl, monofluoromethyl, difluoromethyl, trifluoromethyl or ethyl;R³¹ is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl;n″ is 0 or 1;ring D is a group selected from the following (ce1) to (ce4):(ce1) a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;(ce2) a benzene ring or a pyridine ring;(ce3) a benzene ring; and(ce4) a pyridine ring;relationship of carbon atom a and carbon atom b on ring D is selected from the following (cf1) to (cf3):(cf1) 1,4 relationship, or 1,3 relationship;(cf2) 1,4 relationship; and(cf3) 1,3 relationship;ring E is a group selected from the following (cg1) to (cg3):(cg1) a cycloalkane ring or a cycloalkene ring:(cg2) a cycloalkane ring; and(cg3) a cyclopropane ring;s′ is(ch1) 0 or 1;(ch2) 0; and(ch3) 1;when s′ is 1, then R^9′ is a group selected from the following (ci1) to (ci4):(ci1) alkyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or unsubstituted alkyl;(ci2) unsubstituted alkyl;(ci3) methyl: ethyl; methyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or ethyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; and(ci4) methyl or ethyl,or its pharmaceutically acceptable salt or a solvate thereof.

The compound of the formula (VIII-b) of the present invention includes the compounds comprising the combination of some or all of options of the above (ca1) to (ca5), (cc1) and (cc2), (cd1) and (cd2), (ce1) to (ce4), (cf1) to (cf3), (cg1) to (cg3), (ch1) to (ch3) and (ci1) to (ci4).

The following embodiments are examples of the compound (VIII) of the present invention.

A compound of the formula (VIII-c):

whereinHal is halogen;

R^c is

(da1) a group of the formula:

(da2) a group of the formula:

or(da3) a group of the formula

ring B is:(dg1) an aromatic heterocyclic ring;(dg2) a five- or six-membered aromatic heterocyclic ring;(dg3) a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring, or a pyrazole ring;(dg4) a thiazole ring, an isoxazole ring, a thiadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring;(dg5) a six-membered aromatic heterocyclic ring;(dg6) a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring or a triazine ring;(dg7) a five-membered aromatic heterocyclic ring;(dg8) a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, an oxadiazole ring, or a pyrazole ring; or(dg9) a thiazole ring, an isoxazole ring or a thiadiazole ring;a group of the formula (R⁹)s′- is:(dj1) s′ is 0;(dj2) s′ is 1, and R^9′ is hydroxy; carboxy; cyano; alkyl substituted with hydroxy, carboxy, cyano, carbamoyl, amino, sulfamoyl, methansulfonyl or methansulfinyl; substituted or unsubstituted carbamoyl; substituted or unsubstituted amino; substituted or unsubstituted sulfamoyl; substituted sulfonyl; or substituted sulfinyl;(dj3) s′ is 1, and R^9′ is hydroxy; carboxy: cyano: alkyl substituted with hydroxy, carboxy, cyano, carbamoyl, amino, sulfamoyl, methansulfonyl or methansulfinyl; carbamoyl; alkylcarbamoyl; amino substituted with alkyl, haloalkyl, hydroxyalkyl, alkyloxy, haloalkyloxy, carbamoyl, alkylcarbamoyl, alkylcarbamoylalkyl, carbamoylalkyl or carboxyalkyl; sulfamoyl; alkylsulfamoyl: alkylsulfonyl; or alkylsulfinyl:(dj4) s′ is 1, and R^9′ is carboxy; carbamoyl; alkylcarbamoyl; sulfamoyl; alkylsulfamoyl or alkylsulfonyl;(dj5) s′ is 1, and R^9′ is alkyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or unsubstituted alkyl;(bj6) s′ is 1, and R^9′ is unsubstituted alkyl;(dj7) s′ is 1, and R^9′ is methyl; ethyl: methyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or ethyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; and(dj8) s′ is 1, and R^9′ is methyl or ethyl, or its pharmaceutically acceptable salt or a solvate thereof.The compound of the formula (VIII-c) of the present invention includes the compounds comprising the combination of some or all of options of the above. Specifically, the following combinations are included, (da1, dg3, di3), (da1, dg3, di4), (da1, dg3, di5), (da1, dg3, di6), (da1, dg3, di7), (da1, dg3, di8), (da1, dg4, di1), (da1, dg4, di2), (da1, dg4, di3), (da1, dg4, di4), (da1, dg4, di5), (da1, dg4, di6), (da1, dg4, di7), (da1, dg4, di8), (da1, dg5, di1), (da1, dg5, di2), (da1, dg5, di3), (da1, dg5, di4), (da1, dg5, di5), (da1, dg5, di6), (da1, dg5, di7), (da1, dg5, di8), (da1, dg6, di1), (da1, dg6, di2), (da1, dg6, di3), (da1, dg6, di4), (da1, dg6, di5), (da1, dg6, di6), (da1, dg6, di7), (da1, dg6, di8), (da1, dg7, di1), (da1, dg7, di2), (da1, dg7, di3), (da1, dg7, di4), (da1, dg7, di5), (da1, dg7, di6), (da1, dg7, di7), (da1, dg7, di8), (da1, dg8, di1), (da1, dg8, di2), (da1, dg8, di3), (da1, dg8, di4), (da1, dg8, di5), (da1, dg8, di6), (da1, dg8, di7), (da1, dg8, di8), (da1, dg9, di1), (da1, dg9, di2), (da1, dg9, di3), (da1, dg9, di4), (da1, dg9, di5), (da1, dg9, di6), (da1, dg9, di7), (da1, dg9, di8), (da2, dg1, di1), (da2, dg1, di2), (da2, dg1, di3), (da2, dg1, di4), (da2, dg1, di5), (da2, dg1, di6), (da2, dg1, di7), (da2, dg1, di8), (da2, dg2, di1), (da2, dg2, di2), (da2, dg2, di3), (da2, dg2, di4), (da2, dg2, di5), (da2, dg2, di6), (da2, dg2, di7), (da2, dg2, di8), (da2, dg3, di1), (da2, dg3, di2), (da2, dg3, di3), (da2, dg3, di4), (da2, dg3, di5), (da2, dg3, di6), (da2, dg3, di7), (da2, dg3, di8), (da2, dg4, di1), (da2, dg4, di2), (da2, dg4, di3), (da2, dg4, di4), (da2, dg4, di5), (da2, dg4, di6), (da2, dg4, di7), (da2, dg4, di8), (da2, dg5, di1), (da2, dg5, di2), (da2, dg5, di3), (da2, dg5, di4), (da2, dg5, di5), (da2, dg5, di6), (da2, dg5, di7), (da2, dg5, di8), (da2, dg6, di1), (da2, dg6, di2), (da2, dg6, di3), (da2, dg6, di4), (da2, dg6, di5), (da2, dg6, di6), (da2, dg6, di7), (da2, dg6, di8), (da2, dg7, di1), (da2, dg7, di2), (da2, dg7, di3), (da2, dg7, di4), (da2, dg7, di5), (da2, dg7, di6), (da2, dg7, di7), (da2, dg7, di8), (da2, dg8, di1), (da2, dg8, di2), (da2, dg8, di3), (da2, dg8, di4), (da2, dg8, di5), (da2, dg8, di6), (da2, dg8, di7), (da2, dg8, di8), (da2, dg9, di1), (da2, dg9, di2), (da2, dg9, di3), (da2, dg9, di4), (da2, dg9, di5), (da2, dg9, di6), (da2, dg9, di7), (da2, dg9, di8), (da3, dg1, di1), (da3, dg1, di2), (da3, dg1, di3), (da3, dg1, di4), (da3, dg1, di5), (da3, dg1, di6), (da3, dg1, di7), (da3, dg1, di8), (da3, dg2, di1), (da3, dg2, di2), (da3, dg2, di3), (da3, dg2, di4), (da3, dg2, di5), (da3, dg2, di6), (da3, dg2, di7), (da3, dg2, di8), (da3, dg3, di1), (da3, dg3, di2), (da3, dg3, di3), (da3, dg3, di4), (da3, dg3, di5), (da3, dg3, di6), (da3, dg3, di7), (da3, dg3, di8), (da3, dg4, di1), (da3, dg4, di2), (da3, dg4, di3), (da3, dg4, di4), (da3, dg4, di5), (da3, dg4, di6), (da3, dg4, di7), (da3, dg4, di8), (da3, dg5, di1), (da3, dg5, di2), (da3, dg5, di3), (da3, dg5, di4), (da3, dg5, di5), (da3, dg5, di6), (da3, dg5, di7), (da3, dg5, di8), (da3, dg6, di1), (da3, dg6, di2), (da3, dg6, di3), (da3, dg6, di4), (da3, dg6, di5), (da3, dg6, di6), (da3, dg6, di7), (da3, dg6, di8), (da3, dg7, di1), (da3, dg7, di2), (da3, dg7, di3), (da3, dg7, di4), (da3, dg7, di5), (da3, dg7, di6), (da3, dg7, di7), (da3, dg7, di8), (da3, dg8, di1), (da3, dg8, di2), (da3, dg8, di3), (da3, dg8, di4), (da3, dg8, di5), (da3, dg8, di6), (da3, dg8, di7), (da3, dg8, di8), (da3, dg9, di1), (da3, dg9, di2), (da3, dg9, di3), (da3, dg9, di4), (da3, dg9, di5), (da3, dg9, di6), (da3, dg9, di7), (da3, dg9, di8)

The following embodiments are examples of the compound (IX) of the present invention.

A compound of the formula (IX-b):

[Chemical Formula 84]

whereinHal is halogen;

R^c is

(ea1) a group of the formula:

(ea2) a group of the formula:

(ea3) a group of the formula:

ring E is(eg1) a cycloalkane ring or a cycloalkene ring;(eg2) a cycloalkane ring;(eg3) a cyclopropane ring;a group of the formula: (R^9′)s′- is(ej1) s′ is 0;(ej2) s′ is 1, and R^9′ is alkyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or unsubstituted alkyl;(ej3) s′ is 1, and R^9′ is unsubstituted alkyl;(ej4) s′ is 1, and R^9′ is methyl; ethyl; methyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or ethyl substituted with halogen, haloalkyloxy, cycloalkyl, cycloalkenyl, alkyloxy or alkenyloxy; or(ej5) s′ is 1, and R^9′ is methyl or ethyl,or its pharmaceutically acceptable salt or a solvate thereof.

The compound of the formula (IX-b) of the present invention includes the compounds comprising the combination of some or all of options of the above. Specifically, the following combinations are included.

(ea1, eg1, ei1), (ea1, eg1, ei2), (ea1, eg1, ei3), (ea1, eg1, ei4), (ea1, eg1, ei5), (ea1, eg2, ei1), (ea1, eg2, ei2), (ea1, eg2, ei3), (ea1, eg2, ei4), (ea1, eg2, ei5), (ea1, eg3, ei1), (ea1, eg3, ei2), (ea1, eg3, ei3), (ea1, eg3, ei4), (ea1, eg3, ei5), (ea2, eg1, ei1), (ea2, eg1, ei2), (ea2, eg1, ei3), (ea2, eg1, ei4), (ea2, eg1, ei5), (ea2, eg2, ei1), (ea2, eg2, ei2), (ea2, eg2, ei3), (ea2, eg2, ei4), (ea2, eg2, ei5), (ea2, eg3, ei1), (ea2, eg3, ei2), (ea2, eg3, ei3), (ea2, eg3, ei4), (ea2, eg3, ei5), (ea3, eg1, ei1), (ea3, eg1, ei2), (ea3, eg1, ei3), (ea3, eg1, ei4), (ea3, eg1, ei5), (ea3, eg2, ei1), (ea3, eg2, ei2), (ea3, eg2, ei3), (ea3, eg2, ei4), (ea3, eg2, ei5), (ea3, eg3, ei1), (ea3, eg3, ei2), (ea3, eg3, ei3), (ea3, eg3, ei4), (ea3, eg3, ei5)

The following is a general method for synthesizing the compounds of this invention. The starting materials and reagents used for synthesizing these compounds are commercially available or can be manufactured in accordance with a widely known method in this field using commercially available compounds.

For example, the compounds of the general formula (I), general formula (II), general formula (III), general formula (IV), general formula (VII), general formula (VIII) and general formula (IX) described in this invention can be manufactured by the following synthesis route:

[Method A]

wherein, Lg is a leaving group of the formula:

R¹⁰ is alkyl, R²⁷ is alkyl, n′ is an integer from 0 to 3, Lg¹ is a leaving group and other symbols are as defined above.

(Step 1)

The compound (i) or its hydrochloride or bromate is reacted with isocyanate (ii) or 1-carbamoyl imidazole (ii)′ in a solvent, such as N,N-dimethylformamide, N,N-dimethylacetamide, N,N′-dimethyl imidazolidinone and dimethylsulfoxide, in the presence of a base, such as DBU, triethylamine and pyridine (preferably DBU) at a temperature between −20 and 50° C., preferably at a temperature between −10° C. and below zero. After that, the compound (iii) can be manufactured by reacting the reactive mixture with a carbonylating or thiocarbonylating agent, such as 1,1′-carbonyldiimidazole, 1,1′-thiocarbonyldiimidazole, phosgene, thiophosgene and triphosgene, etc., and a base, such as DBU, triethylamine or pyridine (preferably DBU) at a temperature between −20 and 50° C., preferably at a temperature between −10° C. and below zero.

(Step 2)

The compound (v) can be manufactured by reacting the compound (iii) with the compound (iv) in a solvent, such as acetonitrile, acetone, DMF and DMSO, in the presence of a base, such as potassium carbonate and sodium carbonate, at a temperature between 50° C. to reflux, preferably at reflux.

The examples of leaving group include halogen and —OSO₂ (C_tF_2t+1) wherein t is an integer from 1 to 4. As halogen, chloro, iodo and bromo are preferred. As —OSO₂(C_tF_2t+1) group, —OTf group (trifluoromethanesulfonate) is preferred. This leaving group can also be used in the aforementioned (60′).

The base and/or carbonylating agent or thiocarbonylating agent in (Step 1) and (Step 2) can also be used in the aforementioned (60′).

The “carbonylating agent” and “thiocarbonylating agent” include a reagent that is used in a reaction where —C(═O) or —C(═S)— is inserted.

(Step 3)

The compound indicated by the general formula (II) can be manufactured by reacting the compound (v) with the compound (vii) in a solvent, such as NMP, DMF and DMSO, or under solvent-free conditions under microwave irradiation at a temperature between 150° C. and 250° C. preferably at a temperature between 200° C. and 230° C., or in a solvent, such as t-butanol, in the presence of an acid, such as acetic acid, at a temperature between 60° C. and 150° C., preferably at a temperature between 80° C. and 120° C.

Using optically active isocyanate (ii) enables to synthesize optically active compound (II).

[Method B]

wherein Hal² and Hal³ are halogen and other symbols are as defined above.

(Step 1)

The compound (ix) can be manufactured by reacting the compound (vii) with alkylating agent (viii), such as methyl iodide and ethyl iodide, in a solvent, such as methanol and ethanol, at a temperature between −40 and 30° C., preferably below zero.

(Step 2)

The compound (x) can be manufactured by reacting the compound (ix) with isocyanate, such as N-(chlorocarbonyl)isocyanate, in a solvent, such as dichloromethane, chloroform, 1,2-dichloroethane, in the presence of a base, such as triethylamine and N,N-diisopropylethylamine, at a temperature between −20 and 30° C., preferably below zero.

(Step 3)

The compound (xi) can be manufactured by reacting the compound (x) with the compound (vi) in a solvent, such as t-butanol, isopropanol, ethanol and acetonitrile, in the presence of an acid, such as acetic acid, formic acid and methanesulfonic acid, at reflux.

(Step 4)

The compound indicated by the general formula (II) can be manufactured by reacting the compound (xi) with the compound (xii) in a solvent, such as DMF and NMP, in the presence of a base, such as potassium t-butoxide and sodium hydride, at a temperature between 40 and 100° C., preferably at a temperature between 50 and 70° C.

Using optically-active compound (xii) enables to synthesize optically-active compound (II).

[Method C]

wherein Pg¹ is an appropriate hydroxy protecting group, s is an integer from 1 to 4 and other symbols are as defined above.

(Step 1)

The compound (xiii) can be manufactured by reacting a mixture of the compound (x) obtained by the method B, the alcohol (xii) whose one hydroxyl group is protected, such as 2-(tetrahydro-2H-pyran-2-yloxy)ethanol and a solvent, such as THF and dioxane, etc., with triphenylphosphine, and diethyl azodicarboxylate, etc.

(Step 2)

The compound (xiv) can be manufactured by reacting the compound (xiii) with the compound (vi) in the presence of an acid, such as formic acid and acetic acid, etc., at reflux.

[Method D]

wherein Pg² is an appropriate amino protecting group. R¹¹ 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R¹² is hydroxy or halogen, t is an integer from 1 to 4 and other symbols are as defined above.)

(Step 1)

The compound (xvi) can be manufactured by reacting the compound (xv) obtained by the method A or B with acid, such as hydrochloric acid-dioxane solution, hydrochloric acid-methanol, hydrochloric acid-ethyl acetate solution and trifluoroacetic acid, etc.

(Step 2)

The compound (xviii) can be manufactured by reacting the compound (xvi) with the acid halide (xvii) (R¹² is halogen) in a solvent, such as THF and dioxane, etc., in the presence of a base, such as triethylamine and diisopropylethylamine, etc. If necessary, dimethylaminopyridine, etc., can be added.

Alternatively, the compound (xviii) can be manufactured by reacting the compound (xvi) with the carboxylic acid (xvii, R¹² is hydroxy) in a solvent, such as THF and DMF, in the presence of a condensing agent, such as 1-hydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and a base, such as triethylamine and diisipropylethylamine, etc.

[Method E]

wherein R¹³ 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, a 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 or R^20a and R^20b are taken together to form oxo or thioxo, u is an integer from 1 to 4, and other symbols are as defined above.

(Step 1)

The compound (xx) can be manufactured by reacting the compound (x) obtained by the method B with the compound (xix) in a solvent, such as DMF, NMP and THF, in the presence of a base, such as DBU, potassium t-butoxide and sodium hydride, at a temperature between 0 and 80° C., preferably at a temperature between 30 and 50° C.

(Step 2)

The compound (xxi) can be manufactured by reacting the compound (xx) with the compound (vi) in a solvent, such as t-butanol, isopropanol, ethanol and acetonitrile, in the presence of an acid such as formic acid, acetic acid and methanesulfonic acid, etc., at reflux.

(Step 3)

The compound (xxii) can be manufactured by reacting the compound (xxi) with a solution, such as lithium hydroxide aqueous solution, sodium hydroxide aqueous solution and potassium hydroxide aqueous solution, in a solvent, such as methanol and ethanol, or in a mixture of such solvent and a solvent, such as THF and dioxane, etc.

[Method F]

wherein R¹⁴ is substituted or unsubstituted alkyl, R¹⁵ and R¹⁶ 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, u is an integer from 1 to 4 and other symbols are as defined above.

(Step 1)

The compound (xxiv) can be manufactured by reacting the compound (xxiii) obtained by the method A or B with a solution, such as lithium hydroxide aqueous solution, sodium hydroxide aqueous solution and potassium hydroxide aqueous solution, in a solvent, such as methanol and ethanol, or in a mixture of such solvent and a solvent, such as dioxane and THF, etc.

(Step 2)

The compound (xxvi) can be manufactured by reacting the compound (xxiv) with the compound (xxv) in a solvent, such as THF, DMF and NMP, in the presence of a condensing agent, such as 1-hydroxybenzotriazole, HOAt, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, HATU and PyBOP, and a base, such as triethylamine and diisipropylethylamine, etc.

[Method G]

wherein Pg¹ is an appropriate hydroxy protecting group and other symbols are as defined above.

(Step 1)

The compound (xxvii) can be manufactured by reacting the compound (xi) obtained by the method B with a halogenating agent, such as phosphorous oxychloride and phosphorous oxybromide, under solvent-free conditions or in a solvent, such as toluene and tetrahydrofuran, at a temperature between 0 and 100° C., preferably at a temperature between 40 and 60° C.

(Step 2)

The compound (xxviii) can be manufactured by reacting a mixture of the alcohol (xv) whose one hydroxyl group is protected, such as 2-(tetrahydro-2H-pyran-2-yloxy)ethanol, and a solvent, such as THF, dioxane and DMF, with the compound (xv) after adding a base, such as sodium hydride and potassium t-butoxide.

(Step 3)

The compound (xxix) can be manufactured by reacting the compound (xxviii) with an acid, such as hydrochloric acid, p-toluenesulfonic acid or its hydrate and pyridine p-toluenesulfonate, in a solvent, such as methanol, etc.

[Method H]

wherein R²¹ 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, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, R²² is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl, and other symbols are as defined above.

(Step 1)

The compound (xxxi) can be manufactured by reacting the compound (xxvii) obtained by the method G with the compound (xxx) in a solvent, such as THF and dioxane, etc.

[Method I]

wherein the symbols in the formula are as defined above.

(Step 1)

The compound (xxxiii) can be manufactured by reacting the compound (xxvii) obtained by the method G with the compound (xxxii) in a solvent, such as THF and dioxane, after adding a base, such as sodium hydride, etc.

[Method J]

wherein R¹⁸ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl, Q is dihydroxyboran, dialkoxyboran or dialkylboran,

and other symbols are as defined above.

The compound (xxxiv) can be manufactured by reacting the compound (xxvii) obtained by the method G with the compound (xxxiii) in a solvent, such as THF and dioxane, in the presence of a palladium catalyst, and a solution, such as potassium carbonate, cesium carbonate and sodium carbonate aqueous solution, etc., at a temperature between 50° C. and reflux, preferably at reflux, or under microwave irradiation at a temperature of 120 and 200° C., preferably at a temperature between 130 and 150° C.

[Method K]

wherein R¹⁹ is substituted or unsubstituted alkyl, v is an integer from 0 to 4 and other symbols are as defined above.

The compound (xxxvi) can be manufactured by hydrolyzing the compound (xxxv) using a mixture of an ethers solvent, such as dioxane. THF and DME, etc., an alcohols solvent, such as ethanol and methanol, or a solvent, such as DMF, DMA. DMSO and NMP, and water, as well as using a base, such as sodium hydroxide and lithium hydroxide. Although the preferable reaction temperature is room temperature, it can be increased if the reaction proceeds slowly.

(Step 2)

The compound (xxxvii) can be obtained by dissolving the compound (xxxvi) in an alcohols solvent, such as methanol and ethanol, and performing catalytic reduction using a hydrogenation reactor (such as H-Cube [10% Pt—C, H2=1 atm]) or a metallic catalyst, such as palladium-carbon, platinum oxide and chlorotris (triphenylphosphine) rodiumu (I), etc.

[Method L]

wherein the symbols in the formula are as defined above.

(Step 1)

The compound (ixl) can be manufactured by reacting a mixture of the compound (x) obtained by the method B, the alcohol (xxxviii) and a solvent, such as THF and dioxane, with triphenylphosphine, etc., and diethyl azodicarboxylate, etc.

(Step 2)

The compound (II) can be manufactured by reacting the compound (ixl) with the compound (vi) in the presence of an acid, such as formic acid and acetic acid, at reflux.

Using the optically-active alcohol (xxxviii) enables to synthesize the optically-active compound (II).

The alcohol used as an intermediate (xxxviii) is commercially available or can be manufactured according to a method specified in the following documents:

• 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.

[Method M]

wherein R²¹ is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy, etc., R²² is bromo or iodo, R²³ and R²⁴ are each independently substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, and other symbols are as defined above.

(Step 1)

The compound (xxxix) can be manufactured by reacting the compound (xxxvii) obtained by the method from A to F or L with the compound (xxxviii) in a solvent, such as THF and dioxane, in the presence of a palladium catalyst and a solution, such as potassium carbonate, cesium carbonate and sodium carbonate aqueous solution, etc., at a temperature between 50° C. and reflux, preferably at reflux, or under microwave irradiation at a temperature between 120 and 200° C., preferably at a temperature between 130 and 150° C.

(Step 2)

The compound (xl) can be obtained by dissolving the compound (xxxix) in an alcohols solvent, such as methanol and ethanol, and performing catalytic reduction using a hydrogenation reactor (such as H-Cube (10% Pt—C, H2=1 atm)) or a metallic catalyst, such as palladium-carbon, platinum oxide, chlorotris(triphenylphosphine)rhodium (I), etc.

[Method N]

wherein the symbols in the formula are as defined above.

(Step 1)

The compound (xlii) can be manufactured by reacting the compound (xli) obtained by the method from A to F or L with the compound (xxxviii) in a solvent, such as THF and dioxane, in the presence of a palladium catalyst and a solution, such as potassium carbonate, cesium carbonate and sodium carbonate aqueous solution, etc., at a temperature between 50° C. and reflux, preferably at reflux, or under microwave irradiation at a temperature between 120 and 200° C., preferably at a temperature between 130 and 150° C.

(Step 2)

The compound (xliii) can be obtained by dissolving the compound (xlii) in an alcohols solvent, such as methanol and ethanol, and performing catalytic reduction using a hydrogenation reactor (such as H-Cube (10% Pt—C, H2=1 atm)) or a metallic catalyst, such as palladium-carbon, platinum oxide and chlorotris (triphenylphosphine) rhodium (I), etc.

[Method O]

wherein R²⁵ is substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy, R²⁶ is bromo or iodo, and other symbols are as defined above.

(Step 1)

The compound (xlvi) can be obtained from the compound (xlvi) in the presence of Lewis acid or trifluoroacetic acid, etc., under solvent-free conditions or in an appropriate solvent at a temperature between 0° C. and reflux.

(Step 2)

The compound (xlviii) can be manufactured by reacting the compound (xlvi) with the compound (xlvii) in a solvent, such as THF and dioxane, in the presence of a palladium catalyst and a solution, such as potassium carbonate, cesium carbonate and sodium carbonate aqueous solution, etc. at a temperature between 50° C. and reflux, preferably at reflux, or under microwave irradiation at a temperature of 120 and 200° C., preferably at a temperature between 130 and 150° C.

[Method P]

wherein the symbols in the formula are as defined above.

(Step 1)

The compound (xli) can be manufactured by reacting a mixture of the compound (iii) obtained by the method A, the alcohol (xl) and a solvent, such as THF and dioxane, with triphenylphosphine, etc. and diethyl azodicarboxylate, etc.

(Step 2)

The compound (xlii) can be manufactured by reacting the compound (xli) with the compound (vi) in the presence of formic acid and acetic acid, etc., at reflux.

[Method Q]

wherein the symbols in the formula are as defined above.

(Step 1)

The compound (xliii) can be manufactured by reacting the compound (v) obtained by the method A in a solvent, such as water, acetic acid and methanol, in the presence of an oxidation agent, such as hydrogen peroxide water and MCPBA, at a temperature between −20 and 100° C., preferably at room temperature.

(Step 2)

The compound (xlv) can be manufactured by reacting the compound (xliii) with the compound (xliv) in a solvent, such as acetonitrile, acetone, DMF and DMSO, in the presence of a base, such as potassium carbonate and sodium carbonate, at a temperature between 50° C. and reflux, preferably at reflux.

The compounds of this invention (I) are not limited to a specific isomer but include all possible isomers and racemates. For example, they include a tautomer as shown below. The compounds indicated by the formula (VIII), formula (IX) and formula (VII), etc., also include similar tautomers.

In addition, one or more hydrogen atoms, carbon atoms or other atoms of the compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like can be replaced by an isotope of the hydrogen atom, carbon atom or other atoms. Compounds of the formula (I), formula (VIII), formula (IX), formula (VII) and the like include all radiolabeled forms of compounds of the formula (I), formula (VIII), formula (IX), formula (VII) and the like. The “radiolabeled,” “radiolabeled form” and the like of the compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like are encompassed by the present invention and useful as a research and/or diagnostic tool in metabolism pharmacokinetic studies and in binding assays. It is also useful for a medicament.

Examples of isotopes that can be incorporated into the compound of the formula (I), formula (VIII), formula (IX), formula (VIT) and the like of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹²³I and ³⁶Cl, respectively. Radiolabeled compounds of the present invention can be prepared by methods known in the art. For example, tritiated compounds of formula (I) can be prepared by introducing tritium into the particular compound of formula (I), for example, by catalytic dehalogenation with tritium. This method may include reacting a suitably halogen-substituted precursor of a compound of formula (I), formula (VIII), formula (IX), formula (VII) and the like with tritium gas in the presence of a suitable catalyst such as Pd/C, in the presence or absence of a base. Other suitable methods for preparing tritiated compounds can be found in Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A) Chapter 6, (1987). ¹⁴C-labeled compounds can be prepared by employing starting materials having a ¹⁴C carbon.

The compounds of the above formula (I), formula (VIII), formula (IX), formula (VII) and the like or its salt can be converted into hydrate or solvate thereof by known methods. Examples of suitable solvates are solvate with acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether or the like. For example, it includes a non-toxic and water-soluble hydrate or solvate such as a solvate with ethanol.

As pharmaceutically acceptable salt of the compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like, examples include salts with alkaline metals (e.g. lithium, sodium and potassium), alkaline earth metals (e.g. calcium and barium), magnesium, transition metal (e.g. zinc and iron), ammonia, organic bases (e.g. trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline), and amino acids, and salts with inorganic acids (e.g. hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid and hydroiodic acid) and organic acids (e.g. 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, methanesulfonic acid and ethanesulfonic acid). Especially preferable are salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, or methanesulfonic acid. These salts may be formed by usual methods.

The compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like or its pharmaceutically acceptable salt may form solvate such as hydrate, and/or crystalline polymorphism, and the present invention also includes such various kinds of solvate and crystalline polymorphism. The “solvate” includes a compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like which coordinate arbitrary number of solvent molecules such as water molecules. The compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like or its pharmaceutically acceptable salt can adhere water or form hydrate by absorbing water molecules after leaving in the atmosphere. Moreover, the compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like or its pharmaceutically acceptable salt can form the crystalline polymorphism by recrystallization.

The compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like of the present invention or its pharmaceutically acceptable salt may form prodrug, and the present invention also includes such various kinds of prodrug. Prodrug is a derivative of the compound of the present invention having a group which can be chemically or metabolically decomposed and the one which becomes a pharmaceutically active compound of the present invention by solvolysis or physiological conditions in vivo. Prodrug includes a compound which converts into the compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like by enzymatical oxidation, reduction, hydrolysis or the like under physiological conditions in a living body, and a compound which converts into the compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like by hydrolyzing by stomach acid or the like. The method of selecting suitable prodrug derivatives and the method of manufacturing them are disclosed in Design of Prodrugs, Elsevier, and Amsterdam 1985. Prodrug itself may possess the activity.

When the compound of the formula (I), formula (VIII), formula (IX), formula (VII) and the like or its pharmaceutically acceptable salt has a hydroxy group, examples of the prodrug includes acyloxy derivatives and sulfonyloxy derivatives which can be manufactured by reacting a compound having a hydroxy group with a suitable acid halide, suitable acid anhydride, suitable sulfonyl chloride, suitable sulfonylanhydride and mixed anhydride. For example, CH₃COO—, C₂H₅COO—, t-BuCOO—, C₁₅H₃₁COO—, PhCOO—, (m-NaOOCPh)COO—, NaOOCCH₂CH₂COO—, CH₃CH(NH₂)COO—, CH₂N(CH₃)₂COO—, CH₃SO₃—, CH₃CH₂SO₃—, CF₃SO₃—, CH₃FSO₃—, CF₃CH₂SO₃—, p-CH₃—O-PhSO₃—, PhSO₃—, and p-CH₃PhSO₃— are exemplified.

The compound of the general formula (I), formula (VIII), formula (IX), formula (VII) and the like has an antagonistic effect on P2X₃ and/or P2X_2/3 receptor, and therefore, is useful as a therapeutic agent for diseases associated with a P2X₃ and/or P2X_2/3 receptor. Since P2X₃ and/or P2X_2/3 receptor is believed to associate with pain and diseases in urinary system (Nature 407, 26, 1011-1015 (2000), Nature, Vol. 407, No. 26, 1015-1017 (2000), Non-Patent Document 1, Non-Patent Document 2, etc.), the compound of the invention is useful in the treatment, alleviation of symptoms or prevention of diseases, such as for example, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, headache, migraine, orofacial pain, toothache, glossagra, pain associated with temporomandibular arthrosis, trigeminal neuralgia, shoulder pain, pain associated with hernia of intervertebral disk, pain associated with cervical spondylosis deformans, pain associated with spinal canal stenosis, pain associated with thoracic outlet syndrome, pain associated with traumatic brachial plexus injury syndrome, pain associated with shoulder-hand syndrome, pain associated with whiplash injury, chest pain, abdominal pain, colic pain, pain associated with cholelithiasis, pain associated with pancreatitis, pain associated with urinary calculosis, pain associated with irritable bowel syndrome, lumbar backache, sciatica, pain associated with bone fracture, pain associated with osteoporosis, joint pain, pain associated with gout, pain associated with cauda equina syndrome, pain associated with ankylosing spondylitis, sore muscle, pain associated with painful spasm, pain associated with myofascial pain syndrome, pain associated with fibromyalgia syndrome, complex regional pain syndrome, pain associated with arteriosclerosis obliterans, pain associated with Buerger's disease, pain associated with Raynaud's phenomenon, pain associated with zoster, causalgic pain, pain associated with entrapment neuropathy, pain associated with carpal canal syndrome, pain associated with diabetes, pain associated with Guillain-Barre syndrome, pain associated with Hansen's disease, pain associated with drug therapy, pain associated with radiation therapy, pain associated with cord injury, pain associated with syringomyelia, pain associated with stroke, thalamic pain, pain associated with deafferentation, sympathetically-maintained pain. ABC syndrome, multiple sclerosis, pain associated with skin disease, cancer pain, postoperative pain, pain associated with injury, pain associated with gangrene, pain associated with somatoform disorder, pain associated with somatization disorder, pain associated with depression, pain associated with Parkinson's disease, knee joint pain, pain associated with arthritis, neuropathic pain such as menstrual pain, intermenstrual pain, labor pain, etc., inflammatory pain, nociceptive pain, psychogenic pain, pain of bladder such as overactive bladder, blader inflammation etc. incontinence, pollakiuria, urinary urgency, cystatrophia, prostatic hypertrophy, prostatitis, prostate pain, detrusor hyperreflesxia, urination disorder, nervous pollakiuria, chronic prostatitis, chronic cystitis, etc.

“A pharmaceutical composition having an improving effect of urination disorder” includes “a pharmaceutical composition for treating overactive bladder”, “a pharmaceutical composition for treating interstitial bladder cystitis” and the like.

The compound of the present invention or the pharmaceutical composition of the present invention can be a drug with reduced side-effect such as effect on motor function because it has a high affinity for ATP receptor, especially P2X₃ receptor, and also has high subtype selectivity and high selectivity for other receptors. Also, the compound encompassed by the present invention or the pharmaceutical composition encompassed by the present invention is advantageous because of its high P2X3 receptor inhibitor activity in the presence of RSA, high metabolic stability, high oral absorption, good bioavailability, low clearance, long half-life, prolonged duration of action, low activity of hepatic enzyme inhibition, high unbound fraction in serum and/or high safety etc.

In another embodiment, the present invention provides a pharmaceutical composition comprising an effective amount of the compound of the present invention, in combination with a pharmaceutically acceptable carrier.

For use of the compound of the present invention as a medicament, a pharmaceutical composition can be prepared according to conventional methods, using pharmaceutically acceptable carriers well-known in the art, such as excipients, binders, disintegrants, lubricants, colourants, flavors, surfactants, etc.

For the pharmaceutical composition of the present invention to be administered in the treatment of mammals including human, an appropriate unit dosage form may be selected depending on the purpose of the treatment and the route of administration. Specifically, such unit dosage form includes oral formulations such as tablet, coated tablet, powder, granule, capsule, liquid, pill, suspension, emulsion, etc., and parenteral formulations such as injectable solution, suppository, ointment, patch, aerosol, etc. Such unit dosage form can be formulated according to methods well-known in the art.

The amount of the present compound in a formulation can vary depending on its dosage form, route for administration, dosing regimen, etc.

Means for administration of the present pharmaceutical composition may be selected depending on dosage form, patient's age, sex, body weight, severity of the disease, and other factors, etc., and route for administration can be selected from various routes such as oral, subcutaneous, transdermal, rectal, intranasal, buccal, etc.

Dose of the present compound in the present pharmaceutical composition can be determined depending on the choice of route for administration, patient's age, sex, body weight, severity of the disease, the compound to be administered, and other factors, etc., and can be generally from 0.05 to 1000 mg/kg/day, preferably from 0.1 to 10 mg/kg/day, for oral administration to adults. For parenteral administration, dose can vary widely depending on its route but generally from 0.005 to 100 mg/kg/day, preferably from 0.01 to 1 mg/kg/day. Such pharmaceutical composition of the present invention may be administered once a day or in several times at a divided dosage in a day.

In some embodiments of the present compounds, there is provided compounds of the following general formula (V) and the general formula (VI) having the following groups are provided:

wherein R^p, R^q, and R^r are selected from the following Tables 1 to 3.

TABLE 1
     Rp
Rp1  HO(CH2)2
Rp2  HO(CH2)3
Rp3  (HOCH2)2CHCH2
Rp4  (HOCH2)2C(Me)CH2
Rp5  HOCH2CH(OH)CH2
Rp6  HOCO(CH2)2
Rp7  HOCOC(Me)2CH2
Rp8  HOCOC(—CH2CH2—)CH2
Rp9  HOCOCH(Me)CH2
Rp10 HOCOCH(Me)CH(Me)
Rp11 HOCOC(CH2)3

TABLE 2
    Rq
Rq1 4-Me—Ph
Rq2 4-Et—Ph
Rq3 4-Cl—Ph
Rq4 4-Br—Ph
Rq5 cyclohexyl

TABLE 3
	Rr		Rr
Rr1	2-Me-benzothiazol-6-yl	Rr20	2-Piperidine-5-pyridyl
Rr2	2-Me-benzothiazol-5-yl	Rr21	5-c-PrCH2O-2-pyridyl
Rr3	2-Me-benzimidazol-6-yl	Rr22	5-c-BuO-2-pyridyl
Rr4	2-Me-benthoiphen-5-yl	Rr23	5-PhO-2-pyridyl
Rr5	3-Me-benzisoxazol-6-yl	Rr24	5-Piperidino-2-pyridyl
Rr6	3-Me-2H-1,4-benzoxazin-7-yl	Rr25	2-c-BuO-3-Cl-5-pyridyl
Rr7	7-Me-1,8-naphthyridin-3-yl	Rr26	2-c-BuO-3-Me-5-pyridyl
Rr8	7-Me-quinolin-3-yl	Rr27	2-c-PentylO-3-Cl-5-pyridyl
Rr9	2-Me-quinazolin-6-yl	Rr28	2-c-PentylO-3-Me-5-pyridyl
Rr10	4-c-PrO—Ph	Rr29	2-PhO-3-Cl-5-pyridyl
Rr11	3-Me-4-c-PrO—Ph	Rr30	3-Me-4-i-PrCONH—Ph
Rr12	3-Cl-4-c-PrO—Ph	Rr31	3-Cl-4-i-PrCONH—Ph
Rr13	4-c-PrCH2—Ph	Rr32	3-Me-4-i-PrNHCO—Ph
Rr14	3-Me-4-c-PrCH2—Ph	Rr33	3-Cl-4-i-PrNHCO—Ph
Rr15	3-Cl-4-c-PrCH2—Ph	Rr34	3-Me-4-i-PrSO2NH—Ph
Rr16	4-c-BuCH2—Ph	Rr35	3-Cl-4-i-PrSO2NH—Ph
Rr17	3-MeO-4-c-BuCH2—Ph	Rr36	3-Me-4-i-PrNHSO2—Ph
Rr18	2-c-PrCH2O-5-pyridyl	Rr37	3-Cl-4-i-PrNHSO2—Ph
Rr19	2-PhO-5-pyridyl

In the above tables, Me is methyl, Et is ethyl, i-Pr is isopropyl, c-Pr is cyclopropyl, c-Bu is cyclobutyl, and Ph is phenyl.

The combination of Rp, Rq and Rr, i.e. (Rp, Rq, Rr), is any one of the following combinations:

(Rp,Rq,Rr)=

(Rp1,Rq1,Rr1),(Rp1,Rq1,Rr2),(Rp1,Rq1,Rr3),(Rp1,Rq1,Rr4),(Rp1,Rq1,Rr5),(Rp1,Rq1,Rr6),(Rp1,Rq1,Rr7),(Rp1,Rq1,Rr8),(Rp1,Rq1,Rr9),(Rp1,Rq1,Rr10),(Rp1,Rq1,Rr11),(Rp1,Rq1,Rr12),(Rp1,Rq1,Rr13),(Rp1,Rq1,Rr14),(Rp1,Rq1,Rr15),(Rp1,Rq1,Rr16),(Rp1,Rq1,Rr17),(Rp1,Rq1,Rr18),(Rp1,Rq1,Rr19),(Rp1,Rq1,Rr20),(Rp1,Rq1,Rr21),(Rp1,Rq1,Rr22),(Rp11,Rq1,Rr23),(Rp1,Rq1,Rr24),(Rp1,Rq1,Rr25),(Rp1,Rq1,Rr26),(Rp1,Rq1,Rr27),(Rp1,Rq1,Rr28),(Rp1,Rq1,Rr29),(Rp1,Rq1,Rr30),(Rp1,Rq1,Rr31),(Rp1,Rq1,Rr32),(Rp1,Rq1,Rr33),(Rp1,Rq1,Rr34),(Rp1,Rq1,Rr35),(Rp1,Rq1,Rr36),(Rp1,Rq1,Rr37),(Rp1,Rq2,Rr1),(Rp1,Rq2,Rr2),(Rp1,Rq2,Rr3),(Rp1,Rq2,Rr4),(Rp1,Rq2,Rr5),(Rp1,Rq2,Rr6),(Rp1,Rq2,Rr7),(Rp1,Rq2,Rr8),(Rp1,Rq2,Rr9),(Rp1,Rq2,Rr10),(Rp1,Rq2,Rr11),(Rp1,Rq2,Rr12),(Rp1,Rq2,Rr13),(Rp1,Rq2,Rr14),(Rp1,Rq2,Rr15),(Rp1,Rq2,Rr16),(Rp1,Rq2,Rr17),(Rp1,Rq2,Rr18),(Rp1,Rq2,Rr19),(Rp1,Rq2,Rr20),(Rp1,Rq2,Rr21),(Rp1,Rq2,Rr22),(Rp1,Rq2,Rr23),(Rp1,Rq2,Rr24),(Rp1,Rq2,Rr25),(Rp1,Rq2,Rr26),(Rp1,Rq2,Rr27),(Rp1,Rq2,Rr28),(Rp1,Rq2,Rr29),(Rp1,Rq2,Rr30),(Rp1,Rq2,Rr31),(Rp1,Rq2,Rr32),(Rp1,Rq2,Rr33),(Rp1,Rq2,Rr34),(Rp1,Rq2,Rr35),(Rp1,Rq2,Rr36),(Rp1,Rq2,Rr37),(Rp1,Rq3,Rr1),(Rp1,Rq3,Rr2),(Rp1,Rq3,Rr3),(Rp1,Rq3,Rr4),(Rp1,Rq3,Rr5),(Rp1,Rq3,Rr6),(Rp1,Rq3,Rr7),(Rp1,Rq3,Rr8),(Rp1,Rq3,Rr9),(Rp1,Rq3,Rr10),(Rp1,Rq3,Rr11),(Rp1,Rq3,Rr12),(Rp1,Rq3,Rr13),(Rp1,Rq3,Rr14),(Rp1,Rq3,Rr15),(Rp1,Rq3,Rr16),(Rp1,Rq3,Rr17),(Rp1,Rq3,Rr18),(Rp1,Rq3,Rr19),(Rp1,Rq3,Rr20),(Rp1,Rq3,Rr21),(Rp1,Rq3,Rr22),(Rp11,Rq3,Rr23),(Rp1,Rq3,Rr24),(Rp1,Rq3,Rr25),(Rp1,Rq3,Rr26),(Rp1,Rq3,Rr27),(Rp1,Rq3,Rr28),(Rp1,Rq3,Rr29),(Rp1,Rq3,Rr30),(Rp1,Rq3,Rr31),(Rp1,Rq3,Rr32),(Rp1,Rq3,Rr33),(Rp1,Rq3,Rr34),(Rp1,Rq3,Rr35),(Rp1,Rq3,Rr36),(Rp1,Rq3,Rr37),(Rp1,Rq4,Rr1),(Rp1,Rq4,Rr2),(Rp1,Rq4,Rr3),(Rp1,Rq4,Rr4),(Rp1,Rq4,Rr5),(Rp1,Rq4,Rr6),(Rp1,Rq4,Rr7),(Rp1,Rq4,Rr8),(Rp1,Rq4,Rr9),(Rp1,Rq4,Rr10),(Rp1,Rq4,Rr11),(Rp1,Rq4,Rr12),(Rp1,Rq4,Rr13),(Rp1,Rq4,Rr14),(Rp1,Rq4,Rr15),(Rp1,Rq4,Rr16),(Rp1,Rq4,Rr17),(Rp1,Rq4,Rr18),(Rp1,Rq4,Rr19),(Rp1,Rq4,Rr20),(Rp1,Rq4,Rr21),(Rp1,Rq4,Rr22),(Rp1,Rq4,Rr23),(Rp1,Rq4,Rr24),(Rp1,Rq4,Rr25),(Rp1,Rq4,Rr26),(Rp1,Rq4,Rr27),(Rp1,Rq4,Rr28),(Rp1,Rq4,Rr29),(Rp1,Rq4,Rr30),(Rp1,Rq4,Rr31),(Rp1,Rq4,Rr32),(Rp1,Rq4,Rr33),(Rp1,Rq4,Rr34),(Rp1,Rq4,Rr35),(Rp1,Rq4,Rr36),(Rp1,Rq4,Rr37),(Rp1,Rq5,Rr1),(Rp1,Rq5,Rr2),(Rp1,Rq5,Rr3),(Rp1,Rq5,Rr4),(Rp1,Rq5,Rr5),(Rp1,Rq5,Rr6),(Rp1,Rq5,Rr7),(Rp1,Rq5,Rr8),(Rp1,Rq5,Rr9),(Rp1,Rq5,Rr10),(Rp1,Rq5,Rr11),(Rp1,Rq5,Rr12),(Rp1,Rq5,Rr13),(Rp1,Rq5,Rr14),(Rp1,Rq5,Rr15),(Rp1,Rq5,Rr16),(Rp1,Rq5,Rr17),(Rp1,Rq5,Rr18),(Rp1,Rq5,Rr19),(Rp1,Rq5,Rr20),(Rp1,Rq5,Rr21),(Rp1,Rq5,Rr22),(Rp1,Rq5,Rr23),(Rp1,Rq5,Rr24),(Rp1,Rq5,Rr25),(Rp1,Rq5,Rr26),(Rp1,Rq5,Rr27),(Rp1,Rq5,Rr28),(Rp1,Rq5,Rr29),(Rp1,Rq5,Rr30),(Rp1,Rq5,Rr31),(Rp1,Rq5,Rr32),(Rp1,Rq5,Rr33),(Rp1,Rq5,Rr34),(Rp1,Rq5,Rr35),(Rp1,Rq5,Rr36),(Rp1,Rq5,Rr37),(Rp2,Rq1,Rr1),(Rp2,Rq1,Rr2),(Rp2,Rq1,Rr3),(Rp2,Rq1,Rr4),(Rp2,Rq1,Rr5),(Rp2,Rq1,Rr6),(Rp2,Rq1,Rr7),(Rp2,Rq1,Rr8),(Rp2,Rq1,Rr9),(Rp2,Rq1,Rr10),(Rp2,Rq1,Rr1),(Rp2,Rq1,Rr12),(Rp2,Rq1,Rr13),(Rp2,Rq1,Rr14),(Rp2,Rq1,Rr15),(Rp2,Rq1,Rr16),(Rp2,Rq1,Rr17),(Rp2,Rq1,Rr18),(Rp2,Rq1,Rr19),(Rp2,Rq1,Rr20),(Rp2,Rq1,Rr21),(Rp2,Rq1,Rr22),(Rp2,Rq1,Rr23),(Rp2,Rq1,Rr24),(Rp2,Rq1,Rr25),(Rp2,Rq1,Rr26),(Rp2,Rq1,Rr27),(Rp2,Rq1,Rr28),(Rp2,Rq1,Rr29),(Rp2,Rq1,Rr30),(Rp2,Rq1,Rr31),(Rp2,Rq1,Rr32),(Rp2,Rq1,Rr33),(Rp2,Rq1,Rr34),(Rp2,Rq1,Rr35),(Rp2,Rq1,Rr36),(Rp2,Rq1,Rr37),(Rp2,Rq2,Rr1),(Rp2,Rq2,Rr2),(Rp2,Rq2,Rr3),(Rp2,Rq2,Rr4),(Rp2,Rq2,Rr5),(Rp2,Rq2,Rr6),(Rp2,Rq2,Rr7),(Rp2,Rq2,Rr8),(Rp2,Rq2,Rr9),(Rp2,Rq2,Rr10),(Rp2,Rq2,Rr11),(Rp2,Rq2,Rr12),(Rp2,Rq2,Rr13),(Rp2,Rq2,Rr14),(Rp2,Rq2,Rr15),(Rp2,Rq2,Rr16),(Rp2,Rq2,Rr17),(Rp2,Rq2,Rr18),(Rp2,Rq2,Rr19),(Rp2,Rq2,Rr20),(Rp2,Rq2,Rr21),(Rp2,Rq2,Rr22),(Rp2,Rq2,Rr23),(Rp2,Rq2,Rr24),(Rp2,Rq2,Rr25),(Rp2,Rq2,Rr26),(Rp2,Rq2,Rr27),(Rp2,Rq2,Rr28),(Rp2,Rq2,Rr29),(Rp2,Rq2,Rr30),(Rp2,Rq2,Rr31),(Rp2,Rq2,Rr32),(Rp2,Rq2,Rr33),(Rp2,Rq2,Rr34),(Rp2,Rq2,Rr35),(Rp2,Rq2,Rr36),(Rp2,Rq2,Rr37),(Rp2,Rq3,Rr1),(Rp2,Rq3,Rr2),(Rp2,Rq3,Rr3),(Rp2,Rq3,Rr4),(Rp2,Rq3,Rr5),(Rp2,Rq3,Rr6),(Rp2,Rq3,Rr7),(Rp2,Rq3,Rr8),(Rp2,Rq3,Rr9),(Rp2,Rq3,Rr10),(Rp2,Rq3,Rr11),(Rp2,Rq3,Rr12),(Rp2,Rq3,Rr13),(Rp2,Rq3,Rr14),(Rp2,Rq3,Rr15),(Rp2,Rq3,Rr16),(Rp2,Rq3,Rr17),(Rp2,Rq3,Rr18),(Rp2,Rq3,Rr19),(Rp2,Rq3,Rr20),(Rp2,Rq3,Rr21),(Rp2,Rq3,Rr22),(Rp2,Rq3,Rr23),(Rp2,Rq3,Rr24),(Rp2,Rq3,Rr25),(Rp2,Rq3,Rr26),(Rp2,Rq3,Rr27),(Rp2,Rq3,Rr2),(Rp2,Rq3,Rr29),(Rp2,Rq3,Rr30),(Rp2,Rq3,Rr31),(Rp2,Rq3,Rr32),(Rp2,Rq3,Rr33),(Rp2,Rq3,Rr34),(Rp2,Rq3,Rr35),(Rp2,Rq3,Rr36),(Rp2,Rq3,Rr37),(Rp2,Rq4,Rr1),(Rp2,Rq4,Rr2),(Rp2,Rq4,Rr3),(Rp2,Rq4,Rr4),(Rp2,Rq4,Rr5),(Rp2,Rq4,Rr6),(Rp2,Rq4,Rr7),(Rp2,Rq4,Rr8),(Rp2,Rq4,Rr9),(Rp2,Rq4,Rr10),(Rp2,Rq4,Rr11),(Rp2,Rq4,Rr12),(Rp2,Rq4,Rr13),(Rp2,Rq4,Rr14),(Rp2,Rq4,Rr15),(Rp2,Rq4,Rr16),(Rp2,Rq4,Rr17),(Rp2,Rq4,Rr18),(Rp2,Rq4,Rr19),(Rp2,Rq4,Rr20),(Rp2,Rq4,Rr21),(Rp2,Rq4,Rr22),(Rp2,Rq4,Rr23),(Rp2,Rq4,Rr24),(Rp2,Rq4,Rr25),(Rp2,Rq4,Rr26),(Rp2,Rq4,Rr27),(Rp2,Rq4,Rr28),(Rp2,Rq4,Rr29),(Rp2,Rq4,Rr30),(Rp2,Rq4,Rr31),(Rp2,Rq4,Rr32),(Rp2,Rq4,Rr33),(Rp2,Rq4,Rr34),(Rp2,Rq4,Rr35),(Rp2,Rq4,Rr36),(Rp2,Rq4,Rr37),(Rp2,Rq5,Rr1),(Rp2,Rq5,Rr2),(Rp2,Rq5,Rr3),(Rp2,Rq5,Rr4),(Rp2,Rq5,Rr5),(Rp2,Rq5,Rr6),(Rp2,Rq5,Rr7),(Rp2,Rq5,Rr8),(Rp2,Rq5,Rr9),(Rp2,Rq5,Rr10),(Rp2,Rq5,Rr11),(Rp2,Rq5,Rr12),(Rp2,Rq5,Rr13),(Rp2,Rq5,Rr14),(Rp2,Rq5,Rr15),(Rp2,Rq5,Rr16),(Rp2,Rq5,Rr17),(Rp2,Rq5,Rr18),(Rp2,Rq5,Rr19),(Rp2,Rq5,Rr20),(Rp2,Rq5,Rr21),(Rp2,Rq5,Rr22),(Rp2,Rq5,Rr23),(Rp2,Rq5,Rr24),(Rp2,Rq5,Rr25),(Rp2,Rq5,Rr26),(Rp2,Rq5,Rr27),(Rp2,Rq5,Rr28),(Rp2,Rq5,Rr29),(Rp2,Rq5,Rr30),(Rp2,Rq5,Rr31),(Rp2,Rq5,Rr32),(Rp2,Rq5,Rr33),(Rp2,Rq5,Rr34),(Rp2,Rq5,Rr35),(Rp2,Rq5,Rr36),(Rp2,Rq5,Rr37),(Rp3,Rq1,Rr1),(Rp3,Rq1,Rr2),(Rp3,Rq1,Rr3),(Rp3,Rq1,Rr4),(Rp3,Rq1,Rr5),(Rp3,Rq1,Rr6),(Rp3,Rq1,Rr7),(Rp3,Rq1,Rr8),(Rp3,Rq1,Rr9),(Rp3,Rq1,Rr10),(Rp3,Rq1,Rr11),(Rp3,Rq1,Rr12),(Rp3,Rq1,Rr13),(Rp3,Rq1,Rr14),(Rp3,Rq1,Rr15),(Rp3,Rq1,Rr16),(Rp3,Rq1,Rr17),(Rp3,Rq1,Rr18),(Rp3,Rq1,Rr19),(Rp3,Rq1,Rr20),(Rp3,Rq1,Rr21),(Rp3,Rq1,Rr22),(Rp3,Rq1,Rr23),(Rp3,Rq1,Rr24),(Rp3,Rq1,Rr25),(Rp3,Rq1,Rr26),(Rp3,Rq1,Rr27),(Rp3,Rq1,Rr28),(Rp3,Rq1,Rr29),(Rp3,Rq1,Rr30),(Rp3,Rq1,Rr31),(Rp3,Rq1,Rr32),(Rp3,Rq1,Rr33),(Rp3,Rq1,Rr34),(Rp3,Rq1,Rr35),(Rp3,Rq1,Rr36),(Rp3,Rq1,Rr37),(Rp3,Rq2,Rr1),(Rp3,Rq2,Rr2),(Rp3,Rq2,Rr3),(Rp3,Rq2,Rr4),(Rp3,Rq2,Rr5),(Rp3,Rq2,Rr6),(Rp3,Rq2,Rr7),(Rp3,Rq2,Rr8),(Rp3,Rq2,Rr9),(Rp3,Rq2,Rr10),(Rp3,Rq2,Rr11),(Rp3,Rq2,Rr12),(Rp3,Rq2,Rr13),(Rp3,Rq2,Rr14),(Rp3,Rq2,Rr15),(Rp3,Rq2,Rr16),(Rp3,Rq2,Rr17),(Rp3,Rq2,Rr18),(Rp3,Rq2,Rr19),(Rp3,Rq2,Rr20),(Rp3,Rq2,Rr21),(Rp3,Rq2,Rr22),(Rp3,Rq2,Rr23),(Rp3,Rq2,Rr24),(Rp3,Rq2,Rr25),(Rp3,Rq2,Rr26),(Rp3,Rq2,Rr27),(Rp3,Rq2,Rr28),(Rp3,Rq2,Rr29),(Rp3,Rq2,Rr30),(Rp3,Rq2,Rr31),(Rp3,Rq2,Rr32),(Rp3,Rq2,Rr33),(Rp3,Rq2,Rr34),(Rp3,Rq2,Rr35),(Rp3,Rq2,Rr36),(Rp3,Rq2,Rr37),(Rp3,Rq3,Rr1),(Rp3,Rq3,Rr2),(Rp3,Rq3,Rr3),(Rp3,Rq3,Rr4),(Rp3,Rq3,Rr5),(Rp3,Rq3,Rr6),(Rp3,Rq3,Rr7),(Rp3,Rq3,Rr8),(Rp3,Rq3,Rr9),(Rp3,Rq3,Rr10),(Rp3,Rq3,Rr11),(Rp3,Rq3,Rr12),(Rp3,Rq3,Rr13),(Rp3,Rq3,Rr14),(Rp3,Rq3,Rr15),(Rp3,Rq3,Rr16),(Rp3,Rq3,Rr17),(Rp3,Rq3,Rr18),(Rp3,Rq3,Rr19),(Rp3,Rq3,Rr20),(Rp3,Rq3,Rr21),(Rp3,Rq3,Rr22),(Rp3,Rq3,Rr23),(Rp3,Rq3,Rr24),(Rp3,Rq3,Rr25),(Rp3,Rq3,Rr26),(Rp3,Rq3,Rr27),(Rp3,Rq3,Rr28),(Rp3,Rq3,Rr29),(Rp3,Rq3,Rr30),(Rp3,Rq3,Rr31),(Rp3,Rq3,Rr32),(Rp3,Rq3,Rr33),(Rp3,Rq3,Rr34),(Rp3,Rq3,Rr35),(Rp3,Rq3,Rr36),(Rp3,Rq3,Rr37),(Rp3,Rq4,Rr1),(Rp3,Rq4,Rr2),(Rp3,Rq4,Rr3),(Rp3,Rq4,Rr4),(Rp3,Rq4,Rr5),(Rp3,Rq4,Rr6),(Rp3,Rq4,Rr7),(Rp3,Rq4,Rr8),(Rp3,Rq4,Rr9),(Rp3,Rq4,Rr10),(Rp3,Rq4,Rr11),(Rp3,Rq4,Rr12),(Rp3,Rq4,Rr13),(Rp3,Rq4,Rr14),(Rp3,Rq4,Rr15),(Rp3,Rq4,Rr16),(Rp3,Rq4,Rr17),(Rp3,Rq4,Rr18),(Rp3,Rq4,Rr19),(Rp3,Rq4,Rr20),(Rp3,Rq4,Rr21),(Rp3,Rq4,Rr22),(Rp3,Rq4,Rr23),(Rp3,Rq4,Rr24),(Rp3,Rq4,Rr25),(Rp3,Rq4,Rr26),(Rp3,Rq4,Rr27),(Rp3,Rq4,Rr28),(Rp3,Rq4,Rr29),(Rp3,Rq4,Rr30),(Rp3,Rq4,Rr31),(Rp3,Rq4,Rr32),(Rp3,Rq4,Rr33),(Rp3,Rq4,Rr34),(Rp3,Rq4,Rr35),(Rp3,Rq4,Rr36),(Rp3,Rq4,Rr37),(Rp3,Rq5,Rr1),(Rp3,Rq5,Rr2),(Rp3,Rq5,Rr3),(Rp3,Rq5,Rr4),(Rp3,Rq5,Rr5),(Rp3,Rq5,Rr6),(Rp3,Rq5,Rr7),(Rp3,Rq5,Rr8),(Rp3,Rq5,Rr9),(Rp3,Rq5,Rr10),(Rp3,Rq5,Rr11),(Rp3,Rq5,Rr12),(Rp3,Rq5,Rr13),(Rp3,Rq5,Rr14),(Rp3,Rq5,Rr15),(Rp3,Rq5,Rr16),(Rp3,Rq5,Rr17),(Rp3,Rq5,Rr18),(Rp3,Rq5,Rr19),(Rp3,Rq5,Rr20),(Rp3,Rq5,Rr21),(Rp3,Rq5,Rr22),(Rp3,Rq5,Rr23),(Rp3,Rq5,Rr24),(Rp3,Rq5,Rr25),(Rp3,Rq5,Rr26),(Rp3,Rq5,Rr27),(Rp3,Rq5,Rr28),(Rp3,Rq5,Rr29),(Rp3,Rq5,Rr30),(Rp3,Rq5,Rr31),(Rp3,Rq5,Rr32),(Rp3,Rq5,Rr33),(Rp3,Rq5,Rr34),(Rp3,Rq5,Rr35),(Rp3,Rq5,Rr36),(Rp3,Rq5,Rr37),(Rp4,Rq1,Rr1),(Rp4,Rq1,Rr2),(Rp4,Rq1,Rr3),(Rp4,Rq1,Rr4),(Rp4,Rq1,Rr5),(Rp4,Rq1,Rr6),(Rp4,Rq1,Rr7),(Rp4,Rq1,Rr8),(Rp4,Rq1,Rr9),(Rp4,Rq1,Rr10),(Rp4,Rq1,Rr1),(Rp4,Rq1,Rr2),(Rp4,Rq1,Rr13),(Rp4,Rq1,Rr14),(Rp4,Rq1,Rr15),(Rp4,Rq1,Rr16),(Rp4,Rq1,Rr17),(Rp4,Rq1,Rr18),(Rp4,Rq1,Rr19),(Rp4,Rq1,Rr20),(Rp4,Rq1,Rr21),(Rp4,Rq1,Rr22),(Rp4,Rq1,Rr23),(Rp4,Rq1,Rr24),(Rp4,Rq1,Rr25),(Rp4,Rq1,Rr26),(Rp4,Rq1,Rr27),(Rp4,Rq1,Rr28),(Rp4,Rq1,Rr29),(Rp4,Rq1,Rr30),(Rp4,Rq1,Rr31),(Rp4,Rq1,Rr32),(Rp4,Rr1,Rr33),(Rp4,Rq1,Rr34),(Rp4,Rq1,Rr35),(Rp4,Rq1,Rr36),(Rp4,Rq1,Rr37),(Rp4,Rq2,Rr1),(Rp4,Rq2,Rr2),(Rp4,Rq2,Rr3),(Rp4,Rq2,Rr4),(Rp4,Rq2,Rr5),(Rp4,Rq2,Rr6),(Rp4,Rq2,Rr7),(Rp4,Rq2,Rr8),(Rp4,Rq2,Rr9),(Rp4,Rq2,Rr1),(Rp4,Rq2,Rr1),(Rp4,Rq2,Rr12),(Rp4,Rq2,Rr13),(Rp4,Rq2,Rr14),(Rp 4,Rq2,Rr15),(Rp4,Rq2,Rr16),(Rp4,Rq2,Rr17),(Rp4,Rq2,Rr18),(Rp4,Rq2,Rr19),(Rp4,Rq2,Rr20),(Rp4,Rq2,Rr21),(Rp4,Rq2,Rr22),(Rp4,Rq2,Rr23),(Rp4,Rq2,Rr24),(Rp4,Rq2,Rr25),(Rp4,Rq2,Rr26),(Rp4,Rq2,Rr27),(Rp4,Rq2,Rr28),(Rp4,Rq2,Rr29),(Rp4,Rq2,Rr30),(Rp4,Rq2,Rr31),(Rp4,Rq2,Rr32),(Rp4,Rq2,Rr33),(Rp4,Rq2,Rr34),(Rp4,Rq2,Rr35),(Rp4,Rq2,Rr36),(Rp4,Rq2,Rr37),(Rp4,Rq3,Rr1),(Rp4,Rq3,Rr2),(Rp4,Rq3,Rr3),(Rp4,Rq3,Rr4),(Rp4,Rq3,Rr5),(Rp4,Rq3,Rr6),(Rp4,Rq3,Rr7),(Rp4,Rq3,Rr8),(Rp4,Rq3,Rr9),(Rp4,Rq3,Rr1),(Rp4,Rq3,Rr1),(Rp4,Rq3,Rr12),(Rp4,Rq3,Rr13),(Rp4,Rq3,Rr14),(Rp4,Rq3,Rr15),(Rp4,Rq3,Rr16),(Rp4,Rq3,Rr17),(Rp4,Rq3,Rr18),(Rp4,Rq3,Rr19),(Rp4,Rq3,Rr20),(Rp4,Rq3,Rr21),(Rp4,Rq3,Rr22),(Rp4,Rq3,Rr23),(Rp4,Rq3,Rr24),(Rp4,Rq3,Rr25),(Rp4,Rq3,Rr26),(Rp4,Rq3,Rr27),(Rp4,Rq3,Rr28),(Rp4,Rq3,Rr29),(Rp4,Rq3,Rr30),(Rp4,Rq3,Rr31),(Rp4,Rq3,Rr32),(Rp4,Rq3,Rr33),(Rp4,Rq3,Rr34),(Rp4,Rq3,Rr35),(Rp4,Rq3,Rr36),(Rp4,Rq3,Rr37),(Rp4,Rq4,Rr1),(Rp4,Rq4,Rr2),(Rp4,Rq4,Rr3),(Rp4,Rq4,Rr4),(Rp4,Rq4,Rr5),(Rp4,Rq4,Rr6),(Rp4,Rq4,Rr7),(Rp4,Rq4,Rr8),(Rp4,Rq4,Rr9),(Rp4,Rq4,Rr1),(Rp4,Rq4,Rr11),(Rp4,Rq4,Rr12),(Rp4,Rq4,Rr13),(Rp4,Rq4,Rr14),(Rp4,Rq4,Rr15),(Rp4,Rq4,Rr16),(Rp4,Rq4,Rr17),(Rp4,Rq4,Rr18),(Rp4,Rq4,Rr19),(Rp4,Rq4,Rr20),(Rp4,Rq4,Rr21),(Rp4,Rq4,Rr22),(Rp4,Rq4,Rr23),(Rp4,Rq4,Rr24),(Rp4,Rq4,Rr25),(Rp4,Rq4,Rr26),(Rp4,Rq4,Rr27),(Rp4,Rq4,Rr28),(Rp4,Rq4,Rr29),(Rp4,Rq4,Rr30),(Rp4,Rq4,Rr31),(Rp4,Rq4,Rr32),(Rp4,Rq4,Rr33),(Rp4,Rq4,Rr34),(Rp4,Rq4,Rr35),(Rp4,Rq4,Rr36),(Rp4,Rq4,Rr37),(Rp4,Rq5,Rr1),(Rp4,Rq5,Rr2),(Rp4,Rq5,Rr3),(Rp4,Rq5,Rr4),(Rp4,Rq5,Rr5),(Rp4,Rq5,Rr6),(Rp4,Rq5,Rr7),(Rp4,Rq5,Rr8),(Rp4,Rq5,Rr9),(Rp4,Rq5,Rr10),(Rp4,Rq5,Rr11),(Rp4,Rq5,Rr12),(Rp4,Rq5,Rr1.3),(Rp4,Rq5,Rr14),(Rp4,Rq5,Rr15),(Rp4,Rq6,Rr16),(Rp4,Rq5,Rr17),(Rp4,Rq5,Rr18),(Rp4,Rq5,Rr19),(Rp4,Rq5,Rr20),(Rp4,Rq5,Rr21),(Rp4,Rq5,Rr22),(Rp4,Rq5,Rr23),(Rp4,Rq5,Rr24),(Rp4,Rq5,Rr2),(Rp4,Rq5,Rr2),(Rp4,Rq5,Rr27),(Rp4,Rq5,Rr28),(Rp4,Rq5,Rr29),(Rp4,Rq5,Rr30),(Rp4,Rq5,Rr31),(Rp4,Rq5,Rr32),(Rp4,Rq5,Rr33),(Rp4,Rq5,Rr34),(Rp4,Rq5,Rr35),(Rp4,Rq5,Rr36),(Rp4,Rq5,Rr37),(Rp5,Rq1,Rr1),(Rp5,Rq1,Rr2),(Rp5,Rq1,Rr3),(Rp5,Rq1,Rr4),(Rp5,Rq1,Rr5),(Rp5,Rq1,Rr6),(Rp5,Rq1,Rr7),(Rp5,Rq1,Rr8),(Rp5,Rq1,Rr9),(Rp5,Rq1,Rr10),(Rp5,Rq1,Rr11),(Rp5,Rq1,Rr12),(Rp5,Rq1,Rr13),(Rp5,Rq1,Rr14),(Rp5,Rq1,Rr15),(Rp5,Rq1,Rr16),(Rp5,Rq1,Rr17),(Rp5,Rq1,Rr18),(Rp5,Rq1,Rr19),(Rp5,Rq1,Rr20),(Rp5,Rq1,Rr21),(Rp5,Rq1,Rr22),(Rp5,Rq1,Rr23),(Rp5,Rq1,Rr24),(Rp5,Rq1,Rr26),(Rp5,Rq1,Rr26),(Rp5,Rq1,Rr27),(Rp5,Rq1,Rr28),(Rp5,Rq1,Rr29),(Rp5,Rq1,Rr30),(Rp5,Rq1,Rr31),(Rp5,Rq1,Rr32),(Rp5,Rq1,Rr33),(Rp5,Rq1,Rr34),(Rp5,Rq1,Rr35),(Rp5,Rq1,Rr36),(Rp5,Rq1,Rr37),(Rp5,Rq2,Rr1),(Rp5,Rq2,Rr2),(Rp5,Rq2,Rr3),(Rp5,Rq2,Rr4),(Rp5,Rq2,Rr5),(Rp5,Rq2,Rr6),(Rp5,Rq2,Rr7),(Rp5,Rq2,Rr8),(Rp5,Rq2,Rr9),(Rp5,Rq2,Rr10),(Rp5,Rq2,Rr11),(Rp5,Rq2,Rr12),(Rp5,Rq2,Rr13),(Rp5,Rq2,Rr14),(Rp5,Rq2,Rr15),(Rp5,Rq2,Rr16),(Rp5,Rq2,Rr17),(Rp5,Rq2,Rr18),(Rp5,Rq2,Rr19),(Rp5,Rq2,Rr20),(Rp5,Rq2,Rr21),(Rp5,Rq2,Rr22),(Rp5,Rq2,Rr23),(Rp5,Rq2,Rr24),(Rp5,Rq2,Rr2),(Rp5,Rq2,Rr26),(Rp5,Rq2,Rr27),(Rp5,Rq2,Rr28),(Rp5,Rq2,Rr29),(Rp5,Rq2,Rr30),(Rp5,Rq2,Rr31),(Rp5,Rq2,Rr32),(Rp5,Rq2,Rr33),(Rp5,Rq2,Rr34),(Rp5,Rq2,Rr35),(Rp5,Rq2,Rr36),(Rp5,Rq2,Rr37),(Rp5,Rq3,Rr1),(Rp5,Rq3,Rr2),(Rp5,Rq3,Rr3),(Rp5,Rq3,Rr4),(Rp5,Rq3,Rr5),(Rp5,Rq3,Rr6),(Rp5,Rq3,Rr7),(Rp5,Rq3,Rr8),(Rp5,Rq3,Rr9),(Rp5,Rq3,Rr10),(Rp5,Rq3,Rr11),(Rp5,Rq3,Rr12),(Rp5,Rq3,Rr13),(Rp5,Rq3,Rr14),(Rp5,Rq3,Rr15),(Rp5,Rq3,Rr6),(Rp5,Rq3,Rr7),(Rp5,Rq3,Rr18),(Rp5,Rq3,Rr19),(Rp5,Rq3,Rr20),(Rp5,Rq3,Rr21),(Rp5,Rq3,Rr22),(Rp5,Rq3,Rr23),(Rp5,Rq3,Rr24),(Rp5,Rq3,Rr25),(Rp5,Rq3,Rr26),(Rp5,Rq3,Rr27),(Rp5,Rq3,Rr28),(Rp5,Rq3,Rr29),(Rp5,Rq3,Rr30),(Rp5,Rq3,Rr31),(Rp5,Rq3,Rr32),(Rp5,Rq3,Rr33),(Rp5,Rq3,Rr34),(Rp5,Rq3,Rr35),(Rp5,Rq3,Rr36),(Rp5,Rq3,Rr37),(Rp5,Rq4,Rr1),(Rp5,Rq4,Rr2),(Rp5,Rq4,Rr3),(Rp5,Rq4,Rr4),(Rp5,Rq4,Rr5),(Rp5,Rq4,Rr6),(Rp5,Rq4,Rr7),(Rp5,Rq4,Rr8),(Rp5,Rq4,Rr9),(Rp5,Rq4,Rr10),(Rp5,Rq4,Rr11),(Rp5,Rq4,Rr12),(Rp5,Rq4,Rr13),(Rp5,Rq4,Rr14),(Rp5,Rq4,Rr15),(Rp5,Rq4,Rr16),(Rp5,Rq4,Rr17),(Rp5,Rq4,Rr18),(Rp5,Rq4,Rr19),(Rp5,Rq4,Rr20),(Rp5,Rq4,Rr21),(Rp5,Rq4,Rr22),(Rp5,Rq4,Rr23),(Rp5,Rq4,Rr24),(Rp5,Rq4,Rr25),(Rp5,Rq4,Rr26),(Rp5,Rq4,Rr27),(Rp5,Rq4,Rr28),(Rp5,Rq4,Rr29),(Rp5,Rq4,Rr30),(Rp5,Rq4,Rr31),(Rp5,Rq4,Rr32),(Rp5,Rq4,Rr33),(Rp5,Rq4,Rr34),(Rp5,Rq4,Rr35),(Rp5,Rq4,Rr36),(Rp5,Rq4,Rr37),(Rp5,Rq5,Rr1),(Rp5,Rq5,Rr2),(Rp5,Rq5,Rr3),(Rp5,Rq5,Rr4),(Rp5,Rq5,Rr5),(Rp5,Rq5,Rr6),(Rp5,Rq5,Rr7),(Rp5,Rq5,Rr8),(Rp5,Rq5,Rr9),(Rp5,Rq5,Rr10),(Rp5,Rq5,Rr1),(Rp5,Rq5,Rr12),(Rp5,Rq5,Rr13),(Rp5,Rq5,Rr14),(Rp5,Rq5,Rr15),(Rp5,Rq5,Rr16),(Rp5,Rq5,Rr17),(Rp5,Rq5,Rr18),(Rp5,Rq5,Rr19),(Rp5,Rq5,Rr20),(Rp5,Rq5,Rr2),(Rp5,Rq5,Rr22),(Rp5,Rq5,Rr23),(Rp5,Rq5,Rr24),(Rp5,Rq5,Rr25),(Rp5,Rq5,Rr26),(Rp5,Rq5,Rr27),(Rp5,Rq5,Rr28),(Rp5,Rq5,Rr29),(Rp5,Rq5,Rr30),(Rp5,Rq5,Rr31),(Rp5,Rq5,Rr32),(Rp5,Rq5,Rr33),(Rp5,Rq5,Rr34),(Rp5,Rq5,Rr35),(Rp5,Rq5,Rr36),(Rp5,Rq5,Rr37),(Rp6,Rq1,Rr1),(Rp6,Rq1,Rr2),(Rp6,Rq1,Rr3),(Rp6,Rq1,Rr4),(Rp6,Rq1,Rr5),(Rp6,Rq1,Rr6),(Rp6,Rq1,Rr7),(Rp6,Rq1,Rr8),(Rp6,Rq1,Rr9),(Rp6,Rq1,Rr10),(Rp6,Rq1,Rr11),(Rp6,Rq1,Rr12),(Rp6,Rq1,Rr13),(Rp6,Rq1,Rr14),(Rp6,Rq1,Rr15),(Rp6,Rq1,Rr16),(Rp6,Rq1,Rr7),(Rp6,Rq1,Rr18),(Rp6,Rq1,Rr19),(Rp6,Rq1,Rr20),(Rp6,Rq1,Rr21),(Rp6,Rq1,Rr22),(Rp6,Rq1,Rr23),(Rp6,Rq1,Rr24),(Rp6,Rq1,Rr25),(Rp6,Rq1,Rr26),(Rp6,Rq1,Rr27),(Rp6,Rq1,Rr28),(Rp6,Rq1,Rr29),(Rp6,Rq1,Rr30),(Rp6,Rq1,Rr31),(Rp6,Rq1,Rr32),(Rp6,Rq1,Rr33),(Rp6,Rq1,Rr34),(Rp6,Rq1,Rr35),(Rp6,Rq1,Rr36),(Rp6,Rq1,Rr37),(Rp6,Rq2,Rr1),(Rp6,Rq2,Rr2),(Rp6,Rq2,Rr3),(Rp6,Rq2,Rr4),(Rp6,Rq2,Rr5),(Rp6,Rq2,Rr6),(Rp6,Rq2,Rr7),(Rp6,Rq2,Rr8),(Rp6,Rq2,Rr9),(Rp6,Rq2,Rr10),(Rp6,Rq2,Rr11),(Rp6,Rq2,Rr12),(Rp6,Rq2,Rr13),(Rp6,Rq2,Rr14),(Rp6,Rq2,Rr15),(Rp6,Rq2,Rr16),(Rp6,Rq2,Rr17),(Rp6,Rq2,Rr18),(Rp6,Rq2,Rr19),(Rp6,Rq2,Rr20),(Rp6,Rq2,Rr21),(Rp6,Rq2,Rr22),(Rp6,Rq2,Rr23),(Rp6,Rq2,Rr24),(Rp6,Rq2,Rr25),(Rp6,Rq2,Rr26),(Rp6,Rq2,Rr27),(Rp6,Rq2,Rr28),(Rp6,Rq2,Rr29),(Rp6,Rq2,Rr30),(Rp6,Rq2,Rr31),(Rp6,Rq2,Rr32),(Rp6,Rq2,Rr33),(Rp6,Rq2,Rr34),(Rp6,Rq2,Rr35),(Rp6,Rq2,Rr36),(Rp6,Rq2,Rr37),(Rp6,Rq3,Rr1),(Rp6,Rq3,Rr2),(Rp6,Rq3,Rr3),(Rp6,Rq3,Rr4),(Rp6,Rq3,Rr5),(Rp6,Rq3,Rr6),(Rp6,Rq3,Rr7),(Rp6,Rq3,Rr8),(Rp6,Rq3,Rr9),(Rp6,Rq3,Rr10),(Rp6,Rq3,Rr11),(Rp6,Rq3,Rr12),(Rp6,Rq3,Rr13),(Rp6,Rq3,Rr14),(Rp6,Rq3,Rr15),(Rp6,Rq3,Rr16),(Rp6,Rq3,Rr17),(Rp6,Rq3,Rr18),(Rp6,Rq3,Rr19),(Rp6,Rq3,Rr20),(Rp6,Rq3,Rr21),(Rp6,Rq3,Rr22),(Rp6,Rq3,Rr23),(Rp6,Rq3,Rr24),(Rp6,Rq3,Rr25),(Rp6,Rq3,Rr26),(Rp6,Rq3,Rr27),(Rp6,Rq3,Rr28),(Rp6,Rq3,Rr29),(Rp6,Rq3,Rr30),(Rp6,Rq3,Rr31),(Rp6,Rq3,Rr32),(Rp6,Rq3,Rr33),(Rp6,Rq3,Rr34),(Rp6,Rq3,Rr35),(Rp6,Rq3,Rr36),(Rp6,Rq3,Rr37),(Rp6,Rq4,Rr1),(Rp6,Rq4,Rr2),(Rp6,Rq4,Rr3),(Rp6,Rq4,Rr4),(Rp6,Rq4,Rr5),(Rp6,Rq4,Rr6),(Rp6,Rq4,Rr7),(Rp6,Rq4,Rr8),(Rp6,Rq4,Rr9),(Rp6,Rq4,Rr10),(Rp6,Rq4,Rr11),(Rp6,Rq4,Rr12),(Rp6,Rq4,Rr13),(Rp6,Rq4,Rr14),(Rp6,Rq4,Rr15),(Rp6,Rq4,Rr16),(Rp6,Rq4,Rr17),(Rp6,Rq4,Rr18),(Rp6,Rq4,Rr19),(Rp6,Rq4,Rr20),(Rp6,Rq4,Rr21),(Rp6,Rq4,Rr22),(Rp6,Rq4,Rr23),(Rp6,Rq4,Rr24),(Rp6,Rq4,Rr25),(Rp6,Rq4,Rr26),(Rp6,Rq4,Rr27),(Rp6,Rq4,Rr28),(Rp6,Rq4,Rr29),(Rp6,Rq4,Rr30),(Rp6,Rq4,Rr31),(Rp6,Rq4,Rr32),(Rp6,Rq4,Rr33),(Rp6,Rq4,Rr34),(Rp6,Rq4,Rr35),(Rp6,Rq4,Rr36),(Rp6,Rq4,Rr37),(Rp6,Rq5,Rr1),(Rp6,Rq5,Rr2),(Rp6,Rq5,Rr3),(Rp6,Rq5,Rr4),(Rp6,Rq5,Rr5),(Rp6,Rq5,Rr6),(Rp6,Rq5,Rr7),(Rp6,Rq5,Rr8),(Rp6,Rq5,Rr9),(Rp6,Rq5,Rr10),(Rp6,Rq5,Rr11),(Rp6,Rq5,Rr12),(Rp6,Rq5,Rr13),(Rp6,Rq5,Rr14),(Rp6,Rq5,Rr15),(Rp6,Rq5,Rr16),(Rp6,Rq5,Rr17),(Rp6,Rq5,Rr18),(Rp6,Rq5,Rr19),(Rp6,Rq5,Rr20),(Rp6,Rq5,Rr21),(Rp6,Rq5,Rr22),(Rp6,Rq5,Rr23),(Rp6,Rq5,Rr24),(Rp6,Rq5,Rr25),(Rp6,Rq5,Rr26),(Rp6,Rq5,Rr27),(Rp6,Rq5,Rr28),(Rp6,Rq5,Rr29),(Rp6,Rq5,Rr30),(Rp6,Rq5,Rr31),(Rp6,Rq5,Rr32),(Rp6,Rq5,Rr33),(Rp6,Rq5,Rr34),(Rp6,Rq5,Rr35),(Rp6,Rq5,Rr36),(Rp6,Rq5,Rr37),(Rp7,Rq1,Rr1),(Rp7,Rq1,Rr2),(Rp7,Rq1,Rr3),(Rp7,Rq1,Rr4),(Rp7,Rq1,Rr5),(Rp7,Rq1,Rr6),(Rp7,Rq1,Rr7),(Rp7,Rq1,Rr8),(Rp7,Rq1,Rr9),(Rp7,Rq1,Rr10),(Rp7,Rq1,Rr11),(Rp7,Rq1,Rr12),(Rp7,Rq1,Rr13),(Rp7,Rq1,Rr14),(Rp7,Rq1,Rr15),(Rp7,Rq1,Rr16),(Rp7,Rq1,Rr17),(Rp7,Rq1,Rr18),(Rp7,Rq1,Rr19),(Rp7,Rq1,Rr20),(Rp7,Rq1,Rr21),(Rp7,Rq1,Rr22),(Rp7,Rq1,Rr23),(Rp7,Rq1,Rr24),(Rp7,Rq1,Rr25),(Rp7,Rq1,Rr26),(Rp7,Rq1,Rr27),(Rp7,Rq1,Rr28),(Rp7,Rq1,Rr29),(Rp7,Rq1,Rr30),(Rp7,Rq1,Rr31),(Rp7,Rq1,Rr32),(Rp7,Rq1,Rr33),(Rp7,Rq1,Rr34),(Rp7,Rq1,Rr35),(Rp7,Rq1,Rr36),(Rp7,Rq1,Rr37),(Rp7,Rq2,Rr1),(Rp7,Rq2,Rr2),(Rp7,Rq2,Rr3),(Rp7,Rq2,Rr4),(Rp7,Rq2,Rr5),(Rp7,Rq2,Rr6),(Rp7,Rq2,Rr7),(Rp7,Rq2,Rr8),(Rp7,Rq2,Rr9),(Rp7,Rq2,Rr10),(Rp7,Rq2,Rr11),(Rp7,Rq2,Rr12),(Rp7,Rq2,Rr13),(Rp7,Rq2,Rr14),(Rp7,Rq2,Rr15),(Rp7,Rq2,Rr16),(Rp7,Rq2,Rr17),(Rp7,Rq2,Rr18),(Rp7,Rq2,Rr19),(Rp7,Rq2,Rr20),(Rp7,Rq2,Rr21),(Rp7,Rq2,Rr22),(Rp7,Rq2,Rr23),(Rp7,Rq2,Rr24),(Rp1,Rq2,Rr25),(Rp7,Rq2,Rr26),(Rp7,Rq2,Rr27),(Rp7,Rq2,Rr28),(Rp7,Rq2,Rr29),(Rp7,Rq2,Rr3),(Rp7,Rq2,Rr31),(Rp7,Rq2,Rr32),(Rp7,Rq2,Rr33),(Rp7,Rq2,Rr34),(Rp7,Rq2,Rr35),(Rp7,Rq2,Rr36),(Rp7,Rq2,Rr37),(Rp7,Rq1,Rr1),(Rp7,Rq3,Rr2),(Rp7,Rq3,Rr3),(Rp7,Rq3,Rr4),(Rp7,Rq3,Rr5),(Rp7,Rq3,Rr6),(Rp7,Rq3,Rr7),(Rp7,Rq3,Rr8),(Rp7,Rq3,Rr9),(Rp7,Rq3,Rr10),(Rp7,Rq3,Rr11),(Rp7,Rq3,Rr12),(Rp7,Rq3,Rr13),(Rp7,Rq3,Rr14),(Rp7,Rq3,Rr15),(Rp7,Rq3,Rr16),(Rp7,Rq3,Rr17),(Rp7,Rq3,Rr18),(Rp7,Rq3,Rr19),(Rp7,Rq3,Rr20),(Rp7,Rq3,Rr21),(Rp7,Rq3,Rr22),(Rp7,Rq3,Rr23),(Rp7,Rq3,Rr24),(Rp7,Rq3,Rr25),(Rp7,Rq3,Rr26),(Rp7,Rq3,Rr27),(Rp7,Rq3,Rr28),(Rp7,Rq3,Rr29),(Rp7,Rq3,Rr30),(Rp7,Rq3,Rr31),(Rp7,Rq3,Rr32),(Rp7,Rq3,Rr33),(Rp7,Rq3,Rr34),(Rp7,Rq3,Rr35),(Rp7,Rq3,Rr36),(Rp7,Rq3,Rr37),(Rp7,Rq4,Rr1),(Rp7,Rq4,Rr2),(Rp7,Rq4,Rr3),(Rp7,Rq4,Rr4),(Rp7,Rq4,Rr5),(Rp7,Rq4,Rr6),(Rp7,Rq4,Rr7),(Rp7,Rq4,Rr8),(Rp7,Rq4,Rr9),(Rp7,Rq4,Rr10),(Rp7,Rq4,Rr11),(Rp7,Rq4,Rr12),(Rp7,Rq4,Rr13),(Rp7,Rq4,Rr14),(Rp7,Rq4,Rr15),(Rp7,Rq4,Rr16),(Rp7,Rq4,Rr17),(Rp7,Rq4,Rr8),(Rp7,Rq4,Rr19),(Rp7,Rq4,Rr20),(Rp7,Rq4,Rr21),(Rp7,Rq4,Rr22),(Rp7,Rq4,Rr23),(Rp7,Rq4,Rr24),(Rp7,Rq4,Rr25),(Rp7,Rq4,Rr26),(Rp7,Rq4,Rr27),(Rp7,Rq4,Rr28),(Rp7,Rq4,Rr29),(Rp7,Rq4,Rr30),(Rp7,Rq4,Rr31),(Rp7,Rq4,Rr32),(Rp7,Rq4,Rr33),(Rp7,Rq4,Rr34),(Rp7,Rq4,Rr35),(Rp7,Rq4,Rr36),(Rp7,Rq4,Rr37),(Rp7,Rq5,Rr1),(Rp7,Rq5,Rr2),(Rp7,Rq5,Rr3),(Rp7,Rq5,Rr4),(Rp7,Rq5,Rr5),(Rp7,Rq5,Rr6),(Rp7,Rq5,Rr7),(Rp7,Rq5,Rr8),(Rp7,Rq5,Rr9),(Rp7,Rq5,Rr10),(Rp7,Rq5,Rr11),(Rp7,Rq5,Rr12),(Rp7,Rq5,Rr13),(Rp7,Rq5,Rr14),(Rp7,Rq5,Rr15),(Rp7,Rq5,Rr16),(Rp7,Rq5,Rr17),(Rp7,Rq5,Rr18),(Rp7,Rq5,Rr19),(Rp7,Rq5,Rr20),(Rp7,Rq5,Rr21),(Rp7,Rq5,Rr22),(Rp7,Rq5,Rr23),(Rp7,Rq5,Rr24),(Rp7,Rq5,Rr25),(Rp7,Rq5,Rr26),(Rp7,Rq5,Rr27),(Rp7,Rq5,Rr28),(Rp7,Rq5,Rr29),(Rp7,Rq5,Rr30),(Rp7,Rq5,Rr31),(Rp7,Rq5,Rr32),(Rp7,Rq5,Rr33),(Rp7,Rq5,Rr34),(Rp7,Rq5,Rr35),(Rp7,Rq5,Rr36),(Rp7,Rq5,Rr37),(Rp8,Rq5,Rr1),(Rp8,Rq1,Rr2),(Rp8,Rq1,Rr3),(Rp8,Rq1,Rr4),(Rp8,Rq1,Rr5),(Rp8,Rq1,Rr6),(Rp8,Rq1,Rr7),(Rp8,Rq1,Rr8),(Rp8,Rq1,Rr9),(Rp8,Rq1,Rr10),(Rp8,Rq1,Rr11),(Rp8,Rq1,Rr12),(Rp8,Rq1,Rr13),(Rp8,Rq1,Rr14),(Rp8,Rq1,Rr15),(Rp8,Rq1,Rr16),(Rp8,Rq1,Rr17),(Rp8,Rq1,Rr18),(Rp8,Rq1,Rr19),(Rp8,Rq1,Rr20),(Rp8,Rq1,Rr21),(Rp8,Rq1,Rr22),(Rp8,Rq1,Rr23),(Rp8,Rq1,Rr24),(Rp8,Rq1,Rr25),(Rp8,Rq1,Rr26),(Rp8,Rq1,Rr27),(Rp8,Rq1,Rr28),(Rp8,Rq1,Rr29),(Rp8,Rq1,Rr30),(Rp8,Rq1,Rr31),(Rp8,Rq1,Rr32),(Rp8,Rq1,Rr33),(Rp8,Rq1,Rr34),(Rp8,Rq1,Rr35),(Rp8,Rq1,Rr36),(Rp8,Rq1,Rr37),(Rp8,Rq2,Rr1),(Rp8,Rq2,Rr2),(Rp8,Rq2,Rr3),(Rp8,Rq2,Rr4),(Rp8,Rq2,Rr5),(Rp8,Rq2,Rr6),(Rp8,Rq2,Rr7),(Rp8,Rq2,Rr8),(Rp8,Rq2,Rr9),(Rp8,Rq2,Rr10),(Rp8,Rq2,Rr11),(Rp8,Rq2,Rr12),(Rp8,Rq2,Rr13),(Rp8,Rq2,Rr14),(Rp8,Rq2,Rr15),(Rp8,Rq2,Rr16),(Rp8,Rq2,Rr17),(Rp8,Rq2,Rr18),(Rp8,Rq2,Rr19),(Rp8,Rq2,Rr20),(Rp8,Rq2,Rr21),(Rp8,Rq2,Rr22),(Rp8,Rq2,Rr23),(Rp8,Rq2,Rr24),(Rp8,Rq2,Rr25),(Rp8,Rq2,Rr26),(Rp8,Rq2,Rr27),(Rp8,Rq2,Rr28),(Rp8,Rq2,Rr29),(Rp8,Rq2,Rr30),(Rp8,Rq2,Rr31),(Rp8,Rq2,Rr32),(Rp8,Rq2,Rr33),(Rp8,Rq2,Rr34),(Rp8,Rq2,Rr35),(Rp8,Rq2,Rr36),(Rp8,Rq2,Rr37),(Rp8,Rq3,Rr1),(Rp8,Rq3,Rr2),(Rp8,Rq3,Rr3),(Rp8,Rq3,Rr4),(Rp8,Rq3,Rr5),(Rp8,Rq3,Rr6),(Rp8,Rq3,Rr7),(Rp8,Rq3,Rr8),(Rp8,Rq3,Rr9),(Rp8,Rq3,Rr10),(Rp8,Rq3,Rr11),(Rp8,Rq3,Rr12),(Rp8,Rq3,Rr13),(Rp8,Rq3,Rr14),(Rp8,Rq3,Rr15),(Rp8,Rq3,Rr16),(Rp8. Rq3,Rr17),(Rp8,Rq3,Rr18),(Rp8,Rq3,Rr19),(Rp8,Rq3,Rr20),(Rp8,Rq3,Rr21),(Rp8,Rq3,Rr22),(Rp8,Rq3,Rr23),(Rp8,Rq3,Rr24),(Rp8,Rq3,Rr25),(Rp8,Rq3,Rr26),(Rp8,Rq3,Rr27),(Rp8,Rq3,Rr28),(Rp8,Rq3,Rr29),(Rp8,Rq3,Rr30),(Rp8,Rq3,Rr31),(Rp8,Rq3,Rr32),(Rp8,Rq3,Rr33),(Rp8,Rq3,Rr34),(Rp8,Rq3,Rr35),(Rp8,Rq3,Rr36),(Rp8,Rq3,Rr37),(Rp8,Rq4,Rr1),(Rp8,Rq4,Rr2),(Rp8,Rq4,Rr3),(Rp8,Rq4,Rr4), (Rp8,Rq4,Rr5),(Rp8,Rq4,Rr6),(Rp8,Rq4,Rr7),(Rp8,Rq4,Rr8),(Rp8,Rq4,Rr9),(Rp8,Rq4,Rr10),(Rp8,Rq4,Rr11),(Rp8,Rq4,Rr12),(Rp8,Rq4,Rr13),(Rp8,Rq4,Rr14),(Rp8,Rq4,Rr15),(Rp8,Rq4,Rr16),(Rp8,Rq4,Rr17),(Rp8,Rq4,Rr18),(Rp8,Rq4,Rr19),(Rp8,Rq4,Rr20),(Rp8,Rq4,Rr21),(Rp8,Rq4,Rr22),(Rp8,Rq4,Rr23),(Rp8,Rq4,Rr24),(Rp8,Rq4,Rr25),(Rp8,Rq4,Rr26),(Rp8,Rq4,Rr27),(Rp8,Rq4,Rr28),(Rp8,Rq4,Rr29),(Rp8,Rq4,Rr30),(Rp8,Rq4,Rr31),(Rp8,Rq4,Rr32),(Rp8,Rq4,Rr33),(Rp8,Rq4,Rr34),(Rp8,Rq4,Rr35),(Rp8,Rq4,Rr36),(Rp8,Rq4,Rr37),(Rp8,Rq5,Rr1),(Rp8,Rq5,Rr2),(Rp8,Rq5,Rr3),(Rp8,Rq5,Rr4),(Rp8,Rq5,Rr5),(Rp8,Rq5,Rr6),(Rp8,Rq5,Rr7),(Rp8,Rq5,Rr8),(Rp8,Rq5,Rr9),(Rp8,Rq5,Rr10),(Rp8,Rq5,Rr11),(Rp8,Rq5,Rr12),(Rp8,Rq5,Rr13),(Rp8,Rq5,Rr14),(Rp8,Rq5,Rr15),(Rp8,Rq5,Rr16),(Rp8,Rq5,Rr17),(Rp8,Rq5,Rr18),(Rp8,Rq5,Rr19),(Rp8,Rq5,Rr20),(Rp8,Rq5,Rr21),(Rp8,Rq5,Rr22),(Rp8,Rq5,Rr23),(Rp8,Rq5,Rr24),(Rp8,Rq5,Rr25),(Rp8,Rq5,Rr26),(Rp8,Rq5,Rr27),(Rp8,Rq5,Rr28),(Rp8,Rq5,Rr29),(Rp8,Rq5,Rr30),(Rp8,Rq5,Rr31),(Rp8,Rq5,Rr32),(Rp8,Rq5,Rr33),(Rp8,Rq5,Rr34),(Rp8,Rq5,Rr35),(Rp8,Rq5,Rr36),(Rp8,Rq5,Rr37),(Rp9,Rq1,Rr1),(Rp9,Rq1,Rr2),(Rp9,Rq1,Rr3),(Rp9,Rq1,Rr4),(Rp9,Rq1,Rr5),(Rp9,Rq1,Rr6),(Rp9,Rq1,Rr7),(Rp9,Rq1,Rr8),(Rp9,Rq1,Rr9),(Rp9,Rq4,Rr10),(Rp9,Rq1,Rr11),(Rp9,Rq1,Rr12),(Rp9,Rq1,Rr13),(Rp9,Rq1,Rr14),(Rp9,Rq1,Rr15),(Rp9,Rq1,Rr16),(Rp9,Rq1,Rr17),(Rp9,Rq1,Rr18),(Rp9,Rq1,Rr19),(Rp9,Rq1,Rr20),(Rp9,Rq1,Rr21),(Rp9,Rq1,Rr22),(Rp9,Rq1,Rr23),(Rp9,Rq1,Rr24),(Rp9,Rq1,Rr25),(Rp9,Rq1,Rr26),(Rp9,Rq1,Rr27),(Rp9,Rq1,Rr28),(Rp9,Rq1,Rr29),(Rp9,Rq1,Rr30),(Rp9,Rq1,Rr31),(Rp9,Rq1,Rr32),(Rp9,Rq1,Rr33),(Rp9,Rq1,Rr34),(Rp9,Rq1,Rr35),(Rp9,Rq1,Rr36),(Rp9,Rq1,Rr37),(Rp9,Rq2,Rr1),(Rp9,Rq2,Rr2),(Rp9,Rq2,Rr3),(Rp9,Rq2,Rr4),(Rp9,Rq2,Rr5),(Rp9,Rq2,Rr6),(Rp9,Rq2,Rr7),(Rp9,Rq2,Rr8),(Rp9,Rq2,Rr9),(Rp9,Rq2,Rr10),(Rp9,Rq2,Rr11),(Rp9,Rq2,Rr12),(Rp9,Rq2,Rr13),(Rp9,Rq2,Rr14),(Rp9,Rq2,Rr15),(Rp9,Rq2,Rr16),(Rp9,Rq2,Rr17),(Rp9,Rq2,Rr18),(Rp9,Rq2,Rr19),(Rp9,Rq2,Rr20),(Rp9,Rq2,Rr21),(Rp9,Rq2,Rr22),(Rp9,Rq2,Rr23),(Rp9,Rq2,Rr24),(Rp9,Rq2,Rr25),(Rp9,Rq2,Rr26),(Rp9,Rq2,Rr27),(Rp9,Rq2,Rr28),(Rp9,Rq2,Rr29),(Rp9,Rq2,Rr30),(Rp9,Rq2,Rr31),(Rp9,Rq2,Rr32),(Rp9,Rq2,Rr33),(Rp9,Rq2,Rr34),(Rp9,Rq2,Rr35),(Rp9,Rq2,Rr36),(Rp9,Rq2,Rr37),(Rp9,Rq3,Rr1),(Rp9,Rq3,Rr2),(Rp9,Rq3,Rr3),(Rp9,Rq3,Rr4),(Rp9,Rq3,Rr5),(Rp9,Rq3,Rr6),(Rp9,Rq3,Rr7),(Rp9,Rq3,Rr8),(Rp9,Rq3,Rr9),(Rp9,Rq3,Rr10),(Rp9,Rq3,Rr11),(Rp9,Rq3,Rr12),(Rp9,Rq3,Rr13),(Rp9,Rq3,Rr14),(Rp9,Rq3,Rr15),(Rp9,Rq3,Rr16),(Rp9,Rq3,Rr17),(Rp9,Rq3,Rr18),(Rp9,Rq3,Rr19),(Rp9,Rq3,Rr20),(Rp9,Rq3,Rr21),(Rp9,Rq3,Rr22),(Rp9,Rq3,Rr23),(Rp9,Rq3,Rr24),(Rp9,Rq3,Rr25),(Rp9,Rq3,Rr26),(Rp9,Rq3,Rr27),(Rp9,Rq3,Rr28),(Rp9,Rq3,Rr29),(Rp9,Rq3,Rr30),(Rp9,Rq3,Rr31),(Rp9,Rq3,Rr32),(Rp9,Rq3,Rr33),(Rp9,Rq3,Rr34),(Rp9,Rq3,Rr35),(Rp9,Rq3,Rr36),(Rp9,Rq3,Rr37),(Rp9,Rq4,Rr1),(Rp9,Rq4,Rr2),(Rp9,Rq4,Rr3),(Rp9,Rq4,Rr4),(Rp9,Rq4,Rr5),(Rp9,Rq4,Rr6),(Rp9,Rq4,Rr7),(Rp9,Rq4,Rr8),(Rp9,Rq4,Rr9),(Rp9,Rq4,Rr10),(Rp9,Rq4,Rr11),(Rp9,Rq4,Rr12),(Rp9,Rq4,Rr13),(Rp9,Rq4,Rr14),(Rp9,Rq4,Rr15),(Rp9,Rq4,Rr16),(Rp9,Rq4,Rr17),(Rp9,Rq4,Rr18),(Rp9,Rq4,Rr19),(Rp9,Rq4,Rr20),(Rp9,Rq4,Rr21),(Rp9,Rq4,Rr22),(Rp9,Rq4,Rr23),(Rp9,Rq4,Rr24),(Rp9,Rq4,Rr25),(Rp9,Rq4,Rr26),(Rp9,Rq4,Rr27),(Rp9,Rq4,Rr28),(Rp9,Rq4,Rr29),(Rp9,Rq4,Rr30),(Rp9,Rq4,Rr31),(Rp9,Rq4,Rr32),(Rp9,Rq4,Rr33),(Rp9,Rq4,Rr34),(Rp9,Rq4,Rr35),(Rp9,Rq4,Rr36),(Rp9,Rq4,Rr37),(Rp9,Rq5,Rr1),(Rp9,Rq5,Rr2),(Rp9,Rq5,Rr3),(Rp9,Rq5,Rr4),(Rp9,Rq1,Rr5),(Rp9,Rq5,Rr6),(Rp9,Rq5,Rr7),(Rp9,Rq5,Rr8),(Rp9,Rq5,Rr9),(Rp9,Rq5,Rr10),(Rp9,Rq5,Rr11),(Rp9,Rq5,Rr12),(Rp9,Rq5,Rr13),(Rp9,Rq5,Rr14),(Rp9,Rq5,Rr15),(Rp9,Rq5,Rr16),(Rp9,Rq5,Rr17),(Rp9,Rq5,Rr18),(Rp9,Rq5,Rr19),(Rp9,Rq5,Rr20),(Rp9,Rq5,Rr21),(Rp9,Rq5,Rr22),(Rp9,Rq5,Rr23),(Rp9,Rq5,Rr24),(Rp9,Rq5,Rr25),(Rp9,Rq5,Rr26),(Rp9,Rq5,Rr27),(Rp9,Rq5,Rr28),(Rp9,Rq5,Rr29),(Rp9,Rq5,Rr30),(Rp9,Rq5,Rr31),(Rp9,Rq5,Rr32),(Rp9,Rq5,Rr33),(Rp9,Rq5,Rr34),(Rp9,Rq5,Rr35),(Rp9,Rq5,Rr36),(Rp9,Rq5,Rr37),(Rp10,Rq1,Rr1),(Rp10,Rq1,Rr2),(Rp10,Rq1,Rr3),(Rp10,Rq1,Rr4),(Rp10,Rq1,Rr5),(Rp10,Rq1,Rr6),(Rp10,Rq1,Rr7),(Rp10,Rq1,Rr8),(Rp10,Rq1,Rr9),(Rp10,Rq1,Rr10),(Rp10,Rq1,Rr11),(Rp10,Rq1,Rr12),(Rp10,Rq1,Rr13),(Rp10,Rq1,Rr14),(Rp10,Rq1,Rr15),(Rp10,Rq1,Rr16),(Rp10,Rq1,Rr17),(Rp10,Rq1,Rr18),(Rp10,Rq1,Rr19),(Rp10,Rq1,Rr20),(Rp10,Rq1,Rr21),(Rp10,Rq1,Rr22),(Rp10,Rq1,Rr23),(Rp10,Rq1,Rr24),(Rp10,Rq1,Rr25),(Rp10,Rq1,Rr26),(Rp10,Rq1,Rr27),(Rp10,Rq1,Rr28),(Rp10,Rq1,Rr29),(Rp10,Rq1,Rr30),(Rp10,Rq1,Rr31),(Rp10,Rq1,Rr32),(Rp10,Rq1,Rr33),(Rp10,Rq1,Rr34),(Rp10,Rq1,Rr35),(Rp10,Rq1,Rr36),(Rp10,Rq1,Rr37),(Rp10,Rq2,Rr1),(Rp1,Rq2,Rr2),(Rp1,Rq2,Rr3),(Rp1,Rq2,Rr4),(Rp10,Rq2,Rr5),(Rp10,Rq2,Rr6),(Rp1,Rq2,Rr7),(Rp10,Rq2,Rr8),(Rp10,Rq2,Rr9),(Rp10,Rq2,Rr10),(Rp10,Rq2,Rr1),(Rp10,Rq2,Rr12),(Rp10,Rq2,Rr13),(Rp10,Rq2,Rr14),(Rp10,Rq2,Rr15),(Rp10,Rq2,Rr10),(Rp10,Rq2,Rr17),(Rp1,Rq2,Rr18),(Rp10,Rq2,Rr19),(Rp10,Rq2,Rr20),(Rp10,Rq2,Rr21),(Rp10,Rq2,Rr22),(Rp10,Rq2,Rr23),(Rp10,Rq2,Rr24),(Rp1,Rq2,Rr25),(Rp10,Rq2,Rr26),(Rp10,Rq2,Rr27),(Rp10,Rq2,Rr28),(Rp10,Rq2,Rr29),(Rp10,Rq2,Rr30),(Rp10,Rq2,Rr31),(Rp10,Rq2,Rr32),(Rp10,Rq2,Rr33),(Rp10,Rq2,Rr34),(Rp10,Rq2,Rr35),(Rp10,Rq2,Rr36),(Rp10,Rq2,Rr37),(Rp10,Rq3,Rr1),(Rp10,Rq3,Rr2),(Rp10,Rq3,Rr3),(Rp10,Rq3,Rr4),(Rp10,Rq3,Rr5),(Rp10,Rq3,Rr6),(Rp10,Rq3,Rr7),(Rp10,Rq3,Rr8),(Rp10,Rq3,Rr9),(Rp10,Rq3,Rr10),(Rp10,Rq3,Rr11),(Rp10,Rq3,Rr12),(Rp10,Rq3,Rr13),(Rp10,Rq3,Rr14),(Rp10,Rq3,Rr15),(Rp10,Rq3,Rr16),(Rp10,Rq3,Rr17),(Rp10,Rq3,Rr18),(Rp10,Rq3,Rr19),(Rp10,Rq3,Rr20),(Rp10,Rq3,Rr21),(Rp10,Rq3,Rr22),(Rp10,Rq3,Rr23),(Rp10,Rq3,Rr24),(Rp10,Rq3,Rr25),(Rp10,Rq3,Rr26),(Rp10,Rq3,Rr27),(Rp10,Rq3,Rr28),(Rp10,Rq3,Rr29),(Rp10,Rq3,Rr30),(Rp10,Rq3,Rr31),(Rp10,Rq3,Rr32),(Rp10,Rq3,Rr33),(Rp10,Rq3,Rr34),(Rp10,Rq3,Rr35),(Rp10,Rq3,Rr36),(Rp10,Rq3,Rr37),(Rp10,Rq4,Rr1),(Rp10,Rq4,Rr2),(Rp10,Rq4,Rr3),(Rp10,Rq4,Rr4),(Rp10,Rq4,Rr5),(Rp10,Rq4,Rr6),(Rp10,Rq4,Rr7),(Rp10,Rq4,Rr8),(Rp10,Rq4,Rr9),(Rp10,Rq4,Rr10),(Rp10,Rq4,Rr11),(Rp10,Rq4,Rr12),(Rp10,Rq4,Rr13),(Rp10,Rq4,Rr14),(Rp10,Rq4,Rr15),(Rp10,Rq4,Rr16),(Rp10,Rq4,Rr17),(Rp10,Rq4,Rr18),(Rp10,Rq4,Rr19),(Rp10,Rq4,Rr20),(Rp10,Rq4,Rr21),(Rp10,Rq4,Rr22),(Rp10,Rq4,Rr23),(Rp10,Rq4,Rr24),(Rp10,Rq4,Rr25),(Rp10,Rq4,Rr26),(Rp10,Rq4,Rr27),(Rp10,Rq4,Rr28),(Rp10,Rq4,Rr29),(Rp10,Rq4,Rr30),(Rp10,Rq4,Rr31),(Rp10,Rq4,Rr32),(Rp10,Rq4,Rr33),(Rp10,Rq4,Rr34),(Rp10,Rq4,Rr35),(Rp10,Rq4,Rr36),(Rp10,Rq4,Rr37),(Rp10,Rq5,Rr1),(Rp10,Rq5,Rr2),(Rp10,Rq5,Rr3),(Rp10,Rq5,Rr4),(Rp10,Rq5,Rr5),(Rp10,Rq5,Rr6),(Rp10,Rq5,Rr7),(Rp10,Rq5,Rr8),(Rp10,Rq5,Rr9),(Rp10,Rq5,Rr10),(Rp10,Rq5,Rr11),(Rp10,Rq5,Rr12),(Rp10,Rq5,Rr13),(Rp10,Rq5,Rr14),(Rp10,Rq5,Rr15),(Rp10,Rq5,Rr16),(Rp10,Rq5,Rr17),(Rp10,Rq5,Rr18),(Rp10,Rq5,Rr19),(Rp10,Rq5,Rr20),(Rp10,Rq5,Rr21),(Rp10,Rq5,Rr22),(Rp10,Rq5,Rr23),(Rp10,Rq5,Rr24),(Rp10,Rq5,Rr25),(Rp10,Rq5,Rr26),(Rp10,Rq5,Rr27),(Rp10,Rq5,Rr28),(Rp10,Rq5,Rr29),(Rp10,Rq5,Rr30),(Rp10,Rq5,Rr31),(Rp10,Rq5,Rr32),(Rp10,Rq5,Rr33),(Rp10,Rq5,Rr34),(Rp10,Rq5,Rr35),(Rp10,Rq5,Rr36),(Rp10,Rq5,Rr37),(Rp11,Rq1,Rr1),(Rp11,Rq1,Rr2),(Rp11,Rq1,Rr3),(Rp11,Rq1,Rr4),(Rp11,Rq1,Rr5),(Rp11,Rq1,Rr6),(Rp11,Rq1,Rr7),(Rp11,Rq1,Rr8),(Rp11,Rq1,Rr9),(Rp11,Rq1,Rr10),(Rp11,Rq1,Rr11),(Rp11,Rq1,Rr12),(Rp11,Rq1,Rr13),(Rp11,Rq1,Rr14),(Rp11,Rq1,Rr15),(Rp11,Rq1,Rr16),(Rp11,Rq1,Rr17),(Rp11,Rq1,Rr18),(Rp11,Rq1,Rr19),(Rp11,Rq1,Rr20),(Rp11,Rq1,Rr21),(Rp11,Rq1,Rr22),(Rp11,Rq1,Rr23),(Rp11,Rq1,Rr24),(Rp11,Rq1,Rr25),(Rp11,Rq1,Rr26),(Rp11,Rq1,Rr27),(Rp11,Rq1,Rr28),(Rp11,Rq1,Rr29),(Rp11,Rq1,Rr30),(Rp11,Rq1,Rr31),(Rp11,Rq1,Rr32),(Rp11,Rq1,Rr33),(Rp11,Rq1,Rr34),(Rp11,Rq1,Rr35),(Rp11,Rq1,Rr36),(Rp1,Rq1,Rr37),(Rp11,Rq2,Rr1),(Rp11,Rq2,Rr2),(Rp11,Rq2,Rr3),(Rp11,Rq2,Rr4),(Rp11,Rq2,Rr5),(Rp11,Rq2,Rr6),(Rp11,Rq2,Rr7),(Rp11,Rq2,Rr8),(Rp11,Rq2,Rr9),(Rp11,Rq2,Rr10),(Rp11,Rq2,Rr1),(Rp1,Rq2,Rr12),(Rp11,Rq2,Rr13),(Rp11,Rq2,Rr14),(Rp11,Rq2,Rr15),(Rp11,Rq2,Rr16),(Rp11,Rq2,Rr17),(Rp11,Rq2,Rr18),(Rp11,Rq2,Rr19),(Rp11,Rq2,Rr20),(Rp11,Rq2,Rr21),(Rp11,Rq2,Rr22),(Rp11,Rq2,Rr23),(Rp11,Rq2,Rr24),(Rp11,Rq2,Rr25),(Rp11,Rq2,Rr26),(Rp11,Rq2,Rr27),(Rp11,Rq2,Rr28),(Rp11,Rq2,Rr29),(Rp11,Rq2,Rr30),(Rp11,Rq2,Rr31),(Rp11,Rq2,Rr32),(Rp11,Rq2,Rr33),(Rp11,Rq2,Rr34),(Rp11,Rq2,Rr35),(Rp11,Rq2,Rr36),(Rp11,Rq2,Rr37),(Rp11,Rq3,Rr1),(Rp11,Rq3,Rr2),(Rp11,Rq3,Rr3),(Rp11,Rq3,Rr4),(Rp11,Rq3,Rr5),(Rp11,Rq3,Rr6),(Rp11,Rq3,Rr7),(Rp11,Rq3,Rr8),(Rp11,Rq3,Rr9),(Rp11,Rq3,Rr10),(Rp11,Rq3,Rr11),(Rp11,Rq3,Rr12),(Rp11,Rq3,Rr13),(Rp11,Rq3,Rr14),(Rp11,Rq3,Rr15),(Rp11,Rq3,Rr16),(Rp11,Rq3,Rr17),(Rp11,Rq3,Rr18),(Rp11,Rq3,Rr19),(Rp11,Rq3,Rr20),(Rp11,Rq3,Rr21),(Rp11,Rq3,Rr22),(Rp11,Rq3,Rr23),(Rp11,Rq3,Rr24),(Rp11,Rq3,Rr25),(Rp11,Rq3,Rr26),(Rp11,Rq3,Rr27),(Rp11,Rq3,Rr28),(Rp11,Rq3,Rr29),(Rp11,Rq3,Rr30),(Rp11,Rq3,Rr31),(Rp11,Rq3,Rr32),(Rp11,Rq3,Rr33),(Rp11,Rq3,Rr34),(Rp11,Rq3,Rr35),(Rp11,Rq3,Rr36),(Rp11,Rq3,Rr37),(Rp11,Rq4,Rr1),(Rp11,Rq4,Rr2),(Rp1,Rq4,Rr3),(Rp11,Rq4,Rr4),(Rp11,Rq4,Rr5),(Rp11,Rq4,Rr6),(Rp11,Rq4,Rr7),(Rp1,Rq4,Rr8),(Rp11,Rq4,Rr9),(Rp11,Rq4,Rr10),(Rp11,Rq4,Rr11),(Rp11,Rq4,Rr12),(Rp11,Rq4,Rr13),(Rp11,Rq4,Rr14),(Rp11,Rq4,Rr15),(Rp11,Rq4,Rr16),(Rp1,Rq4,Rr17),(Rp11,Rq4,Rr18),(Rp11,Rq4,Rr9),(Rp11,Rq4,Rr20),(Rp11,Rq4,Rr21),(Rp11,Rq4,Rr22),(Rp11,Rq4,Rr23),(Rp11,Rq4,Rr24),(Rp11,Rq4,Rr25),(Rp11,Rq4,Rr26),(Rp11,Rq4,Rr27),(Rp11,Rq4,Rr28),(Rp11,Rq4,Rr29),(Rp11,Rq4,Rr30),(Rp11,Rq4,Rr31),(Rp11,Rq4,Rr32),(Rp11,Rq4,Rr33),(Rp1,Rq4,Rr34),(Rp11,Rq4,Rr35),(Rp11,Rq4,Rr36),(Rp11,Rq4,Rr37),(Rp11,Rq5,Rr1),(Rp11,Rq5,Rr2),(Rp11,Rq5,Rr3),(Rp11,Rq5,Rr4),(Rp11,Rq5,Rr5),(Rp11,Rq5,Rr6),(Rp11,Rq5,Rr7),(Rp11,Rq5,Rr8),(Rp11,Rq5,Rr9),(Rp11,Rq5,Rr10),(Rp11,Rq5,Rr11),(Rp11,Rq5,Rr12),(Rp11,Rq5,Rr13),(Rp11,Rq5,Rr14),(Rp11,Rq5,Rr15),(Rp11,Rq5,Rr16),(Rp11,Rq5,Rr7),(Rp11,Rq5,Rr18),(Rp11,Rq5,Rr19),(Rp11,Rq5,Rr20),(Rp11,Rq5,Rr21),(Rp11,Rq5,Rr22),(Rp11,Rq5,Rr23),(Rp11,Rq5,Rr24),(Rp11,Rq5,Rr25),(Rp11,Rq5,Rr26),(Rp11,Rq6,Rr27),(Rp11,Rq5,Rr28),(Rp11,Rq5,Rr29),(Rp11,Rq5,Rr30),(Rp11,Rq5,Rr31),(Rp1,Rq5,Rr32),(Rp11,Rq5,Rr32),(Rp11,Rq5,Rr33),(Rp11,Rq5,Rr34),(Rp11,Rq5,Rr35),(Rp11,Rq5,Rr36),(Rp11,Rq5,Rr37).

Following examples illustrate the present invention in more detail, but the present invention is not limited by these examples. The meaning of each abbreviation is as follows:

Me: methyl

Et: ethyl

Bu: butyl

Ac: acetyl

TMS: tetramethylsilane

TMS-Cl: trimethylsilyl chloride

DMSO: dimethyl sulfoxide

DMF: dimethylformamide

THF: tetrahydrofuran

DBU: 1,8-diazabicyclo[5.4.0]undeca-7-ene

NMP: N-methyl-2-pyrrolidone

HOAt: 1-hydroxy-7-azabenzotriazole

HATU: 2-(7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

PyBOP: benzotriazole-1-yl-oxytrispyrrolidinophosphonium hexafluorophosphate

rt: room temperature

M: mol/L

Example 1

Preparation of 6-(ethylthio)-1-(4-fluorbenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion

To a mixture of S-ethylisothiourea hydrobromide (14.8 g, 80 mmol) and DMF (75 mL) were added isopropyl isocyanate (8.2 mL, 84 mmol) and DBU (12.6 mL, 84 mmol) under ice-cooling, and the resulting mixture was stirred for 6 hours under ice-cooling. To the reaction mixture were added 1,1′-carbonyldiimidazole (15.57 g, 96 mmol) and DBU (18.0 mL, 120 mmol) under ice-cooling, and the resulting mixture was stirred for additional 2 hours. To the reaction mixture was added 2 mol/L hydrochloric acid (240 mL) under ice-cooling over 50 minutes, and the precipitated solid was filtered off. The resulting solid was dissolved in ethyl acetate, and the mixture was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 6-(ethylthio)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (12.29 g, Yield: 71%) as pale brown solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, t, J=7.2 Hz)), 1.33 (6H, d, J=6.9 Hz), 3.05 (2H, q, J=7.2 Hz), 4.81 (1H, sept, J=6.9 Hz).

To a mixture of 6-(ethylthio)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (4.09 g, 19 mmol), potassium carbonate (7.88 g, 57 mmol) and acetonitrile (80 mL), 4-fluorbenzyl bromide (3.55 mL, 28.5 mmol) was added, and the resulting mixture was heated under reflux for 1.5 hours. To the mixture was added iced water (200 mL), and the mixture was extracted with ethyl acetate (100 mL). The extract was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by ethyl acetate and hexane to give 6-(ethylthio)-1-(4-fluorbenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (5.96 g, Yield: 97%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (3H, t, J=7.5 Hz), 1.47 (6H, d, J=6.9 Hz), 3.21 (2H, q, J=7.5 Hz), 5.02 (1H, sept, J=6.9), 5.06 (2H, s), 7.01-7.07 (2H, m), 7.31-7.36 (2H, m).

Example 2

Preparation of 1-(4-fluorbenzyl)-6-(4-isopropoxyphenylamino)-3 isopropyl 1,3,5-triazine-2,4(1H,3H)-dion (I-0133)

A mixture of 6-(ethylthio)-1-(4-fluorbenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.323 g, 1 mmol), 4-isopropoxyaniline (0.907 g, 6 mmol) and 1-methyl-2-pyrrolidone (1 mL) was stirred at 230° C. for 30 minutes under microwave irradiation. To the mixture was added water (100 mL), and the resulting mixture was extracted with ethyl acetate (100 mL). The extract was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by ethyl acetate and hexane to give 1-(4-fluorbenzyl)-6-(4-isopropoxyphenylamino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.21 g, Yield: 51%) as colorless solid.

Melting point: 176-177° C.

1H-NMR (δ ppm TMS/CDCl₃): 1.34 (6H, d, J=6.0 Hz), 1.44 (6H, d, J=6.9 Hz), 4.49 (1H, sept, J=6.0 Hz), 4.96 (1H, sept, J=6.9 Hz), 5.18 (2H, s), 6.75-7.06 (6H, m), 7.53-7.57 (2H, m).

Example 3

Preparation of 6-(3-chloro-4-isopropoxyphenylamino)-1-(4-chlorobenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (I-0228)

A mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.60 g, 1.78 mmol), 3-chloro-4-isopropoxyaniline (0.99 g, 5.3 mmol) and acetic acid (10 mL) was stirred at 90° C. for 6 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL). The extract was washed by saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by diethyl ether and hexane to give 6-(3-chloro-4-isopropoxyphenylamino)-1-(4-chlorobenzyl)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.605 g, Yield: 73%) as colorless solid.

Melting point: 167° C.

1H-NMR (δ ppm TMS/DMSO-d6): 1.28 (6H, d, J=6.0 Hz), 1.34 (6H, d, J=6.9 Hz), 4.62 (1H, m), 4.83 (1H, sept, J=6.9 Hz), 5.18 (2H, brs), 7.12-7.15 (2H, m), 7.34-7.37 (3H, m), 7.43 (2H, d, J=8.7 Hz), 9.23 (1H, brs).

Example 4

Preparation of 1-(4-chlorobenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion

To a mixture of 1-(4-chlorobenzyl)thiourea (11.19 g, 55.8 mmol) and methanol (50 mL) was added methyl iodide (4.18 ml, 66.9 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours. The mixture was concentrated in vacuo. To the resulting residue were added dichloromethane (60 ml) and N,N-diisopropylethylamine (29.2 ml, 167 mmol), and then a solution of N-chlorocarbonyl isocyanate (4.94 ml, 61.4 mmol) in dichloromethane (20 ml) was added gradually under ice-cooling. The resulting mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered off and the resulting solid was washed by small amount on dichloromethane. The mixture was dried under reduced pressure to give 1-(4-chlorobenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion (9.19 g, Yield: 58%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 2.46 (3H, s), 5.04 (2H, s), 7.31-7.43 (4H, m), 11.60 (1H, brs).

Example 5

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion (I-0269)

A mixture of 1-(4-chlorobenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion (4.21 g, 14.8 mmol), 3-fluoro-4-isopropoxyaniline (3.77 g, 22.3 mmol), t-butanol (84 ml) and acetic acid (17 mL) was heated under reflux for 8 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (300 mL), and the resulting mixture was extracted with ethyl acetate (100 mL). The extract was washed by saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue is precipitated by diisopropyl ether to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion (4.54 g, Yield: 76%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.36 (6H, d, J=6.1 Hz), 4.49 (1H, sept, J=6.1 Hz), 5.14 (2H, s), 6.47 (1H, m), 6.59 (1H, m), 6.97 (1H, m), 7.30 (2H, d, J=8.5 Hz), 7.47 (2H, d, J=8.5 Hz), 8.06 (1H, brs).

Example 6

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-pyridylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (I-300)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion (0.15 g, 0.37 mmol) and DMF (3 mL) was added potassium tert-butoxide (0.09 mg, 0.82 mmol) at room temperature and stirred for 5 minutes. To the mixture was added 2-(bromomethyl)pyridine hydrobromide (0.103 g, 0.41 mmol) and the resulting mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added water (20 mL), and the mixture was extracted with ethyl acetate (20 mL×2). The extract was washed by brine (20 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-pyridylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.069 g, Yield: 37%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.36 (2H, d, J=6.2 Hz), 4.47 (1H, sept, J=6.2 Hz), 5.15 (2H, s), 5.19 (2H, s), 6.51 (1H, m), 6.62 (1H, m), 6.97 (1H, m), 7.17-7.48 (7H, m), 7.65 (1H, m), 8.53 (1H, m).

Example 7

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-hydroxyethyl)-1,3,5-triazine-2,4(1H,3H)-dion (I-0273)

To a mixture of 1-(4-chlorobenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion (0.28 g, 1 mmol), 2-(tetrahydro-2H-pyrane-2-yloxy)ethanol (0.15 g, 1.000 mmol), triphenylphosphine (0.53 g, 2 mmol) and THF (5 mL) was gradually added diisopropyl azodicarboxylate (0.23 ml, 1.2 mmol) under ice-cooling, and then the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water (20 mL), and the resulting mixture was extracted with ethyl acetate (20 mL×2). The extract was washed by brine (20 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(methylthio)-3-[2-(tetrahydro-2H-pyrane-2-yloxy)ethyl]-1,3,5-triazine-2,4(1H,3H)-dion (0.32 g, Yield: 78%) as colorless amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.42-1.83 (6H, m), 2.58 (3H, s), 3.47 (1H, m), 3.74-4.32 (5H, m), 4.63 (1H, m), 5.10 (2H, s), 7.28-7.33 (4H, m).

A mixture of 1-(4-chlorobenzyl)-6-(methylthio)₃-[2-(tetrahydro-2H-pyrane-2-yloxy)ethyl]-1,3,5-triazine-2,4(1H,3H)-dion (0.32 g, 0.78 mmol), 3-fluoro-4-isopropoxyaniline (0.40 g, 2.4 mmol) and acetic acid (3 mL) was stirred at 100° C. for 3 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with chloroform (100 mL×2). The extract was dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (methanol/chloroform), and The obtained residue was precipitated by diisopropyl ether and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-hydroxyethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.12 g, Yield: 33%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=5.9 Hz), 1.96 (1H, t. J=5.9 Hz), 3.83 (2H, m), 4.05 (2H, m), 4.47 (1H, sept. J=5.9 Hz), 5.17 (2H, s), 6.48 (1H, m), 6.58 (1H, m), 6.97 (1H, m), 7.30 (2H, d, J=8.5), 7.47 (2H, d, J=8.5), 7.56 (1H, brs).

Example 8

Preparation of 3-(2-aminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion hydrochloride (I-0290)

To 3-(2-t-butoxycarbonylaminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion (0.44 g, 0.8 mmol) was added 4 mol/L hydrogen chloride in dioxane (5 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The resulting precipitated solid was filtered off. The resulting solid was washed by diethyl ether and dried under reduced pressure to give 3-(2-aminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion hydrochloride (0.31 g, Yield: 81%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.9 Hz), 3.01 (2H, m), 3.98 (2H, m), 4.57 (1H, sept, J=5.9 Hz), 5.27 (2H, brs), 6.98-7.17 (3H, m), 7.42 (3H, s), 7.87 (2H, brs).

Example 9

Preparation of 3-(2-acetylaminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion (I-0292)

To a mixture of 3-(2-aminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion hydrochloride (0.104 g, 0.22 mmol), triethylamine (0.074 mL, 0.54 mmol), dimethylaminopyridine (0.026 g, 0.22 mmol) and THF (2 mL) was added dropwise acetyl chloride (0.023 mL, 0.32 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added water (20 mL), and the mixture was extracted with ethyl acetate (10 mL×2). The extract was washed by brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by diisopropyl ether and hexane to give 3-(2-acetylaminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion (0.104 g, Yield: 99%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₈): 1.37 (6H, d, J=6.1 Hz), 1.86 (3H, s), 3.51 (2H, m), 4.00 (2H, m), 4.47 (1H, sept, J=6.1 Hz), 5.16 (2H, s), 5.83 (1H, m), 6.51 (1H, m), 6.60 (1H, m), 6.97 (1H, m), 7.27-7.51 (5H, m).

Example 10

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(methoxycarbonylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (I-0338)

To a mixture of 1-(4-chlorobenzyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion (0.28 g, 1 mmol) and THF (3 mL) was added DBU (0.166 mL, 1.1 mmol), and the mixture was stirred at room temperature for 5 minutes. Further, methyl bromoacetate (0.104 mL, 1.1 mmol) was added to the mixture, and the resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water (20 mL). The precipitated solid was filtered off, dried, and purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-3-(methoxycarbonylmethyl)-6-(methylthio)-1,3,5-triazine-2,4(1H,3H)-dion (0.25 g, Yield: 69%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 2.59 (3H, s), 3.78 (3H, s), 4.69 (2H, s), 5.13 (2H, s), 7.27-7.35 (4H, m).

A mixture of 1-(4-chlorobenzyl)-3-(methoxycarbonylmethyl)-6-(methyl thio)-1,3,5-triazine-2,4(1H,3H)-dion (0.24 g, 0.68 mmol), 3-fluoro-4-isopropoxyaniline (0.17 mg, 1.03 mmol), t-butanol (4.8 mL) and acetic acid (0.4 mL) was heated at reflux for 32 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (20 mL), and the resulting mixture was extracted with ethyl acetate (10 mL). The extract was washed by brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane), and The obtained residue was precipitated by diisopropyl ether to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(methoxycarbonylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.31 g, Yield: 95%) as colorless amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=5.9 Hz), 3.78 (3H, s), 4.47 (1H, sept, J=5.9 Hz), 4.58 (2H, s), 5.17 (2H, s), 6.50 (1H, m), 6.60 (1H, m), 6.97 (1H, m), 7.28-7.47 (5H, m).

Example 11

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(hydroxycarbonylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (I-0284)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(methoxycarbonylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.30 g, 0.63 mmol), methanol (3 mL), and THF (3 mL) was added 1 mol/L lithium hydroxide (3.8 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The pH of the mixture was adjusted with 2 mol/L hydrochloric acid to a pH of less than 2. To the mixture was added brine (20 mL), and the resulting mixture was extracted by chloroform (10 mL×3). The extract was dried over anhydrous sodium sulphate and concentrated in vacuo. The obtained residue was precipitated by diethyl ether and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy phenylamino)-3-(hydroxycarbonylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.28 g, Yield: 97%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.36 (6H, d, J=6.1 Hz), 4.47 (1H, sept, J=6.1 Hz), 4.62 (2H, s), 5.18 (2H, s), 6.51 (1H, m), 6.60 (1H, m), 6.96 (1H, m), 7.30 (2H, d, J=8.7 Hz), 7.45 (2H, d, J=8.7 Hz), 7.64 (1H, brs).

Example 12

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(methylcarbamoymethyl)-1,3,5-triazine-2,4(1H,3H)-dion (I-0294)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(hydroxycarbonylmethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.083 g, 0.19 mmol) and DMF (2 mL) were added methylamine hydrochloride (0.015 g, 0.21 mmol, 1-hydroxybenzotriazole hydrate (0.03 g, 0.2 mmol), 4-dimethylaminopyridine (0.002 g, 0.02 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.038 g, 0.2 mmol) and triethylamine (0.03 mL, 0.21 mmol), and the resulting mixture was stirred at 60° C. for 4 hours. The reaction mixture was poured into water (20 mL), and extracted with ethyl acetate (20 mL). The extract was washed by brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by diisopropyl ether to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(methylcarbamoylmethyl) 1,3,5-triazine-2,4(1H,3H)-dion (0.076 g. Yield: 89%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=6.1 Hz), 2.85 (3H, d, J=4.9 Hz), 4.37 (2H, s), 4.46 (1H, sept, J=6.1 Hz), 5.15 (2H, s), 5.78 (1H, d, J=4.7 Hz), 6.46 (1H, m), 6.57 (1H, m), 6.95 (1H, m), 7.27-7.46 (4H, m), 7.99 (1H, ms).

Example 13

Preparation of 4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one

Phosphorus oxychloride (2.24 mL, 24 mmol) was added to 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2,4(1H,3H)-dion (0.486 g, 1.2 mmol), and the mixture was stirred at 50° C. for 2 hours. The resulting mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (30 mL), and the mixture was washed by saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL). The extract was dried over anhydrous sodium sulphate and concentrated in vacuo to give 4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (0.57 g) as crude product.

1H-NMR (δ ppm TMS/CDCl₃): 1.35 (6H, d, J=6.3 Hz), 4.51 (1H, sept, J=6.3 Hz), 5.28 (2H, s), 6.72 (1H, brs), 6.80 (1H, m), 6.91 (1H, m), 7.08 (1H, m), 7.30 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz).

Example 14

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-4-(2-hydroxyethoxy)-1,3,5-triazine-2(1H)-one (I-0434)

To a mixture of 2-(tetrahydro-2H-pyrane-2-yloxy)ethanol (0.17 mL, corresponding to 1.25 mmol) and THF (5.6 mL) was added 60% sodium hydride (0.05 g, 1.25 mmol), and the mixture was stirred at room temperature for 10 minutes. To the mixture was added a solution of crude 4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (0.224 g, corresponding to 0.5 mmol) in THF (2 mL) under ice-cooling, and the resulting mixture was stirred at room temperature for 5 hours. To the reaction mixture was added half-saturated aqueous ammonium chloride (50 mL), and the mixture was extracted with ethyl acetate (50 mL). The extract was washed by brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-4-(2-(tetrahydro-2H-pyrane-2-yloxy)ethoxy)-1,3,5-triazine-2(1H)-one (0.166 g, Yield: 62%) as colorless as oil.

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-4-(2-(tetrahydro-2H-pyrane-2-yloxy)ethoxy)-1,3,5-triazine-2(1H)-one (0.15 g, 0.28 mmol) and methanol (1.5 mL) was added p-toluenesulfonic acid hydrate (0.08 g, 0.4 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into half-saturated aqueous sodium bicarbonate (10 mL), and the mixture was extracted with ethyl acetate (20 mL). The extract was washed by brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (methanol/chloroform). The obtained residue was precipitated by hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-4-(2-hydroxyethoxy)-1,3,5-triazine-2(1H)-one (0.104 g. Yield: 83%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.34 (6H, d, J=6.1 Hz), 2.53 (1H, brs), 3.91 (2H, brs), 4.44-4.52 (3H, m), 5.30 (2H, s), 6.60 (1H, brs), 6.75-7.10 (3H, m), 7.27-7.43 (4H, m).

Example 15

Preparation of 4-benzylamino-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (I-0435)

To a mixture of crude 4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (0.19 g, corresponding to 0.4 mmol) and THF (4.7 mL) was added benzylamine (0.108 mL, 1 mmol), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture were added water (10 mL) and ethyl acetate (10 mL), and the precipitated solid was filtered off. The resulting solid was washed by ethyl acetate, dried under reduced pressure to give 4-benzylamino-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (0.102 g, Yield: 52%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.25 (6H, d, J=5.7 Hz), 4.28 (1H, m), 4.41 (1H, m), 4.54 (1H, sept, J=5.7 Hz), 5.22 (2H, m), 7.08-7.52 (8H, m), 7.90 (1H, brs), 8.94 (1H, brs).

Example 16

Preparation of 1-(4-chlorobenzyl)-4-(dodecylthio)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (I-0436)

To a mixture of 1-dodecanthiol (0.24 mL, 1.0 mmol) and THF (4.8 mL) was added 60% sodium hydride (0.045 g, 1.0 mmol), and the mixture was stirred at room temperature for minutes. To the resulting mixture was added a solution of crude 4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (0.19 g, corresponding to 0.4 mmol) in THF (2 mL) under ice-cooling, and the mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added half-saturated aqueous ammonium chloride (50 mL), and the mixture was extracted with ethyl acetate (50 mL). The extract was washed by brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by hexane to give 1-(4-chlorobenzyl)-4-(dodecylthio)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (0.092 g, Yield: 39%) as colorless oil.

1H-NMR (δ ppm TMS/CDCl₃): 0.89 (3H, t, J=6.9 Hz), 1.27 (14H, s), 1.34 (6H, d, J=6 Hz), 1.50-1.70 (6H, m), 3.02 (2H, t. J=7.5 Hz), 4.48 (1H, sept, J=6 Hz), 5.26 (2H, s), 6.52 (1H, brs), 6.75 (1H, m), 6.88 (1H, m), 7.10 (1H, m), 7.28-7.50 (4H, m).

Example 17

Preparation of 1-(4-chlorobenzyl)-6-(4-hydroxycarbonylphenylamino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (I-0252)

To a mixture of 1-(4-chlorobenzyl)-6-(4-methoxycarbonylphenylamino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.70 g, 1.63 mmol), methanol (4 mL) and TI-IF (4 mL) was added 2 mol/L lithium hydroxide (4.9 mL) under ice-cooling, and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water (50 mL), adjusted with 2 mol/L hydrochloric acid to a pH of less than 3, and extracted with ethyl acetate (50 mL×2). The extract was washed by brine (50 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting solid was washed by diethyl ether to give 1-(4-chlorobenzyl) 6-(4-hydroxycarbonylphenylamino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.60 g, Yield: 89%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.46 (6H, d, J=6.9 Hz), 4.98 (1H, sept, J=6.9 Hz), 5.19 (2H, s), 6.90 (2H, d, J=8.1 Hz), 7.31 (2H, d, J=8.7 Hz), 7.50 (2H, d, J=8.7 Hz), 7.90 (2H, d, J=8.1 Hz).

Example 181

Preparation of 1-(4-chlorobenzyl-6-[4-(N-benzylcarbamoyl)phenylamino]-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (I-0259)

To a mixture of 1-(4-chlorobenzyl)-6-(4-hydroxycarbonylphenylamino)-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.08 g, 0.19 mmol) and THF (2 mL) were added benzylamine (0.023 mL, 0.21 mmol), 1-hydroxybenzotriazole (0.03 g, 0.21 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.041 g, 0.2 mmol) and triethylamine (0.03 mL, 0.21 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water (30 mL), and the mixture was extracted with ethyl acetate (30 mL). The extract was washed by brine (30 mL), dried over anhydrous sodium sulphate, concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by diethyl ether to give 1-(4-chlorobenzyl)-6-[4-(N-benzylcarbamoyl)phenylamino]-3-isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.07 g, Yield: 72%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.43 (6H, d, J=6.9 Hz), 4.67 (2H, d, J=4.0 Hz), 4.96 (1H, sept, J=6.9 Hz), 5.18 (2H, s), 6.34 (1H, m), 6.88 (2H, d, J=8.4 Hz), 7.17 (1H, brs), 7.29-7.34 (6H, m), 7.50 (2H, d, J=8.4 Hz), 7.80 (2H, d, J=8.4 Hz).

Example 19

Preparation of 1-(4-chlorobenzyl)6-(3-chloro-4-isopropoxyphenylamino)-4-hydroxycarbonylethyl1,3,5-triazine-2(1H)-one (I-0579)

To a mixture of 4-chloro-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-1,3,5-triazine-2(1H)-one (0.15 g, 0.34 mmol), [1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium (II) (22.23 mg, 0.034 mmol) and THF (3 mL) were added (E)-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)acrylate (0.063 g, 0.49 mmol) and 2 mol/L potassium carbonate (0.682 ml, 1.364 mmol) under nitrogen atmosphere, and the resulting mixture was heated at reflux for 7 hours. To the mixture was added water (30 mL), and the resulting mixture was extracted with chloroform (30 mL). The extract was dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 50-80%) to give 1-(4-chlorobenzyl)6-(3-chloro-4-isopropoxyphenylamino)-ethoxycarbonylethenyl-1,3,5-triazine-2(1H)-one (0.05 g, Yield: 30%) as pale orange oil.

1H-NMR (δ ppm TMS/DMSO-d6): 1.20-1.28 (9H, m), 4.17-4.22 (2H, m), 4.54 (1H, brs), 5.10 (2H, brs), 7.40 (8H, brs), 8.14 (1H, s), 9.77 (1H, s).

To a mixture of 1-(4-chlorobenzyl)6-(3-chloro-4-isopropoxyphenylamino)-ethoxycarbonylethenyl-1,3,5-triazine-2(1H)-one (0.05 g, 0.1 mmol), THF (1 ml), EtOH (1 ml) and water (0.3 ml) was added lithium hydroxide hydrate (12.5 mg, 0.3 mmol), and the resulting mixture was stirred at room temperature for 3 days. The reaction mixture was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylamino)-4-hydroxycarbonylethenyl-1,3,5-triazine-2(1H)-one (27 mg. Yield: 57%) as pale orange oil.

The obtained intermediate was dissolved in methanol (3 mL) and conducted by catalytic reduction by using H-Cube (10% Pt—C. H2=1 atm). Then, the mixture was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 50-80%) to give 1-(4-chlorobenzyl)6-(3-chloro-4-isopropoxyphenylamino)-4-hydroxycarbonylethyl-1,3,5-tri azine-2(1H)-one (2.3 mg, Yield: 8.5%) as colorless oil.

1H-NMR (δ ppm TMS/CDCl₃): 1.36 (6H, d, J=5.7 Hz), 2.22 (1H, t, J=7.8 Hz), 2.74 (3H, brs), 4.48 (1H, sept, J=5.7 Hz), 5.18 (2H, s), 6.88 (2H, s), 7.13 (1H, s), 7.30 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz).

Example 20

Preparation of (R)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0461)

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (1.00 g, 3.4 mmol), di-2-methoxyethylazodicarboxylate (1.02 g, 4.4 mmol), triphenylphosphine (1.15 g, 4.4 mmol) and dioxane (8 mL) was gradually added (R)-(−)-3-methyl 2-hydroxyisobutyrate (0.52 g, 4.4 mmol), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water (40 mL), and the resulting mixture was extracted with ethyl acetate (20 mL×2). The extract was washed by brine (20 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (R)-1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methoxycarbonylpropyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.98 g, Yield: 74%) as colorless amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.19 (3, d, J=5.7 Hz), 1.37 (3H, t, J=7.1 Hz), 2.96 (1H, m), 3.12 (2H, q, J=7.1 Hz), 3.60 (3H, s), 3.98 (1H, m), 4.21 (1H, m), 5.08 (2H, s), 7.29-7.34 (4H, m).

A mixture of (R)-1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methoxycarbonylpropyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.32 g, 0.8 mmol), 3-fluoro-4-isopropoxyaniline (0.20 g, 1.2 mmol), acetic acid (0.72 g, 12 mmol) and t-butanol (6) was heated at reflux over night. The reaction mixture was poured into saturated aqueous sodium bicarbonate (40 mL), and the mixture was extracted with ethyl acetate (40 mL×2). The extract was washed by 2 mol/L aqueous hydrochloric acid (20 mL×2), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by diethyl ether to give (R)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (0.29 g. Yield: 71%) as pale purple powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.19 (3H, d, J=5.7 Hz), 1.37 (6H, d, J=5.7 Hz), 2.90 (1H, m), 3.60 (3H, s), 3.91 (1H, m), 4.10 (1H, m), 4.47 (1H, sept, J=5.7 Hz), 5.16 (2H, m), 6.49-6.62 (2H, m), 6.96 (1H, m), 7.29-7.47 (5H, m).

Example 211

Preparation of (R)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0464)

To a mixture of (R)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (0.26 g, 0.5 mmol) and dioxane (4 mL) was added 1 mol/L lithium hydroxide (1.6 mL), and the mixture was stirred at 50° C. for 6 hours. To the mixture was added water (50 mL), adjusted with 2 mol/L hydrochloric acid to a pH of about 3, and the precipitated solid was filtered off. The solid was dried at 40° C. to give (R)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.21 g, Yield: 84%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.19 (3H, d, J=5.7 Hz), 1.34 (6H, d, J=5.7 Hz), 2.91 (1H, m), 3.89 (1H, m), 4.11 (1H, m), 4.44 (1H, sept, J=5.7 Hz), 5.16 (2H, s), 6.47-6.60 (2H, m), 6.93 (1H, m), 7.28-7.44 (4H, m), 7.94 (1H, brs).

Example 22

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-[2,2-di(hydroxymethyl)propyl]-1,3,5-triazine-2,4(1H,3H)-dion (I-0274)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-(2,2,5-trimethyl-1,3-dioxane5-yl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (7.9 g, 14.44 mmol) and methanol (160 mL) was added p-toluenesulfonic acid monohydrate (5.49 g, 28.9 mmol) and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into saturated aqueous sodium bicarbonate (200 mL), and extracted with ethyl acetate (300 mL×2). The extract was washed by brine (300 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by water and the filtered off. The residue was dried at 70° C. for 6 hours to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylamino)-3-[2,2-di(hydroxymethyl)propyl]-1,3,5-triazine-2,4(1H,3H)-dion (5.12 g, Yield: 70%) as a white powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=6.0 Hz), 3.26-3.46 (6H, m), 3.99 (2H, s), 4.48 (1H, sept, J=6.0 Hz), 5.19 (2H, s), 6.49-6.64 (2H, m), 6.99 (1H, m), 7.30-7.51 (5H, m).

Elementary analysis

Calculated value C24H28ClFN4O5-1/3H2O,

C, 56.19; H, 5.63; Cl, 6.91; F, 3.70; N, 10.92

water: 1.18%

Measured value C, 56.33; H, 5.60; Cl, 6.79; F, 3.58; N, 11.06

Karl Fischer water determination: 1.02%

Example 23

Preparation of 1-(4-chlorobenzyl)-6-(Ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion

To a mixture of S-ethylisothiourea hydrobromide (1.85 g, 10 mmol) and DMF (9.3 mL) were added t-butylisocyanide (1.2 mL, 10.5 mmol) and DBU (1.9 mL, 12.8 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 6 hours. To the reaction mixture were added 1,1′-carbonyldiimidazole (1.95 g, 12 mmol) and DBU (1.9 mL, 12.8 mmol) under ice-cooling, and the resulting mixture was stirred for additional 2 hours. To the mixture was added 2 mol/L hydrochloric acid (80 mL) under ice-cooling over about 50 minutes, and the precipitated solid was filtered off. The resulting solid was dissolved in ethyl acetate, and the mixture was dried over anhydrous magnesium sulfate and concentrated in vacuo to give 6-(ethylthio)-3-t-butyl-1,3,5-triazine-2,4(1H,3H)-dion (1.15 g. Yield: 50%) as pale brown solid.

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)

To a mixture of 6-(ethylthio)-3-t-butyl-1,3,5-triazine-2,4(1H,3H)-dion (22.93 g, 100 mmol), 4-chlorobenzylbromide (22.60 g, 110 mmol) and acetonitrile (200 mL) was added potassium carbonate (17.97 g, 130 mmol), and the mixture was heated at reflux for 3 hours. The reaction mixture was filtered to remove the insoluble. The filtrate was concentrated in vacuo to give 39.9 g of crude 3-t-butyl-1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion as pale brown oil. To the obtained crude product was added trifluoroacetic acid (100 mL) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated in vacuo to give crude residue. The residue was precipitated to give 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (29.03 g, Yield: 97%) as pale brown solid.

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).

Example 24

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-sulfoethyl)-1,3,5-triazinane-2,4-dion (I-0654)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazine-2,4(1H,3H)-dion (100 mg, 0.247 mmol) and DMF (2 mL) was added cesium carbonate (105 mg, 0.321 mmol), and the mixture was stirred at room temperature for 5 minutes. Further, 2-bromoethanesulfonic acid sodium (62.5 mg, 0.296 mmol) was added to the mixture, and the resulting mixture was stirred at 120° C. for 1 hour. To the reaction mixture was added 1 mol/L aqueous hydrochloric acid to be acidic. The resulting mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H HO₂/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-sulfoethyl)-1,3,5-triazinane-2,4-dion (22 mg, Yield: 17%) as pale brown solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (6H, d, J=6.1 Hz), 2.62-2.67 (2H, m), 3.93-3.99 (2H, m), 4.54 (1H, sept, J=6.1 Hz), 5.17 (2H, s), 6.90 (1H, m), 7.07-7.12 (2H, m), 7.35-7.42 (4H, m).

Example 25

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(3-sulfopropyl)-1,3,5-triazinane-2,4-dion (I-0645)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazine-(1H,3H)-2,4-dion (200 mg, 0.494 mmol) and DMF (4 mL) was added potassium tert-butoxide (83 mg, 0.741 mmol), and the mixture was stirred at room temperature for 10 minutes. Further, 1,3-propanesultone (91 mg, 0.741 mmol) was added and the resulting mixture was stirred at 90° C. for 2 hours. To the reaction mixture was added 4 mol/L hydrogen chloride in dioxane (20 mL) to be acidic. The mixture was concentrated in vacuo and the resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%). The resulting residue was precipitated by ethyl acetate to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(3-sulfopropyl)-1,3,5-triazinane-2,4-dion (96 mg. Yield: 37%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (6H, d, J=6.1 Hz), 1.81 (2H, m), 2.35-2.40 (2H, m), 3.70-3.74 (2H, m), 4.54 (1H, sept, J=6.1 Hz), 5.19 (2H, s), 6.90 (1H, m), 7.07-7.13 (2H, m), 7.34-7.42 (4H, m).

Example 26

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(5-tetrazolylmethyl)-1,3,5-triaz inane-2,4-dion (I-1297)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4(1H,3H)-dion (1.214 g, 3 mmol), 2-bromoacetonitrile (0.4 g, 3.3 mmol) and DMF (6 mL) was added potassium carbonate (0.54 g, 3.9 mmol), and the mixture was stirred at 60° C. for 1 hour. To the reaction mixture was added water (150 mL), and the mixture was extracted with ethyl acetate (150 mL). The extract was washed by brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The obtained residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-cyanomethyl-1,3,5-triazinane-2,4-dion (0.78 g, Yield: 59%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=6.1 Hz), 4.47 (1H, sept, J=6.1 Hz), 4.69 (2H, s), 5.18 (2H, s), 6.49 (1H, m), 6.59 (1H, m), 6.99 (1H, m), 7.32 (2H, d, J=6.6 Hz), 7.49 (2H, d, J=6.6 Hz), 7.74 (1H, s).

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-cyanomethyl-1,3,5-triazinane-2,4-dion (0.10 g, 0.23 mmol), ammonium chloride (84 mg, 1.58 mmol) and DMF (2 mL) was added sodium azide (73.2 mg, 1.13 mmol), and the mixture was stirred at 95° C. for 2 hours. To the reaction mixture was added water (150 mL), and the mixture was extracted with ethyl acetate (150 mL). The extract was washed by brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by HPLC and the obtained residue was precipitated by ethyl ether to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(5-tetrazolylmethyl)-1,3,5-triaz inane-2,4-dion (60 mg, Yield: 55%) as colorless powder.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.9 Hz), 4.59 (1H, m), 5.15-5.27 (4H, m), 6.60 (1H, brs), 7.00-7.45 (7H, m), 9.44 (1H, mbrs).

Example 27

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-amino-2-hydroxyiminoethyl)-1,3,5-triazinane-2,4-dion (I-0599)

To a mixture of sodium methoxide (34.1 mg, 0.63 mmol and methanol (2 mL) was added hydroxylamine hydrochloride (43.8 mg, 0.631 mmol) under ice-cooling. After the mixture was neutralized, 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-cyanomethyl-1,3,5-triazinane-2,4-dion (0.14 g, 0.315 mmol) was added and the resulting mixture was heated at reflux for 2 hours. To the mixture was added water (150 mL), and the mixture was extracted with ethyl acetate (150 mL). The extract was washed by brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was precipitated by ethyl ether to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy phenylimino)-3-(2-amino-2-hydroxyiminoethyl)-1,3,5-triazinane-2,4-dion (91 mg, Yield: 61%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.9 Hz), 4.34 (2H, brs), 4.58 (1H, m), 5.25 (2H, brs), 5.43 (2H, brs), 7.00-7.45 (7H, m), 8.99 (1H, brs), 9.28 (1H, brs).

Example 28

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-ylmethyl)-1,3,5-triazinane-2,4-dion (I-0601)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-amino-2-hydroxyiminoethyl)-1,3,5-triazinane-2,4-dion (80 mg, 0.1.7 mmol) and pyridine (2 mL) was added ethyl chlorocarbonate (20 mg, 0.19 mmol), and the mixture was stirred at room temperature overnight. Further, the reaction mixture was heated at reflux for 7 hours. The resulting reaction mixture was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-ylmethyl)-1,3,5-triazinane-2,4-dion (20 mg, Yield: 24%) as colorless amorphous.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.9 Hz), 4.60 (1H, sept, J=5.9 Hz), 4.86 (2H, s), 5.27 (2H, s), 7.00-7.50 (7H, m), 9.44 (1H, brs), 12.48 (1H, brs).

Example 29

Preparation of (R)-1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-(2,3-dihydroxypropyl)-1,3,5-triazinane-2,4-dion (I-0638)

A mixture of 1-(4-chlorobenzyl)-6-(3-chloro-4 isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion (300 mg, 0.712 mmol), (S)-4-(bromomethyl)-2,2-dimethyl-1,3-dioxolane (222 mg, 1.14 mmol), potassium tert-butoxide (176 mg, 1.57 mmol) and DMF (6 mL) was stirred at 60° C. for 16 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (R)-1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-[(2,2-dimethyl-1,3-dioxolane-4-yl)methyl]-1,3,5-triazinane-2,4-dion (116 mg, Yield: 30%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.23-1.32 (12H, m), 3.73-3.76 (2H, m), 3.94-3.98 (2H, m), 4.24-4.26 (1H, m), 4.64 (1H, brs), 5.25 (2H, s), 7.16-7.25 (2H, m), 7.38-7.47 (5H, m), 9.30 (1H, s).

To a solution of (R)-1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-[(2,2-dimethyl-1,3-dioxolane-4-yl)methyl]-1,3,5-triazinane-2,4-dion (110 mg, 0.205 mmol) in methanol (4 mL) was added p-toluenesulfonic acid monohydrate (59 mg, 0.31 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by dichloromethane and hexane to give (R)-1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-(2,3-dihydroxypropyl)-1,3,5-triazinane-2,4-dion (88 mg, Yield: 86%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.28 (6H, d, J=5.6 Hz), 3.68-3.84 (4H, m), 4.54 (1H, brs), 4.73 (1H, brs), 5.25 (2H, s), 7.16-7.25 (2H, m), 7.38-7.46 (5H, m), 9.23 (1H, s).

Example 30

Preparation of 6-(3-chloro-4-isopropoxyphenylimino)-3-(2-ethoxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion (I-0866)

To a mixture of S-ethylisothiourea hydrobromide (6.00 g, 32.4 mmol) and DMF (30 mL) were added ethyl 6-isocyanatocaproate (4.48 mL, 34.0 mmol) and DBU (5.1.3 mL, 34.0 mmol) under ice-cooling, and the mixture was stirred under ice-cooling for 5 hours. To the reaction mixture were added 1,1′-carbonyldiimidazole (6.31 g, 38.9 mmol) and DBU (7.33 mL, 49.0 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2 mol/L hydrochloric acid (96 mL) under ice-cooling over 15 minutes, and the mixture was extracted with ethyl acetate. The extract was washed by water and brine, dried over anhydrous sodium sulphate. The extract was concentrated in vacuo to give 6-(ethylthio)-3-(2-ethoxycarbonylethyl)-1,3,5-triazine-2,4(1H,3H)-dion (7.86 g, Yield: 89%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl3): 1.22 (3H, t, J=7.1 Hz), 1.33 (3H, t, J=7.3 Hz), 2.67 (2H, t, J=7.2 Hz), 3.16 (2H, q, J=7.3 Hz), 4.07-4.17 (4H, m).

To the mixture of 6-(ethylthio)-3-(2-ethoxycarbonylethyl)-1,3,5-triazine-2,4(1H,3H)-dion (4.00 g, 14.6 mmol), 4-methylbenzylbromide (3.25 g, 17.6 mmol) and acetonitrile (80 mL) was added potassium carbonate (3.03 g, 22.0 mmol), and the mixture was heated at reflux for 2 hours. The reaction mixture was filtered off to remove insoluble, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 6-(ethylthio)-3-(2-ethoxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazine-2,4(1H,3H)-dion (5.10 g, Yield: 92%) as pale yellow solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.25 (3H, t, J=7.1 Hz), 1.37 (3H, t, J=7.4 Hz), 2.35 (3H, s), 2.71 (2H, t, J=7.3 Hz), 3.21 (2H, q, J=7.4 Hz), 4.12 (2H, q, J=7.1 Hz), 4.24 (2H, t. J=7.3 Hz), 5.09 (2H, s), 7.16 (4H, d, J=8.2 Hz), 7.23 (4H, d, J=8.2 Hz).

A mixture of 6-(ethylthio)-3-(2-ethoxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazine-2,4(1H,3H)-dion (398 mg, 1.05 mmol), 3-chloro-4-isopropoxyaniline (294 mg, 1.58 mmol), acetic acid (0.905 mL) and t-butanol (4 mL) was heated at reflux for 5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 6-(3-chloro-4-isopropoxyphenylimino)-3-(2-ethoxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion (393 mg. Yield: 74%) as pale pink solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.13-1.20 (3H, m), 1.28 (6H, d, J=6.1 Hz), 2.28 (3H, s), 2.55 (2H, t, J=6.9 Hz), 3.33-3.39 (2H, m), 3.98-4.06 (2H, m), 4.60-4.62 (1H, m), 5.21 (2H, s), 7.12-7.23 (6H, m), 7.41-7.46 (1H, m), 9.26 (1H, brs).

Example 31

Preparation of 6-(3-chloro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion (I-0896)

To a mixture of 6-(3-chloro-4-isopropoxyphenylimino)-3-(2-ethoxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion (371 mg, 0.741 mmol), methanol (2 mL) and THF (2 mL) was added 1 mol/L lithium hydroxide (2.4 mL, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated. To the reaction mixture was added 2 mol/L hydrochloric acid (1.3 mL). The precipitated crystalline was filtered off, and the residue was precipitated by ethyl acetate/hexane to give 6-(3-chloro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-1-(4-methylbenzyl)-1,3,5-triazinane-2,4-dion (247 mg, Yield: 71%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.28 (6H, d, J=5.8 Hz), 2.28 (3H, s), 2.49-2.52 (2H, m), 3.93-3.95 (2H, m), 4.59-4.62 (1H, m), 5.19 (2H, s), 7.12-7.23 (7H, m).

Example 32

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydrazinecarbonylethyl)-1,3,5-triazinane-2,4-dion (I-0644)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazine-2,4(1H,3H)-dion (2 g, 4.94 mmol) and DMF (30 mL) was added potassium tert-butoxide (1.331 g, 11.86 mmol) at room temperature and the resulting mixture was stirred for 5 minutes. Further, to the reaction mixture was added methylacrylate (1.074 mL, 11.86 mmol), and the resulting mixture was stirred at 60° C. for 1.5 hours. To the reaction mixture were added potassium tert-butoxide (0.554 g, 4.94 mmol) and methylacrylate (0.448 mL, 4.94 mmol), and the resulting mixture was stirred at 60° C. for 2 hours. Water (0.5 mL) was added to the mixture and the resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated in vacuo and 2 mol/L aqueous hydrochloric acid (80 mL) was added to the resulting residue. The mixture was extracted with ethyl acetate (50 mL×3). The extract was washed by brine (100 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (methanol/chloroform). The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl) 1,3,5-triazinane-2,4-dion (1.64 g, Yield: 70%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=6.1 Hz), 2.71 (2H, t, J=7.2 Hz), 4.16 (2H, t, J=7.2 Hz), 4.47 (1H, sept, J=6.1 Hz), 5.17 (2H, s), 6.50 (1H, br. d, J=8.8 Hz), 6.60 (1H, br. d, 11.1 Hz), 6.97 (1H, t, J=8.8 Hz), 7.31 (2H, d, J=8.2 Hz), 7.48 (2H, d, J=8.2 Hz), 7.57 (1H, br, s).

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-1,3,5-triazinane-2,4-dion (300 mg, 0.629 mmol), O-(7-azabenzotriazol1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (287 mg, 0.755 mmol), triethylamine (0.13 mL, 0.94 mmol) and DMF (6 mL) was added hydrazine monohydrate (0.015 g, 0.21 mmol), and the mixture was stirred at room temperature overnight. The mixture was added to water (200 mL), and the resulting mixture was extracted with ethyl acetate (300 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%). The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4 isopropoxyphenylimino)-3-(2-hydrazinecarbonylethyl)-1,3,5-triazinane-2,4-dion (184 mg, Yield: 60%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.31 (6H, m), 2.55 (4H, m), 4.08 (2H, m), 4.42 (1H, m), 5.16 (1H, m), 6.48 (2H, m), 6.90 (2H, m), 7.28 (2H, m), 7.40 (1H, m).

Example 33

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl-1,3,5-triazinane-2,4-dion (I-0646)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydrazinecarbonylethyl-1,3,5-triazinane-2,4-dion (134.6 mg, 0.274 mmol) and DMF (2 mL) was added 1,1′-carbonyldiimidazole (53.3 mg, 0.329 mmol), and the mixture was stirred at room temperature overnight. The mixture was added to water (200 mL), and extracted with ethyl acetate (300 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was precipitated by hexane to give 1-(4-chlorobenzyl-6-(3-fluoro-4-isopropoxyphenylimino)-3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl-1,3,5-triazinane-2,4-dion (113 mg, Yield: 80%) as colorless powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=6.1 Hz), 2.89 (2H, m), 4.16 (2H, m), 4.48 (1H, sept, J=6.0 Hz), 5.16 (2H, s), 6.49-6.62 (2H, m), 6.98 (1H, t, J=9.0 Hz), 7.31-7.48 (4H, m), 8.00-8.40 (1H, m).

Example 34

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-[2-(1,2,4-triazol-5-yl)ethyl]-1,3,5-triazinane-2,4-dion (I-0672)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-ispropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-1,3,5-triazinane-2,4-dion (2.86 g, 6 mmol) and DMF (20 mL) were added ammonium chloride (0.385 g, 7.20 mmol), 1-hydroxybenzotriazole hydrate (1.011 g, 6.60 mmol), 4-dimethylaminopyridine (0.073 g, 0.600 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.265 g, 6.60 mmol) and triethylamine (0.998 mL, 7.20 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (200 mL), and the mixture was extracted with ethyl acetate (200 mL). The extract was washed by saturated aqueous sodium bicarbonate (200 mL) and brine (200 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-carbamoylethyl)-1,3,5-triazinane-2,4-dion (2.29 g, Yield: 84%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.28 (6H, d, J=6.1 Hz), 2.34 (2H, t, J=7.6 Hz), 3.90 (2H, t, J=7.6 Hz), 4.55 (1H, m), 5.22 (2H, brs), 6.50 (1H, brs), 6.84 (brs), 7.00-7.40 (7H, m), 9.25 (1H, brs)

A mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-carbamoylethyl)-1,3,5-triazinane-2,4-dion (150 mg, 0.315 mmol) and N,N-dimethylformamide dimethyl acetal (2 mL) was stirred at 80° C. for 1.5 hours. The reaction mixture was concentrated in vacuo. To the residue were added acetic acid (1 mL) and hydrazine monohydrate (0.046 mL, 0.944 mmol), and the mixture was stirred at 90° C. for 0.5 hour. The reaction mixture was poured into water (200 mL), and the resulting mixture was extracted with chloroform (200 mL×2). The extract was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-[2-(1,2,4-triazol-5-yl)ethyl]-1,3,5-triazinane-2,4-dion (75.3 mg, Yield: 48%) as colorless powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=6.3 Hz), 3.20 (2H, t, J=6.4 Hz), 4.24 (2H, t, J=6.4 Hz), 4.47 (1H, sept, J=5.9 Hz), 5.14 (2H, s), 6.48-6.52 (1H, m), 6.59 (1H, dd, J=11.7, 2.6 Hz), 6.97 (1H, t, 8.5 Hz), 7.30 (2H, d, J=8.2 Hz), 7.46 (2H, d, J=8.2 Hz), 7.78-7.89 (1H, m), 11.2 (1H, brs).

Example 35

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)₃-[2-(cyanocarbamoyl)ethyl]-1,3,5-triazinane-2,4-dion (I-0758)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylethyl)-1,3,5-triazinane-2,4-dion (300 mg, 0.629 mmol), triethylamine (0.105 mL, 0.755 mmol) and DMF (3 mL), methyl chlorocarbonate (0.063 mL, 0.755 mmol) was added under ice-cooling, and the resulting mixture was stirred at 0° C. for 2 hours. To the mixture were added cyanamide monosodium salt (121 mg, 1.89 mmol) and 4-dimethylaminopyridine (23 mg, 0.19 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-[2-(cyanocarbamoyl)ethyl]-1,3,5-triazinane-2,4-dion (20 mg, Yield: 6%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (6H, d, J=5.8 Hz), 2.50 (2H, m), 3.93-3.97 (2H, m), 4.42-4.64 (1H, m), 5.06, 5.23 (2H, s), 6.43-6.60 (1H, m), 7.01-7.10 (2H, m), 7.28-7.43 (4H, m), 9.26 (1H, s).

Example 36

Preparation of 1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(4-methoxycarbonyl-2-oxazolyl)-1,3,5-triazinane-2,4-dion (I-0780)

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (300 mg, 1.01 mmol) and DMF (3 mL) were added potassium carbonate (167 mg, 1.21 mmol) and methyl 2-(chloromethyl)-1,3-oxazole-4-carboxylate (212 mg, 1.21 mmol), and the resulting mixture was stirred at 70° C. for 2 hours. The reaction mixture was poured into water (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-(4-methoxycarbonyl-2-oxazolyl)-1,3,5-triazinane-2,4-dion (520 mg) as crude product as yellow amorphous.

To the obtained crude 1-(4-chlorobenzyl)-6-(ethylthio)-3-(4-methoxycarbonyl-2-oxazolyl)-1,3,5-triazinane-2,4-dion were added 3-methyl-4-isopropoxyaniline (248 mg, 1.5 mmol), t-butyl alcohol (8 mL) and acetic acid (0.86 mL), and the resulting mixture was heated under reflux for 5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL). The extract was washed by saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(4-methoxycarbonyl-2-oxazolyl)-1,3,5-triazinane-2,4-dion (535 mg, Yield: 99%) as colorless amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.31, 1.35 (6H, d, J=6.1 Hz), 2.15, 2.20 (31H, s), 3.91 (3H, s), 4.47 (1H, sept, J=6.1 Hz), 5.17, 5.19, 5.23, 5.32 (4H, m), 6.57-6.63 (2H, m), 6.82-6.88 (1H, m), 7.28-7.34 (2H, m), 7.45-7.53 (2H, m), 8.17 (1H, s).

Example 37

Preparation of 1-(4-chlorobenzyl)-6-(3-methyl-4 isopropoxyphenylimino)-3-(4-hydroxycarbonyl-2-oxazolyl)-1,3,5-triazinane-2,4-dion (I-0800)

To a mixture of 1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(4 methoxycarbonyl-2-oxazolyl)-1,3,5-triazinane-2,4-dion (520 mg, 0.963 mmol), methanol (5 mL), and water (2.5 mL) was added 4 mol/L lithium hydroxide (0.722 mL), and the resulting mixture was stirred at room temperature for 2 hours. To the mixture were added water (100 mL) and 2 mol/L hydrochloric acid (10 mL), and the resulting mixture was extracted with ethyl acetate (300 mL). The extract was washed by brine (100 ml), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4 chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(4-hydroxycarbonyl-2-oxazolyl)-1,3,5-triazinane-2,4-dion (370 mg, Yield: 73%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.35 (6H, d, J=5.9 Hz), 2.19 (3H, s), 4.47 (1H, sept, J=5.9 Hz), 5.20 (2H, s), 5.20 (2H, s), 6.64-6.81 (3H, m), 7.31-7.59 (4H, m), 8.26 (1H, s).

Example 38

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-cyanoimino-4-phenoxy-3-isobutyl)-1,3,5-triazinane-2,4-dion (I-0652)

To a mixture of 3-(2-aminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion hydrochloride (200 mg, 0.413 mmol) and ethyl ether (8 mL) were added triethylamine (0.126 mL, 0.908 mmol) and diphenyl-N-cyanocarbonimidate (216 mg, 0.908 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-cyanoimino-4-phenoxy-3-aza butyl)-1,3,5-triazinane-2,4-dion (170 mg. Yield: 70%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.40 (6H, d, J=6.0 Hz), 3.70 (2H, m), 4.07 (2H, m), 4.49 (1H, sept, J=6.0 Hz), 5.17 (2H, s), 6.47-6.61 (1H, m), 6.94 (1H, t, J=8.7 Hz), 7.16-7.20 (4H, m), 7.30-7.46 (4H, m), 7.79 (1H, m), 8.25 (1H, s).

Example 39

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-cyanoimino-4-methylamino-3-azabutyl)-1,3,5-triazinane-2,4-dion (I-0653)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-cyanoimino-4-phenoxy-3-azabutyl)-1,3,5-triazinane-2,4-dion (155 mg, 0.262 mmol), 2-propanol (2 mL) and ethyl acetate (1 mL) was added 2 mol/L methylamine in THF (1.964 mL, 3.93 mmol), and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-cyanoimino-4-methylamino-3-azabutyl)-1,3,5-triazinane-2,4-dion (135 mg, Yield: 98%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (6H, d, J=5.9 Hz), 2.71-2.84 (3H, m), 3.47-3.56 (2H, m), 4.01-4.16 (2H, m), 4.48 (1H, sept, J=5.9 Hz), 5.18-5.27 (2H, m), 5.40-5.46 (1H, m), 6.57-6.68 (1H, m), 6.80-7.02 (2H, m), 7.32 (2H, d, J=8.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.73 (1H, br. s).

Example 40

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-imino-4-amino-3-azabutyl)-1,3,5-triazinane-2,4-dion (I-0659)

To a mixture of 3-(2-aminoethyl)-1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion hydrochloride (150 mg, 0.31 mmol) and DMF (3 mL) were added diisopropylethylamine (0.270 mL, 1.548 mmol) and 1H-pyrazole-1-carboxyimidate hydrochloride (136 mg, 0.929 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%). The resulting residue was precipitated by ethyl acetate to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(4-imino-4 amino-3-azabutyl)-1,3,5-triazinane-2,4-dion (96 mg, Yield: 63%) flesh color solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.22 (6H, d, J=6.1 Hz), 3.19 (2H, m), 3.70 (2H, t, J=6.25 Hz), 4.35 (1H, sept, J=5.9 Hz), 5.09 (2H, s), 6.65-6.68 (1H, m), 6.84 (1H, t, J=9.0 Hz), 7.07 (1H, dd, J=14.3, 2.4 Hz), 7.17 (2H, brs), 7.30-7.38 (4H, m), 7.59 (1H, m).

Example 41

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy phenylimino)-3-(6-methoxy-3-pyridyl)methyl-1,3,5-triazinane-2,4-dion (I-0641)

To a mixture of 1-(4-chlorobenzyl)-6-(Ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (0.5 g, 1.68 mmol), (6-methoxy-3-pyridyl)methanol (0.3 g, 2.18 mmol), triphenylphosphine (0.57 g, 2.18 mmol) and dioxane (10 mL) was gradually added di-2-methoxyethylazodicarboxylate (0.57 g, 2.18 mmol), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-(6-methoxy-3-pyridyl)methyl-1,3,5-triazinane-2,4-dion (0.64 g, Yield: 91%) as colorless amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.40 (3H, t, J=7.2 Hz), 3.25 (2H, q, J=7.4 Hz), 3.96 (3H, s), 5.06 (2H, s), 5.11 (2H, s), 6.73 (1H, d, J=8.66 Hz), 7.29-7.38 (4H, m), 7.82 (1H, dd, J=8.4, 2.4 Hz), 8.39 (1H, m).

The mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-(6-methoxy-3-pyridyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (0.32 g, 0.76 mmol), 3-fluoro-4-isopropoxyaniline (0.19 g, 1.15 mmol), t-butanol (6.4 mL) and acetic acid (0.66 mL) was heated at reflux for 24 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL), and extracted with ethyl acetate (100 mL). The extract was washed by saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate. The extract was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting residue was precipitated by hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(6-methoxy-3-pyridyl)methyl-1,3,5-triazinane-2,4-dion (0.33 g, Yield: 82%) as colorless powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (611, d, J=6.1 Hz), 3.93 (3H, s), 4.74 (1H, sept, J=6.1 Hz), 4.93 (2H, s), 5.16 (2H, s), 6.47 (1H, m), 6.58 (1H, m), 6.70 (1H, d, J=8.8 Hz), 6.96 (1H, t, J=8.8 Hz), 7.29-7.49 (4H, m), 7.71 (1H, m), 8.30 (1H, m).

Example 42

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(6-oxo-1,6-dihydro-3-pyridyl)methyl-1,3,5-triazinane-2,4-dion (I-0649)

A mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(6-methoxy-3-pyridyl)methyl 1,3,5-triazinane-2,4-dion (245 mg, 0.466 mmol), sodium iodide (209 mg, 1.397 mmol), acetonitrile (5 mL) and chlorotrimethylsilane (0.179 mL, 1.397 mmol) was heated at reflux for 1 hour. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (300 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(6-oxo-1,6-dihydro-3-pyridyl)methyl-1,3,5-triazinane-2,4-dion (237 mg, Yield: 99%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (6H, d, J=6.0 Hz), 4.62 (3H, m), 5.22 (2H, m), 6.26 (1H, d, J=9.3 Hz), 7.05-7.15 (2H, m), 7.31-7.42 (5H, m), 9.31 (1H, m), 11.5 (1H, m).

Example 43

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(1-methyl-2-oxo-1,2-dihydro-3-pyridyl)methyl-1,3,5-triazinane-2,4-dion (I-0689)

A mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methyl-2-oxo-1,2-dihydro-3-pyridyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (340 mg, 0.812 mmol), sodium iodide (365 mg, 2.44 mmol), chlorotrimethylsilane (0.311 mL, 2.44 mmol) and acetonitrile (14 mL) was stirred at 100° C. for 1 hour. To the reaction mixture was added 10% aqueous sodium hydrogensulfate, and the resulting mixture was extracted with ethyl acetate and THF. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-oxo-1,2-dihydro-3-pyridyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (260 mg, Yield: 79%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.28 (3H, t, J=7.6 Hz), 3.13 (2H, q, J=7.6 Hz), 4.70 (2H, s), 5.09 (2H, s), 6.14 (1H, t, J=6.8 Hz), 7.20 (1H, d, J=6.0 Hz), 7.31 (1H, d, J=6.0 Hz), 7.37-7.43 (4H, m), 11.71 (1H, s).

A mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-oxo-1,2-dihydro-3-pyridyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (150 mg, 0.370 mmol), 60% sodium hydride (21 mg, 0.52 mmol), trifluoromethanesulfonic acid methyl ester (0.049 mL, 0.45 mmol) and DMF (3 mL) was stirred at room temperature for 3 hours. To the mixture was added 10% aqueous citric acid and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-(1-methyl-2-oxo-1,2-dihydro-3-pyridyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (130 mg, Yield: 84%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.28 (3H, t, J=7.6 Hz), 3.13 (2H, q, J=7.6 Hz), 3.46 (3H, s), 4.72 (2H, s), 5.09 (2H, s), 6.17 (1H, t, J=6.8 Hz), 7.20 (1H, d, J=6.0 Hz), 7.37-7.43 (4H, m), 7.63 (1H, d, J=6.0 Hz).

A mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-(1-methyl-2-oxo-1,2-dihydro-3-pyridyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (125 mg, 0.298 mmol), 3-fluoro-4-isopropoxyaniline (76 mg, 0.45 mmol), acetic acid (0.256 mL) and t-butanol (2.4 mL) was heated at reflux for 9 hours. The reaction mixture was concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(1-methyl-2-oxo-1,2-dihydro-3-pyridyl)methyl-1,3,5-triazinane-2,4-dion (50 mg, Yield: 32%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.6 Hz), 3.45 (3H, s), 4.57 (1H, brs), 4.68 (2H, s), 5.24 (2H, brs), 5.09 (2H, s), 6.17 (1H, t, J=6.8 Hz), 7.11-7.14 (3H, m), 7.42 (4H, brs), 7.62 (1H, d, J=6.0 Hz).

Example 44

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-sulfamoylethyl)-1,3,5-triazinane-2,4-dion (I-0693)

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (500 mg 1.679 mmol) and N-methyl-2-pyrrolidone (2.5 mL) were added cesium carbonate (1094 mg, 3.36 mmol) and 2-bromoethanesulfonic acid sodium (709 mg, 3.36 mmol), and the resulting mixture was stirred at 140° C. under microwave irradiation for 1 hour. To the reaction mixture was added 2 mol/L aqueous hydrochloric acid (2.5 mL) and purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-sulfoethyl)-1,3,5-triazine-2,4(1H,3H)-dion (120 mg, Yield: 18%) as pale yellow amorphous.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04, 1.24 (3H, t, J=7.0 Hz), 2.63-2.72 (2H, m), 3.09, 3.42 (2H, q, J=7.0 Hz), 3.91-4.03 (2H, m), 4.83 (2H, s), 7.35-7.38 (4H, m), 11.7 (1H, s).

To 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-sulfoethyl)-1,3,5-triazine-2,4(1H,3H)-dion (120 mg, 0.296 mmol) was added phosphorus oxychloride (2.5 mL), and the mixture was heated at reflux for 2 hours. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in dioxane (5 mL). The dioxane solution of the residue was gradually added to 0.5 mol/L ammonia in dioxane (5.9 mL) under ice-cooling, and the resulting mixture was stirred at room temperature overnight. The precipitated insoluble were filtered off and the filtrate was concentrated in vacuo. The resulting residue was purified by HPLC to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-sulfamoylethyl)-1,3,5-triazine-2,4(1H,3H)-dion (7.4 mg, Yield: 6%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.37 (3H, t, J=7.5 Hz), 3.22 (2H, q, J=7.5 Hz), 3.48-3.51 (2H, m), 4.43-4.49 (2H, m), 5.12 (1H, s), 5.20 (2H, s), 7.25-7.35 (4H, m).

A mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-sulfamoylethyl)-1,3,5-triazine-2,4(1H,3H)-dion (6.9 mg, 0.017 mmol), 3-fluoro-4-isopropoxyaniline (4.33 mg, 0.026 mmol), t-butanol (1 mL) and acetic acid (0.015 mL) was heated at reflux for 24 hours. The reaction was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-sulfamoylethyl)-1,3,5-triazinane-2,4-dion (5 mg, Yield: 57%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.25 (6H, d, J=5.8 Hz), 3.19-3.26 (2H, m), 4.06-4.12 (2H, m), 4.50 (1H, sept, J=5.8 Hz), 5.17 (2H, s), 6.83-7.38 (9H, m).

Example 45

Preparation of (S)-1-(4-chlorobenzyl)-3-(2-methoxycarbonylpropyl)-6-(4-phenoxyphenylimino)-1,3,5-triazinane-2,4-dion (I-0989)

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (5.96 g, 20 mmol), triphenylphosphine (6.29 g, 24 mmol), (S)-3-methyl 2-hydroxyisobutyrate (2.84 g, 24 mmol) and dioxane (40 mL) was added di-2-methoxyethylazodicarboxylate (5.62 g, 24 mmol) over 10 minutes, and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (250 mL) and the resulting mixture was extracted with ethyl acetate (250 mL). The extract was washed by brine (250 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methoxycarbonylpropyl)-1,3,5-triazine-2,4(1H,3H)-dion (6.0 g, Yield: 75%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.19 (3H, d, J=5.7 Hz), 1.37 (3H, t, J=7.1 Hz), 2.96 (1H, m), 3.12 (2H, q, J=7.1 Hz), 3.60 (3H, s), 3.98 (1H, m), 4.21 (1H, m), 5.08 (2H, s), 7.29-7.34 (4H, m).

A mixture of (S)-1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methoxycarbonylpropyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.279 g, 0.7 mmol), 4-phenoxyaniline (0.194 g, 1.05 mmol), acetic acid (0.6 mL) and t-butanol (6 mL) was heated at reflux for 5 hours. The reaction mixture was poured into saturated aqueous sodium bicarbonate (150 mL), and the resulting mixture was extracted with ethyl acetate (150 mL). The extract was washed by brine (150 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-3-(2-methoxycarbonylpropyl)-6-(4-phenoxyphenylimino)-1,3,5-triazinane-2,4-dion (0.34 g, Yield: 93%) as pale brown amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.19 (3H, d, J=7.1 Hz), 2.90 (1H, m), 3.61 (3H, s), 3.90 (1H, m), 4.12 (1H, m), 5.15 (1H, d, J=14.3 Hz), 5.23 (1H, d, J=14.3 Hz), 6.80 (2H, d, J=8.5 Hz), 7.01-7.40 (10H, m), 7.50 (2H, d, J=8.5 Hz).

Example 46

Preparation of (S)-1-(4-chlorobenzyl)-3-(2-hydroxycarbonylpropyl)-6-(4-phenoxyphenylimino)-1,3,5-triazinane-2,4-dion (I-0991)

To a mixture of (S)-1-(4-chlorobenzyl)-3-(2-methoxycarbonylpropyl)-6-(4-phenoxyphenylimino)-1,3,5-triazinane-2,4-dion (0.313 g, 0.6 mmol), methanol (1 mL) and THF (1 mL) was added 4 mol/L lithium hydroxide (0.75 mL), and the resulting mixture was stirred at 60° C. for 1 hour. To the reaction mixture were added water (100 mL) and 2 mol/L hydrochloric acid (2 mL) and the resulting mixture was extracted with ethyl acetate (100 mL). The extract was washed by brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-chlorobenzyl)-3-(2-hydroxycarbonylpropyl)-6-(4-phenoxyphenylimino)-1,3,5-triazinane-2,4-dion (0.29 g, Yield: 95%) as pale brown powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.20 (3H, d, J=6.6 Hz), 2.95 (1H, m), 3.90 (1H, m), 4.10 (1H, m), 5.19 (2H, s), 6.79 (2H, d, J=8.5 Hz), 6.98-7.36 (9H, m), 7.47 (2H, d, J=8.0 Hz), 7.80 (1H, s).

Example 47

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isoproppoxyphenylimino)-3-(2-ethoxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazinane-2,4-dion (I-0735)

To a mixture of ethyl 3-bromo-2-oxo-propionate (5.85 g, 30 mmol) and ethanol (30 mL) was added O-methoxyamine hydrochloride (5.01 g, 60.0 mmol), and the resulting mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give crude ethyl 3-bromo-2-methoxyiminopropionate 6.02 g as colorless oil.

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (1.49 g, 5 mmol), ethyl 3-bromo-2-methoxyiminopropionate (1.34 g, 6.00 mmol), and DMF (10 mL) was added potassium carbonate (0.898 g, 6.50 mmol), and the resulting mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added water (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-ethoxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazine-2,4(1H,3H)-dion (2.10 g, Yield: 95%) as colorless oil.

1H-NMR (δ ppm TMS/CDCl₃): 1.28-1.38 (6H, m), 3.21 (2H, q, J=7.4 Hz), 4.03 (3H, s), 4.28 (2H, q, J=7.1 Hz), 4.97 (2H, s), 5.11 (2H, s), 7.26-7.34 (4H, m).

A mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-ethoxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.35 g, 0.8 mmol), 3-fluoro-4-isopropoxyaniline (0.20 g, 1.2 mmol), acetic acid (0.72 g, 12 mmol) and t-butanol (7 mL) was heated at reflux overnight. The reaction mixture was poured into saturated aqueous sodium bicarbonate (100 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-ethoxycarbonyl ethoxyiminoethyl)-1,3,5-triazinane-2,4-dion (0.31 g, Yield: 70%) as colorless amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.30 (3H, t, J=7.3 Hz), 1.37 (6H, d, J=6.1 Hz), 4.04 (3H, s), 4.27 (2H, q, J=7.3 Hz), 4.48 (1H, sept, J=6.1 Hz), 4.89 (2H, s), 5.17 (2H, s), 6.48-6.52 (1H, m), 6.60 (1H, dd, J=11.7, 2.6 Hz), 6.97 (1H, t, J=8.5 Hz), 7.28-7.47 (5H, m).

Example 48

Preparation of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazinane-2,4-dion (I-0737)

To a mixture of 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy phenylimino)-3-(2-ethoxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazinane-2,4-dion (0.29 g, 0.53 mmol), methanol (3 mL) and water (1.5 mL) was added 4 mol/L lithium hydroxide (0.4 mL), and the resulting mixture was stirred at room temperature overnight. To the reaction mixture was added water (100 mL). The pH of the mixture was adjusted with 2 mol/L hydrochloric acid to a pH of about 3, and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give 1-(4-chlorobenzyl)-6-(3-fluoro-4-isopropoxy phenylimino)-3-(2-hydroxycarbonyl-2-methoxyiminoethyl)-1,3,5-triazinane-2,4-dion (0.27 g, Yield: 99%) as colorless powder.

1H-NMR (δ ppm TMS/DMSO-d6): 1.28 (6H, d, J=6.0 Hz), 3.81 (3H, s), 4.53 (1H, sept, J=6.0 Hz), 4.68 (2H, s), 5.21 (2H, s), 7.05 (3H, m), 7.41 (4H, m).

Example 49

Preparation of (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-ethoxycarbonyl-propyl)-6-(3-methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion (I-0717)

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (1.2 g, 4.03 mmol), (S)-4-hydroxy-2-t-butoxycarbonylamino-ethyl butyrate (1.034 g, 4.18 mmol), triphenylphosphine (1.268 g, 4.84 mmol) and dioxane (12 mL) was gradually added di-2-methoxyethylazodicarboxylate (1.133 g, 4.84 mmol), and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (200 mL), and the resulting mixture was extracted with ethyl acetate (300 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-ethoxycarbonylpropyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (2.15 g, Yield: 100%) as colorless amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.23 (3H, t, J=7.1 Hz), 1.33 (3H, t, J=7.4 Hz), 1.42 (9H, s), 2.10-2.16 (2H, m), 3.17 (2H, q, J=7.4 Hz), 3.97-4.02 (2H, m), 4.05-4.14 (2H, m), 4.34 (1H, m), 5.06 (2H, m), 5.49 (1H, m), 7.28-7.35 (4H, m).

A mixture of (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-ethoxycarbonylpropyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (500 mg, 0.949 mmol), 3-methyl-4-isopropoxyaniline (235 mg, 1.423 mmol), acetic acid (0.814 mL) and t-butanol (10 mL) was heated at reflux overnight. The reaction mixture was added to saturated aqueous sodium bicarbonate (100 mL), and the resulting mixture was extracted with ethyl acetate (300 mL). The extract was washed by brine (200 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting residue was precipitated by methanol to give (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-ethoxycarbonylpropyl)-6-(3-methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion (550 mg, Yield: 92%) as pale purple powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.24-1.32 (3H, m), 1.35 (6H, d, J=6.1 Hz), 1.45 (9H, s), 2.05-2.14 (2H, m), 2.19 (3H, s), 3.94 (2H, t, J=7.2 Hz), 4.09-4.18 (2H, m), 4.33-4.40 (1H, m), 4.46 (1H, sept, J=6.1 Hz), 5.17 (2H, s), 5.31 (1H, m), 6.54-6.60 (2H, m), 6.82 (1H, d, J=8.4 Hz), 7.29-7.53 (5H, m).

Example 50

Preparation of (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-hydroxycarbonylpropyl)-6-(3-methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion (I-0732)

To a mixture of (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-ethoxycarbonylpropyl)-6-(3-methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion (530 mg, 0.841 mmol), methanol (5 mL) and water (2.5 mL) was added 4 mol/L lithium hydroxide (0.63 mL), and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water (100 mL) and saturated aqueous ammonium chloride (10 mL), and the resulting mixture was extracted with ethyl acetate (300 mL). The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to give (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-hydroxycarbonylpropyl)-6-(3-methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion (474 mg, Yield: 94%) as pale purple amorphous.

1H-NMR (δ ppm TMS/CDCl₃): 1.33 (6H, d, J=5.8 Hz), 1.44 (9H, s), 2.17 (5H, m), 3.97 (2H, m), 4.32 (1H, m), 4.45 (1H, sept, J=5.8 Hz), 5.17 (2H, s), 5.40 (1H, m), 6.60-6.81 (3H, m), 7.33-7.46 (4H, m).

Example 51

Preparation of (S)-1-(4-chlorobenzyl)-3-(3-amino-3-hydroxycarbonylpropyl)-6-(3-methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion hydrochloride (I-0736)

To a mixture of (S)-1-(4-chlorobenzyl)-3-(3-t-butoxycarbonylamino-3-hydroxycarbonylpropyl)-6-(3-methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion (460 mg, 0.764 mmol) and dioxane (2.3 mL) was added 4 mol/L hydrogen chloride in dioxane (3.82 mL) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. To the reaction mixture were added ethyl acetate (2 mL) and hexane (10 mL). The precipitated solid was filtered off and obtained solid was washed by hexane. The obtained solid was dried under reduced pressure to give (S)-1-(4-chlorobenzyl)-3-(3-amino-3-hydroxycarbonylpropyl)-6-(3 methyl-4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dion hydrochloride (403 mg, Yield: 98%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (6H, d, J=6.1 Hz), 1.94-2.14 (2H, m), 2.10 (3H, s), 3.86-3.96 (3H, m), 4.54 (1H, sept, J=6.1 Hz), 5.25 (2H, s), 6.90-7.03 (3H, m), 7.36 (2H, d, J=8.7 Hz), 7.43 (2H, d, J=8.7 Hz), 8.30 (3H, brs), 9.28 (1H, brs).

Example 52

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4 isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-methoxy-ethyl)-1,3,5-triazinane-2,4-dion (I-0806)

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (550 mg, 1.85 mmol), di-2-methoxyethylazodicarboxylate (606 mg, 2.59 mmol), triphenylphosphine (969 mg, 3.69 mmol) and dioxane (11 mL) was gradually added (S)-3-hydroxy-2-methoxy-methylpropionate (297 mg, 2.22 mmol), and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methoxycarbonyl-2-methoxyethyl)-1,3,5-triazine-2,4(1H,3H)-dion (559 mg, Yield: 73%) as colorless oil.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (3H, t, J=7.6 Hz), 3.12 (2H, q, J=7.6 Hz), 3.27 (3H, s), 3.61 (3H, s), 3.99-4.10 (3H, m), 5.08 (2H, s), 7.32 (2H, d, J=8.0 Hz), 7.44 (2H, d, J=8.0 Hz).

A mixture of (S)-1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methoxycarbonyl-2-methoxy-ethyl)-1,3,5-triazine-2,4(1H,3H)-dion (300 mg, 0.725 mmol), 3-methyl-4-isopropoxyaniline (180 mg, 1.09 mmol), acetic acid (0.622 mL) and t-butanol (6 mL) was heated at reflux for 8 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-methoxyethyl)-1,3,5-triazinane-2,4-dion (365 mg, Yield: 97%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.6 Hz), 2.11 (3H, s), 3.26 (3H, s), 3.57 (3H, s), 3.98-4.05 (3H, m), 4.56 (1H, sept, J=5.9 Hz), 5.26 (2H, s), 6.94 (1H, d, J=8.0 Hz), 7.04-7.07 (2H, m), 7.33 (2H, d, J=8.0 Hz), 7.46 (2H, d, J=8.0 Hz), 9.25 (1H, s).

Example 53

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-meth oxyethyl)-1,3,5-triazinane-2,4-dion (I-0807)

To a mixture of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-meth oxyethyl)-1,3,5-triazinane-2,4-dion (340 mg, 0.658 mmol), methanol (2 mL) and THF (2 mL) was added 1 mol/L lithium hydroxide (2 mL), and the resulting mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added 10% aqueous citric acid, extracted with ethyl acetate. The extract was washed, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by dichloromethane and hexane to give (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-methoxyethyl)-1,3,5-triazinane-2,4-dion (243 mg, Yield: 74%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (6H, d, J=5.6 Hz), 2.11 (3H, s), 3.25 (3H, s), 3.94-4.05 (3H, m), 4.55 (1H, sept, J=5.9 Hz), 5.27 (2H, s), 6.93 (1H, d, J=8.0 Hz), 7.04-7.07 (2H, m), 7.33 (2H, d, J=8.0 Hz), 7.45 (2H, d, J=8.0 Hz), 9.20 (1H, s), 12.89 (1H, brs).

Example 54

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-hydroxyethyl)-1,3,5-triazinane-2,4-dion (I-0852)

To a solution of sodium iodide (119 mg, 0.795 mmol) in acetonitrile (3.2 mL) were added chlorotrimethylsilane (0.102 mL, 0.795 mmol) and (S)-1-(4-chlorobenzyl)-6 (3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-meth oxyethyl)-1,3,5-triazinane-2,4-dion (80 mg, 0.16 mmol), and the resulting mixture was heated at reflux for 4 hours. The reaction mixture was added to 10% aqueous sodium hydrogensulfate, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-hydroxyethyl)-1,3,5-triazinane-2,4-dion (23 mg, Yield: 30%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (6H, d, J=5.6 Hz), 2.11 (3H, s), 3.93-3.95 (2H, m), 4.24-4.28 (1H, m), 4.55 (1H, sept, J=5.9 Hz), 5.27 (2H, s), 6.93 (1H, d, J=8.0 Hz), 7.04-7.07 (2H, m), 7.34 (2H, d, J=8.0 Hz), 7.45 (2H, d, J=8.0 Hz), 9.15 (1H, s), 12.57 (1H, brs).

Example 55

Preparation of (S)-1-(4-chlorobenzyl)-6-(3 methyl-4-isopropoxyphenylimino)-3-[2-methoxycarbonyl-2-(methoxy-methyloxy)ethyl]-1,3,5-triazinane-2,4-dion (I-0993)

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (440 mg, 1.48 mmol), di-2-methoxyethylazodicarboxylate (485 mg, 2.07 mmol), triphenylphosphine (775 mg, 2.96 mmol) and dioxane (9 mL) was gradually added (S)-3-hydroxy-2-methoxy-methyloxypropanoic acid methyl (291 mg, 1.77 mmol), and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-6-(ethylthio)-3-[2-methoxycarbonyl-2-(methoxymethyloxy)ethyl]-1,3,5-triazine-2,4(1H,3H)-dion (650 mg. Yield: 99%) as colorless oil.

1H-NMR (δ ppm TMS/DMSO-d6): 1.26 (3H, t, J=7.6 Hz), 3.07-3.15 (5H, m), 3.63 (3H, s), 4.01-4.21 (2H, m), 4.38-4.4.42 (1H, m), 4.58 (2H, s), 5.09 (2H, s), 7.33 (2H, d, J=8.0 Hz), 7.44 (2H, d, J=8.0 Hz).

A mixture of (S)-1-(4-chlorobenzyl)-6-(ethylthio)-3-[2-methoxycarbonyl-2-(methoxymethyloxy)ethyl]-1,3,5-triazine-2,4(1H,3H)-dion (650 mg, 1.46 mmol), 3-methyl-4-isopropoxyaniline (363 mg, 2.20 mmol), acetic acid (1.26 mL) and t-butanol (6.5 mL) was heated at reflux for 6 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-[2-methoxycarbonyl-2-(methoxymethyloxy)ethyl]1,3,5-triazinane-2,4-dion (590 mg, Yield: 74%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.6 Hz), 2.11 (3H, s), 3.17 (3H, s), 3.59 (3H, s), 3.97-4.12 (2H, m), 4.34-4.40 (1H, m), 4.56 (3H, s), 5.26 (2H, s), 6.95 (1H, d, J=8.0 Hz), 7.04 (2H, brs), 7.35 (2H, d, J=8.0 Hz), 7.46 (2H, d, J=8.0 Hz), 9.25 (1H, s).

Example 56

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-hydr oxyethyl)-1,3,5-triazinane-2,4-dion (I-0994)

A mixture of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-[2-methoxycarbonyl-2-(methoxymethyloxy)ethyl]-1,3,5-triazinane-2,4-dion (585 mg, 1.07 mmol) and 4 mol/L hydrogen chloride in dioxane (6 mL), and the resulting mixture was stirred at room temperature for minutes. The reaction mixture was added to saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo to give (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-hydr oxyethyl)-1,3,5-triazinane-2,4-dion (537 mg, Yield: 100%) as pale purple solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.6 Hz), 2.11 (3H, s), 3.53 (3H, s), 3.94-3.96 (2H, m), 4.27-4.30 (1H, m), 4.54-4.57 (1H, m), 5.26 (2H, s), 5.72-5.79 (1H, m), 6.94 (1H, d, J=8.0 Hz), 7.04-7.07 (2H, m), 7.35 (2H, d, J=8.0 Hz), 7.46 (2H, d, J=8.0 Hz), 9.20 (1H, s).

Example 57

Preparation of 1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-oxoethyl)-1,3,5-triazinane-2,4-dion (I-0996)

To a solution of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-hydr oxyethyl)-1,3,5-triazinane-2,4-dion (150 mg, 0.298 mmol) in dichloromethane (6 mL) was added 0.3 mol/L Dess-Martin reagent in dichloromethane (1.19 mL, 0.358 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added 10% aqueous sodium hydrogensulfate and saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 50-80%), to give 1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-oxoethyl)-1,3,5-triazinane-2,4-dion (17 mg, Yield: 11%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.6 Hz), 2.12 (3H, s), 3.81 (3H, s), 4.54-4.57 (1H, m), 5.03 (2H, s), 5.28 (2H, s), 6.94 (1H, d, J=8.0 Hz), 7.05 (2H, brs), 7.35 (2H, d, J=8.0 Hz), 7.47 (2H, d, J=8.0 Hz), 9.37 (1H, s).

Example 58

Preparation of 1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-oxoethyl)-1,3,5-triazinane-2,4-dion (I-1009)

To a mixture of 1-(4-chlorobenzyl)-6-(3-methyl-4 isopropoxyphenylimino)-3-(2-methoxycarbonyl-2-oxoethyl)-1,3,5-triazinane-2,4-dion (15 mg, 0.030 mmol), methanol (0.3 mL) and THF (0.3 mL) was added 1 mol/L lithium hydroxide (0.09 mL), and the resulting mixture was stirred at 50° C. for 3 hours. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by dichloromethane and hexane to give 1-(4-chlorobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonyl-2-oxoethyl)-1,3,5-triazinane-2,4-dion (5 mg. Yield: 34%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.27 (6H, d, J=5.6 Hz), 2.11 (3H, s), 4.53-4.57 (1H, m), 4.98 (2H, s), 5.28 (2H, s), 6.94 (1H, d, J=8.0 Hz), 7.05 (2H, brs), 7.35 (2H, d, J=8.0 Hz), 7.47 (2H, d, J=8.0 Hz), 9.35 (1H, s).

Example 59

Preparation of (S)-1-(4-methylbenzyl)-6-(3-vinyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0907)

A mixture of (S)-1-(4-methylbenzyl)-6-(3-bromo-4 isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (350 mg, 0.642 mmol), vinyl boronic acid pinacol ester (0.163 mL, 0.963 mmol), dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (42 mg, 0.064 mmol), THF (7 mL), and 2 mol/L aqueous potassium carbonate (1.28 mL) was heated at reflux for 40 minutes. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-methylbenzyl)-6-(3-vinyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (302 mg, Yield: 96%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04-1.07 (3H, m), 1.27 (6H, d, J=5.6 Hz), 2.28 (3H, s), 2.80-2.83 (1H, m), 3.49 (3H, s), 3.78-3.97 (2H, m), 4.58-4.61 (1H, m), 5.24-5.28 (3H, m), 5.70 (1H, d, J=16.0 Hz), 6.90-7.04 (2H, m), 7.20 (5H, s), 7.39 (1H, s), 9.24 (1H, s).

Example 60

Preparation of (S)-1-(4-methylbenzyl)-6-(3-vinyl-4-isopropoxyphenylimino)-3 (2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0910)

To a mixture of (S)-1-(4-methylbenzyl)-6-(3-vinyl-4 isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (85 mg, 0.17 mmol), methanol (0.6 mL) and THF (0.6 mL) was added 1 mol/L lithium hydroxide (0.52 mL), and the resulting mixture was stirred at room temperature for 3 days. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-methylbenzyl)-6-(3-vinyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (59 mg, Yield: 71%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04-1.07 (3H, m), 1.27 (6H, d, J=5.6 Hz), 2.28 (3H, s), 2.80-2.83 (1H, m), 3.78-3.97 (2H, m), 4.58-4.61 (1H, m), 5.24-5.28 (3H, m), 5.70 (1H, d, J=16.0 Hz), 6.90-7.04 (2H, m), 7.20-7.38 (5H, m), 7.47 (1H, s), 9.24 (1H, brs).

Example 61

Preparation of (S)-1-(4-methylbenzyl)-6-(3-ethyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0908)

A solution of (S)-1-(4-methylbenzyl)-6-(3-vinyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl) 1,3,5-triazinane-2,4-dion (200 mg, 0.406 mmol) in methanol (20 mL) was hydrogenated under 5% Pt/C. The reaction mixture was concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-methylbenzyl)-6-(3-ethyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (188 mg, Yield: 94%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.03-1.12 (6H, m), 1.27 (6H, d, J=5.6 Hz), 2.28 (3H, s), 2.50-2.53 (2H, m), 2.80-2.83 (1H, m), 3.56 (3H, s), 3.78-3.96 (2H, m), 4.56-4.58 (1H, m), 5.20 (2H, m), 6.93-7.11 (3H, m), 7.20 (4H, s), 9.16 (1H, s).

Example 62

Preparation of (S)-1 (4-methylbenzyl)-6-(3-ethyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0911)

To a mixture of (S)-1-(4-methylbenzyl)-6-(3-ethyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (160 mg, 0.324 mmol), methanol (1 mL) and THF (1 mL) was added 1 mol/L lithium hydroxide (1 mL), and the resulting mixture was stirred at 60° C. for 1 hour. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-methylbenzyl)-6-(3-ethyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (122 mg, Yield: 79%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.01 (3H, d, J=6.8 Hz), 1.10 (311, t, J=7.6 Hz), 1.27 (6H, d, J=5.6 Hz), 2.28 (3H, a), 2.50-2.53 (2H, m), 2.80-2.83 (1H, m), 3.78-3.96 (2H, m), 4.56-4.58 (1H, m), 5.24 (2H, m), 6.81-7.19 (3H, m), 7.28 (4H, s), 9.11 (1H, s), 12.30 (1H, brs).

Example 63

Preparation of (S)-1-(4-vinylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0892)

To a mixture of (S)-1-(4-bromobenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (300 mg, 0.550 mmol), vinyl boronic acid pinacol ester (0.140 mL, 0.825 mmol), dichloro[1,1′-bis(di-tert-butylphosphino)ferrocene]palladium(II) (36 mg, 0.055 mmol), THF (6 mL) and 2 mol/L aqueous potassium carbonate (1.10 mL) was heated at reflux for 1 hour. To the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-vinylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (256 mg, Yield: 95%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04 (311, d, J=6.8 Hz), 1.27 (6H, d, J=5.6 Hz), 2.11 (3H, s), 2.80-2.83 (1H, m), 3.49 (3H, s), 3.79-3.96 (2H, m), 4.53-4.56 (1H, m), 5.24-5.27 (3H, m), 5.83 (1H, d, J=16.0 Hz), 6.69-6.76 (1H, m), 6.93 (1H, d, J=8.0 Hz), 7.05-7.07 (2H, m), 7.28 (2H, d, J=8.0 Hz), 7.49 (2H, d, J=8.0 Hz), 9.19 (1H, s).

Example 64

Preparation of (S)-1-(4-vinylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0897)

A mixture of (S)-1-(4-vinylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (50 mg, 0.10 mmol), methanol (0.4 mL) and THF (0.4 mL) was added 1 mol/L lithium hydroxide (0.3 mL), and the resulting mixture was stirred at room temperature 6 hours. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-vinylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (36 mg, Yield: 74%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.01 (3H, d, J=6.8 Hz), 1.26 (6H, d, J=5.6 Hz), 2.10 (3H, s), 2.76-2.80 (1H, m), 3.78-3.97 (2H, m), 4.50-4.55 (1H, m), 5.24-5.27 (3H, m), 5.83 (1H, d, J=16.0 Hz), 6.69-6.76 (1H, m), 6.93 (1H, d, J=8.0 Hz), 7.04-7.07 (2H, m), 7.28 (2H, d, J=8.0 Hz), 7.49 (2H, d, J=8.0 Hz), 9.14 (1H, s), 12.29 (1H, brs).

Example 65

Preparation of (S)-1-(4-ethylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0894)

A solution of (S)-1-(4-vinylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (190 mg, 0.386 mmol) in methanol (19 mL) was hydrogenated under 5% Pt/C. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-ethylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (99 mg, Yield: 52%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04 (3H, d, J=6.8 Hz), 1.16 (3H, t, J=7.6 Hz), 1.27 (6H, d, J=5.6 Hz), 2.11 (3H, s), 2.58 (2H, q. J=7.6 Hz), 2.79-2.84 (1H, m), 3.47 (3H, s), 3.78-3.96 (2H, m), 4.53-4.57 (1H, m), 5.23 (2H, s), 6.93 (1H, d, J=8.0 Hz), 7.05-7.08 (2H, m), 7.22 (4H, s), 9.18 (1H, s).

Example 66

Preparation of (S)-1-(4-ethylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-0898)

To a mixture of (S)-1-(4-ethylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (94 mg, 0.19 mmol), methanol (1 mL) and THF (1 mL) was added 1 mol/L lithium hydroxide (0.57 mL), and the resulting mixture was stirred at 60° C. for 3 hours. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-ethylbenzyl)-6-(3-methyl-4-isopropoxyphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (78 mg, Yield: 85%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.01 (3H, d, J=6.8 Hz), 1.16 (3H, t, J=7.6 Hz), 1.26 (6H, d, J=5.6 Hz), 2.10 (3H, s), 2.58 (2H, q, J=7.6 Hz), 2.79-2.84 (1H, m), 3.74-3.97 (2H, m), 4.53-4.57 (1H, m), 5.24 (2H, s), 6.92 (1H, d, J=8.0 Hz), 7.05-7.08 (2H, m), 7.22 (4H, s), 9.12 (1H, s), 12.31 (1H, brs).

Example 67

Preparation of 1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-(1-hydroxymethyl-3-oxacyclobutyl)methyl-1,3,5-triazinane-2,4-dion (I-1010)

To a solution of 2-(t-butyl-diphenylsilyloxymethyl)-2-hydroxymethyl-propane-1,3-diol (441 mg, 1.18 mmol) in THF (9 mL) were added 1.67 mol/L n-butyllithium/n-hexane solution (1.55 mL, 2.59 mmol) and p-toluenesulfonyl chloride (247 mg, 1.30 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 20 hours. To the reaction mixture was added water, and the resulting mixture was extracted with diethyl ether. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(t-butyl-diphenylsilyloxymethyl)-1-hydroxymethyl-3-oxacylcobutane (148 mg, Yield: 35%) as colorless oil.

1H-NMR (δ ppm TMS/DMSO-d6): 1.01 (9H, s), 3.67 (2H, d, J=4.8 Hz), 3.80 (2H, s), 4.33-4.36 (4H, m), 4.90-4.93 (1H, m), 7.42-7.47 (6H, m), 7.63 (4H, d, J=6.8 Hz).

To a mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-1,3,5-triazine-2,4(1H,3H)-dion (150 mg, 0.504 mmol), 1-(t-butyl-diphenylsilylocxymethyl)-1-hydroxymethyl-3-oxacyclobutane (198 mg, 0.554 mmol), triphenylphosphine (198 mg, 0.756 mmol) and dioxane (2 mL) was added di-2-methoxyethylazodicarboxylate (165 mg, 0.705 mmol), and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water, extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(ethylthio)-3-[1-(t-butyly-diphenylsilyloxymethyl)-3-oxacyclobutyl]methyl-1,3,5-triazine-2,4(1H,3H)-dion (273 mg, Yield: 85%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 0.99 (9.0H, s), 1.26 (3.0H, t, J=7.2 Hz), 3.11 (2.0H, q, J=7.2 Hz), 3.86 (2.0H, s), 4.11 (2.0H, s), 4.20 (2.0H, d, J=6.1 Hz), 4.47 (2.0H, d, J=6.1 Hz), 5.06 (2.0H, s), 7.32-7.37 (4.0H, m), 7.41-7.47 (6.0H, m), 7.61 (4.0H, d, J=7.3 Hz).

A mixture of 1-(4-chlorobenzyl)-6-(ethylthio)-3-[1-(t-butyl-diphenylsilyloxymethyl)-3-oxacylobutyl]methyl-1,3,5-triazine-2,4(1H,3H)-dion (273 mg, 0.429 mmol), 3-chloro-4-isopropoxyaniline (119 mg, 0.644 mmol), acetic acid (0.368 mL) and t-butanol (3 mL) was heated at reflux for 7 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-[1-(t-butyl-diphenylsilyloxymethyl)-3-oxacylobutyl]methyl-1,3,5-triazinane-2,4-dion (248 mg, Yield: 76%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.00 (9H, s), 1.29 (6H, d, J=5.8 Hz), 3.83 (2H, s), 4.05 (2H, s), 4.19 (2H, d, J=6.1 Hz), 4.44 (2H, d, J=6.1 Hz), 4.57-4.66 (1H, m), 5.22 (2H, s), 7.10-7.50 (13H, m), 7.61 (4H, d, J=7.1 Hz), 9.35 (1H, brs).

To a solution of 1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-[1-(t-butyl-diphenylsilyloxymethyl)-3-oxacylobutyl]methyl-1,3,5-triazinane-2,4-dion (240 mg, 0.316 mmol) in THF (3 mL) was added a solution of 1 mol/L tetra-n-butylammonium fluoride in THF (0.88 mL, 0.88 mmol), and the resulting mixture was stirred at 45° C. for 3 hours. The reaction mixture was added to aqueous ammonium chloride, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-(1-hydroxymethyl-3-oxacyclobutyl)methyl-1,3,5-triazinane-2,4-dion (120 mg, Yield: 73%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.29 (6H, d, J=5.8 Hz), 3.61 (2H, d, J=4.5 Hz), 3.95 (2H, s), 4.18 (2H, d, J=6.1 Hz), 4.40 (2H, d, J=6.1 Hz), 4.60-4.62 (1H, m), 4.93-4.95 (1H, m), 5.22 (2H, s), 7.12-7.44 (7H, m).

Example 68

Preparation of 1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-(1-hydroxycarbonyl-3-oxacyclobutyl)methyl-1,3,5-triazinane-2,4-dion (I-1011)

To a solution of 1-(4-chlorobenzyl)-6-(3-chloro-4-isopropoxyphenylimino)-3-(1-hydroxymethyl-3-oxacyclobutyl)methyl-1,3,5-triazinane-2,4-dion (50 mg, 0.096 mmol) in acetone (0.8 mL) was added 2.67 mol/L Jones reagent (0.079 mL, 0.21 mmol), and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture were added isopropanol and water, and the resulting mixture was extracted with ethyl acetate. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give 1-(4-chlorobenzyl)-6 (3-chloro-4-isopropoxyphenylimino)-3-(1-hydroxycarbonyl-3-oxacyclobutyl)methyl-1,3,5-triazinane-2,4-dion (8 mg, Yield: 16%) as colorless solid.

1H-NMR (δ ppm TMS/CDCl3): 1.36 (6H, d, J=6.0 Hz), 4.43 (2H, s), 4.44-4.52 (1H, m), 4.67 (2H, d, J=6.7 Hz), 4.76 (2H, d, J=6.7 Hz), 5.16 (2H, s), 6.65-6.67 (1H, m), 6.86-6.90 (2H, m), 7.31 (2H, d, J=8.4 Hz), 7.41 (2H, d, J=8.4 Hz).

Example 69

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-cyclopropylethynylphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-1041)

A mixture of (S)-1-(4-chlorobenzyl)-6-(4-iodo-3-methylphenylimino)-3-(2-methoxycarbonylpropyl) 1,3,5-triazinane-2,4-dion (268 mg, 0.471 mmol), ethynylcyclopropane (0.080 mL, 0.94 mmol), bis(triphenylphosphine)palladium (II) dichloride (8.3 mg, 0.012 mmol), cuprous iodide (1) (4.5 mg, 0.024 mmol), triethylamine (0.131 mL, 0.942 mmol) and DMF (3 mL) was stirred at 60° C. for 2 hours. To the reaction mixture was added 5% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-cyclopropylethynylphenylimino)-3-(2-methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (200 mg, Yield: 84%) as brown solid.

1H-NMR (δ ppm TMS/CDCl3): 0.75-0.95 (4H, m), 1.18 (3H, d, J=6.9 Hz), 1.49 (1H, m), 2.37 (3H, s), 2.89 (1H, m), 3.60 (3H, s), 3.87 (1H, dd, J=6.0, 13.8 Hz), 4.09 (1H, m), 5.10-5.24 (2H, m), 6.57 (1H, m), 6.63 (1H, m), 7.26-7.36 (4H, m), 7.48 (2H, d, J=8.4 Hz).

Example 70

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-cyclopropylethynylphenylimino)-3-(2-hydroxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (I-1042)

To a mixture of (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-cycloropylethynylphenylimino)-3-(2 methoxycarbonylpropyl)-1,3,5-triazinane-2,4-dion (180 mg, 0.355 mmol), methanol (1 mL) and THF (1 mL) was added 1 mol/L sodium hydroxide (1.1 mL), and the resulting mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-chlorobenzyl)-6-(3-methyl-4-cyclopropylethynylphenylimino)-3-(2-hydroxycarbonyl propyl)-1,3,5-triazinane-2,4-dion (78 mg, Yield: 85%) as pale brown solid.

1H-NMR (δ ppm TMS/CDCl3): 0.75-0.95 (4H, m), 1.19 (3H, d, J=6.9 Hz), 1.48 (1H, m), 2.35 (3H, s), 2.92 (1H, m), 3.87 (1H, dd, J=6.3, 13.5 Hz), 4.10 (1H, dd, J=7.2, 13.2 Hz), 5.16 (2H, s), 6.55 (1H, m), 6.61 (1H, s), 7.24-7.34 (311, min), 7.44 (2H, d, J=8.4 Hz), 7.66 (1H, s).

Example 71

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyiminoethylphenylimino)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (I-0881)

A mixture of (S)-1-(4-chlorobenzyl)-6-(ethylthio)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (1.00 g, 2.51 mmol), 2,4-dimethoxybenzylamine (630 mg, 3.77 mmol), acetic acid (2.16 mL) and t-butanol (20 mL) was heated at reflux for 15 hours. The reaction mixture was added to saturated aqueous sodium bicarbonate, and the resulting mixture was extracted with ethyl acetate. The extract was washed by 2 mol/L hydrochloric acid and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-6-(2,4-dimethoxybenzylimino)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (1.19 g, Yield: 94%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04 (3H, d, J=6.8 Hz), 2.82 (1H, q, J=6.8 Hz), 3.48 (3H, s), 3.72 (6H, s), 3.77-3.82 (1H, m), 3.90-3.95 (1H, m), 4.37 (2H, s), 5.15 (2H, s), 6.35 (1H, d, J=8.4 Hz), 6.51 (1H, s), 6.73 (1H, d, J=8.4 Hz), 7.27 (2H, d, J=7.6 Hz), 7.44 (2H, d, J=7.6 Hz), 7.94 (1H, brs).

A solution of (S)-1-(4-chlorobenzyl)-6-(2,4-dimethoxy-benzylimino)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (1.15 g, 2.29 mmol) in trifluoro acetic acid (1 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo, and the residue was extracted with chloroform. The extract was washed by saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-6-amino-1-(4-chlorobenzyl)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (0.80 g, Yield: 99%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04 (3H, d, J=6.8 Hz), 2.81 (1H, q, J=6.8 Hz), 3.49 (3H, s), 3.74-3.81 (1H, m), 3.89-3.94 (1H, m), 5.03 (2H, s), 7.27 (2H, d, J=7.6 Hz), 7.43 (2H, d, J=7.6 Hz), 7.86 (2H, brs).

A mixture of (S)-6-amino-1-(4-chlorobenzyl)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazine-2,4(1H,3H)-dion (80 mg, 0.35 mmol), 3-fluoro-4-methoxyiminomethylaniline (146 mg, 0.414 mmol), acetic acid palladium (7.7 mg, 0.034 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-xanthene (30 mg, 0.052 mmol), cesium carbonate (157 mg, 0.483 mmol) and dioxane (2.4 mL) was heated at reflux for 24 hours. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate and THF. The extract was washed by brine, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-1-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyiminomethylphenylimino)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (53 mg, Yield: 31%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.07 (3H, d, J=6.8 Hz), 2.81 (1H, q, J=6.8 Hz), 3.50 (3H, s), 3.83 (1H, brs), 3.90 (4H, brs), 5.09 (2H, s), 6.65-6.69 (1H, m), 7.41 (5H, brs), 7.63 (1H, brs), 8.25 (1H, s), 10.97 (1H, brs).

Example 72

Preparation of (S)-1-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyiminomethylphenylimino)-3-(2-hydroxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (I-0893)

To a mixture of (S)-1-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyiminomethylphenylimino)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (50 mg, 0.099 mmol), methanol (1 mL) and THF (1 mL) was added 1 mol/L lithium hydroxide (0.3 mL), and the resulting mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-1-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyiminomethylphenylimino)-3-(2-hydroxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (44 mg, Yield: 91%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.04 (3H, d, J=6.8 Hz), 2.76 (1H, q, J=6.8 Hz), 3.81 (1H, brs), 3.90 (4H, brs), 5.12 (2H, s), 6.67 (1H, brs), 7.40 (5H, s), 7.65 (1H, brs), 8.24 (1H, s), 10.92 (1H, brs), 12.36 (1H, brs).

Example 73

Preparation of (S)-6-(3-chloro-4-isopropoxyphenylimino)-1-(4-methoxybenzyl)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (I-1143)

A mixture of (S)-6-(3-chloro-4-isopropoxyphenylimino)-1-(4-chlorobenzyl)-3 (2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (800 mg, 1.53 mmol) in methanol (75 mL) and DMF (5 mL) was hydrogenated under 10% Pd/C. The reaction mixture was concentrated in vacuo, The resulting residue was purified by high speed liquid chromatography (0.3% HCO₂H H₂O/MeCN 40-70%) to give (S)-6-(3-chloro-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (498 mg, Yield: 82%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.05 (3H, d, J=6.8 Hz), 1.29 (6H, d, J=5.6 Hz), 2.81 (1H, q, J=6.8 Hz), 3.56 (3H, s), 3.77-3.82 (1H, m), 3.87-3.92 (1H, m), 4.62 (1H, sept, J=5.6 Hz), 7.16 (1H, d, J=8.4 Hz), 7.34 (1H, d, J=8.4 Hz), 7.69 (1H, s), 8.14 (1H, s).

To a mixture of (S)-6-(3-chloro-4-isopropoxyphenylimino)-3-(2-methoxycarbonylpropyl)methyl 1,3,5-triazinane-2,4-dion (480 mg, 1.21 mmol), 4-methoxybenzyl chloride (341 mg, 2.18 mmol) and DMF (10 mL) was added potassium carbonate (301 mg, 2.18 mmol), and the resulting mixture was stirred at room temperature 12 hours. To the reaction mixture was added water, extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (S)-6-(3-chloro-4-isopropoxy phenylimino)-1-(4-methoxybenzyl)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (190 mg, Yield: 30%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.05 (311, d, J=6.8 Hz), 1.29 (6H, d, J=5.6 Hz), 2.81 (1H, q, J=6.8 Hz), 3.49 (3H, s), 3.73 (3H, s), 3.77-3.82 (1H, m), 3.87-3.92 (1H, m), 4.64 (1H, sept, J=5.6 Hz), 5.20 (2H, s), 6.94 (2H, d, J=7.2 Hz), 7.16-7.28 (4H, m), 7.47 (1H, s), 9.28 (1H, s).

Example 74

Preparation of (S)-6-(3-chloro-4-isopropoxyphenylimino)-1-(4-methoxybenzyl)-3-(2-hydroxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (I-1159)

To a mixture of (S)-6-(3-chloro-4-isopropoxyphenylimino)-1-(4-methoxybenzyl)-3-(2-methoxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (180 mg, 0.348 mmol), methanol (2 mL) and THF (2 mL) was added 1 mol/L lithium hydroxide (1 mL), and the resulting mixture was stirred at 50° C. for 5 hours. To the reaction mixture was added 10% aqueous citric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed by water, dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by ethyl acetate and hexane to give (S)-6-(3-chloro-4-isopropoxyphenylimino)-1-(4-methoxybenzyl)-3-(2-hydroxycarbonylpropyl)methyl-1,3,5-triazinane-2,4-dion (160 mg, Yield: 91%) as colorless solid.

1H-NMR (δ ppm TMS/DMSO-d6): 1.02 (3H, d, J=6.8 Hz), 1.29 (6H, d, J=5.6 Hz), 2.76 (1H, q, J=6.8 Hz), 3.73 (3H, s), 3.77-3.82 (1H, m), 3.87-3.92 (1H, m), 4.63 (1H, sept, J=5.6 Hz), 5.21 (2H, s), 6.93 (2H, d, J=7.2 Hz), 7.15-7.28 (4H, m), 7.47 (1H, s), 9.23 (1H, s), 12.33 (1H, brs).

Example 75

Preparation of 6-(4-chlorobenzyloxy)-4-(3-fluoro-4-isopropoxyphenylimino)-1-t-butyl-1,3,5-triazine-2(1H)-one (I-1296)

To a mixture of 6-(ethylthio)-3-t-butyl-1,3,5-triazine-2,4(1H,3H)-dion (1.0 g, 4.4 mmol), 4-chlorobenzyl alcohol (1.02 g, 4.4 mmol), triphenylphosphine (1.49 g, 5.7 mmol) and THF (10 mL) was gradually added di-2-methoxyethylazodicarboxylate (1.33 g, 5.7 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was water (200 mL), and the resulting mixture was extracted with ethyl acetate (200 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give crude 6-(4-chlorobenzyloxy)-4-ethylthio-1-t-butyl-1,3,5-triazine-2(1H)-one. To the obtained crude product were added 3-fluoro-4-isopropoxyaniline (0.18 g, 1.09 mmol) and acetic acid (10 mL), and the resulting mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added saturated aqueous sodium bicarbonate (200 ml), and the resulting mixture was extracted with ethyl acetate (300 mL). The extract was washed by brine (200 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting residue was precipitated by ethyl acetate and hexane to give 6-(4-chlorobenzyloxy)-4-(3-fluoro-4-isopropoxyphenylimino)-1-t-butyl-1,3,5-triazine-2(1H)-one (0.12 g, Yield: 6%) as a white powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.35 (6H, d, J=6.1 Hz), 1.66 (9H, s), 4.48 (1H, sept, J=6.1 Hz), 5.37 (2H, s), 6.93 (1H, m), 7.26-7.43 (7H, m).

Example 76

Preparation of 1-(4-chlorobenzyl)-3-isopropyl-5-(4-trifluoromethylbenzyl)-1,3,5-triazine-2,4,6-trione (I-1289)

To a mixture of 1-(4-chlorobenzyl)-6-(methylthio)-3 isopropyl-1,3,5-triazine-2,4(1H,3H)-dion (0.2 g, 0.6 mmol) and acetic acid (10 mL) was added 30% hydrogen peroxide solution (0.7 g, 6 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 18 hours. To the reaction mixture was added brine (30 mL), and the resulting mixture was extracted with dichloromethane (30 mL×2). The extract was washed by brine (30 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was precipitated by hexane to give 1-(4-chlorobenzyl)-3-isopropyl-1,3,5-triazine-2,4,6-trione (0.2 g) as a white powder.

1H-NMR (δ ppm TMS/DMSO-d6): 1.35 (6H, d, J=6.9 Hz), 4.81 (1H, q, J=6.9 Hz), 4.84 (2H, s), 7.36 (4H, d, J=8.7 Hz), 11.66 (1H, s).

To a mixture of 1-(4-chlorobenzyl)-3-isopropyl-1,3,5-triazine-2,4,6-trione (80 mg, 0.27 mmol), 4-trifluorbenzyl alcohol (52.4 mg, 0.3 mmol), triphenylphosphine (92 mg, 0.35 mmol) and THF (2 mL) was gradually added di-2-methoxyethylazodicarboxylate (82 mg, 0.35 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting residue was precipitated by hexane to give 1-(4-chlorobenzyl)-3-isopropyl-5-(4-trifluoromethylbenzyl)-1,3,5-triazine-2,4,6-trione (65 mg, Yield: 53%) as a white powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.45 (6H, d, J=6.9 Hz), 4.96 (1H, m), 4.98 (2H, s), 5.05 (2H, s), 7.26-7.32 (2H, m), 7.36-7.44 (2H, m), 7.52-7.62 (4H, m).

Example 77

Preparation of 1-(4-chlorobenzyl)-3-isopropyl-6-(4 isopropoxyphenylimino)-2-thioxo-1,3,5-triazinane-4-one (I-2253)

To a suspension of 1-(4-chlorobenzyl)-3-(4-isopropoxyphenyl)guanidine (500 mg, 1.57 mmol) in toluene (5.0 mL) was added 2-isocyanatepropane (0.187 mL, 1.89 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 17 hours. The resulting pale yellow solution was concentrated in vacuo, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-((4-chlorobenzylamino)(4-isopropoxyphenylamino)methylene)-3-isopropylurea (629 mg, Yield: 99%) as colorless gum.

The isopropylurea derivative (201 mg, 0.500 mmol) was dissolved in THF (2.2 mL). To the mixture was added thiophosgene (0.042 mL, 0.550 mmol), and the resulting mixture was heated at reflux for 16 hours. Further, potassium carbonate (152 mg, 1.10 mmol) was added to the mixture, and the resulting mixture was heated at reflux for 2.5 hours. To the resulting solution was added ethyl acetate (50 mL), and the resulting mixture was washed by water (20 mL×2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by reversed-phase HPLC (0.1% formic acid in acetonitrile/water) and silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-3-isopropyl-6-(4 isopropoxyphenylimino)-2-thioxo-1,3,5-triazinane-4-one (0.32 mg, Yield: 0.1%) as colorless oil.

1H-NMR (δ ppm TMS/CDCl3): 1.34 & 1.37 (d×2, 6H), 1.53 (d, 6H), 4.52-4.64 (m, 1H), 5.17 (s, 2H), 5.86-5.97 (m, 1H), 6.85 & 7.39 (s×2, 1H), 6.98 (d, 2H), 7.08 (d, 2H), 7.28 (d, 2H), 7.45 (d, 2H).

Example 78

Preparation of 1-(4-chlorobenzyl)-3-isopropyl-6-(4-isopropoxyphenylimino)-4-thioxo-1,3,5-triazinane-2-one (I-2254)

To a suspension of 1-(4-chlorobenzyl)-3-(4-isopropoxyphenyl)guanidine (654 mg, 2.06 mmol) in toluene (6.5 mL) was added isopropyl isocyanate (0.307 mL, 2.88 mmol) under ice-cooling, and the resulting mixture was stirred at room temperature for 18 hours, 60° C. for 2 hours, and 70° C. for 2.5 hours. The resulting mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-((4-chlorobenzylamino)(4-isopropoxyphenylamino)methylene)-3-isopropyl-thiourea (619 mg, Yield: 72%) as white solid.

The thiourea derivative (200 mg, 0.477 mmol) was dissolved in THF (2.0 mL), and carbonyldiimidazole (77 mg, 0.477 mmol) was added to the solution under ice-cooling. The resulting mixture was heated at reflux for 22 hours under nitrogen atmosphere. Further, carbonyldiimidazole (77 mg, 0.477 mmol) and triethylamine (0.066 mL, 0.477 mmol) were added to the mixture, and the resulting mixture was heated at reflux for 3.5 hours. To the mixture was added ethyl acetate (50 mL), and the resulting mixture was washed by water (20 mL×2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the resulting residue was precipitated by ethyl acetate/hexane to give aimed 1-(4-chlorobenzyl)-3-isopropyl-6-(4-isopropoxyphenylimino)-4-thioxo-1,3,5-triazinane-2-one (8.3 mg, Yield: 3.9%) as a white powder.

1H-NMR (δ ppm TMS/CDCl₃): 1.35 (d, 6H), 1.49 (d, 6H), 4.45-4.55 (m, 1H), 5.14 (s, 2H), 5.65-5.80 (m, 1H), 6.74 (d, 2H), 6.89 (d, 2H), 7.30 (d, 2H), 7.48 (d, 2H), 8.48 (br, s, 1H).

Example 79

Preparation of 1-(4-chlorobenzyl)-3-isopropyl-6-(4-ispropoxyphenylimino)-1,3,5-triazinane-2,4-dithione (I-2256)

In the similar manner as described the above, 1-((4-chlorobenzylamino) (4-isopropoxyphenylamino)methylene)-3-isopropylthiourea was synthesized. The thiourea derivative (199 mg, 0.475 mmol) was dissolved in THF (2.0 mL). To the colorless solution was added thiophosgene (0.040 mL, 0.522 mmol) under ice-cooling, and the resulting mixture was stirred for 2 hours in an ice-bath. To the resulting yellow solution was added ethyl acetate (50 mL), and washed by saturated aqueous sodium bicarbonate (20 mL×2), 5% aqueous citric acid (20 mL×2), and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The resulting residue was crystallized by ethyl acetate/hexane to give 1-(4-chlorobenzyl)-3-isopropyl-6-(4-isopropoxyphenylimino)-1,3,5-triazinane-2,4-dithione (14.8 mg; Yield 6.8%) as yellow crystalline.

1H-NMR (δ ppm TMS/CDCl3): 1.16 (d, 6H), 1.32 (d, 6H), 4.00 & 4.61 (br, s×2, 1H), 4.44-4.54 (m, 1H), 6.08 (s, 2H), 6.82 (d, 2H), 6.99 (d, 2H), 7.26 (d, 2H), 7.46 (d, 2H).

Example 80

Preparation of 1-(4-chlorobenzyl)-3-isopropyl-6-(3-chloro-4-isopropoxyphenylimino)-4-thioxo-1,3,5-triazinane-2-one (I-2257)

To a suspension of 6-(3-chloro-4-isopropoxyphenylamino)-1-(4-chlorobenzyl)-3-1,3,5-triazine-2,4-dion (95.4 mg, 0.206 mmol) in toluene (2.0 mL) was added Lawesson's reagent (666 mg, 1.65 mmol). The resulting mixture was heated at reflux for 10 hours. To the resulting yellow suspension was added ethyl acetate, and the insoluble are filtered off by using Celite. The filtrate (about 100 mL) was washed by saturated aqueous sodium bicarbonate (30 mL×2) and brine (15 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane). The residue was crystallized by hot hexane to give 1-(4-chlorobenzyl)-3-isopropyl-6-(3-chloro-4-isopropoxyphenylimino)-4-thioxo-1,3,5-triazinane-2-one (73.7 mg, Yield: 75%) as white solid.

1H-NMR (δ ppm TMS/CDCl3): 1.39 (d, 6H), 1.50 (d, 6H), 4.43-4.57 (m, 1H), 5.12 (s, 2H), 5.65-5.81 (m, 1H), 6.66 (dd, 1H), 6.89 (d, 1H), 6.95 (d, 1H), 7.31 (d, 1H), 7.47 (d, 1H), 8.41 (br, s, 1H).

Example 81

Preparation of 1-(4-chlorobenzyl)-3-isopropyl-6-(3-chloro-4-isopropoxyphenylimino)-4-methylimino-1,3,5-triazinane-2-one (I-2259)

To a solution of 4-thiocarbonyl derivative (37.5 mg, 0.078 mmol) in acetone (0.8 mL) was added methyl iodide (0.0073 mL, 0.117 mmol), and resulting mixture was heated at reflux for 15 hours. Methyl iodide and solvate were removed under reduced pressure, and methanol (0.36 mL) and 40% methylaminemethanol solution (0.04 mL, 0.391 mmol) were added to the residue. The resulting mixture was heated at reflux for 8.5 hours, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give aimed 1-(4-chlorobenzyl)-3-isopropyl-6-(3-chloro-4-isopropoxyphenylimino)-4-methylimino-1,3,5-triazinane-2-one (23.6 mg, Yield: 63%) as pale yellow oil.

1H-NMR (δ ppm TMS/CDCl₃): 1.35 (d, 6H), 1.47 (d, 6H), 2.90 (d, 3H), 4.45 (sept, 1H), 4.70 (br, s, 1H), 4.82 (sept, 1H), 5.20 (s, 2H), 6.88 (d, 1H), 7.00 (dd, 1H), 7.26 (d, 2H), 7.40 (d, 1H), 7.50 (d, 2H).

Example 82

Preparation of 1-(4-chlorobenzyl)-3-ethyl-6-[4-(5-methoxycarbonyl-3-pyridyloxy)phenylimino]-4-thioxo-1,3,5-triazinane-2-one (I-2262)

To a solution of 1-(4-chlorobenzyl)-3-ethyl-6-(ethylthio)-1,3,5-triazine-2,4-(1H, 3H)-dion (1.02 g, 3.13 mmol) in toluene (10 mL) was added Lawesson's reagent (2.53 g, 6.26 mmol), and the resulting mixture was stirred at reflux for 3 hours. To the resulting yellow suspension was added ethyl acetate (200 mL), and the resulting mixture was washed by water (100 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-3-ethyl-6-(ethylthio)-4-thioxo-3,4-dihydro-1,3,5-triazine-2(1H)-one (939 mg, Yield: 88%) as yellow solid.

4-Thioxo derivative (257 mg, 0.752 mmol) and 5-(-4-aminophenoxy)nicotinic acid methyl ester (257 mg, 1.05 mmol) were suspended in t-butanol (2.5 mL), and the suspension was heated at reflux for 5 hours. To the resulting reaction mixture was added ethyl acetate (60 mL), and the mixture was washed by saturated aqueous sodium bicarbonate (25 mL×2) and brine (15 mL). The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1-(4-chlorobenzyl)-3-ethyl-6-[4-(5-methoxycarbonyl-3-pyridyloxy)phenylimino]-4-thioxo-1,3,5-triazinane-2-one (258 mg, Yield: 66%) as white solid.

1H-NMR (δ ppm TMS/CDCl3): 1.30 (t, 3H), 3.94 (s, 3H), 4.35 (q, 2H), 5.19 (s, 2H), 6.87 (dt, 2H), 7.07 (dt, 2H), 7.32 (dt, 2H), 7.51 (dt, 2H), 7.85 (dd, 1H), 8.40 (br, s, 1H), 8.60 (d, 1H), 8.96 (d, 1H).

Example 83

Preparation of 1-(4-chlorobenzyl)-3-ethyl methylthio-6-[4-(5-methoxycarbonyl-3-pyridyloxy)phenylimino]-1,3,5-triazine-2-(1H)-one (I-2264)

Thiocarbonyl derivative (50 mg, 0.095 mmol) was suspended in acetone (1.0 mL), and methyl iodide (0.009 mL, 0.143 mmol) was added to the suspension. The mixture was stirred at room temperature for 15 hours and at 40° C. for 15 hours. To the reaction mixture was added ethyl acetate (30 mL). The organic layer was washed by saturated aqueous sodium bicarbonate (10 mL×2) and brine (10 mL), dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane), 1-(4-chlorobenzyl)-3-ethyl-4-methylthio-6-[4-(5-methoxycarbonyl-3-pyridyloxy)phenylimino]-1,3,5-triazine-2-(1H)-one (40.5 mg, Yield: 79%) as white solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.30 (t, 3H), 2.32 (s, 3H), 3.92 (s, 3H), 3.93 (q, 2H), 5.22 (s, 2H), 6.97 (d, 2H), 7.08 (d, 2H), 7.29 (d, 2H), 7.54 (d, 2H), 7.73-7.79 (m, 1H), 8.54 (d, 1H), 8.89 (s, 1H).

Example 84

Preparation of (E)-3-(4-chlorobenzyl)-4-(4-isopropoxyphenylimino)-1-isopropyl-3,4-dihydro-1,3,5-triazine-2(1H)-one (I-2276)

• (Reference: Tetrahedron Lett. 2004, 45, 7197-7199.)

To a solution of thiocarbonyl derivative (49.3 mg, 0.111 mmol) in methanol (1.0 mL) was added hydrogen peroxide urea (52.1 mg, 0.554 mmol), and the resulting mixture was stirred at room temperature for 5.5 hours. To the reaction mixture was added ethyl acetate (30 mL), and the mixture was washed by 5% aqueous citric acid (15 mL×2), saturated aqueous sodium bicarbonate (15 mL×2) and brine (10 mL). The organic layer was dried over anhydrous sodium sulphate, and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give (E)-3-(4-chlorobenzyl)-4-(4-isopropoxyphenylimino)-1-isopropyl-3,4-dihydro-1,3,5-triazine-2(1H)-one (31.6 mg, Yield: 69%) as brown solid.

1H-NMR (δ ppm TMS/CDCl₃): 1.32 (d, 6H, J=6.1 Hz), 1.37 (d, 6H, J=6.6 Hz), 4.44-4.50 (m, 1H), 4.66-4.72 (m, 1H), 5.21 (s, 2H), 6.84 (d, 2H, J=11.7 Hz), 6.91 (d, 2H, J=6.6 Hz), 7.28 (d, 2H, J=8.1 Hz), 7.55 (d, 2H, J=8.1 Hz), 7.61 (s, 1H).

Example 85

Preparation of 2-methyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dion

To a mixture of methylamine hydrochloride (276 g, 4.09 mol) and DMA (2 L) was added DBU (679 mL, 4.50 mol) at 10° C. over 4 minutes. Then, 1,1′-carbonyldiimidazole (730 g, 4.50 mol) was added to the mixture at 20° C., and the resulting mixture was stirred at 0° C. for 2 hours. To the reaction mixture was added 1-amidinopyrazole-hydrochloride (500 g, 3.41 mol) at −5° C. over 3 minutes. Then. DBU (540 mL, 3.58 mol) was added to the mixture at 10° C. over 25 minutes, and the resulting mixture was stirred at 45° C. for 7.5 hours. Further, to the reaction mixture was added 1,1′-carbonyldiimidazole (830 g, 5.11 mol), and DBU (771 mL, 5.11 mol) was added to the mixture at 6° C. over 2 hours. The resulting mixture was stirred at 0° C. for 40 minutes. To the reaction mixture was added 2.8 mol/L hydrochloric acid (10 L) at 20° C. over 1 hour. The precipitated solid was filtered off to give 2-methyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dion (421 g, Yield: 64%) as pale brown powder.

1H-NMR (δ ppm TMS/DMSO-d6): 3.16 (3H, s), 6.71 (1H, dd, J=3.0, 1.5 Hz), 8.04 (1H, d, J=1.0 Hz), 8.57 (1H, d, =3.0 Hz).

Example 86

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

To the mixture of 1-amidinopyrazole-hydrochloride (58.6 g, 400 mmol), ethyl isocyanate (33.2 mL, 420 mmol) and DMA (240 ml) was added DBU (63.3 mL, 420 mmol) dropwise at −10° C. over 15 minutes, and the resulting mixture was stirred under ice-cooling for 30 minutes. To the reaction mixture was added 1,1′-carbonyldiimidazole (30 g, 600 mmol) under ice-cooling, and DBU (93 mL, 620 mmol) was added −5° C. over 30 minutes to the mixture. The resulting mixture was stirred under ice-cooling for 1 hour. Further, the mixture was stirred at room temperature for 1 hour. To the mixture was added 2 mol/L hydrochloric acid (1.16 L) at 20° C. over 1 hour. The precipitated solid was filtered off to give 2-ethyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dion (73.0 g, Yield: 88%) as pale 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).

Example 87

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

To a mixture of 2-ethyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dion (89 g, 480 mmol), 4-chlorobenzylbromide (108 g, 528 mmol) and DMA (400 mL) was added diisopropylethylamine (92 mL, 528 mmol) dropwise at room temperature over 10 minutes, and the mixture was stirred at 60° C. for 2 hours. To the reaction mixture was added water (800 mL) dropwise under ice-cooling for 40 minutes, and hexane (200 mL) was added to the mixture. The precipitated solid was filtered off to give 1-(4-chlorobenzyl)-2-ethyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dion (II-3, 156 g. Yield: 97.6%) as pale brown powder.

1H-NMR (δ ppm TMS/CDCl₃): 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).

Example 88

Preparation of 1-(4-chlorobenzyl)-6-[4-(3-cyanophenoxy)phenylimino]-3-ethyl-1,3,5-triazinane-2,4-dion (I-2305)

A mixture of 1-(4-chlorobenzyl)-2-ethyl-6-(1-pyrazolyl)-1,3,5-triazine-2,4(1H,3H)-dion (0.30 g, 0.9 mmol), 4-(3-cyanophenoxy)aniline (0.209 g, 1 mmol) and t-butanol (6 mL) was stirred at 90° C. for 15 hours. To the reaction mixture was added 50% ethyl acetate/hexane (6 mL), and the precipitated solid was filtered off to give 1-(4-chlorobenzyl)-6-[4-(3-cyanophenoxy)phenylimino]-3-ethyl-1,3,5-triazinane-2,4-dion (1-2305, 0.385 g, Yield: 89.8%) as pale brown powder.

1H-NMR (δ ppm TMS/CDCl3): 1.24 (3H, t, J=7.2 Hz), 3.91 (2H, q. J=7.2 Hz), 5.20 (2H, s), 6.84 (2H, d, J=8.7 Hz), 7.04 (2H, d, J=8.4 Hz), 7.2-7.46 (6H, m), 7.51 (2H, d, J=8.4 Hz).

The following compound of the invention and intermediate thereof were synthesized in a manner similar to those described in the above general procedures for the synthesis of the compound of the invention and Examples. The chemical structure of the compounds and the physical properties of them are described below.

(Method of Identification for the Compound)

LC/MS data of compound of the present invention were measured under any one of the following 2 conditions (Method 1 and 2), and a retention time and [M+H]+ are shown.

(Method 1)

Column: Luna C18(2) (5 μm, i.d. 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, and [B] is 0.1% formic acid-containing acetonitrile solution

Gradient: Linear gradient of 10% to 100% solvent [B] for 3 minutes was performed, and 100% solvent [B] was maintained for 1 minute.

(Method 2)

Column: Xbridge C18 (5 μm, i.d. 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, and [B] is 0.1% formic acid-containing acetonitrile solution

Gradient: Linear gradient of 10% to 100% solvent [B] for 3 minutes was performed, and 100% solvent [B] was maintained for 1 minute.

(Method 3)

Column: Shim-pack XR-ODS (2.2 μm, i.d. 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, and [B] is 0.1% formic acid-containing acetonitrile solution

Gradient: Linear gradient of 10% to 100% solvent [B] for 3 minutes was performed, and 100% solvent [B] was maintained for 1 minute.

(Method 4)

Column: Develo sil RPAq, (50×4.6 mm)

Flow rate: 1.5 mL/min

UV detection wavelength: 254 nm

Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, and [B] is 0.1% formic acid-containing acetonitrile solution

Gradient: 60% solvent [B] was maintained for 0.5 minute, linear gradient of 60% to 100% solvent [B] for 4.5 minutes was performed, and 100% solvent [B] was maintained for minutes.

(Method 5)

Column: ACQUITY UPLC (registered trademark) BEH C18 (1.7 μm, i.d. 2. 1×3.0 mm)

Flow rate: 0.8 mL/min

UV detection wavelength: 254 nm

Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, and [B] is 0.1% formic acid-containing acetonitrile solution

Gradient: Linear gradient of 10% to 100% solvent [B] for 3.5 minutes was performed, and 100% solvent [B] was maintained for 0.5 minute.

Lengthy table referenced here
US20130172317A1-20130704-T00001
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00002
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00003
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00004
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00005
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00006
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00007
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00008
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00009
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00010
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00011
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00012
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00013
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00014
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00015
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00016
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00017
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00018
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00019
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00020
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00021
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00022
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00023
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00024
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00025
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00026
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00027
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00028
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00029
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00030
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00031
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00032
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00033
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00034
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00035
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00036
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00037
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00038
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00039
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00040
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00041
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00042
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00043
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00044
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00045
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00046
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00047
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00048
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00049
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00050
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00051
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00052
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00053
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00054
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00055
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00056
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00057
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00058
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00059
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00060
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00061
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00062
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00063
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00064
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00065
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00066
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00067
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00068
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00069
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00070
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00071
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00072
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00073
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00074
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00075
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00076
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00077
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00078
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00079
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00080
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00081
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00082
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00083
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00084
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00085
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00086
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00087
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00088
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00089
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00090
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00091
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00092
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00093
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00094
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00095
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00096
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00097
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00098
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00099
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00100
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00101
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00102
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00103
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00104
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00105
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00106
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00107
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00108
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00109
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00110
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00111
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00112
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00113
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00114
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00115
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00116
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00117
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00118
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00119
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00120
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00121
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00122
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00123
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00124
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00125
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00126
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00127
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00128
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00129
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00130
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00131
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00132
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00133
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00134
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00135
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00136
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00137
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00138
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00139
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00140
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00141
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00142
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00143
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00144
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00145
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00146
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00147
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00148
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00149
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00150
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00151
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00152
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00153
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00154
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00155
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00156
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00157
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00158
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00159
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00160
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00161
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00162
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00163
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00164
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00165
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00166
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00167
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00168
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00169
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00170
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00171
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00172
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00173
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00174
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00175
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00176
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00177
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00178
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00179
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00180
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00181
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00182
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00183
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00184
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00185
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00186
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00187
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00188
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00189
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00190
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00191
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00192
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00193
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00194
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00195
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00196
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00197
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00198
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00199
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00200
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00201
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00202
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00203
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00204
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00205
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00206
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00207
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00208
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00209
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00210
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00211
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00212
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00213
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00214
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00215
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00216
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00217
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00218
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00219
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00220
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00221
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00222
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00223
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00224
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00225
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00226
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00227
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00228
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00229
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00230
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00231
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00232
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00233
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00234
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00235
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00236
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00237
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00238
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00239
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00240
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00241
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00242
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00243
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00244
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00245
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00246
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00247
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00248
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00249
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00250
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00251
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00252
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00253
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00254
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00255
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00256
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00257
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00258
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00259
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00260
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00261
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00262
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00263
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00264
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00265
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00266
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00267
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00268
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00269
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00270
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00271
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00272
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00273
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00274
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00275
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00276
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00277
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00278
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00279
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00280
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00281
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00282
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00283
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00284
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00285
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00286
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00287
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00288
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00289
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00290
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00291
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00292
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00293
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00294
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00295
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00296
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00297
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00298
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00299
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00300
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00301
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00302
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00303
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00304
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00305
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00306
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00307
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00308
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00309
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00310
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00311
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00312
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00313
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00314
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00315
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00316
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00317
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00318
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00319
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00320
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00321
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00322
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00323
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00324
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00325
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00326
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00327
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00328
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00329
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00330
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00331
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00332
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00333
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00334
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00335
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00336
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00337
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00338
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00339
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00340
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00341
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00342
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00343
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00344
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00345
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00346
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00347
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00348
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00349
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00350
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00351
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00352
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00353
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00354
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00355
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00356
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00357
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00358
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00359
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00360
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00361
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00362
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00363
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00364
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00365
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00366
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00367
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00368
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00369
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00370
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00371
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00372
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00373
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00374
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00375
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00376
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00377
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00378
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00379
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00380
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00381
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00382
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00383
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00384
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00385
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00386
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00387
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00388
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00389
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00390
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00391
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00392
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00393
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00394
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00395
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00396
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00397
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00398
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00399
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00400
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00401
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00402
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00403
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00404
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00405
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00406
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00407
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00408
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00409
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00410
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00411
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00412
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00413
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00414
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00415
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00416
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00417
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00418
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00419
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00420
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00421
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00422
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00423
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00424
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00425
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00426
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00427
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00428
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00429
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00430
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00431
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00432
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00433
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00434
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00435
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00436
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00437
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00438
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00439
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00440
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00441
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00442
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00443
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00444
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00445
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00446
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00447
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00448
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00449
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00450
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00451
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00452
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00453
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00454
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00455
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00456
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00457
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00458
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00459
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00460
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00461
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00462
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00463
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00464
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00465
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00466
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00467
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00468
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00469
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00470
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00471
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00472
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00473
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00474
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00475
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00476
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00477
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00478
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00479
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00480
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00481
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00482
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00483
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00484
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00485
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00486
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00487
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00488
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00489
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00490
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00491
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00492
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00493
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00494
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00495
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00496
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00497
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00498
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00499
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00500
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00501
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00502
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00503
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00504
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00505
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00506
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00507
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00508
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00509
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00510
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00511
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00512
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00513
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00514
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00515
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00516
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00517
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00518
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00519
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00520
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00521
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00522
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00523
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00524
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00525
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00526
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00527
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00528
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00529
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00530
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00531
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00532
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00533
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00534
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00535
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00536
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00537
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00538
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00539
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00540
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00541
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00542
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00543
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00544
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00545
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00546
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00547
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00548
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00549
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00550
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00551
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00552
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00553
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00554
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00555
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00556
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00557
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00558
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00559
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00560
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00561
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00562
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00563
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00564
Please refer to the end of the specification for access instructions.

Lengthy table referenced here
US20130172317A1-20130704-T00565
Please refer to the end of the specification for access instructions.

Test Examples

Test Example 1

Evaluation of Human P2X₃ Receptor Inhibitory Activity

Stably expressing cell line (C6BU-1 cell transfected with human P2X₃ receptor gene (GenBank accession number Y07683) was used. The cells were seeded in a 96-well microtiter plate at a concentration of 8000 cells/well and cultured in the medium (8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic and antifungal in DMEM) for one day at 37° C. under 5% carbon dioxide atmosphere. The medium was replaced with 4 μM Fluo-3-AM solution (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA, and 0.08% Pluronic F-127, pH 7.5) and incubated at 37° C. under 5% dioxide carbon atmosphere for one hour. The plate was washed with washing buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, pH7.5), and each well was added with 40 μL of this buffer. The plate was placed in High-Throughput Screening System FDSS 3000 (Hamamatsu Photonics K.K.). Measurement of fluorescence intensity by FDSS 3000 was started, and 40 μL of DMSO solutions containing different concentrations of the test compound as prepared by dilution with dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, 0.1% Pluronic F-127, pH7.5) were dispensed to each well through the built-in automatic dispenser. Five minutes after, 50 nM ATP solution (50 μL) prepared by dilution with the dilution buffer was dispensed through the built-in automatic dispenser, and the measurement of fluorescence intensity was continued for 3 min. For each well, the specific maximum fluorescence intensity was calculated as the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the starting of the measurement. The 50% inhibitory concentration (IC₅₀) was calculated under the assumption that the specific maximum fluorescence intensity without test compound is 0% inhibition and that the specific maximum fluorescence intensity when the dilution buffer was added in place of ATP solution is 100% inhibition, to evaluate the inhibitory activity of the test compound. FDSS software (Hamamatsu Photonics K.K.) was used for calculation of the specific maximum fluorescence intensity. IC₅₀ was calculated using Microsoft Excel (Microsoft Corporation) and XLfit (idbs Ltd.)

The data of the compounds of the present invention are as shown in the following Tables.

TABLE 569
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0020	0.384	I-0897	0.025	I-1555	0.016
I-0021	0.197	I-0898	0.020	I-1556	0.011
I-0029	0.595	I-0899	0.023	I-1558	0.008
I-0097	0.505	I-0900	0.018	I-1559	0.005
I-0116	0.484	I-0901	0.007	I-1560	0.051
I-0117	0.387	I-0902	0.010	I-1561	0.032
I-0118	0.231	I-0903	0.004	I-1562	0.006
I-0121	0.246	I-0904	0.011	I-1563	0.031
I-0123	0.815	I-0905	0.022	I-1564	0.013
I-0126	0.689	I-0906	0.008	I-1565	0.008
I-0128	0.840	I-0907	0.007	I-1566	0.008
I-0130	0.953	I-0908	0.013	I-1567	0.012
I-0133	0.339	I-0909	0.007	I-1568	0.010
I-0138	0.619	I-0910	0.008	I-1569	0.004
I-0141	0.685	I-0911	0.015	I-1570	0.008
I-0162	0.379	I-0912	0.010	I-1571	0.004
I-0164	0.860	I-0913	0.009	I-1572	0.005
I-0181	0.985	I-0914	0.074	I-1573	0.004
I-0182	0.714	I-0915	0.075	I-1574	0.018
I-0200	0.128	I-0916	0.019	I-1575	0.009
I-0203	0.110	I-0917	0.019	I-1576	0.008
I-0204	0.558	I-0918	0.014	I-1577	0.007
I-0217	0.268	I-0919	0.014	I-1578	0.006
I-0218	0.505	I-0920	0.037	I-1579	0.007
I-0221	0.276	I-0921	0.030	I-1580	0.006
I-0223	0.909	I-0922	0.029	I-1581	0.007
I-0227	0.910	I-0923	0.015	I-1582	0.007
I-0228	0.031	I-0924	0.030	I-1583	0.332
I-0234	0.298	I-0925	0.059	I-1585	0.014
I-0235	0.985	I-0926	0.031	I-1586	0.013
I-0237	0.230	I-0927	0.021	I-1587	0.038
I-0238	0.658	I-0928	0.014	I-1588	0.067
I-0239	0.116	I-0929	0.045	I-1589	0.158
I-0249	0.953	I-0930	0.030	I-1590	0.998
I-0241	0.447	I-0931	0.012	I-1595	0.006
I-0242	0.787	I-0932	0.021	I-1596	0.004
I-0243	0.450	I-0933	0.082	I-1597	0.004
I-0244	0.045	I-0934	0.057	I-1598	0.005
I-0245	0.168	I-0935	0.038	I-1599	0.005
I-0246	0.996	I-0936	0.065	I-1600	0.011
I-0248	0.420	I-0937	0.022	I-1601	0.024
I-0254	0.144	I-0938	0.035	I-1602	0.005
I-0255	0.520	I-0939	0.034	I-1603	0.005
I-0256	0.867	I-0949	0.008	I-1604	0.008
I-0257	0.682	I-0941	0.005	I-1605	0.018
I-0258	0.683	I-0942	0.022	I-1606	0.015
I-0268	0.861	I-0943	0.061	I-1607	0.035
I-0269	0.415	I-0945	0.173	I-1608	0.100
I-0270	0.271	I-0946	0.239	I-1609	0.187
I-0271	0.032	I-0947	0.024	I-1610	0.251
I-0272	0.180	I-0948	0.019	I-1611	0.008
I-0273	0.038	I-0949	0.021	I-1612	0.005
I-0274	0.009	I-0950	0.020	I-1613	0.006
I-0275	0.021	I-0951	0.033	I-1614	0.009
I-0276	0.012	I-0952	0.741	I-1615	0.012

TABLE 570
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0277	0.038	I-0953	0.042	I-1616	0.007
I-0278	0.931	I-0954	0.023	I-1617	0.027
I-0280	0.030	I-0955	0.028	I-1618	0.008
I-0281	0.012	I-0956	0.139	I-1619	0.006
I-0282	0.027	I-0957	0.025	I-1620	0.014
I-0283	0.019	I-0958	0.030	I-1621	0.004
I-0284	0.629	I-0959	0.007	I-1622	0.004
I-0285	0.014	I-0960	0.070	I-1623	0.007
I-0286	0.277	I-0961	0.074	I-1624	0.008
I-0287	0.222	I-0962	0.031	I-1625	0.006
I-0288	0.093	I-0963	0.662	I-1626	0.018
I-0289	0.066	I-0964	0.344	I-1627	0.009
I-0290	0.266	I-0965	0.021	I-1628	0.683
I-0291	0.009	I-0966	0.017	I-1629	0.004
I-0292	0.034	I-0967	0.019	I-1630	0.015
I-0293	0.351	I-0968	0.107	I-1631	0.008
I-0294	0.040	I-0969	0.047	I-1632	0.389
I-0295	0.046	I-0970	0.020	I-1633	0.016
I-0296	0.176	I-0971	0.030	I-1635	0.005
I-0297	0.045	I-0972	0.038	I-1636	0.009
I-0298	0.027	I-0973	0.019	I-1637	0.012
I-0299	0.046	I-0974	0.029	I-1638	0.013
I-0300	0.025	I-0975	0.043	I-1639	0.014
I-0301	0.048	I-0976	0.069	I-1640	0.013
I-0305	0.946	I-0977	0.015	I-1641	0.020
I-0307	0.250	I-0978	0.013	I-1642	0.551
I-0309	0.357	I-0979	0.006	I-1643	0.005
I-0310	0.389	I-0980	0.011	I-1644	0.005
I-0311	0.142	I-0981	0.010	I-1646	0.043
I-0312	0.104	I-0982	0.017	I-1947	0.677
I-0313	0.178	I-0983	0.007	I-1648	0.160
I-0314	0.555	I-0984	0.021	I-1649	0.285
I-0315	0.183	I-0985	0.026	I-1650	0.009
I-0316	0.712	I-0986	0.031	I-1651	0.054
I-0317	0.137	I-0987	0.015	I-1653	0.014
I-0320	0.083	I-0988	0.093	I-1654	0.066
I-0321	0.033	I-0989	0.068	I-1655	0.667
I-0322	0.112	I-0990	0.051	I-1656	0.007
I-0323	0.148	I-0991	0.022	I-1657	0.009
I-0324	0.309	I-0992	0.024	I-1658	0.006
I-0325	0.665	I-0993	0.020	I-1659	0.006
I-0326	0.011	I-0994	0.020	I-1660	0.005
I-0328	0.124	I-0995	0.276	I-1661	0.006
I-0329	0.266	I-0996	0.032	I-1662	0.011
I-0330	0.594	I-0997	0.680	I-1663	0.008
I-0331	0.066	I-0998	0.024	I-1665	0.007
I-0332	0.008	I-0999	0.174	I-1666	0.010
I-0333	0.192	I-1000	0.116	I-1668	0.309
I-0334	0.099	I-1001	0.292	I-1670	0.007
I-0335	0.007	I-1002	0.298	I-1671	0.006
I-0338	0.053	I-1003	0.229	I-1673	0.014
I-0339	0.775	I-1004	0.085	I-1674	0.971
I-0340	0.336	I-1005	0.031	I-1676	0.854
I-0341	0.149	I-1006	0.118	I-1677	0.017
I-0342	0.005	I-1007	0.015	I-1678	0.111

TABLE 571
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0343	0.021	I-1008	0.108	I-1679	0.007
I-0344	0.128	I-1009	0.069	I-1680	0.730
I-0346	0.016	I-1010	0.004	I-1682	0.140
I-0347	0.251	I-1011	0.021	I-1683	0.310
I-0348	0.013	I-1012	0.051	I-1686	0.115
I-0349	0.113	I-1013	0.005	I-1689	0.882
I-0350	0.010	I-1014	0.017	I-1691	0.022
I-0351	0.015	I-1015	0.007	I-1692	0.582
I-0352	0.036	I-1016	0.017	I-1700	0.012
I-0353	0.018	I-1017	0.550	I-1701	0.003
I-0354	0.008	I-1018	0.008	I-1702	0.004
I-0355	0.020	I-1019	0.007	I-1703	0.004
I-0356	0.012	I-1020	0.006	I-1704	0.015
I-0357	0.047	I-1021	0.007	I-1705	0.014
I-0358	0.055	I-1022	0.014	I-1708	0.017
I-0359	0.040	I-1023	0.300	I-1709	0.167
I-0360	0.148	I-1024	0.161	I-1710	0.006
I-0361	0.076	I-1025	0.134	I-1711	0.005
I-0362	0.007	I-1026	0.182	I-1712	0.004
I-0363	0.078	I-1027	0.041	I-1713	0.003
I-0364	0.030	I-1028	0.078	I-1714	0.003
I-0365	0.018	I-1029	0.035	I-1715	0.021
I-0366	0.046	I-1030	0.014	I-1717	0.002
I-0367	0.040	I-1031	0.064	I-1725	0.953
I-0368	0.041	I-1032	0.033	I-1729	0.669
I-0369	0.007	I-1033	0.067	I-1731	0.005
I-0370	0.154	I-1034	0.005	I-1732	0.011
I-0371	0.063	I-1035	0.065	I-1733	0.003
I-0372	0.964	I-1036	0.005	I-1734	0.005
I-0373	0.185	I-1037	0.093	I-1735	0.003
I-0374	0.080	I-1038	0.006	I-1736	0.009
I-0375	0.152	I-1039	0.083	I-1737	0.019
I-0377	0.755	I-1040	0.128	I-1738	0.005
I-0378	0.347	I-1041	0.101	I-1739	0.007
I-0379	0.330	I-1042	0.148	I-1741	0.055
I-0380	0.034	I-1043	0.010	I-1742	0.135
I-0382	0.096	I-1044	0.019	I-1743	0.861
I-0383	0.532	I-1045	0.159	I-1744	0.242
I-0385	0.908	I-1046	0.028	I-1746	0.129
I-0386	0.041	I-1047	0.154	I-1747	0.201
I-0387	0.037	I-1048	0.038	I-1748	0.236
I-0388	0.036	I-1049	0.177	I-1750	0.021
I-0389	0.064	I-1050	0.389	I-1752	0.004
I-0390	0.067	I-1051	0.100	I-1753	0.009
I-0391	0.133	I-1052	0.019	I-1754	0.005
I-0392	0.038	I-1053	0.079	I-1756	0.030
I-0394	0.435	I-1054	0.018	I-1757	0.012
I-0396	0.019	I-1055	0.091	I-1759	0.408
I-0397	0.007	I-1056	0.177	I-1764	0.035
I-0398	0.008	I-1057	0.089	I-1765	0.009
I-0399	0.044	I-1058	0.043	I-1766	0.018
I-0400	0.007	I-1059	0.123	I-1767	0.055
I-0401	0.443	I-1060	0.029	I-1768	0.006
I-0402	0.015	I-1061	0.174	I-1769	0.003
I-0403	0.012	I-1062	0.037	I-1770	0.788

TABLE 572
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0404	0.032	I-1063	0.152	I-1771	0.014
I-0405	0.030	I-1064	0.257	I-1772	0.297
I-0406	0.027	I-1065	0.085	I-1773	0.029
I-0407	0.010	I-1066	0.425	I-1774	0.255
I-0408	0.012	I-1067	0.093	I-1777	0.636
I-0409	0.044	I-1068	0.541	I-1779	0.203
I-0410	0.061	I-1069	0.111	I-1780	0.932
I-0412	0.099	I-1070	0.471	I-1781	0.518
I-0413	0.007	I-1071	0.998	I-1783	0.170
I-0414	0.314	I-1072	0.252	I-1784	0.950
I-0415	0.035	I-1073	0.092	I-1786	0.621
I-0416	0.035	I-1074	0.086	I-1788	0.005
I-0417	0.200	I-1076	0.177	I-1789	0.030
I-0418	0.071	I-1077	0.064	I-1792	0.020
I-0419	0.053	I-1078	0.218	I-1793	0.984
I-0420	0.019	I-1080	0.066	I-1794	0.380
I-0421	0.006	I-1081	0.030	I-1795	0.795
I-0422	0.004	I-1082	0.063	I-1796	0.587
I-0423	0.049	I-1083	0.125	I-1797	0.006
I-0424	0.016	I-1084	0.392	I-1798	0.150
I-0425	0.211	I-1085	0.034	I-1799	0.382
I-0426	0.678	I-1086	0.291	I-1800	0.510
I-0428	0.779	I-1087	0.071	I-1801	0.687
I-0430	0.004	I-1088	0.548	I-1804	0.162
I-0431	0.026	I-1089	0.487	I-1805	0.005
I-0432	0.199	I-1090	0.135	I-1807	0.006
I-0434	0.079	I-1091	0.179	I-1808	0.004
I-0438	0.398	I-1092	0.069	I-1809	0.339
I-0440	0.943	I-1093	0.038	I-1810	0.682
I-0441	0.034	I-1094	0.103	I-1812	0.630
I-0442	0.349	I-1095	0.144	I-1814	0.299
I-0443	0.407	I-1096	0.094	I-1815	0.367
I-0444	0.006	I-1097	0.141	I-1816	0.300
I-0445	0.008	I-1098	0.074	I-1817	0.052
I-0446	0.006	I-1099	0.070	I-1818	0.829
I-0447	0.005	I-1100	0.043	I-1819	0.873
I-0448	0.018	I-1101	0.053	I-1820	0.204
I-0449	0.055	I-1102	0.148	I-1821	0.429
I-0450	0.011	I-1103	0.423	I-1822	0.332
I-0451	0.117	I-1104	0.011	I-1826	0.751
I-0452	0.207	I-1105	0.152	I-1827	0.913
I-0453	0.017	I-1106	0.007	I-1829	0.092
I-0454	0.008	I-1107	0.043	I-1830	0.869
I-0455	0.020	I-1108	0.050	I-1831	0.739
I-0456	0.279	I-1109	0.430	I-1832	0.032
I-0457	0.388	I-1110	0.397	I-1833	0.580
I-0459	0.036	I-1111	0.161	I-1834	0.325
I-0460	0.016	I-1112	0.872	I-1835	0.008
I-0461	0.003	I-1113	0.123	I-1836	0.787
I-0462	0.005	I-1114	0.214	I-1839	0.107
I-0463	0.024	I-1115	0.516	I-1840	0.007
I-0464	0.030	I-1118	0.387	I-1841	0.006
I-0465	0.008	I-1120	0.534	I-1842	0.005
I-0466	0.003	I-1122	0.008	I-1843	0.004
I-0467	0.004	I-1123	0.014	I-1844	0.004

TABLE 573
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0468	0.039	I-1124	0.532	I-1845	0.033
I-0469	0.016	I-1125	0.004	I-1846	0.015
I-0470	0.009	I-1126	0.008	I-1847	0.006
I-0471	0.004	I-1127	0.068	I-1848	0.014
I-0472	0.074	I-1128	0.021	I-1849	0.007
I-0473	0.564	I-1129	0.011	I-1851	0.004
I-0474	0.057	I-1130	0.133	I-1852	0.005
I-0475	0.037	I-1131	0.105	I-1853	0.004
I-0476	0.037	I-1132	0.586	I-1854	0.004
I-0477	0.137	I-1133	0.051	I-1855	0.021
I-0478	0.101	I-1134	0.035	I-1856	0.008
I-0479	0.080	I-1135	0.018	I-1857	0.007
I-0480	0.024	I-1136	0.204	I-1858	0.005
I-0481	0.047	I-1137	0.678	I-1859	0.005
I-0482	0.583	I-1139	0.052	I-1860	0.150
I-0483	0.014	I-1140	0.044	I-1862	0.552
I-0484	0.571	I-1141	0.911	I-1863	0.005
I-0485	0.035	I-1142	0.802	I-1864	0.186
I-0486	0.056	I-1143	0.024	I-1865	0.357
I-0487	0.629	I-1144	0.764	I-1869	0.328
I-0488	0.007	I-1146	0.009	I-1870	0.004
I-0489	0.012	I-1147	0.010	I-1871	0.006
I-0490	0.012	I-1148	0.086	I-1872	0.015
I-0492	0.100	I-1149	0.065	I-1873	0.002
I-0493	0.290	I-1150	0.551	I-1874	0.013
I-0494	0.198	I-1151	0.046	I-1875	0.013
I-0495	0.042	I-1152	0.110	I-1876	0.035
I-0496	0.027	I-1153	0.071	I-1877	0.036
I-0497	0.124	I-1154	0.131	I-1878	0.010
I-0498	0.010	I-1155	0.009	I-1879	0.128
I-0499	0.046	I-1156	0.006	I-1880	0.015
I-0500	0.027	I-1157	0.052	I-1881	0.006
I-0501	0.102	I-1158	0.063	I-1882	0.016
I-0502	0.952	I-1159	0.043	I-1883	0.007
I-0503	0.034	I-1160	0.973	I-1884	0.296
I-0504	0.125	I-1161	0.148	I-1885	0.007
I-0505	0.125	I-1162	0.179	I-1886	0.003
I-0506	0.458	I-1163	0.823	I-1887	0.003
I-0507	0.009	I-1166	0.126	I-1888	0.010
I-0508	0.137	I-1168	0.004	I-1889	0.023
I-0509	0.013	I-1171	0.025	I-1892	0.113
I-0510	0.191	I-1172	0.097	I-1893	0.178
I-0511	0.020	I-1173	0.009	I-1894	0.023
I-0512	0.050	I-1174	0.027	I-1896	0.014
I-0513	0.015	I-1175	0.883	I-1897	0.024
I-0514	0.120	I-1176	0.834	I-1898	0.011
I-0515	0.279	I-1177	0.273	I-1899	0.004
I-0516	0.301	I-1178	0.017	I-1900	0.016
I-0517	0.511	I-1179	0.033	I-1901	0.015
I-0518	0.652	I-1182	0.056	I-1902	0.008
I-0519	0.098	I-1183	0.047	I-1903	0.004
I-0524	0.006	I-1184	0.138	I-1904	0.008
I-0525	0.005	I-1185	0.116	I-1905	0.005
I-0526	0.015	I-1186	0.033	I-1906	0.006
I-0527	0.007	I-1187	0.058	I-1907	0.008

TABLE 574
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0528	0.012	I-1188	0.131	I-1908	0.070
I-0529	0.080	I-1189	0.033	I-1911	0.253
I-0530	0.004	I-1190	0.005	I-1912	0.029
I-0531	0.029	I-1191	0.022	I-1913	0.019
I-0532	0.072	I-1192	0.020	I-1914	0.046
I-0533	0.060	I-1193	0.040	I-1915	0.023
I-0534	0.054	I-1194	0.031	I-1916	0.995
I-0535	0.024	I-1195	0.221	I-1917	0.023
I-0536	0.033	I-1197	0.008	I-1918	0.012
I-0537	0.053	I-1198	0.035	I-1919	0.214
I-0538	0.022	I-1199	0.036	I-1923	0.084
I-0539	0.034	I-1200	0.045	I-1925	0.006
I-0540	0.010	I-1201	0.788	I-1926	0.010
I-0541	0.029	I-1202	0.093	I-1927	0.007
I-0542	0.010	I-1203	0.532	I-1928	0.005
I-0543	0.018	I-1204	0.005	I-1930	0.029
I-0544	0.052	I-1205	0.002	I-1931	0.009
I-0545	0.046	I-1206	0.043	I-1932	0.095
I-0546	0.019	I-1207	0.015	I-1934	0.198
I-0547	0.016	I-1208	0.021	I-1935	0.009
I-0548	0.007	I-1209	0.006	I-1937	0.022
I-0549	0.027	I-1210	0.037	I-1938	0.312
I-0550	0.058	I-1211	0.030	I-1939	0.030
I-0551	0.096	I-1212	0.090	I-1940	0.055
I-0552	0.172	I-1213	0.104	I-1941	0.005
I-0553	0.601	I-1214	0.070	I-1942	0.049
I-0554	0.006	I-1215	0.027	I-1943	0.258
I-0555	0.459	I-1216	0.013	I-1944	0.011
I-0556	0.011	I-1217	0.005	I-1945	0.008
I-0557	0.012	I-1218	0.061	I-1946	0.025
I-0558	0.019	I-1219	0.029	I-1947	0.353
I-0559	0.033	I-1220	0.013	I-1948	0.022
I-0560	0.034	I-1221	0.117	I-1949	0.005
I-0561	0.023	I-1222	0.017	I-1950	0.029
I-0562	0.034	I-1223	0.297	I-1951	0.025
I-0563	0.139	I-1224	0.054	I-1952	0.781
I-0564	0.013	I-1225	0.082	I-1953	0.016
I-0565	0.005	I-1226	0.122	I-1954	0.005
I-0566	0.019	I-1227	0.030	I-1955	0.097
I-0567	0.005	I-1228	0.009	I-1956	0.034
I-0568	0.097	I-1229	0.004	I-1957	0.022
I-0569	0.007	I-1230	0.004	I-1958	0.016
I-0570	0.008	I-1231	0.036	I-1959	0.065
I-0571	0.027	I-1232	0.005	I-1960	0.054
I-0572	0.040	I-1233	0.325	I-1961	0.013
I-0573	0.048	I-1234	0.230	I-1962	0.065
I-0574	0.015	I-1235	0.214	I-1963	0.013
I-0576	0.568	I-1236	0.013	I-1964	0.277
I-0577	0.430	I-1237	0.183	I-1965	0.003
I-0578	0.254	I-1238	0.002	I-1966	0.011
I-0579	0.614	I-1239	0.732	I-1967	0.008
I-0581	0.145	I-1240	0.018	I-1968	0.015
I-0582	0.365	I-1241	0.108	I-1969	0.021
I-0583	0.038	I-1242	0.015	I-1970	0.082
I-0584	0.248	I-1243	0.012	I-1971	0.061

TABLE 575
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0586	0.611	I-1244	0.473	I-1972	0.243
I-0587	0.299	I-1245	0.003	I-1973	0.002
I-0589	0.006	I-1246	0.006	I-1974	0.007
I-0590	0.004	I-1247	0.028	I-1976	0.017
I-0593	0.004	I-1248	0.006	I-1977	0.005
I-0596	0.010	I-1249	0.021	I-1978	0.005
I-0597	0.507	I-1250	0.054	I-1979	0.004
I-0599	0.038	I-1251	0.017	I-1980	0.007
I-0600	0.013	I-1252	0.023	I-1981	0.354
I-0601	0.031	I-1253	0.281	I-1982	0.009
I-0602	0.020	I-1254	0.045	I-1983	0.010
I-0603	0.012	I-1255	0.048	I-1984	0.009
I-0604	0.013	I-1256	0.018	I-1985	0.011
I-0605	0.025	I-1257	0.009	I-1986	0.016
I-0606	0.021	I-1258	0.008	I-1987	0.007
I-0607	0.012	I-1259	0.011	I-1988	0.391
I-0608	0.006	I-1260	0.031	I-1989	0.619
I-0609	0.031	I-1261	0.018	I-1990	0.002
I-0610	0.035	I-1262	0.163	I-1991	0.006
I-0611	0.037	I-1263	0.025	I-1992	0.240
I-0612	0.038	I-1264	0.031	I-1993	0.006
I-0613	0.011	I-1265	0.022	I-1994	0.010
I-0614	0.010	I-1266	0.049	I-1995	0.005
I-0615	0.005	I-1267	0.009	I-1996	0.004
I-0616	0.010	I-1268	0.052	I-1997	0.004
I-0617	0.067	I-1269	0.008	I-1998	0.034
I-0618	0.121	I-1270	0.012	I-1999	0.028
I-0619	0.014	I-1271	0.032	I-2000	0.003
I-0620	0.044	I-1272	0.007	I-2001	0.005
I-0621	0.058	I-1273	0.007	I-2002	0.008
I-0622	0.030	I-1274	0.006	I-2004	0.013
I-0623	0.020	I-1275	0.006	I-2005	0.003
I-0624	0.042	I-1276	0.078	I-2006	0.036
I-0625	0.066	I-1277	0.015	I-2007	0.017
I-0626	0.022	I-1278	0.033	I-2008	0.007
I-0627	0.091	I-1279	0.158	I-2009	0.472
I-0628	0.061	I-1280	0.027	I-2010	0.054
I-0629	0.127	I-1281	0.006	I-2011	0.010
I-0630	0.030	I-1282	0.004	I-2012	0.009
I-0631	0.010	I-1283	0.004	I-2013	0.003
I-0632	0.011	I-1284	0.015	I-2014	0.360
I-0633	0.004	I-1285	0.051	I-2015	0.032
I-0634	0.011	I-1286	0.034	I-2016	0.005
I-0635	0.019	I-1289	0.510	I-2017	0.041
I-0636	0.010	I-1291	0.683	I-2018	0.022
I-0637	0.069	I-1292	0.445	I-2019	0.005
I-0638	0.006	I-1296	0.918	I-2020	0.006
I-0639	0.216	I-1297	0.026	I-2021	0.230
I-0640	0.005	I-1298	0.026	I-2022	0.007
I-0641	0.026	I-1299	0.051	I-2023	0.004
I-0642	0.005	I-1300	0.018	I-2024	0.005
I-0643	0.054	I-1301	0.514	I-2025	0.005
I-0644	0.040	I-1302	0.169	I-2026	0.022
I-0645	0.102	I-1303	0.066	I-2027	0.017
I-0646	0.028	I-1304	0.574	I-2028	0.013

TABLE 576
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0647	0.316	I-1305	0.227	I-2029	0.004
I-0648	0.336	I-1306	0.080	I-2030	0.006
I-0649	0.021	I-1307	0.007	I-2031	0.052
I-0650	0.020	I-1308	0.029	I-2032	0.004
I-0651	0.097	I-1309	0.021	I-2033	0.622
I-0652	0.102	I-1310	0.066	I-2034	0.009
I-0653	0.037	I-1311	0.023	I-2035	0.022
I-0654	0.026	I-1312	0.045	I-2036	0.006
I-0655	0.067	I-1313	0.062	I-2037	0.340
I-0656	0.100	I-1314	0.059	I-2038	0.013
I-0657	0.471	I-1315	0.040	I-2039	0.009
I-0658	0.109	I-1316	0.054	I-2040	0.023
I-0659	0.134	I-1317	0.105	I-2041	0.109
I-0660	0.011	I-1318	0.544	I-2042	0.023
I-0661	0.007	I-1320	0.365	I-2043	0.009
I-0662	0.022	I-1321	0.007	I-2044	0.125
I-0663	0.005	I-1322	0.020	I-2045	0.975
I-0664	0.006	I-1323	0.033	I-2047	0.384
I-0665	0.004	I-1324	0.009	I-2048	0.491
I-0666	0.008	I-1325	0.028	I-2049	0.085
I-0667	0.020	I-1326	0.217	I-2052	0.068
I-0669	0.193	I-1327	0.073	I-2053	0.952
I-0670	0.008	I-1328	0.012	I-2054	0.611
I-0671	0.015	I-1329	0.049	I-2056	0.026
I-0672	0.008	I-1330	0.009	I-2057	0.021
I-0673	0.008	I-1331	0.056	I-2058	0.007
I-0674	0.126	I-1332	0.054	I-2059	0.056
I-0675	0.037	I-1333	0.052	I-2060	0.022
I-0676	0.030	I-1334	0.011	I-2061	0.148
I-0677	0.173	I-1335	0.030	I-2063	0.120
I-0678	0.008	I-1336	0.071	I-2064	0.040
I-0679	0.032	I-1337	0.014	I-2065	0.054
I-0680	0.026	I-1338	0.036	I-2066	0.023
I-0681	0.049	I-1339	0.030	I-2067	0.021
I-0682	0.023	I-1340	0.057	I-2068	0.016
I-0683	0.009	I-1341	0.036	I-2069	0.007
I-0684	0.030	I-1342	0.010	I-2070	0.019
I-0685	0.008	I-1343	0.035	I-2071	0.008
I-0686	0.605	I-1344	0.033	I-2072	0.008
I-0687	0.012	I-1345	0.069	I-2073	0.010
I-0688	0.005	I-1346	0.812	I-2074	0.007
I-0689	0.005	I-1348	0.918	I-2075	0.021
I-0691	0.048	I-1349	0.015	I-2076	0.007
I-0692	0.029	I-1350	0.028	I-2077	0.003
I-0693	0.013	I-1351	0.041	I-2078	0.008
I-0694	0.013	I-1352	0.026	I-2079	0.038
I-0696	0.129	I-1353	0.041	I-2082	0.833
I-0697	0.057	I-1354	0.139	I-2085	0.852
I-0698	0.026	I-1355	0.177	I-2086	0.234
I-0699	0.037	I-1356	0.048	I-2095	0.005
I-0700	0.006	I-1357	0.025	I-2096	0.035
I-0701	0.035	I-1358	0.009	I-2097	0.005
I-0702	0.107	I-1359	0.724	I-2098	0.004
I-0703	0.015	I-1360	0.032	I-2099	0.008
I-0704	0.023	I-1361	0.015	I-2100	0.007

TABLE 577
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0705	0.011	I-1362	0.054	I-2101	0.026
I-0706	0.014	I-1363	0.056	I-2102	0.034
I-0707	0.021	I-1364	0.043	I-2103	0.020
I-0708	0.966	I-1365	0.094	I-2104	0.040
I-0709	0.007	I-1366	0.020	I-2105	0.001
I-0710	0.019	I-1367	0.014	I-2106	0.002
I-0711	0.040	I-1368	0.005	I-2107	0.007
I-0712	0.025	I-1369	0.003	I-2108	0.026
I-0713	0.016	I-1370	0.019	I-2109	0.011
I-0714	0.030	I-1371	0.009	I-2110	0.012
I-0715	0.013	I-1372	0.005	I-2111	0.044
I-0716	0.102	I-1373	0.004	I-2112	0.047
I-0717	0.021	I-1374	0.017	I-2113	0.001
I-0718	0.093	I-1375	0.005	I-2114	0.007
I-0719	0.115	I-1376	0.015	I-2115	0.018
I-0721	0.013	I-1377	0.007	I-2116	0.015
I-0722	0.014	I-1378	0.012	I-2117	0.023
I-0723	0.024	I-1379	0.010	I-2118	0.035
I-0724	0.250	I-1380	0.026	I-2119	0.001
I-0725	0.014	I-1381	0.020	I-2120	0.033
I-0726	0.016	I-1382	0.257	I-2121	0.021
I-0727	0.012	I-1384	0.050	I-2122	0.093
I-0728	0.014	I-1386	0.028	I-2123	0.004
I-0729	0.007	I-1387	0.044	I-2124	0.027
I-0730	0.023	I-1388	0.009	I-2125	0.007
I-0731	0.012	I-1389	0.012	I-2128	0.287
I-0732	0.041	I-1390	0.015	I-2130	0.790
I-0733	0.287	I-1391	0.016	I-2133	0.182
I-0735	0.007	I-1392	0.018	I-2137	0.134
I-0736	0.131	I-1393	0.035	I-2138	0.171
I-0737	0.140	I-1394	0.044	I-2139	0.022
I-0738	0.019	I-1395	0.023	I-2140	0.007
I-0739	0.029	I-1396	0.004	I-2141	0.007
I-0740	0.221	I-1397	0.003	I-2142	0.006
I-0741	0.050	I-1398	0.025	I-2143	0.023
I-0742	0.038	I-1399	0.050	I-2145	0.008
I-0743	0.013	I-1400	0.013	I-2147	0.014
I-0744	0.053	I-1401	0.022	I-2148	0.002
I-0745	0.125	I-1402	0.033	I-2149	0.791
I-0746	0.140	I-1403	0.050	I-2150	0.044
I-0747	0.012	I-1404	0.024	I-2151	0.012
I-0748	0.295	I-1405	0.026	I-2152	0.041
I-0749	0.027	I-1406	0.064	I-2153	0.006
I-0750	0.022	I-1407	0.036	I-2154	0.133
I-0751	0.021	I-1408	0.016	I-2155	0.004
I-0752	0.034	I-1409	0.017	I-2156	0.002
I-0753	0.011	I-1410	0.056	I-2157	0.001
I-0754	0.016	I-1411	0.058	I-2158	0.029
I-0755	0.024	I-1412	0.011	I-2159	0.047
I-0756	0.131	I-1413	0.072	I-2160	0.003
I-0757	0.035	I-1414	0.986	I-2161	0.014
I-0758	0.019	I-1415	0.532	I-2162	0.006
I-0760	0.037	I-1416	0.141	I-2163	0.054
I-0761	0.015	I-1417	0.207	I-2164	0.125
I-0762	0.082	I-1419	0.304	I-2165	0.979

TABLE 578
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0763	0.080	I-1420	0.607	I-2166	0.010
I-0764	0.254	I-1421	0.883	I-2167	0.054
I-0765	0.040	I-1422	0.529	I-2168	0.057
I-0766	0.438	I-1423	0.041	I-2189	0.051
I-0767	0.088	I-1424	0.035	I-2170	0.819
I-0769	0.207	I-1425	0.050	I-2171	0.296
I-0770	0.405	I-1426	0.050	I-2172	0.001
I-0772	0.477	I-1427	0.008	I-2173	0.012
I-0773	0.790	I-1428	0.926	I-2174	0.006
I-0774	0.054	I-1429	0.232	I-2175	0.013
I-0775	0.041	I-1430	0.709	I-2176	0.004
I-0777	0.116	I-1431	0.242	I-2177	0.014
I-0778	0.084	I-1432	0.002	I-2178	0.005
I-0779	0.016	I-1434	0.002	I-2179	0.003
I-0780	0.015	I-1435	0.061	I-2180	0.011
I-0781	0.009	I-1436	0.054	I-2181	0.004
I-0782	0.192	I-1438	0.063	I-2182	0.003
I-0783	0.065	I-1439	0.039	I-2183	0.001
I-0784	0.022	I-1440	0.006	I-2184	0.010
I-0785	0.011	I-1441	0.009	I-2185	0.015
I-0786	0.015	I-1442	0.008	I-2186	0.104
I-0787	0.024	I-1443	0.006	I-2187	0.044
I-0788	0.032	I-1444	0.004	I-2188	0.009
I-0789	0.181	I-1445	0.004	I-2189	0.047
I-0790	0.013	I-1447	0.006	I-2190	0.033
I-0791	0.266	I-1448	0.012	I-2191	0.005
I-0792	0.170	I-1449	0.004	I-2192	0.008
I-0794	0.168	I-1450	0.448	I-2193	0.006
I-0795	0.724	I-1451	0.005	I-2194	0.052
I-0796	0.386	I-1452	0.014	I-2195	0.014
I-0797	0.701	I-1453	0.013	I-2196	0.446
I-0798	0.465	I-1454	0.023	I-2197	0.215
I-0799	0.281	I-1455	0.032	I-2199	0.515
I-0800	0.021	I-1456	0.014	I-2200	0.545
I-0801	0.010	I-1457	0.014	I-2201	0.092
I-0802	0.021	I-1458	0.025	I-2203	0.001
I-0804	0.132	I-1459	0.034	I-2204	0.028
I-0805	0.029	I-1460	0.272	I-2205	0.009
I-0806	0.012	I-1461	0.025	I-2206	0.012
I-0807	0.013	I-1462	0.003	I-2207	0.069
I-0808	0.203	I-1463	0.632	I-2208	0.012
I-0809	0.034	I-1464	0.070	I-2209	0.008
I-0810	0.016	I-1465	0.006	I-2210	0.014
I-0811	0.040	I-1466	0.121	I-2211	0.014
I-0812	0.033	I-1467	0.012	I-2212	0.002
I-0818	0.018	I-1468	0.010	I-2213	0.002
I-0814	0.017	I-1469	0.009	I-2214	0.022
I-0815	0.189	I-1470	0.010	I-2215	0.006
I-0816	0.037	I-1471	0.007	I-2216	0.005
I-0817	0.027	I-1473	0.012	I-2217	0.006
I-0818	0.529	I-1474	0.138	I-2218	0.003
I-0819	0.022	I-1475	0.039	I-2219	0.014
I-0820	0.035	I-1476	0.262	I-2220	0.037
I-0821	0.050	I-1477	0.068	I-2222	0.005
I-0822	0.026	I-1478	0.019	I-2223	0.006

TABLE 579
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0823	0.011	I-1479	0.020	I-2224	0.033
I-0824	0.018	I-1480	0.002	I-2225	0.061
I-0825	0.025	I-1481	0.039	I-2226	0.012
I-0826	0.019	I-1482	0.098	I-2227	0.004
I-0827	0.026	I-1483	0.087	I-2228	0.005
I-0828	0.025	I-1484	0.006	I-2229	0.023
I-0829	0.216	I-1485	0.235	I-2230	0.002
I-0830	0.089	I-1486	0.043	I-2231	0.003
I-0831	0.077	I-1487	0.106	I-2232	0.013
I-0832	0.103	I-1488	0.652	I-2233	0.002
I-0833	0.015	I-1489	0.254	I-2234	0.002
I-0834	0.018	I-1491	0.284	I-2235	0.004
I-0835	0.078	I-1492	0.461	I-2236	0.062
I-0836	0.095	I-1493	0.444	I-2237	0.020
I-0837	0.017	I-1494	0.571	I-2238	0.148
I-0838	0.033	I-1495	0.026	I-2239	0.049
I-0839	0.012	I-1496	0.009	I-2240	0.021
I-0840	0.017	I-1497	0.619	I-2241	0.001
I-0841	0.150	I-1498	0.022	I-2242	<0.004
I-0843	0.183	I-1499	0.019	I-2243	0.006
I-0845	0.024	I-1500	0.897	I-2244	0.059
I-0846	0.035	I-1501	0.011	I-2245	0.108
I-0847	0.031	I-1502	0.107	I-2246	0.790
I-0848	0.060	I-1503	0.012	I-2247	0.003
I-0849	0.078	I-1504	0.005	I-2248	0.007
I-0850	0.062	I-1505	0.004	I-2249	0.006
I-0851	0.024	I-1506	0.002	I-2250	0.008
I-0852	0.038	I-1507	0.015	I-2251	0.005
I-0853	0.013	I-1508	0.018	I-2252	0.769
I-0854	0.032	I-1509	0.014	I-2254	0.078
I-0855	0.010	I-1510	0.013	I-2255	0.543
I-0856	0.012	I-1511	0.029	I-2257	0.151
I-0857	0.019	I-1512	0.013	I-2258	0.003
I-0858	0.022	I-1513	0.010	I-2262	0.017
I-0859	0.017	I-1514	0.024	I-2263	0.004
I-0860	0.062	I-1515	0.157	I-2264	0.558
I-0861	0.019	I-1516	0.049	I-2265	0.299
I-0862	0.010	I-1517	0.240	I-2266	0.044
I-0864	0.035	I-1518	0.002	I-2267	0.331
I-0865	0.017	I-1519	0.002	I-2268	0.006
I-0866	0.002	I-1520	0.032	I-2269	0.002
I-0867	0.006	I-1521	0.022	I-2270	<0.004
I-0868	0.023	I-1522	0.005	I-2271	0.036
I-0869	0.574	I-1523	0.003	I-2272	0.008
I-0870	0.530	I-1527	0.005	I-2273	0.012
I-0871	0.040	I-1528	0.032	I-2274	0.005
I-0872	0.081	I-1529	0.026	I-2275	0.010
I-0873	0.047	I-1530	0.093	I-2276	0.778
I-0874	0.086	I-1531	0.025	I-2277	0.107
I-0875	0.014	I-1532	0.025	I-2278	0.136
I-0876	0.023	I-1533	0.016	I-2279	0.033
I-0877	0.028	I-1534	0.005	I-2280	0.127
I-0878	0.022	I-1535	0.028	I-2281	0.002
I-0879	0.058	I-1536	0.024	I-2282	<0.004
I-0880	0.049	I-1537	0.003	I-2283	<0.004

TABLE 580
Compound	P2X3	Compound	P2X3	Compound	P2X3
No.	IC50 (μM)	No.	IC50 (μM)	No.	IC50 (μM)
I-0881	0.127	I-1538	0.017	I-2284	<0.004
I-0882	0.100	I-1539	0.004	I-2285	0.015
I-0883	0.024	I-1540	0.052	I-2286	0.005
I-0884	0.016	I-1542	0.004	I-2287	<0.004
I-0885	0.087	I-1543	0.006	I-2288	0.001
I-0886	0.076	I-1544	0.004	I-2289	<0.004
I-0887	0.023	I-1545	0.003	I-2090	<0.004
I-0888	0.030	I-1546	0.007	I-2291	0.004
I-0889	0.053	I-1547	0.003	I-2292	0.012
I-0890	0.032	I-1548	0.005	I-2293	0.006
I-0891	0.013	I-1549	0.008	I-2294	0.005
I-0892	0.018	I-1550	0.833	I-2295	<0.004
I-0893	0.202	I-1551	0.009	I-2296	0.005
I-0894	0.028	I-1552	0.015	I-2297	0.065
I-0895	0.047	I-1553	0.011
I-0896	0.016	I-1554	0.014

TABLE 581
Compound P2X3
No.      IC50 (μM)
I-2300   0.003
I-2301   0.437
I-2302   0.002
I-2303   0.007
I-2304   0.029
I-2305   0.004
I-2306   0.002
I-2307   0.015
I-2308   0.003
I-2309   0.002
I-2310   0.005
I-2311   0.008
I-2312   0.005
I-2313   0.008
I-2314   0.007
I-2315   0.017
I-2316   0.051
I-2317   0.003
I-2318   0.018
I-2319   0.017
I-2320   0.006
I-2321   0.011
I-2322   0.006
I-2323   0.016
I-2324   0.115
I-2325   0.047
I-2326   0.108
I-2327   0.008
I-2328   0.034
I-2329   0.070
I-2330   0.007
I-2331   0.007
I-2332   0.218
I-2333   0.003
I-2334   0.005
I-2335   0.006
I-2336   0.010
I-2338   0.260
I-3339   0.043
I-2340   0.013
I-2341   0.010
I-2342   0.016
I-2343   0.019
I-2344   0.003
I-2345   0.020
I-2346   0.004
I-2347   0.005
I-2348   0.004
I-2349   0.004
I-2350   0.002
I-2351   0.009
I-2352   0.006
I-2353   0.008
I-2354   0.003
I-2355   0.071
I-2356   0.024
I-2357   0.012
I-2358   0.006
I-2359   0.026
I-2360   0.011
I-2361   0.015
I-2362   0.010
I-2363   0.009
I-2364   0.008
I-2365   0.211
I-2366   0.090
I-2367   0.128
I-2368   0.013
I-2369   0.003
I-2370   0.011
I-2371   0.102
I-2372   0.032
I-2373   0.033
I-2374   0.008
I-2375   0.022
I-2376   0.020
I-2377   0.015
I-2378   0.006
I-2379   0.009
I-2380   0.029
I-2381   0.054
I-2382   0.054
I-2383   0.015
I-2384   0.005
I-2385   0.013
I-2386   0.013
I-2387   0.002
I-2388   0.003
I-2389   0.010
I-2390   0.007
I-2391   0.029
I-2392   0.011
I-2393   0.010
I-2394   0.021
I-2395   0.004
I-2396   0.006
I-2397   0.039
I-2398   0.003
I-2399   0.020
I-2400   0.006
I-2401   0.018
I-2402   0.003
I-2403   0.061
I-2404   0.016
I-2405   0.062
I-2406   0.010
I-2407   0.009
I-2408   0.014
I-2409   0.014
I-2410   0.036
I-2411   0.166
I-2412   0.084
I-2413   0.036
I-2414   0.003
I-2415   0.009
I-2416   0.054
I-2417   0.041
I-2418   0.012
I-2419   0.003
I-2420   0.009
I-2421   0.003
I-2422   0.007
I-2423   0.007
I-2424   0.020
I-2425   0.002
I-2426   0.011
I-2427   0.002
I-2428   0.005
I-2429   0.005
I-2430   0.048
I-2431   0.018
I-2432   0.002
I-2433   0.005
I-2434   0.004
I-2435   0.037
I-2436   0.004
I-2437   0.006
I-2438   0.007
I-2439   0.004
I-2440   0.005
I-2441   0.010
I-2442   0.018
I-2443   0.024
I-2444   0.008
I-2445   0.013
I-2446   0.001
I-2447   0.010
I-2448   0.011
I-2449   0.009
I-2450   0.008

TABLE 582
Compound P2X3
No.      IC50 (μM)
I-2451   0.025
I-2452   0.036
I-2453   0.064
I-2454   0.035
I-2455   0.063
I-2456   0.008
I-2457   0.013
I-2458   0.003
I-2459   0.007
I-2460   0.035
I-2461   0.007
I-2462   0.007
I-2463   0.003
I-2464   0.010
I-2465   0.004
I-2466   0.016
I-2467   0.007
I-2468   0.020
I-2469   0.019
I-2470   0.000
I-2471   0.005
I-2472   0.003
I-2473   0.008
I-2474   0.007
I-2475   0.012
I-2476   0.013
I-2477   0.015
I-2478   0.005
I-2479   0.008
I-2480   0.006
I-2481   0.008
I-2482   0.011
I-2483   0.008
I-2484   0.008
I-2485   0.008
I-2486   0.381
I-2488   0.037
I-2489   0.050
I-2490   0.010
I-2491   0.074
I-2492   0.004
I-2493   0.005
I-2494   0.001
I-2495   0.021
I-2496   0.030
I-2497   0.001
I-2498   0.003
I-2499   0.005
I-2500   0.067
I-2501   0.057
I-2502   0.007
I-2503   0.039
I-2504   0.370
I-2505   0.017
I-2506   0.014
I-2507   0.035
I-2508   0.013
I-2509   0.009
I-2510   0.010
I-2511   0.235
I-2512   0.011
I-2513   0.006
I-2514   0.011
I-2515   0.346
I-2516   0.009
I-2517   0.167
I-2518   0.004
I-2519   0.004
I-2520   0.002
I-2521   0.005
I-2522   0.011
I-2523   0.169
I-2524   0.034
I-2525   0.010
I-2526   0.008
I-2527   0.026
I-2529   0.073
I-2530   0.016
I-2531   0.004
I-2532   0.005
I-2533   0.004
I-2534   0.105
I-2535   0.044
I-2536   0.005
I-2537   0.005
I-2538   0.003
I-2539   0.076
I-2540   0.104
I-2541   0.118
I-2542   0.186
I-2543   0.010
I-2544   0.011
I-2545   0.007
I-2546   0.006
I-2547   0.008
I-2548   0.006
I-2549   0.012
I-2550   0.004
I-2551   0.004
I-2552   0.005
I-2553   0.216
I-2554   0.007
I-2555   0.016
I-2556   0.005
I-2557   0.019
I-2558   0.022
I-2559   0.008
I-2560   0.005
I-2561   0.065
I-2562   0.004
I-2563   0.015
I-2564   0.269
I-2565   0.017
I-2566   0.017
I-2567   0.038
I-2568   0.087
I-2569   0.162
I-2570   0.005
I-2571   0.007
I-2573   0.006
I-2574   0.011
I-2575   0.006
I-2576   0.003
I-2577   0.008
I-2578   0.006
I-2579   0.071
I-2580   0.204
I-2581   0.005
I-2582   0.003
I-2583   0.015
I-2584   0.008
I-2585   0.008
I-2586   0.007
I-2587   0.007
I-2588   0.011
I-2589   0.006
I-2590   0.017
I-2591   0.051
I-2592   0.350
I-2593   0.001
I-2594   0.075
I-2595   0.027
I-2596   0.051
I-2597   0.215
I-2598   0.341
I-2599   0.004
I-2600   0.004
I-2601   0.012
I-2602   0.002

TABLE 583
Compound P2X3
No.      IC50 (μM)
I-2603   0.125
I-2604   0.021
I-2605   0.014
I-2606   0.014
I-2607   0.020
I-2608   0.006
I-2609   0.002
I-2610   0.012
I-2611   0.014
I-2612   0.004
I-2613   0.137
I-2614   0.027
I-2615   0.007
I-2616   0.012
I-2617   0.042
I-2618   0.007
I-2619   0.006
I-2620   0.110
I-2621   0.265
I-2622   0.005
I-2623   0.506
I-2624   0.368
I-2625   0.003
I-2626   0.005
I-2627   0.007
I-2628   0.004
I-2629   0.006
I-2630   0.003
I-2631   0.475
I-2633   0.002
I-2634   0.011
I-2635   0.008
I-2636   0.002
I-2637   0.177
I-2638   0.015
I-2639   0.026
I-2640   0.002
I-2641   0.012
I-2642   0.011
I-2643   0.491
I-2644   0.017
I-2645   0.018
I-2646   0.008
I-2647   0.016
I-2648   0.014
I-2649   0.006
I-2650   0.003
I-2651   0.002
I-2652   0.003
I-2653   0.009
I-2654   0.009
I-2655   0.005
I-2656   0.006
I-2657   0.007
I-2658   0.005
I-2659   0.277
I-2660   0.003
I-2661   0.015
I-2663   0.330
I-2664   0.003
I-2665   0.085
I-2666   0.002
I-2667   0.010
I-2671   0.036
I-2672   0.011
I-2673   0.007
I-2674   0.005
I-2675   0.013
I-2676   0.013
I-2677   0.007
I-2678   0.003
I-2679   0.005
I-2680   0.012
I-2681   0.004
I-2682   0.002
I-2683   0.012
I-2684   0.002
I-2685   0.012
I-2686   0.036
I-2687   0.035
I-2688   0.018
I-2689   0.020
I-2690   0.018
I-2691   0.008
I-2692   0.008
I-2693   0.012
I-2694   0.003
I-2695   0.010
I-2696   0.008
I-2697   0.019
I-2698   0.025
I-2699   0.134
I-2700   0.353
I-2701   0.001
I-2702   0.003
I-2704   0.004
I-2705   0.003
I-2706   0.006
I-2707   0.007
I-2708   0.002
I-2709   0.006
I-2710   0.006

Test Example 2

Evaluation of Rat P2X₃ Receptor Inhibitory Activity

Rat P2X3 receptor gene (GenBank accession number NM_—031075) was expressed in C6BU-1 cell. The cells stably expressing rat P2X₃ were seeded in a 96-well microtiter plate at a concentration of 8000 cells/well and cultured in the medium (8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic and antifungal in DMEM) for one day at 37° C. under 5% carbon dioxide atmosphere. In transiently expressing system, the C6BU-1 cells were seeded in a 96-well microtiter plate at a concentration of 2500 cells/well and cultured in the medium for one day at 37° C. under 5% carbon dioxide atmosphere. The plasmid was transfected into the cells using transfection reagent FuGENE6 (Roche). The transfected cells were cultured in the medium for one day at 37° C. under 5% carbon dioxide atmosphere. The medium was replaced with 4 μM Fluo-3-AM solution (pH7.5) containing 20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA, and 0.08% Pluronic F-127, and incubated at 37° C. under 5% dioxide carbon atmosphere for one hour. The plate was washed with washing buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl, 5.6 mM D-glucose, 2.5 mM probenecid, pH7.5), and each well was added with 40 μL of this buffer. The plate was placed in High-Throughput Screening System FDSS 3000 (Hamamatsu Photonics K.K.). Measurement of fluorescence intensity by FDSS 3000 was started, and 40 μL of DMSO solutions containing different concentrations of the test compound as prepared by dilution with dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, 0.1% Pluronic F-127, pH7.5) were dispensed to each well through the built-in automatic dispenser. Five minutes after, 50 nM ATP solution (50 μL) prepared by dilution with the dilution buffer was dispensed through the built-in automatic dispenser, and the measurement of fluorescence intensity was continued for 3 min. For each well, the specific maximum fluorescence intensity was calculated as the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the starting of the measurement. The 50% inhibitory concentration (IC₅₀) was calculated under the assumption that the specific maximum fluorescence intensity without test compound is 0% inhibition and that the specific maximum fluorescence intensity when the dilution buffer was added in place of ATP solution is 100% inhibition, to evaluate the inhibitory activity of the test compound. FDSS software (Hamamatsu Photonics K.K.) was used for calculation of the specific maximum fluorescence intensity. IC₅₀ was calculated using Microsoft Excel (Microsoft Corporation) and XLfit (idbs Ltd.).

The data of the compounds of the present invention are as shown in the following Table.

TABLE 584
Compound rat P2X3
No.      IC50 (μM)
I-0837   0.019
I-2291   0.003
I-1788   0.005
I-1679   0.006

Test Example 3

Evaluation of Rat P2X₃ Receptor Inhibitory Activity in the Presence of Rat Serum Albumin (RSA)

Rat P2X3 receptor gene (GenBank accession number NM_—031075) was expressed in C6BU-1 cell. The cells stably expressing rat P2X₃ were seeded in a 96-well microtiter plate at a concentration of 8000 cells/well and cultured in the medium (8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic and antifungal in DMEM) for one day at 37° C. under 5% carbon dioxide atmosphere. In transiently expressing system, the C6BU-1 cells were seeded in a 96-well microtiter plate at a concentration of 2500 cells/well and cultured in the medium for one day at 37° C. under 5% carbon dioxide atmosphere. The plasmid was transfected into the cells using transfection reagent FuGENE6 (Roche). The transfected cells were cultured in the medium for one day at 37° C. under 5% carbon dioxide atmosphere. The medium was replaced with 4 μM Fluo-3-AM solution (pH7.5) containing 20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA, and 0.08% Pluronic F-127, and incubated at 37° C. under 5% carbon dioxide atmosphere for one hour. The plate was washed with washing buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, pH7.5), and each well was added with 40 μL of this buffer. The plate was placed in High-Throughput Screening System FDSS 3000 (Hamamatsu Photonics K.K.). Measurement of fluorescence intensity by FDSS 3000 was started, and 40 μL of DMSO solutions containing 1% RSA (final concentrations) and different concentrations of the test compound as prepared by dilution with dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose, 2.5 mM probenecid, 0.1% Pluronic F-127, pH7.5) were dispensed to each well through the built-in automatic dispenser. Five minutes after, 50 nM ATP solution (50 μL) prepared by dilution with the dilution buffer was dispensed through the built-in automatic dispenser, and the measurement of fluorescence intensity was continued for 3 min. For each well, the specific maximum fluorescence intensity was calculated as the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the starting of the measurement. The 50% inhibitory concentration (IC₅₀) was calculated under the assumption that the specific maximum fluorescence intensity without test compound is 0% inhibition and that the specific maximum fluorescence intensity when the dilution buffer was added in place of ATP solution is 100% inhibition, to evaluate the inhibitory activity of the test compound. FDSS software (Hamamatsu Photonics K.K.) was used for calculation of the specific maximum fluorescence intensity. IC₅₀ was calculated using Microsoft Excel (Microsoft Corporation) and XLfit (idbs Ltd.).

The data of the compounds of the present invention are as shown in the following Table.

TABLE 585
Compound rat P2X3 (+RSA)
No.      IC50 (μ/M)
I-0837   0.044
I-2291   0.020
I-1788   0.059
I-1679   0.023

Test Example 4

Evaluation of the Urinary Function in a Rat Model of Cystitis

Surgery for Cystometry

A rat was fixed in the supine position after being given anesthesia through the inhalation of 2% isoflurane (Anesthetic background; Nitrous oxide:Oxygen=7:3). A midline incision was made in its abdomen to expose the bladder. A cannula (made by processing a polyethylene tube (PE-50: Becton Dickinson)) was inserted through a small incision on top of the bladder and fixed to create a bladder fistula. The other end of the cannula was led through the hypodermal tissue to the back, and the muscular coat and skin were sutured. The cannula, which was led to the back, was protected with a stainless spring in the middle and connected to the cannula swivel.

Acetic Acid Infusion

Two days after the surgery, 0.3% acetic acid was infused into the bladder through the indwelled cannula at a rate of 4 mL/hr for 30 minutes to induce cystitis. The animals, where acetic acid was not infused, were used as normal animals.

Cystometry Measurement

Three days after the acetic acid infusion, the other end of the cannula inserted into the bladder was connected to a T shape stopcock and then the intravesical pressure was recorded continuously using a pressure amplifier while infusing warmed normal saline solution at a rate of 3.0 mL/hr from one side and through a pressure transducer on the other side. The baseline of the intravesical pressure was measured (for approximately 40 minutes) after a measurement for stable duration (for approximately minutes). After that, a vehicle, positive control compound or test compound were administered, and the value after administration was measured for approximately 120 minutes. At the same time, the voided urine was received on scales under the cage to measure the variation in weight simultaneously.

Data Adoption Criteria

Based on the voiding interval, normal animals whose voiding interval was 10 minutes or longer were adopted and those whose voiding interval was shorter than that were excluded. In the case of the animals into which acetic acid was infused, those whose voiding interval was less than half the average value of the normal animals were adopted as animals with cystitis and those whose voiding interval was longer than that were excluded.

Collection of Residual Urine

After the completion of the measurement, the infusion of normal saline solution was stopped immediately after urination to collect the residual urine under pentobarbital sodium anesthesia. The collected residual urine was transferred to the voided urine receiver and recorded on the chart.

Analysis Items

Intravesical pressure one to two hours after the start of the measurement (pressure during rest and pressure during urination), voiding interval, voided volume per urination, and residual urine volume

The following value was used as an indicator of the effect on the voiding interval:

Improvement rate of the urinary function=(Voiding interval of an animal with cystitis after drug treatment−Voiding interval of an animal with cystitis before drug treatment)/(Mean voiding interval of normal animals before drug treatment−Voiding interval of an animal with cystitis before drug treatment)

The following value was used as an indicator of the effect on the voided volume per urination:

Improvement rate of the voided volume per urination=(Voided volume per urination of a rat with cystitis after drug treatment−Voided volume per urination of an animal with cystitis before drug treatment)/(Mean voided volume per urination of normal animals before drug treatment−Voided volume per urination of an animal with cystitis before drug treatment)

In the above-mentioned test, the compound I-0364 showed improvements in the urinary function in the voiding interval of 74.8% and in the voided volume per urination of 88% after oral administration of 30 mg/kg.

Test Example 5

Analgesic Effect in a Seltzer Model

Preparation of Partial Sciatic Nerve Ligation Model in Rats

Rats were anaesthetized using isoflurane/O2 inhalation anaesthesia. After induction of anesthesia, the left thigh was shaved. An incision was made in the skin just below the hip bone. The muscle was bluntly dissected to expose the sciatic nerve. One third (⅓) to one half (½) of the sciatic nerve thickness was tightly ligated and the wound was closed. The right thigh is used as a sham-operated control. The right thigh undergoes an identical procedure with the left hind limb, however, the sciatic nerve is not manipulated or ligated.

Evaluation (1)

Two weeks after nerve ligation, the effect on mechanical allodynia was assessed using a series of von Frey filaments. For habituation, the rats were placed into a plastic cage on a wire mesh bottom. The mechanical sensitivity (mechanical threshold) of the hind paws was estimated with a series of von Frey filaments (0.4-26 g). The measurement of mechanical sensitivity of the right and left hind paws was performed to obtain predose mechanical sensitivity. The rats showing the threshold change from 0.6 to 2 g (in nerve ligated side) and 8 to 15 g (in sham operated side) were used in the experiments. On the day before the experiment, the rats were evaluated with a series of von Frey filaments to familiarize them with the test procedure. The adopted animal was administrated with the test compounds. The test compounds were homogenized with mortar and pestle and suspended or diluted in 0.5% Methyl Cellulose to prepare 0.1-2.0 mg/mL/kg suspension and orally administered to rat using a syringe attached with a sonde. Post-dose mechanical sensitivities of the right and left hind paws were measured at approximately 1 to 5 hours after drug administration. Percent reversal of mechanical allodynia for each rat was calculated using the following formula. The analgesic effects of the compounds were compared.

$\%\mathrm{Reversal}=\frac{\begin{array}{c}{\mathrm{Log}}_{10}\left(\mathrm{Postdose}\mathrm{mechanical}\mathrm{sensitivity}\mathrm{in}\mathrm{nerve}\mathrm{ligated}\mathrm{side}\right)-\\ {\mathrm{Log}}_{10}\left(\mathrm{Predose}\mathrm{mechanical}\mathrm{sensitivity}\mathrm{in}\mathrm{nerve}\mathrm{ligated}\mathrm{side}\right)\end{array}}{\begin{array}{c}{\mathrm{Log}}_{10}\left(\mathrm{Predose}\mathrm{mechanical}\mathrm{sensitivity}\mathrm{in}\mathrm{sham}\mathrm{operated}\mathrm{side}\right)-\\ {\mathrm{Log}}_{10}\left(\mathrm{Predose}\mathrm{mechanical}\mathrm{sensitivity}\mathrm{in}\mathrm{nerve}\mathrm{ligated}\mathrm{side}\right)\end{array}}$

In the above examination, the analgesic effect of the oral administration of compound I-0364 at dose of 10 mg/kg was 41.2% reversal at 3 hours.

The analgesic effects of the compounds of the present invention after single administration of 3 mg/kg at 3 hours are as shown in the following Table.

TABLE 586
Compound analgesic effects
No.      (% reversal)
I-0837   23.7
I-1788   29.8
I-1679   40.6

Oral administration of I-0826, I-0931, I-1373, I-1849, i-2291, I-2292, I-2293, I-1757, I-2153, I-2272, I-2283, I-2369 and 1-2428 at dose of 3 mg/kg produced analgesic effect more than 30% reversal.

Evaluation (2)

Mechanical hyperalgesia was evaluated using an analgesy meter. Two weeks after nerve ligation, the paw pressure test was performed using an analgesy meter (stimulus pressure increased 16 g per second) to obtain paw withdrawal thresholds (PWT). Measurements were made on both sides of the hind paw and to obtain pre-dose PWT. The rats showing the threshold change from 60 to 90 g (in nerve ligated side) and 100 to 175 g (in sham operated side) were used in the experiments. On the day before the experiment, the rats have their hind paws set on the apparatus to familiarize them with the test procedure. The adopted animal was administrated with the test compounds. The test compounds were homogenized with mortar and pestle and suspended or diluted in 0.5% Methyl Cellulose to prepare 0.03-100 mg/2 mL/kg suspension and orally administered to rat using a syringe attached with a sonde. Post-dose PWT of the right and left hind paws were measured at approximately 1 to 5 hours after drug administration. Percent reversal of mechanical hyperalgesia for each rat was calculated using the following formula. The analgesic effects of the compounds were compared.

$\%\mathrm{Reversal}=\frac{\begin{array}{c}\mathrm{Postdose}PWT\mathrm{in}\mathrm{nerve}\mathrm{ligated}\mathrm{side}-\\ \mathrm{Predose}PWT\mathrm{in}\mathrm{nerve}\mathrm{ligated}\mathrm{side}\end{array}}{\begin{array}{c}\mathrm{Predose}PWT\mathrm{in}\mathrm{sham}\mathrm{operated}\mathrm{side}-\\ \mathrm{Predose}PWT\mathrm{in}\mathrm{nerve}\mathrm{ligated}\mathrm{side}\end{array}}$

In the above examination, the analgesic effect of the oral administration of compound I-0364 at dose of 10 mg/kg was 56.7% reversal at 3 hours.

Test Example 6

CYP3A4 Fluorescent MBI Test

The CYP3A4 fluorescent MBI test is a test of investigating enhancement of CYP3A4 inhibition of a compound by a metabolism reaction, and the test was performed using, as CYP3A4 enzyme expressed in Escherichia coli and employing, as an index, a reaction in which 7-benzyloxytrifluoromethylchmarin (BFC) is debenzylated by the CYP3A4 enzyme to produce a metabolite, 7-hydroxytrifluoromethylchmarin (HFC) emitting fluorescent light.

The reaction conditions were 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 (expressed in Escherichia coli), at pre-reaction 62.5 μmol/mL, at reaction 6.25 μmol/mL (at 10-fold dilution); test drug concentration, 1.5625, 3.125, 6.25, 12.5, 25, 50 μmol/L (six points).

An enzyme in a K-Pi buffer (pH 7.4) and a test drug solution as a pre-reaction solution were added to a 96-well plate at the composition of the pre-reaction, a part of it was transferred to another 96-well plate so that it was 1/10 diluted by a substrate in a K-Pi buffer, NADPH as a co-factor was added to initiate a reaction as an index (without preincubation) and, after a predetermined time of a reaction, acetonitrile:0.5 mol/L Tris (trishydroxyaminomethane)=4:1 was added to stop the reaction. In addition, NADPH was added to a remaining preincubation solution to initiate a preincubation (with preincubation) and, after a predetermined time of a preincubation, a part was transferred to another plate so that it was 1/10 diluted with a substrate and a K-Pi buffer to initiate a reaction as an index. After a predetermined time of a reaction, acetonitrile:0.5 mol/L Tris (trishydroxyaminomethane)=4:1 was added to stop the reaction. For the plate on which each index reaction had been performed, a fluorescent value of 7-HFC which is a metabolite was measured with a fluorescent plate reader. (Ex=420 nm, Em=535 nm).

Addition of only DMSO which is a solvent dissolving a drug to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a test drug added as the solution, and IC₅₀ was calculated by reverse-presumption by a logistic model using a concentration and an inhibition rate. When a difference between IC₅₀ values is 5 μM or more, this was defined as (+) and, when the difference is 3 μM or less, this was defined as (−).

(Result)

Compound No. I-0837: (−)

Test Example 7

CYP Inhibition Test

Using commercially available pooled human hepatic microsome, and employing, as markers, 7-ethoxyresorufin O-deethylation (CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenyloin 4′-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenedine hydroxylation as typical substrate metabolism reactions of human main five CYP enzyme forms (CYP1A2, 2C9, 2C19, 2D6, 3A4), an inhibitory degree of each metabolite production amount by a test compound was assessed.

The reaction conditions were as follows: substrate, 0.5 μmol/L ethoxyresorufin (CYP1A2), 100 μmol/L tolbutamide (CYP2C9), 50 μmol/L S-mephenitoin (CYP2C19), 5 μmol/L dextromethorphan (CYP2D6), 1 μmol/L terfenedine (CYP3A4); reaction time, minutes; reaction temperature, 37° C.; enzyme, pooled human hepatic microsome 0.2 mg protein/mL; test drug concentration, 1.0, 5.0, 10, 20 μmol/L (four points).

Each five kinds of substrates, human hepatic microsome, or a test drug in 50 mmol/L Hepes buffer as a reaction solution was added to a 96-well plate at the composition as described above, NADPH, as a cofactor was added to initiate metabolism reactions as markers and, after the incubation at 37° C. for 15 minutes, a methanol/acetonitrile=1/1 (v/v) solution was added to stop the reaction. After the centrifugation at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant was quantified by a fluorescent multilabel counter and tributamide hydroxide (CYP2CP metabolite), mephenyloin 4′ hydroxide (CYP2C19 metabolite), dextromethorphan (CYP2D6 metabolite), and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC/MS/MS.

Addition of only DMSO being a solvent dissolving a drug to a reaction system was adopted as a control (100%), remaining activity (%) was calculated at each concentration of a test drug added as the solution and IC₅₀ was calculated by reverse presumption by a logistic model using a concentration and an inhibition rate.

(Results)

Compound No. I-0837: five kinds>20 μmol/L

Compound No. I-2291: five kinds>20 μmol/L

Compound No. I-1788: five kinds>20 μmol/L

Compound No. I-1679: five kinds>20 μmol/L

Test Example 8

FAT Test

20 μL of freezing-stored rat typhoid bacillus (Salmonella typhimurium TA98 strain. TA100 strain) is inoculated on 10 mL of a liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and this is cultured before shaking at 37° C. for 10 hours. 9 mL of a bacterial solution of the TA98 strain is centrifuged (2000×g, 10 minutes) to remove a culturing solution, the bacteria is suspended in 9 mL of a Micro F buffer (K₂HPO₄: 3.5 g/L, KH₂PO₄: 1 g/L, (NH₄)₂SOI: 1 g/L, trisodium citrate dihydrate: 0.25 g/L, MgSO₄.7H₂O: 0.1 g/L), the suspension is added to 110 mL of an Exposure medium (Micro F buffer containing Biotin: 8 μg/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL), and the TA100 strain is added to 120 mL of the Exposure medium relative to 3.16 mL of the bacterial solution to prepare a test bacterial solution. Each 12 μL of a test substance DMSO solution (8 stage dilution from maximum dose 50 mg/mL at 2-fold ratio), DMSO as a negative control, 50 μg/mL of 4-nitroquinoline-1-oxide DMSO solution for the TA98 strain, 0.25 μg/mL of 2-(furyl)-3-(5-nitro-2-furyl)acrylamide DMSO solution for the TA100 strain under the non-metabolism activating condition, 40 μg/mL of 2-aminoanthracene DMSO solution for the TA98 strain, 20 μg/mL of 2-aminoanthracene DMSO solution for the TA100 strain under the metabolism activating condition as a positive control, and 588 μL of the test bacterial solution (a mixed solution of 498 μl of the test bacterial solution and 90 μL of S9 mix under the metabolism activating condition) are mixed, and this is shaking-cultured at 37° C. for 90 minutes. 460 μL of the bacterial solution exposed to the test substance is mixed with 2300 μL of an Indicator medium (Micro F buffer containing biotin: 8 g/mL, histidine: 0.2 μg/mL, glucose: 8 mg/mL, Bromo Cresol Purple: 37.5 μg/mL), each 50 μL is dispensed into microplate 48 wells/dose, and this is subjected to stationary culturing at 37° C. for 3 days. Since a well containing a bacterium which has obtained the proliferation ability by mutation of an amino acid (histidine) synthesizing enzyme gene turns from purple to yellow due to a pH change, the bacterium proliferation well which has turned to yellow in 48 wells per dose is counted, and is assessed by comparing with a negative control group. (−) means that mutagenicity is negative and (+) is positive.

Test Example 9

Solubility Test

The solubility of a compound was determined under a condition in which 1% DMSO was added. 10 mmol/L compound solution was prepared using DMSO, and then 6 μL of the compound solution was added to 594 μL of artificial intestinal juice in pH 6.8 (to 250 mL of 0.2 mol/L potassium dihydrogen phosphate reagent solution was added 118 mL of 0.2 mol/L NaOH reagent solution and water to provide a final volume of 1000 mL). After standing at 25 degrees Celsius for 16 hours, the mixed solution was filtrated with suction. The filtrate was diluted twice with methanol/water (1/1), and then a concentration in the filtration was measured with HPLC or LC/MS/MS by the absolute calibration method.

(Results)

Compound No. I-0837: >50 μmol/L

Compound No. I-2291: >50 μmol/L

Compound No. I-1788: >50 μmol/L

Compound No. I-1679: >50 μmol/L

Test Example 10

Metabolism Stability Test

Using commercially available pooled human hepatic microsomes, a test compound is reacted for a constant time, a remaining rate is calculated by comparing a reacted sample and an unreacted sample, thereby, a degree of metabolism in liver is assessed.

A reaction was performed (oxidative reaction) at 37° C. for 0 minute or 30 minutes in the presence of 1 mmol/L NADPH in 0.2 mL of a buffer (50 mmol/L tris-HCl pH 7.4, 150 mmol/L potassium chloride, 10 mmol/L magnesium chloride) containing 0.5 mg protein/mL of human liver microsomes. After the reaction, 50 μL of the reaction solution was added to 100 μL of a methanol/acetonitrile=1/1 (v/v), mixed and centrifuged at 3000 rpm for 15 minutes. The test compound in the supernatant was quantified by LC/MS/MS, and a remaining amount of the test compound after the reaction was calculated, letting a compound amount at 0 minute reaction time to be 100%.

(Results) The remaining rate at the compound concentration 0.5 μmol/L are shown below.

Compound No. I-0837: 99%Compound No. I-2291: 94%

Compound No. I-1788: >99.9%

Test Example 11

hERG Test

For the purpose of assessing risk of an electrocardiogram QT interval prolongation, effects on delayed rectifier K+ current (I_Kr), which plays an important role in the ventricular repolarization process, is studied using HEK293 cells expressing human ether-a-go-go related gene (hERG) channel.

After a cell was retained at a membrane potential of −80 mV by whole cell patch clamp method using an automated patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), I_Kr induced by depolarization pulse stimulation at +50 mV for 2 seconds and, further, repolarization pulse stimulation at −50 mV for 2 seconds is recorded. After the generated current is stabilized, extracellular solution (NaCl: 137 mmol/L, KCl: 4 mmol/L, CaCl₂. 2H₂O: 1.8 mmol/L, MgCl₂.6H₂O: 1 mmol/L, glucose: 10 mmol/L, HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid): 10 mmol/L, pH=7.4) in which the test compound had been dissolved at an objective concentration (1.0 μmol/L) is applied to the cell under the room temperature condition for 10 minutes. From the recording I_Kr, an absolute value of the tail peak current is measured based on the current value at the resting membrane potential using an analysis software (DataXpress ver. 1, Molecular Devices Corporation). Further, the % inhibition relative to the tail peak current before application of the test substance is calculated, and compared with the vehicle-applied group (0.1% dimethyl sulfoxide solution) to assess influence of the test substance on I_Kr.

Test Example 12

Metabolic Stability Test

The test compound is reacted for a given period of time using cryopreserved rat hepatocytes that are prepared and the residual ratio is calculated based on the comparison between reacted and unreacted samples to evaluate the degree of hepatic metabolism.

The compound is reacted in the Williams E medium containing 1.0×10⁶ cells/mL of cryopreserved rat hepatocytes at a temperature of 37° C. for 0, 1 or 2 hours. After reaction, 50 μL of reaction solution is added to and mixed with 100 μL of a solution containing methanol and acetonitrile in the proportion of one to one (v/v) and the mixture is centrifuged at 3000 rpm for 15 minutes. The test compound contained in the centrifugal supernatant is quantitated using a LC/MS/MS system and the residual ratio of the test compound after reaction is calculated regarding the amount of compound after the reaction for 0 minute as 100%.

Test Example 13

Protein Binding Test

The unbound fraction of the present compound in serum was measured using serum of various species.

The reactive conditions are as follows: Evaluation method, Equilibrium dialysis; Reaction time, 24 hours; Reaction temperature, 37° C.; Concentration of the present compound, 2 μg/mL The test solution was added to each serum and the mixture was agitated to prepare the serum samples at the concentration mentioned above. Each serum sample was added into one side of the cell and phosphate buffered saline (PBS) was added into the other side to perform equilibrium dialysis at 37° C. for 24 hours. Then, the concentration of the compounds in the samples that were obtained from both sides was measured by LC/MS/MS.

(Result) The ratio of PBS concentration to serum concentration is expressed as unbound fraction.

Compound No. I-0837: 2.1%Compound No. I-2291: 4.5%Compound No. I-1679: 1.8%Compound No. I-2011: 0.5%

Test Example 14

Bioavailability (BA) Test

Materials and Methods for Experiment of BA

(1) Animals: Mice or SD rats were used(2) Breeding conditions: Mice or SD rats were allowed to freely take solid food and sterilized tap water.(3) Dose and grouping: orally or intravenously administered at a predetermined dose; grouping was as follows (Dose depends on the compound)

Oral administration: 0.3 to 30 mg/kg (n=2 to 3)

Intravenous administration: 0.5 to 10 mg/kg (n=2 to 3)

(4) Preparation of dosing solution: for oral administration, in a solution or a suspension state; for intravenous administration, in a solubilized state(5) Administration method: in oral administration, forcedly administer into ventriculus with oral probe; in intravenous administration, administer from caudal vein with a needle-equipped syringe(6) Evaluation items: blood was collected over time, and the plasma concentration of drug was measured by LC/MS/MS(7) Statistical analysis: regarding the transition of the plasma concentration of the present compound, the area under the plasma concentration-time curve (AUC) was calculated by non-linear least squares program WinNonlin (Registered trade name), and the bioavailability (BA) was calculated from the AUCs of the oral administration group and intravenous administration group

(Results)

Compound No. I-0837: 46%

Compound No. I-2291: 83%

Compound No. I-1788: 31%

Compound No. I-1679: >99.9%

Preparation Example 1

A granule containing the following ingredient is prepared.

	Ingredient	Compound of the formula (I)	10	mg
		Lactose	700	mg
		Corn starch	274	mg
		HPC—L	16	mg

The compound of the formula (I) and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed with a V-type mixing machine. An aqueous solution of HPC-L (low viscosity hydroxypropylcellulose) is added to a mixture powder, and this is kneaded, granulated (extrusion granulation, pore diameter 0.5 to 1 mm), and dried. The resulting dry granule is sieved with a vibration sieve (12/60 mesh) to obtain a granule.

Preparation Example 2

A powder for filling into a capsule containing the following ingredients is prepared.

	Ingredient	Compound of the formula (I)	15	mg
		Lactose	90	mg
		Corn starch	42	mg
		HPC—L	3	mg

The compound of the formula (I), and lactose are passed through a 60 mesh sieve. Corn starch is passed through a 120 mesh sieve. These are mixed, a HPC-L solution is added to the mixed powder, this is kneaded, granulated, and dried. The resulting dry granule is adjusted in a size, and 150 mg of it is filled into a No. 4 hard gelatin capsule.

Preparation Example 3

A tablet containing the following ingredients is prepared.

	Ingredient	Compound of the formula (I)	10	mg
		Lactose	90	mg
		Microcrystaline cellulose	30	mg
		CMC—Na	15	mg
		Magnesium stearate	5	mg

The compound of the formula (Ia), lactose, microcrystalline cellulose, CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve, and mixed. Magnesium stearate is mixed into a mixture powder to obtain a mixture powder for tabletting. The present mixed powder is directly compressed to obtain a 150 mg tablet.

Formulation Example 4

The following ingredients are warmed, mixed, and sterilized to obtain an injectable.

	Ingredient	Compound of the formula (I)	3	mg
		Nonionic surfactant	15	mg
		Purified water for injection	1	ml

Formulation Example 5

A cataplasm containing the following ingredients is prepared.

Ingredient	Compound of the formula (I)	50	mg
	aqueous-based (5% ethanol/5%	950	mg
	butylene glycol/90% purified water)
	glycerin
	kaoline
	aqueous polyvinyl alcohol

The compound of the formula (I) is added to aqueous-based. The mixture is irradiated by ultrasonic for 15 minutes and then is sufficiently stirred to obtain a solution. 5 part of glycerin, 1 part of kaoline and 5 part of aqueous polyvinyl alcohol are homogeneously mixed and 1 part of the resulting solution is added to the above solution including the compound of the formula (I). The obtained solution is mixed and to give a paste form and the resulting paste is applied to an non-woven fabric. The resulting composition is covered by polyester film to give a cataplasm.

As shown, the compounds described in the present specification showed inhibiting activity on P2X₃ receptor and analgesic activity and treating effect on overactive bladder. Furthermore, as the compounds of the invention are effective on P2X₃ subtype, the compounds are also considered to have inhibiting activity on P2X_2/3 receptor, which comprises P2X₃ subtype.

INDUSTRIAL APPLICABILITY

The compounds of the general formula (I), the general formula (II), the general formula (III), the general formula (IV), the general formula (VII), the general formula (VIII) and the general formula (IX) have an antagonistic effect on P2X₃ and/or P2X_2/3 receptor and are useful in the treatment of diseases or conditions associated with a P2X₃ and/or P2X_2/3 receptor, such as chronic pain, urination disorder, etc.

LENGTHY TABLES
The patent application contains a lengthy table section. A copy of the table is available in electronic form from the USPTO web site (). An electronic copy of the table will also be available from the USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

Claims

1. A compound of the formula (VIII):

2. The compound according to claim 1, wherein -L- is —O—, or its pharmaceutically acceptable salt or a solvate thereof.

3. The compound according to claim 1, wherein ring B is an aromatic heterocyclic ring, or its pharmaceutically acceptable salt or a solvate thereof.

4. The compound according to claim 1 wherein ring B is a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a pyrazole ring, an imidazole ring, a triazole ring, a furan ring, a thiophene ring, a thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a triazine ring or a benzoxazole ring, or its pharmaceutically acceptable salt or a solvate thereof.

5. The compound according to claim 1, wherein ring B is a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, a thiadiazole ring, an oxadiazole ring, a pyridine ring, a pyrimidine ring, a pyrazine ring or a pyridazine ring, or its pharmaceutically acceptable salt or a solvate thereof.

6. The compound according to claim 1, wherein s′ is an integer of 1 to 2, and at least one of R9′ is hydroxy, carboxy, cyano, substituted alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt or a solvate thereof.

7. The compound according to claim 1, wherein s′ is 1, and R9′ is carboxy or substituted or unsubstituted carbamoyl, or its pharmaceutically acceptable salt or a solvate thereof.

8. A compound of the formula (IX):

9. The compound according to claim 8, wherein R13a and R13b are both hydrogen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

10. The compound according to claim 8, wherein ring E is a cyclopropane ring, or its pharmaceutically acceptable salt or a solvate thereof.

11. The compound according to claim 1, wherein ring D is a benzene ring, or its pharmaceutically acceptable salt or a solvate thereof.

12. The compound according to claim 1, wherein carbon atom a is positioned on ring D in a 1,4 relationship with respect to carbon atom b, or its pharmaceutically acceptable salt or a solvate thereof.

13. The compound according to claim 1, wherein s and s′ are each independently an integer of 0 to 2; and R9 and R9′ are each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt or a solvate thereof.

14. A compound of the formula (VII):

15. The compound according to claim 14, wherein s is an integer of 0 to 2; and R9 is each 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 alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or substituted sulfinyl, or its pharmaceutically acceptable salt or a solvate thereof.

16. The compound according to claim 1, wherein Z1 and Z2 are both oxygen atoms or both sulfur atoms, or its pharmaceutically acceptable salt or a solvate thereof.

17. The compound according to claim 1, wherein Z1 and Z2 are both oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

18. The compound according to claim 1, wherein Rc is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group A, unsubstituted alkynyl or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

19. The compound according to claim 1, wherein Rc is unsubstituted alkyl, alkyl substituted with one or more substituents selected from Substituent Group B″ (Substituent Group B″: hydroxy, carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), unsubstituted alkenyl, alkenyl substituted with one or more substituents selected from Substituent Group B″, unsubstituted alkynyl or alkynyl substituted with one or more substituents selected from Substituent Group B″, or its pharmaceutically acceptable salt or a solvate thereof.

20. The compound according to claim 1, wherein Rc is unsubstituted alkyl, or its pharmaceutically acceptable salt or a solvate thereof.

21. The compound according to claim 1, wherein Rc is —(CR11aR11b)m-OH; R11a and R11b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R11a and R11b together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; and m is an integer of 2 to 4, or its pharmaceutically acceptable salt or a solvate thereof.

22. The compound according to claim 1, wherein Rc is —(CR11aR11b)m-OH; R11a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R11b is —(CR12aR12b)u-OH; R12a and R12b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; u is an integer of 0 to 2; and m is an integer of 2 to 4, or its pharmaceutically acceptable salt or a solvate thereof.

23. The compound according to claim 1, wherein Rc is a group of the formula:

24. The compound according to claim 1, wherein Rc is —(CR14aR14b)t-N(R15a)(R15b); R14a and R14b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R14a and R14b together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; t is an integer of 2 to 4; and R15a and R15b 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 —(CR14a′R14b′)t′-C(═O)N(R15a′)(R15b′); R14a′ and R14b′ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl or R14a′ and R14b′ together with the carbon atom to which they are attached form a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted cycloalkene ring, or a substituted or unsubstituted non-aromatic heterocyclic ring; t′ is an integer of 1 to 4; and R15a′ and R15b′ are each independently a hydrogen atom, cyano, 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 its pharmaceutically acceptable salt or a solvate thereof.

25. The compound according to claim 1, wherein Rc is a group of the formula:

26. The compound according to claim 1, wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof.

27. The compound according to claim 1, wherein R4a and R4b are both hydrogen atoms, or R4a and R4b attached to the same carbon atom are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof.

28. The compound according to claim 1, wherein n is 1, and R4a and R4b are both hydrogen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

29. The compound according to claim 1, wherein R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

30. The compound according to claim 1, wherein R2 is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

31. The compound according to claim 1, wherein —X— is —N(R5)—, and R5 is as defined in claim 1, or its pharmaceutically acceptable salt or a solvate thereof.

32. The compound according to claim 1, wherein —X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof.

33. A compound of the formula (IV):

34. The compound according to claim 33, wherein Z1, Z2 and Z3 are oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

35. The compound according to claim 33, wherein R6 is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

36. The compound according to claim 33, wherein R6′ is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

37. A pharmaceutical composition comprising the compound according to claim 1, or its pharmaceutically acceptable salt, or a solvate thereof.

38. The pharmaceutical composition according to claim 37, wherein the composition has a P2X3 and/or P2X2/3 receptor antagonistic effect.

39. A compound according to claim 1, or its pharmaceutically acceptable salt, or a solvate thereof for use in a method for treating and/or preventing a disease related to P2X3 and/or P2X2/3 receptor.

40. A method for treating and/or preventing a disease related to P2X3 and/or P2X2/3 receptor comprising administering the compound according to claim 1, or its pharmaceutically acceptable salt, or a solvate thereof.

41. A pharmaceutical composition having an analgesic effect or an improving effect of urination disorder comprising a compound of the formula (I):

42. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 41, comprising the compound of the formula (II):

43. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein Z1 and Z2 are both oxygen atoms or both sulfur atoms, or its pharmaceutically acceptable salt or a solvate thereof.

44. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder, according to claim 42, comprising the compound wherein Z1 and Z2 are both oxygen atoms or its pharmaceutically acceptable salt or a solvate thereof.

45. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein Rc1 is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

46. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein Rc1 is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof.

47. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 41, comprising the compound of the formula (III):

48. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 47, comprising the compound wherein Z2 is an oxygen atom or a sulfur atom, or its pharmaceutically acceptable salt or a solvate thereof.

49. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 47, comprising the compound wherein —Y— is —O—, or its pharmaceutically acceptable salt or a solvate thereof.

50. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 47, comprising the compound wherein R1a is alkyl substituted with one or more substituents selected from Substituent Group A (Substituent Group A: 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, a 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 cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocycyloxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo), alkenyl substituted with one or more substituents selected from Substituent Group A, or alkynyl substituted with one or more substituents selected from Substituent Group A, or its pharmaceutically acceptable salt or a solvate thereof.

51. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 47, comprising the compound wherein R1a is alkyl substituted with one or more substituents selected from Substituent Group B′ (Substituent Group B′: carboxy, sulfo, a substituted or unsubstituted non-aromatic heterocyclic group, tetrazolyl, 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, and substituted or unsubstituted guanidyl), alkenyl substituted with one or more substituents selected from Substituent Group B′, or alkynyl substituted with one or more substituents selected from Substituent Group B′, or its pharmaceutically acceptable salt or a solvate thereof.

52. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein n is 1, or its pharmaceutically acceptable salt or a solvate thereof.

53. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein R4a and R4b are both hydrogen atoms, or R4a and R4b attached to the same carbon atom are taken together to form oxo, or its pharmaceutically acceptable salt or a solvate thereof.

54. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

55. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein R2 is cycloalkyl optionally substituted with one or more substituents selected from Substituent Group C (Substituent Group C: halogen, alkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, and alkylsilylalkynyl), aryl optionally substituted with one or more substituents selected from Substituent Group C, or heteroaryl optionally substituted with one or more substituents selected from Substituent Group C, or its pharmaceutically acceptable salt or a solvate thereof.

56. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein —X— is —N(R5)—, and R5 is as defined in claim 41, or its pharmaceutically acceptable salt or a solvate thereof.

57. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein —X— is —NH—, or its pharmaceutically acceptable salt or a solvate thereof.

58. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein R3 is a group of the formula:

59. The pharmaceutical composition having an analgesic effect or an improving effect of urination disorder according to claim 42, comprising the compound wherein R3 is aryl optionally substituted with one or more substituents selected from Substituent Group D (Substituent Group D: halogen; hydroxy; alkyl optionally substituted with halogen, hydroxy, cyano, alkyloxyimino, dialkylamino, alkyloxy, cycloalkyl, or heteroaryl; alkenyl optionally substituted with cycloalkyl; alkynyl optionally substituted with cycloalkyl; alkyloxy optionally substituted with halogen, alkyloxy, cycloalkyl, aryl or a non-aromatic heterocyclic group optionally substituted with alkyl; alkylthio; cycloalkyl; cycloalkenyl; cycloalkyloxy; aryloxy; heteroaryloxy optionally substituted with alkyl; a non-aromatic heterocyclic group; and alkylamino), or heteroaryl optionally substituted with one or more substituents selected from Substituent Group D, or its pharmaceutically acceptable salt or a solvate thereof.

60. A method of producing a compound of the formula (XI):

61. The method of producing according to claim 60, wherein Z1 and Z2 are oxygen atoms.

62. The method of producing according to claim 60, wherein Rf1 is a group of —(CR4aR4b)n-R2; wherein R4a and R4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R4a and R4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4; andR2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

63. The method of producing according to claim 60, wherein Rc1 is substituted or unsubstituted alkyl.

64. The method of producing according to claim 60, wherein R5 is a hydrogen atom.

65. The method of producing according to claim 60, wherein R3 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

66. A compound of the formula (XII):

67. The compound according to claim 66, wherein Z1 and Z2 are oxygen atoms, or its pharmaceutically acceptable salt or a solvate thereof.

68. The compound according to claim 66, wherein Rf1 is a group of —(CR4aR4b)n-R2; wherein R4a and R4b are each independently a hydrogen atom or substituted or unsubstituted alkyl, or R4a and R4b attached to the same carbon atom are taken together to form oxo or thioxo;n is an integer of 1 to 4; andR2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, a substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or its pharmaceutically acceptable salt or a solvate thereof.

69. The compound according to claim 66, wherein Rc1 is substituted or unsubstituted alkyl, or its pharmaceutically acceptable salt or a solvate thereof.

70. The compound according to claim 66, wherein R5 is a hydrogen atom, or its pharmaceutically acceptable salt or a solvate thereof.