JP2001181187A - Composition containing five-membered heteroaryl compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a medicine for preventing or treating diseases related to inflammatory cytokine. SOLUTION: There is provided a medicine for preventing or treating diseases related to inflammatory cytokine, containing a compound of the general formula (I) A is a heteroaryl; Ar1 and Ar2 are each an aryl or a heteroaryl; Q is a (hetero)arylene or a divalent heterocyclic group; R1 is H, an alkyl, an alkenyl, an alkynyl, a halogen or nitro; R2 is H, an alkyl, an alkenyl or an alkynyl R3 is WR4 [W is an alkylene or the like; R4 is azido, nitro, nitrosooxy, nitrooxy, thiocyanato, PO(OR6)(OR7), C(=NOR8)R9 or CON(OR8)R9; R5, R8 and R9 are each H, an alkyl, an alkenyl, an alkynyl, an aryl, an aralkyl, a heteroaryl, a heteroarylalkyl or a protecting group; R6 and R7 are each H, an alkyl an alkenyl, an alkynyl, an aryl or an aralkyl]}.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a 5-membered heteroaryl compound useful as a prophylactic or therapeutic agent for diseases involving inflammatory cytokines. More specifically, the interface
Autoimmune diseases such as antipyretic, analgesic, anti-inflammatory agents and rheumatoid arthritis, which have an inhibitory effect on the production of inflammatory cytokines such as leukin (IL) -1, IL-6, IL-8 and tumor necrosis factor (TNF); The present invention relates to a 5-membered heteroaryl compound useful as a therapeutic agent for bone diseases such as osteoporosis and other diseases in which the above-mentioned cytokine is involved.

[0002]

2. Description of the Related Art Conventionally, nonsteroidal anti-inflammatory drugs (NSA)
ID) has antipyretic, analgesic, and anti-inflammatory actions as its main pharmacological actions, which are based on the inhibition of prostaglandin (PG) biosynthesis by cyclooxygenase inhibition, and is widely used in various inflammatory and painful diseases. It has been. For rheumatoid arthritis and the like, NSAIDs are used for symptomatic treatment, and immunomodulators (DMARDs) are used for causal treatment.

[0003] Conventional NSAIDs cause gastrointestinal disorders such as gastric ulcer due to their mechanism of action, and have problems in long-term continuous use. In addition, DMARD has not yet stably expressed a clear drug effect. In recent years, active substances collectively referred to as cytokines produced by immunocompetent cells have been found. Interleukin (IL)
-1, IL-6, IL-8, tumor necrosis factor (TNF) and the like are called inflammatory cytokines, and activate arachidonic acid metabolism, which is a PG production system, leukocyte migration, induction of acute phase proteins, Various functions as inflammatory mediators such as activation of osteoclasts have been elucidated, and these inflammatory cytokine production inhibitors have a new generation of antipyretic, analgesic, and anti-inflammatory properties by a different mechanism of action. It is expected to be used as a therapeutic agent for inflammatory agents, autoimmune diseases such as rheumatoid arthritis, bone diseases such as osteoporosis, and other diseases in which the cytokine is involved.

[0004] As the heteroaryl compounds having an action of suppressing the production of these inflammatory cytokines, for example, the following compounds are specifically disclosed in WO97 / 5878. Development of excellent compounds is desired.

[0005]

Embedded image

[0006]

SUMMARY OF THE INVENTION The inventors of the present invention have conducted extensive research on the synthesis and pharmacological action of a 5-membered heteroaryl compound capable of suppressing the production of the above-mentioned inflammatory cytokine, and as a result, have found that The inventors have found that a 5-membered heteroaryl compound having at least three cyclic groups on the heteroaryl ring has an excellent inhibitory action on inflammatory cytokine production, and completed the present invention.

[0007]

The present invention provides (1) an inflammatory cytokine containing as an active ingredient a compound having the following general formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof. Preventive or therapeutic agents for the diseases involved:

[0008]

Embedded imageWherein ring A represents a 5-membered heteroaryl ring;¹
And Ar^TwoAre the same or different,
Group, heteroaryl group, substituent group α and substituent group β
An aryl group or a substituent substituted with a group selected from
Substituted with a group selected from group α and substituent group β
Represents a aryl group, and Q represents an arylene group or a heteroaryl group.
A group selected from a len group, a substituent group α and a substituent group β
Substituted arylene group, substituent group α and substituent group β
A heteroarylene group substituted with a group selected from
Divalent 3-8 members containing at least one nitrogen atom
A saturated heterocyclic group;¹Is attached to a carbon atom on the ring
A hydrogen atom, an alkyl having 1 to 15 carbon atoms
Groups, alkenyl groups having 2 to 15 carbon atoms, 2 to 15 carbon atoms
From 15 alkynyl groups, substituent group α and substituent group γ
1 to 1 carbon atoms substituted by 1 to 3 groups selected
5 alkyl groups, selected from substituent group α and substituent group γ
2 to 15 carbon atoms substituted by 1 to 3 groups
Alkenyl group, selected from substituent group α and substituent group γ
2 to 15 carbon atoms substituted with 1 to 3 groups
An alkynyl group, a halogen atom or a nitro group;^Two
Is a group bonded to the nitrogen atom on the ring,
An alkyl group having 1 to 15 primes and 2 to 15 carbons
An alkenyl group, an alkynyl group having 2 to 15 carbon atoms,
1 to 3 groups selected from the substituent group α and the substituent group γ
An alkyl group having 1 to 15 carbon atoms and a substituent
1 to 3 groups selected from group α and substituent group γ
Substituted alkenyl group having 2 to 15 carbon atoms, or substituted
1 to 3 groups selected from group α and substituent group γ
A substituted alkynyl group having 2 to 15 carbon atoms,
R^ThreeIs the general formula -WR^Four, -OWR^Four, -S (O)_mW
R^Four, -N (WR^Four) R^Five, -SO_TwoN (WR^Four) R^Five, -C
ON (WR^Four) R^Five, -COWR^FourOr -PO (OR ⁶)
(OR⁷Wherein m is 0, 1 or 2
W represents an alkylene group, a lower alkenylene group,
Alkylene group, cycloalkenylene group or lower alkynyl
Represents a len group;^FourRepresents an azide group, nitro group, nitroso
Oxy group, nitroxy group, thiocyanate group, group PO
(OR⁶) (OR⁷), Group C (= NOR⁸) R⁹Or the group CO
N (OR ⁸) R⁹And R^Five, R⁸And R⁹Are the same
Each of which is different from a hydrogen atom, a carbon number of 1 to 15
Alkyl groups, alkenyl groups having 2 to 15 carbon atoms,
An alkynyl group having 2 to 15 carbon atoms, an aryl group,
Alkyl group, heteroaryl group, heteroarylalkyl
A group or a protecting group;⁶And R⁷Are the same or different
Means a hydrogen atom, an alkyl having 1 to 15 carbon atoms, respectively.
Kill group, alkenyl group having 2 to 15 carbon atoms, 2 carbon atoms
And represents 15 to 15 alkynyl groups or aralkyl groups. ]
With the proviso that (a) ring A is an oxygen atom, a sulfur atom and
Containing three atoms selected from nitrogen atoms, and
And (b) ring A is formed from an oxygen atom, a sulfur atom and a nitrogen atom
Contains two selected atoms, one of which is an oxygen atom
R or a sulfur atom¹And R^TwoExists
And (c) when ring A contains two nitrogen atoms,
¹And R^TwoIs not present, and (d) ring A is
When no elemental atom is contained, R^TwoDoes not exist. About｝
You. [Substituent group α] halogen atom, cyano group, nitro group, N
R^TenR¹¹(Where R^TenAnd R¹¹Are the same or different,
A hydrogen atom and an alkyl group having 1 to 15 carbon atoms, respectively
Or a halogeno lower alkyl group, or
Together with the nitrogen atom to which they are attached
To form a heterocyclyl group containing two nitrogen atoms
You. ), OR^Ten(Where R^TenHas the same meaning as above.
You. ) And SR^Ten(Where R^TenHas the same meaning as above.
You. ), [Substituent group β] lower alkyl group, and the above-mentioned substituent group α
Lower alkyl group substituted with one to three groups selected from [substituent group γ] aryl group, heteroaryl group, and
Terocyclyl groups (these groups are the substituent group α and the substituent
May be substituted with 1 to 3 groups selected from the group β.
No. ).

[0009] Among these "prophylactic or therapeutic agents for diseases involving inflammatory cytokines", there are preferably used prophylactic or therapeutic agents for diseases involving inflammatory cytokines containing the following compounds as active ingredients. Can be mentioned.
(2) a compound in which ring A is a 5-membered aromatic heterocyclic ring which contains at least one nitrogen atom and may further contain an oxygen atom or a nitrogen atom; (3) ring A is pyrrole, imidazole or oxazole Certain compounds, (4) the following general formula (IA):

[0010]

Embedded image (5) A compound in which Ar ¹ is a heteroaryl group or a heteroaryl group substituted with a group selected from substituent group α and substituent group β.
r ¹ is a 5- or 6-membered aromatic heterocyclic group containing 1 or 2 nitrogen atoms, or 1 or 2 nitrogen atoms substituted with a group selected from substituent group α and substituent group β A compound which is a 5- or 6-membered aromatic heterocyclic group, (7) Ar
Wherein ¹ is pyridyl, pyrimidinyl, pyridyl substituted with a group selected from substituent group α and substituent group β, or pyrimidinyl substituted with a group selected from substituent group α and substituent group β (8) a compound wherein Ar ¹ is 4-pyridyl or 4-pyridyl substituted with a group selected from substituent group α and substituent group β, (9) Ar
^A compound wherein ² is an aryl group, a heteroaryl group or an aryl group substituted with a group selected from substituent group α and substituent group β, and (10) Ar ² is an aryl group,
Or a compound which is an aryl group substituted with a group selected from the substituent group α and the substituent group β, and a pharmacologically acceptable salt, ester or other derivative thereof.

Further, (11) a compound in which Q is an arylene group, a heteroarylene group, or an arylene group substituted with a group selected from the substituent group α and the substituent group β, (12) a compound wherein Q is an arylene group or an arylene group substituted with a group selected from the substituent group α and the substituent group β;
Q is 1,4-phenylene, or a compound in which 1,4-phenylene substituted with a group selected from substituent group α and substituent group β, (14) R ³ is a compound represented by general formula -WR ⁴ , −
OWR ⁴ or a compound having —S (O) _m WR ⁴ , (15) R ³ is a compound having a general formula —S (O) _m WR ⁴ , and (16) R ³ is General formula -S
(O) a group having _m WR ⁴ , wherein m is 1 or 2, and pharmacologically acceptable salts, esters or other derivatives thereof, and (17)
Q is a divalent 3 containing at least one nitrogen atom
Among the compounds having from 8 to 8 membered saturated heterocyclic groups, (18) Q is preferably azetidinediyl, pyrrolidinediyl, imidazolidinediyl, oxazolidinediyl, thiazolidinediyl, piperidinediyl, piperazindiyl, morpholinediyl or thiomorpholine A compound which is diyl, (19) a compound wherein Q is azetidinediyl, pyrrolidinediyl, piperidinediyl or piperazinediyl, (20) a group wherein -QR ³ is represented by the following general formula (II):

[0012]

Embedded image 中 wherein the cyclic group:

[0013]

Embedded image Is in the definition of Q, a divalent 3-8 membered saturated heterocyclic group containing at least one nitrogen atom, R ³ a
Is a general formula -WR ⁴ , -S (O) _m in the definition of R ^3.
WR ⁴ , -SO ₂ N (WR ⁴ ) R ⁵ , -CON (WR ⁴ )
R ^5, a group having a -COWR ⁴ or ^{-PO (OR 6) (OR 7} ). A compound which is a group having｝, (21) R
³ is a compound represented by the general formula -WR ⁴ , -S (O) _m WR ⁴ or -COWR
^And (22) a compound wherein R ³ is a group having the general formula -WR ⁴ or -COWR ⁴ ;
(23) Compounds in which R ³ is a group having the general formula —WR ⁴ and pharmacologically acceptable salts, esters or other derivatives thereof can be mentioned.

Among the above compounds, more preferred compounds are (24) compounds wherein W is an alkylene group, lower alkenylene group or lower alkynylene group, (25) W
Is an alkylene group; (26) a compound wherein W is a linear or branched alkylene group having 1 to 4 carbon atoms; (27) a compound wherein W is a linear or branched alkylene group having 1 to 3 carbon atoms. A compound which is a branched alkylene group, (28) W
Is a compound in which m is methylene, ethylene or trimethylene; (29) a compound in which W is methylene or ethylene; (30) a compound in which R ⁴ is an azide group, a nitro group, a thiocyanate group or a group PO (OR ⁶ ) (OR ⁷ ) [Wherein, R ⁶ ,
R ⁷ , R ⁸ and R ⁹ are as defined above. (31) a compound wherein R ⁴ is an azide group or a nitro group; (32) a compound wherein R ¹ is a hydrogen atom, a carbon atom of 1 to 1
5 alkyl groups or 1 to 1 carbon atoms substituted with 1 to 3 groups selected from substituent group α and substituent group γ
Five compounds is an alkyl group, (33) R ¹ is a compound which is a hydrogen atom, (34) R ² is a hydrogen atom, an alkyl group of 1 to 15 carbon atoms, or a substituent group α and substituents A compound which is an alkyl group having 1 to 15 carbon atoms and substituted by 1 to 3 groups selected from the group γ, (35)
Examples thereof include compounds in which R ² is a hydrogen atom, and pharmacologically acceptable salts, esters, and other derivatives thereof.

Further, in the compounds specified in the above (1), (2) to (4), (5) to (8), (9) and (10), (11) to (23), (24) ) To (2)
9), (30) and (31), (32) and (33),
Compounds satisfying a combination of requirements arbitrarily selected from the eight groups consisting of (34) and (35) are also suitable.

Among these, particularly preferred compounds include (36) a compound selected from the following or a pharmacologically acceptable salt, ester or other derivative thereof: 5- [4- ( 2-azidoethylsulfinyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (3- Nitropropylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (3-nitropropylsulfonyl) phenyl] -3- (pyridine -4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (3-nitroxypropylsulfinyl) phenyl] -3- (pyridine-4 -Yl) -1H-pyrrole, 5- [4- (2-diethylphosphonoethylsulfinyl) phenyl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 5- [4- (2-diethylphosphonoethylsulfonyl) phenyl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -5- [4- (2-thiocyanatoethylsulfinyl) phenyl] -1H-pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4)
-Yl) -5- [4- (2-thiocyanatoethylsulfonyl) phenyl] -1H-pyrrole, 5- [4- (3-azidopropylsulfinyl) phenyl] -2- (4-fluorophenyl)- 3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (3-azidopropylsulfonyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H -Pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -5- [4- (3-thiocyanatopropylsulfinyl) phenyl] -1H-pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4)
-Yl) -5- [4- (3-thiocyanatopropylsulfonyl) phenyl] -1H-pyrrole, 5- [4- (2-azidoethylsulfonyl) phenyl] -2- (4-fluorophenyl)- 3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (azidomethylsulfinyl) phenyl]
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H-pyrrole, 5- [4- (azidomethylsulfonyl) phenyl]-
2- (4-fluorophenyl) -3- (pyridine-4-
Yl) -1H-pyrrole, 5- [1- (2-diethylphosphonoethyl) piperidin-4-yl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (2-nitroethyl) piperidin-4-yl] -3- (pyridin-4-yl) -1H -Pyrrole, -5- [1- (diethylphosphonomethyl) piperidine-
4-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (3-nitropropionyl) piperidine -4-yl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (dimethylphosphoryl) piperidin-4-yl] -3- (pyridine -2-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (4-nitrobutylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (3-chlorophenyl) -5- [4- (3-nitropropylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole; and 2- (3,4-difluorophenyl)- 5- [ -
(3-Nitropropylsulfinyl) phenyl] -3-
(Pyridin-4-yl) -1H-pyrrole, most preferred compounds include (37) a compound selected from: or a pharmaceutically acceptable salt, ester or other derivative thereof. -[4- (2-azidoethylsulfinyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [ 4- (3-nitropropylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (3-nitropropylsulfonyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (3-azidopropylsulfinyl) phenyl] -2- (4-fluorophenyl) -3- Pyridin-4-yl) -1H-pyrrole, 5- [4- (3-azidopropylsulfonyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (2-azidoethylsulfonyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole; 5- [4- (azidomethylsulfinyl) Phenyl]
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H-pyrrole, 5- [1- (2-diethylphosphonoethyl) piperidin-4-yl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (2-nitroethyl) piperidin-4-yl] -3- (pyridin-4-yl) -1H -Pyrrole, -5- [1- (diethylphosphonomethyl) piperidine-
4-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, and 2- (4-fluorophenyl) -5- [1- (3-nitropropionyl) Piperidin-4-yl] -3- (pyridin-4-yl) -1H-pyrrole.

The “prophylactic or therapeutic agent for diseases involving inflammatory cytokines” of the present invention includes, for example, analgesic / anti-inflammatory agents, antiviral agents, and rheumatoid arthritis, osteoarthritis, allergic diseases, asthma , Sepsis, psoriasis, osteoporosis, autoimmune diseases (eg, systemic lupus erythematosus,
Ulcerative colitis, Crohn's disease, etc.), diabetes, glomerulonephritis,
It can be used as a prophylactic or therapeutic agent for arteriosclerosis, particularly, an analgesic / anti-inflammatory agent, and rheumatoid arthritis,
It can be used as a preventive or therapeutic agent for osteoarthritis, allergic disease, sepsis, psoriasis, osteoporosis, ulcerative colitis, diabetes, and arteriosclerosis.

In the above general formula (I), the term "5-membered heteroaryl ring" in the definition of ring A means furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole and the like. A 5-membered aromatic heterocyclic ring containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms,
Preferably, it is a 5-membered aromatic heterocycle containing at least one nitrogen atom such as pyrrole, imidazole or oxazole, and optionally containing an oxygen atom or nitrogen atom, and most preferably pyrrole. In the compound in which ring A is pyrrole, the compound represented by the following general formula (IA):

[0019]

Embedded image (Wherein, Ar ¹ , Ar ² , Q, R ¹ , R ^2, and R ³ have the same meanings as described above).

Ar ¹ , Ar ² , R ⁵ , R ⁸ , R ⁹ and the “aryl group” in the definition of the substituent group γ; and the “aryl group α and the substituent group β in the definition of Ar ¹ and Ar ^2. The `` aryl group '' of the `` aryl group substituted with a selected group '' is, for example, phenyl, indenyl, naphthyl,
It represents an aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenanthryl and anthracenyl, and is preferably phenyl or naphthyl, and most preferably phenyl.

The "aryl group" may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples of such a group include 5-indanyl.

The “aryl group substituted with a group selected from the substituent group α and the substituent group β” in the definition of Ar ¹ and Ar ² is preferably selected from the substituent group α and the substituent group β. And the aryl group substituted with 1 to 3 groups selected from the substituent group α and the substituent group β is more preferable.

Ar¹, Ar^Two, R^Five, R⁸, R⁹And substituents
“Heteroaryl group” in the definition of group γ; and Ar
¹And Ar^Two"Substituent group α and substituent group β
A heteroaryl group substituted with a group selected from
“Heteroaryl” refers to furyl, thienyl, pyrrolyl.
, Pyrazolyl, imidazolyl, oxazolyl, isoki
Sazolyl, thiazolyl, isothiazolyl, triazolyl
, Tetrazolyl, thiadiazolyl, pyranyl, pyridi
Like pyr, pyridazinyl, pyrimidinyl, pyrazinyl
1 to 3 sulfur, oxygen and / or nitrogen atoms
And represents a 5- to 7-membered aromatic heterocyclic group containing
Ril, thienyl, pyrrolyl, pyrazolyl, imidazoly
, Oxazolyl, isoxazolyl, thiazolyl, iso
Thiazolyl, pyranyl, pyridyl, pyridazinyl, pyri
Sulfur, oxygen, and midinyl and pyrazinyl
And / or 5- or 6-membered fragrance containing one or two nitrogen atoms
Group heterocyclic group, more preferably furyl, thienyl,
Pyridyl or pyrimidinyl. Ar¹about,
Even more preferably, such as pyridyl or pyrimidinyl
5- or 6-membered aromatic heterocycle containing one or two nitrogen atoms
And particularly preferably 4-pyridyl or 4-pyrimidyl.
Jil, most preferably 4-pyridyl. Ar ^Two
Is even more preferably with furyl or thienyl.
is there.

The above “heteroaryl group” may be condensed with another cyclic group. Examples of such a group include indolyl, benzofuranyl, benzothienyl,
Isoquinolyl, quinolyl and the like can be mentioned.

The “heteroaryl group substituted with a group selected from the substituent group α and the substituent group β” in the definition of Ar ¹ and Ar ² is preferably a substituent group α and a substituent group β
A heteroaryl group substituted with 1 to 3 groups selected from the group consisting of, more preferably, a heteroaryl group substituted with 1 to 2 groups selected from the substituent group α and the substituent group β Group.

"Arylene group" in the definition of Q;
The “arylene group” in the “arylene group substituted with a group selected from the substituent group α and the substituent group β” is defined as having 6 carbon atoms.
Represents a divalent group of from 14 to 14 aromatic hydrocarbons, and preferably has 6 to 10 carbon atoms such as phenylene and naphthylene.
Aromatic hydrocarbon divalent groups, more preferably,
1,4-phenylene, 1,3-phenylene or 1,4-
Naphthylene, most preferably 1,4-phenylene.

The above "arylene group" may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples of such a group include indane-4,7-diyl. be able to.

The “arylene group substituted with a group selected from the substituent group α and the substituent group β” in the definition of Q is
Preferably, 1 selected from the substituent group α and the substituent group β
And 2 represents an arylene group substituted with two groups, and more preferably an arylene group substituted with one group selected from the substituent group α and the substituent group β.

"Heteroarylene group" in the definition of Q
And the `` heteroarylene group '' of the `` heteroarylene group substituted with a group selected from the substituent group α and the substituent group β '' refers to furanylene, thienylene, pyrrolylene, azepinylene, pyrazolylen, imidazolylen, oxazolylen, isoxazolyl 5 to 5 containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms such as len, thiazolylene, isothiazolylene, 1,2,3-oxadiazolylene, triazolylene, thiadiazolylene, pyranylene, pyridylene, pyridazinylene, pyrimidinylene, pyrazinylene It represents a divalent group of a 7-membered aromatic heterocycle. Preferably, it is a divalent group of a 5- or 6-membered aromatic heterocyclic ring containing one or two sulfur atoms, oxygen atoms and / or nitrogen atoms,
More preferably, it is thienylene, imidazolylene, pyridylene or pyrazinylene, even more preferably thienylene, and particularly preferably 1,3-thienylene.

The above "heteroarylene group" may be condensed with another cyclic group.
For example, indole-4,7-diyl, benzothiophene-4,7-diyl and the like can be mentioned.

The “heteroarylene group substituted with a group selected from the substituent group α and the substituent group β” in the definition of Q is preferably a 1-membered group selected from the substituent group α and the substituent group β. And represents a heteroarylene group substituted with two or more groups, and more preferably a heteroarylene group substituted with one group selected from the substituent group α and the substituent group β.

In the definition of Q, “a divalent 3- to 8-membered saturated heterocyclic group containing at least one nitrogen atom” contains one nitrogen atom and further contains a sulfur atom, an oxygen atom and / or And a divalent group of a 3- to 8-membered saturated heterocyclic ring which may contain 1 to 2 nitrogen atoms, preferably contains 1 nitrogen atom, and further contains a sulfur atom, an oxygen atom or a nitrogen atom. Represents a divalent group of a 3- to 8-membered saturated heterocyclic ring which may contain one, such as azetidinediyl, pyrrolidinediyl, imidazolidinediyl,
Mention may be made of groups such as oxazolidinediyl, thiazolidinediyl, piperidinediyl, piperazinediyl, morpholinediyl and thiomorpholinediyl.
More preferably, it is a divalent group of a 4- to 6-membered saturated heterocyclic ring which contains one nitrogen atom and may further contain one sulfur atom, oxygen atom or nitrogen atom. Is azetidinediyl, pyrrolidinediyl, piperidinediyl or piperazinediyl, particularly preferably azetidine-1,3-diyl, pyrrolidine-1,3-diyl, piperidine-1,4-diyl or piperazine-1,
4-diyl.

When Q represents “a divalent 3- to 8-membered saturated heterocyclic group containing at least one nitrogen atom”, the group —QR ³ is preferably represented by the following general formula (II):

[0034]

Embedded image (Wherein the cyclic group:

[0035]

Embedded image Represents “a divalent 3- to 8-membered saturated heterocyclic group containing at least one nitrogen atom” in the definition of Q. ).

R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R
“An alkyl group having 1 to 15 carbon atoms” in the definition of ¹⁰ and R ¹¹ and “1 to 3 groups selected from the substituent group α and the substituent group γ in the definition of R ¹ and R ² 1 carbon atom of "substituted alkyl group having 1 to 15 carbon atoms"
As the 15 to 15 alkyl groups, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1
-Methylpentyl, 3,3-dimethylbutyl, 2,2-
Dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methyl Hexyl,
4-methylhexyl, 5-methylhexyl, 1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-
Methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-
Methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl, 1-propylhexyl, 2-
Ethylheptyl, 6,6-dimethylheptyl, decyl,
1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl,
There may be mentioned straight-chain or branched-chain alkyls such as 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl, dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl.
Preferably, methyl, ethyl, propyl, isopropyl,
n-butyl, isobutyl, s-butyl, tert-butyl,
n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl,
-Methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl , A lower alkyl group such as 2-ethylbutyl, and more preferably a lower alkyl group.
From 4 to 4 alkyl groups, even more preferably methyl, ethyl or propyl. R ⁵ , R ⁶ and R ⁸ are particularly preferably methyl or ethyl.

The “lower alkyl group” in the definition of the substituent group β and the “lower alkyl group” of the “lower alkyl group substituted with one to three groups selected from the substituent group α” are It represents a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms, and examples of such a group include those having 1 to 6 carbon atoms among the alkyls mentioned as the “alkyl group having 1 to 15 carbon atoms”. Can be mentioned. It is preferably an alkyl group having 1 to 4 carbon atoms, more preferably methyl, ethyl or propyl, particularly preferably methyl or ethyl, and most preferably methyl.

"An alkenyl group having 2 to 15 carbon atoms" in the definition of R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ ;
And 2 to 15 carbon atoms of the “alkenyl group having 2 to 15 carbon atoms substituted with 1 to 3 groups selected from the substituent group α and the substituent group γ” in the definition of R ¹ and R ^2.
Alkenyl groups include, for example, vinyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2
-Propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1
-Methyl-3-butenyl, 2-methyl-3-butenyl,
1-ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3
-Pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4
-Pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 6-heptenyl, 7-octenyl, 8-nonenyl, 9-decenyl, 10-undecenyl, 11-dodecenyl , 12-tridecenyl, 13-tetradecenyl, 1
A straight-chain or branched-chain alkenyl group such as 4-pentadecenyl may be mentioned, and preferably, vinyl, 2-propenyl, 1-methyl-2-propenyl, 2-methyl-2-
Propenyl, 2-ethyl-2-propenyl, 2-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-
Methyl-3-butenyl, 2-methyl-3-butenyl, 1
-Ethyl-3-butenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-
Pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-
Lower alkenyl groups such as pentenyl, 2-methyl-4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl, and more preferably alkenyl groups having 3 to 5 carbon atoms. .

"An alkynyl group having 2 to 15 carbon atoms" in the definition of R ¹ , R ² , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ ;
And 2 to 15 carbon atoms of "an alkynyl group having 2 to 15 carbon atoms substituted with 1 to 3 groups selected from the substituent group α and the substituent group γ" in the definition of R ¹ and R ^2.
Alkynyl groups include, for example, ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-
2-propynyl, 2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-
Butynyl, 1-ethyl-2-butynyl, 3-butynyl,
1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1-
Methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2
-Methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2
-Hexynyl, 3-hexynyl, 4-hexynyl, 5-
Straight or branched chain alkynyl groups such as hexynyl, 6-heptynyl, 7-octynyl, 8-noninyl, 9-decynyl, 10-undecynyl, 11-dodecinyl, 12-tridecynyl, 13-tetradecynyl, 14-pentadecynyl; And preferably ethynyl, 2
-Propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2-propynyl, 2
-Butynyl, 1-methyl-2-butynyl, 2-methyl-
2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1
-Methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2
-Methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2
-Hexynyl, 3-hexynyl, 4-hexynyl, 5-
It is a lower alkynyl group such as hexynyl, and more preferably an alkynyl group having 3 to 5 carbon atoms.

The "halogen atom" in the definition of R ¹ and the substituent group α indicates a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The substituent group α is preferably a fluorine atom and a chlorine atom.

[0041] In the general formula -S (O) _m WR ^4, "m"
Represents 0, 1 or 2, and is preferably 1 or 2.

The “alkylene group” in the definition of W is
Methylene, ethylene, trimethylene, propylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 1,1-dimethylethylene, pentamethylene, 1,1-dimethyltrimethylene, hexamethylene,
And represents a linear or branched alkylene group having 1 to 10 carbon atoms such as heptamethylene, octamethylene, nonamethylene, and decamethylene. Preferably, it is a straight-chain or branched-chain alkylene group having 1 to 4 carbon atoms, more preferably, a straight-chain or branched-chain alkylene group having 1 to 3 carbon atoms. , Ethylene or trimethylene, particularly preferably methylene or ethylene.

"Lower alkenylene group" in the definition of W
Is vinylene, 1-methylvinylene, propenylene,
1-butenylene, 2-butenylene, 1-pentenylene,
A linear or branched alkenylene group having 2 to 6 carbon atoms such as 2-pentenylene; preferably a linear or branched alkenylene group having 2 to 4 carbon atoms, more preferably Is vinylene, propenylene or butenylene.

"Cycloalkylene group" in the definition of W
Is cyclopropylene, 1,2-cyclobutylene,
1,3-cyclobutylene, 1,2-cyclopentylene,
1,3-cyclopentylene, 1,2-cyclohexylene, 1,3-cyclohexylene, 1,4-cyclohexylene, 1,2-cycloheptanylene, 1,3-cycloheptanylene, 1,4-cyclo A cycloalkylene group having 3 to 7 carbon atoms such as heptanylene is shown. Preferably, it is a cycloalkylene group having 3 to 6 carbon atoms, more preferably cyclopropylene, 1,3-cyclobutylene, 1,3-cyclopentylene or 1,3-cyclohexylene.

The "cycloalkenylene group" in the definition of W means 1,2-cyclopropenylene, 1,3-cyclopropenylene, 1,2-cyclobutenylene, 1,3-cyclopropenylene,
Cyclobutenylene, 1,4-cyclobutenylene, 1,2
-Cyclopentenylene, 1,3-cyclopentenylene,
1,4-cyclopentenylene, 1,5-cyclopentenylene, 3,4-cyclopentenylene, 3,5-cyclopentenylene, 1,2-cyclohexenylene, 1,3-cyclohexenylene Len, 1,4-cyclohexenylene, 1,
5-cyclohexenylene, 1,6-cyclohexenylene, 3,4-cyclohexenylene, 3,5-cyclohexenylene, 3,6-cyclohexenylene, 4,5-cyclohexenylene, 1,2- Cycloheptenylene, 1,3
-Cycloheptenylene, 1,4-cycloheptenylene,
3 carbon atoms such as 2,3-cycloheptenylene, 2,4-cycloheptenylene, 3,4-cycloheptenylene, 3,6-cycloheptenylene, and 3,7-cycloheptenylene And represents 7 to 7 cycloalkenylene groups. Preferably, it is a cycloalkenylene group having 3 to 6 carbon atoms,
More preferably, 1,2-cyclopropenylene, 1,2-
Cyclobutenylene, 1,3-cyclopentenylene or 1,3-cyclohexenylene.

"Lower alkynylene group" in the definition of W
Represents a linear or branched alkynylene group having 2 to 6 carbon atoms, preferably a linear or branched alkynylene group having 2 to 4 carbon atoms, more preferably ethynylene, It is propynylene, 1-butynylene or 2-butynylene, particularly preferably ethynylene or propynylene.

The “aralkyl group” in the definition of R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ means that the above “aryl group” is the above “alkyl group having 1 to 15 carbon atoms” (preferably, Represents a group bonded to the above “lower alkyl group”), such as benzyl, indenylmethyl, phenanthrenylmethyl, anthracenylmethyl, α-naphthylmethyl, β-naphthylmethyl, Diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, piperonyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl, 2-phenylpropyl, 3 -Phenylpropyl, 1-naphthylpropyl, 2
-Naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 1 -Phenylpentyl, 2-phenylpentyl, 3
-Phenylpentyl, 4-phenylpentyl, 5-phenylpentyl, 1-naphthylpentyl, 2-naphthylpentyl, 3-naphthylpentyl, 4-naphthylpentyl, 5-naphthylpentyl, 1-phenylhexyl,
-Phenylhexyl, 3-phenylhexyl, 4-phenylhexyl, 5-phenylhexyl, 6-phenylhexyl, 1-naphthylhexyl, 2-naphthylhexyl, 3-naphthylhexyl, 4-naphthylhexyl, 5
-Naphthylhexyl and 6-naphthylhexyl.

The aryl part of the “aralkyl group” may be substituted with one to three groups selected from the above “substituent group α” and “substituent group β”. Examples of the substituted aralkyl group include 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl,
-Chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 3,5-difluorobenzyl, 2,5-difluorophenethyl, 2,6-difluorobenzyl, 2,4-difluorophenethyl, 3,5
-Dibromobenzyl, 2,5-dibromophenethyl,
2,6-dichlorobenzyl, 2,4-dichlorophenethyl, 2,3,6-trifluorobenzyl, 2,3,4-
Trifluorophenethyl, 3,4,5-trifluorobenzyl, 2,5,6-trifluorophenethyl, 2,
4,6-trifluorobenzyl, 2,3,6-tribromophenethyl, 2,3,4-tribromobenzyl, 3,
4,5-tribromophenethyl, 2,5,6-trichlorobenzyl, 2,4,6-trichlorophenethyl, 1-
Fluoro-2-naphthylmethyl, 2-fluoro-1-naphthylethyl, 3-fluoro-1-naphthylmethyl, 1
-Chloro-2-naphthylethyl, 2-chloro-1-naphthylmethyl, 3-bromo-1-naphthylethyl, 3,8
-Difluoro-1-naphthylmethyl, 2,3-difluoro-1-naphthylethyl, 4,8-difluoro-1-naphthylmethyl, 5,6-difluoro-1-naphthylethyl, 3,8-dichloro-1-naphthyl Methyl, 2,3-
Dichloro-1-naphthylethyl, 4,8-dibromo-1
-Naphthylmethyl, 5,6-dibromo-1-naphthylethyl, 2,3,6-trifluoro-1-naphthylmethyl, 2,3,4-trifluoro-1-naphthylethyl,
3,4,5-trifluoro-1-naphthylmethyl, 4,
5,6-trifluoro-1-naphthylethyl, 2,4
8-trifluoro-1-naphthylmethyl, bis (2-fluorophenyl) methyl, 3-fluorophenylphenylmethyl, bis (4-fluorophenyl) methyl, 4-
Fluorophenylphenylmethyl, bis (2-chlorophenyl) methyl, bis (3-chlorophenyl) methyl,
Bis (4-chlorophenyl) methyl, 4-chlorophenylphenylmethyl, 2-bromophenylphenylmethyl, 3-bromophenylphenylmethyl, bis (4-bromophenyl) methyl, bis (3,5-difluorophenyl) methyl, bis ( 2,5-difluorophenyl) methyl, bis (2,6-difluorophenyl) methyl,
2,4-difluorophenylphenylmethyl, bis (3,5-dibromophenyl) methyl, 2,5-dibromophenylphenylmethyl, 2,6-dichlorophenylphenylmethyl, bis (2,4-dichlorophenyl) methyl, bis (2 An aralkyl group substituted by a halogen atom such as (3,3,6-trifluorophenyl) methyl; 2
-Trifluoromethylbenzyl, 3-trifluoromethylphenethyl, 4-trifluoromethylbenzyl, 2-
Trichloromethylphenethyl, 3-dichloromethylbenzyl, 4-trichloromethylphenethyl, 2-tribromomethylbenzyl, 3-dibromomethylphenethyl, 4
-Dibromomethylbenzyl, 3,5-bistrifluoromethylphenethyl, 2,5-bistrifluoromethylbenzyl, 2,6-bistrifluoromethylphenethyl,
2,4-bistrifluoromethylbenzyl, 3,5-bistribromomethylphenethyl, 2,5-bisdibromomethylbenzyl, 2,6-bisdichloromethylmethylphenethyl, 2,4-bisdichloromethylbenzyl, 2,
3,6-tristrifluoromethylphenethyl, 2,
3,4-tristrifluoromethylbenzyl, 3,4
5-tristrifluoromethylphenethyl, 2,5,6
-Tristrifluoromethylbenzyl, 2,4,6-tristrifluoromethylphenethyl, 2,3,6-tristribromobromobenzyl, 2,3,4-trisdibromomethylphenethyl, 3,4,5-tristri Bromomethylbenzyl, 2,5,6-trisdichloromethylmethylphenethyl, 2,4,6-trisdichloromethylbenzyl, 1-trifluoromethyl-2-naphthylethyl, 2-trifluoromethyl-1-naphthylmethyl, 3
-Trifluoromethyl-1-naphthylethyl, 1-trichloromethyl-2-naphthylmethyl, 2-dichloromethyl-1-naphthylethyl, 3-tribromomethyl-1-
Naphthylmethyl, 3,8-bistrifluoromethyl-1
-Naphthylethyl, 2,3-bistrifluoromethyl-
1-naphthylmethyl, 4,8-bistrifluoromethyl-1-naphthylethyl, 5,6-bistrifluoromethyl-1-naphthylmethyl, 3,8-bistrichloromethyl-1-naphthylethyl, 2,3-bisdichloro Methyl-1-naphthylmethyl, 4,8-bisdibromomethyl-
1-naphthylethyl, 5,6-bistribromomethyl-
1-naphthylmethyl, 2,3,6-tristrifluoromethyl-1-naphthylethyl, 2,3,4-tristrifluoromethyl-1-naphthylmethyl, 3,4,5-tristrifluoromethyl-1- Naphthylethyl, 4,
5,6-tristrifluoromethyl-1-naphthylmethyl, 2,4,8-tristrifluoromethyl-1-naphthylmethyl, bis (4-trifluoromethylphenyl)
Methyl, 4-trifluoromethylphenylphenylmethyl, bis (2-trichloromethylphenyl) methyl, bis (3-trichloromethylphenyl) methyl, bis (4
-Trichloromethylphenyl) methyl, 2-tribromomethylphenylphenylmethyl, 3-tribromomethylphenylphenylmethyl, bis (4-tribromomethylphenyl) methyl, bis (3,5-bistrifluoromethylphenyl) methyl, bis (2,5-bistrifluoromethylphenyl) methyl, bis (2,6-bistrifluoromethylphenyl) methyl, 2,4-bistrifluoromethylphenylphenylmethyl, bis (3,5-bistrifluorobromophenyl) methyl, , 5-bistribromomethylphenylphenylmethyl, 2,6-bistrichloromethylphenylphenylmethyl, bis (2,
Aralkyl groups substituted with halogeno lower alkyl groups such as 4-bistrichloromethylphenyl) methyl and bis (2,3,6-tristrifluoromethylphenyl) methyl; 2-methylbenzyl, 3-methylbenzyl,
4-methylbenzyl, 2-methylphenethyl, 4-methylphenethyl, 2-ethylbenzyl, 3-propylphenethyl, 4-ethylbenzyl, 2-butylphenethyl,
3-pentylbenzyl, 4-pentylphenethyl, 3,
5-dimethylbenzyl, 2,5-dimethylphenethyl,
2,6-dimethylbenzyl, 2,4-dimethylphenethyl, 3,5-dibutylbenzyl, 2,5-dipentylphenethyl, 2,6-dipropylbenzyl, 2,4-dipropylphenethyl, 2,3,6- Trimethylbenzyl,
2,3,4-trimethylphenethyl, 3,4,5-trimethylbenzyl, 2,4,6-trimethylbenzyl,
2,5,6-trimethylphenethyl, 2,3,6-tributylphenethyl, 2,3,4-tripentylbenzyl, 3,4,5-tributylphenethyl, 2,5,6-
Tripropylbenzyl, 2,4,6-tripropylphenethyl, 1-methyl-2-naphthylmethyl, 2-methyl-1-naphthylethyl, 3-methyl-1-naphthylmethyl, 1-ethyl-2-naphthylethyl, 2-propyl-
1-naphthylmethyl, 3-butyl-1-naphthylethyl, 3,8-dimethyl-1-naphthylmethyl, 2,3-
Dimethyl-1-naphthylethyl, 4,8-dimethyl-1
-Naphthylmethyl, 5,6-dimethyl-1-naphthylethyl, 3,8-diethyl-1-naphthylmethyl, 2,3
-Dipropyl-1-naphthylmethyl, 4,8-dipentyl-1-naphthylethyl, 5,6-dibutyl-1-naphthylmethyl, 2,3,6-trimethyl-1-naphthylmethyl, 2,3,4-trimethyl -1-naphthylethyl,
3,4,5-trimethyl-1-naphthylmethyl, 4,
5,6-trimethyl-1-naphthylmethyl, 2,4,8
-Trimethyl-1-naphthylmethyl, bis (2-methylphenyl) methyl, 3-methylphenylphenylmethyl, bis (4-methylphenyl) methyl, 4-methylphenylphenylmethyl, bis (2-ethylphenyl) methyl, bis (3-ethylphenyl) methyl, bis (4-
Ethylphenyl) methyl, 2-propylphenylphenylmethyl, 3-propylphenylphenylmethyl, bis (4-propylphenyl) methyl, bis (3,5-dimethylphenyl) methyl, bis (2,5-dimethylphenyl) methyl, Bis (2,6-dimethylphenyl) methyl, 2,4-dimethylphenylphenylmethyl, bis (3,5-dipropylphenyl) methyl, 2,5-dipropylphenylphenylmethyl, 2,6-diethylphenylphenylmethyl , Bis (2,4-diethylphenyl) methyl, bis (2,3,6-trimethylphenyl)
Aralkyl groups substituted with lower alkyl groups such as methyl; 2-methoxybenzyl, 3-methoxybenzyl,
-Methoxybenzyl, 3-methoxyphenethyl, 2-ethoxyphenethyl, 3-propoxybenzyl, 4-ethoxyphenethyl, 2-butoxybenzyl, 3-pentoxyphenethyl, 4-pentoxybenzyl, 3,5-dimethoxyphenethyl, 2, 5-dimethoxybenzyl, 2,
6-dimethoxyphenethyl, 2,4-dimethoxybenzyl, 3,5-dibutoxyphenethyl, 2,5-dipentoxybenzyl, 2,6-dipropoxyphenethyl, 2,
4-dipropoxybenzyl, 2,3,6-trimethoxyphenethyl, 2,3,4-trimethoxybenzyl, 3,
4,5-trimethoxyphenethyl, 2,5,6-trimethoxybenzyl, 2,4,6-trimethoxyphenethyl, 2,3,6-tributoxybenzyl, 2,3,4-
Tripentoxyphenethyl, 3,4,5-tributoxybenzyl, 2,5,6-tripropoxyphenethyl,
2,4,6-tripropoxybenzyl, 1-methoxy-
2-naphthylmethyl, 2-methoxy-1-naphthylmethyl, 3-methoxy-1-naphthylethyl, 1-ethoxy-2-naphthylmethyl, 2-propoxy-1-naphthylmethyl, 3-butoxy-1-naphthylethyl, 3,8-
Dimethoxy-1-naphthylmethyl, 2,3-dimethoxy-1-naphthylmethyl, 4,8-dimethoxy-1-naphthylethyl, 5,6-dimethoxy-1-naphthylmethyl, 3,8-diethoxy-1-naphthylmethyl , 2, 3
-Dipropoxy-1-naphthylethyl, 4,8-dipentoxy-1-naphthylmethyl, 5,6-dibutoxy-1
-Naphthylmethyl, 2,3,6-trimethoxy-1-naphthylethyl, 2,3,4-trimethoxy-1-naphthylmethyl, 3,4,5-trimethoxy-1-naphthylmethyl, 4,5,6-trimethoxy -1-naphthylethyl, 2,4,8-trimethoxy-1-naphthylmethyl,
Bis (2-methoxyphenyl) methyl, 3-methoxyphenylphenylmethyl, bis (4-methoxyphenyl)
Methyl, 4-methoxyphenylphenylmethyl, bis (2-ethoxyphenyl) methyl, bis (3-ethoxyphenyl) methyl, bis (4-ethoxyphenyl) methyl, 2-propoxyphenylphenylmethyl, 3-propoxyphenylphenylmethyl, Bis (4-propoxyphenyl) methyl, bis (3,5-dimethoxyphenyl) methyl, bis (2,5-dimethoxyphenyl) methyl, bis (2,6-dimethoxyphenyl) methyl, 2,
4-dimethoxyphenylphenylmethyl, bis (3,5
-Dipropoxyphenyl) methyl, 2,5-dipropoxyphenylphenylmethyl, 2,6-diethoxyphenylphenylmethyl, bis (2,4-diethoxyphenyl) methyl, bis (2,3,6-trimethoxyphenyl) ) An aralkyl group substituted with a lower alkoxy group such as methyl; 2-aminophenethyl, 3-aminobenzyl, 4-aminophenethyl, 3,5-diaminobenzyl, 2,5-diaminophenethyl, 2,6-diaminobenzyl 2,4-diaminophenethyl, 2,3,6-triaminobenzyl, 2,3,4-triaminophenethyl, 3,4,5-triaminobenzyl, 2,5,6-triaminophenethyl, 2, 4,6-triaminobenzyl, 1-amino-2-naphthylmethyl, 2-amino-1
-Naphthylethyl, 3-amino-1-naphthylmethyl,
3,8-diamino-1-naphthylmethyl, 2,3-diamino-1-naphthylethyl, 4,8-diamino-1-naphthylmethyl, 5,6-diamino-1-naphthylmethyl, 2,3,6- Triamino-1-naphthylethyl,
2,3,4-triamino-1-naphthylmethyl, 3,
4,5-triamino-1-naphthylmethyl, 4,5,6
-Triamino-1-naphthylethyl, 2,4,8-triamino-1-naphthylmethyl, bis (2-aminophenyl) methyl, 3-aminophenylphenylmethyl, bis (4-aminophenyl) methyl, 4-aminophenyl Phenylmethyl, bis (3,5-diaminophenyl) methyl, bis (2,5-diaminophenyl) methyl, bis (2,6-diaminophenyl) methyl, 2,4-diaminophenylphenylmethyl, bis (2,3 Aralkyl groups substituted with amino groups such as 2,6-triaminophenyl) methyl; 2-nitrophenethyl, 3-nitrobenzyl, 4-nitrobenzyl, 4-nitrophenethyl,
5-dinitrobenzyl, 2,5-dinitrophenethyl,
2,6-dinitrobenzyl, 2,4-dinitrophenethyl, 2,3,6-trinitrobenzyl, 2,3,4-trinitrophenethyl, 3,4,5-trinitrobenzyl, 2,5,6- Trinitrophenethyl, 2,4,6-
Trinitrobenzyl, 1-nitro-2-naphthylmethyl, 2-nitro-1-naphthylethyl, 3-nitro-1
-Naphthylmethyl, 3,8-dinitro-1-naphthylmethyl, 2,3-dinitro-1-naphthylethyl, 4,8
-Dinitro-1-naphthylmethyl, 5,6-dinitro-
1-naphthylmethyl, 2,3,6-trinitro-1-naphthylethyl, 2,3,4-trinitro-1-naphthylmethyl, 3,4,5-trinitro-1-naphthylmethyl, 4,5,6- Trinitro-1-naphthylethyl,
2,4,8-trinitro-1-naphthylmethyl, bis (2
-Nitrophenyl) methyl, 3-nitrophenylphenylmethyl, bis (4-nitrophenyl) methyl, 4-nitrophenylphenylmethyl, bis (3,5-dinitrophenyl) methyl, bis (2,5-dinitrophenyl)
Methyl, bis (2,6-dinitrophenyl) methyl,
2,4-dinitrophenylphenylmethyl, bis (2
Aralkyl groups substituted with nitro groups such as 3,6-trinitrophenyl) methyl; and 2-cyanophenethyl, 3-cyanobenzyl, 4-cyanobenzyl, 4-cyanobenzyldiphenylmethyl, 4-cyanophenethyl, , 5-dicyanobenzyl, 2,5-dicyanophenethyl, 2,6-dicyanobenzyl, 2,4-dicyanophenethyl, 2,3,6-tricyanobenzyl, 2,
3,4-tricyanophenethyl, 3,4,5-tricyanobenzyl, 2,5,6-tricyanophenethyl, 2,
4,6-tricyanobenzyl, 1-cyano-2-naphthylmethyl, 3-cyano-1-naphthylmethyl, 3,8-
Dicyano-1-naphthylmethyl, 2,3-dicyano-1
-Naphthylethyl, 4,8-dicyano-1-naphthylmethyl, 5,6-dicyano-1-naphthylmethyl, 2,
3,6-tricyano-1-naphthylethyl, 2,3,4
-Tricyano-1-naphthylmethyl, 3,4,5-tricyano-1-naphthylmethyl, 4,5,6-tricyano-1-naphthylethyl, 2,4,8-tricyano-1-
Naphthylmethyl, bis (2-cyanophenyl) methyl,
3-cyanophenylphenylmethyl, bis (4-cyanophenyl) methyl, 4-cyanophenylphenylmethyl, bis (3,5-dicyanophenyl) methyl, bis (2,5-dicyanophenyl) methyl, bis (2,6 −
Examples thereof include an aralkyl group substituted with a cyano group such as dicyanophenyl) methyl, 2,4-dicyanophenylphenylmethyl, and bis (2,3,6-tricyanophenyl) methyl.

Preferably, it is an unsubstituted aralkyl group or an aralkyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy group, and more preferably an unsubstituted aralkyl group or a halogen atom or a lower alkyl group. It is a substituted aralkyl group, most preferably an unsubstituted aralkyl group.

The “heteroarylalkyl group” in the definition of R ⁵ , R ⁸ and R ⁹ is the above “heteroaryl group”
Represents a group bonded to the “alkyl group having 1 to 15 carbon atoms” (preferably, the “lower alkyl group”). As such a group, preferably, furylmethyl, thienylmethyl, pyridyl Methyl, pyrimidinylmethyl, 3-
Mention may be made of groups such as methylpyridylmethyl and 4-methylpyrimidinylmethyl.

The term “protecting group” in the definition of R ⁵ , R ⁸ and R ⁹ refers to the “general protecting group” such as “ester of hydroxyl group” and “biological methods such as hydrolysis in vivo”. As the “cleavable protecting group”, the same groups as those described below are shown.

The “halogeno lower alkyl group” in the definition of R ¹⁰ and R ¹¹ is a group in which one or more hydrogen atoms of the above “lower alkyl group” are substituted by the above “halogen atom”. It is preferably a halogenoalkyl group having 1 to 4 carbon atoms, more preferably trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-
Trichloroethyl, 2,2,2-trifluoroethyl,
2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl, even more preferably trifluoromethyl, trichloromethyl, difluoromethyl, fluoromethyl, most preferably trifluoromethyl Methyl.

The "heterocyclyl group containing at least one nitrogen atom" formed by R ¹⁰ and R ¹¹ together with the nitrogen atom to which they are bonded is defined as having one nitrogen atom.
And a 5- to 7-membered non-aromatic heterocyclic group which may further contain one oxygen atom, sulfur atom or nitrogen atom,
Such groups include, for example, morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl.
Preferably, it is a 5- to 6-membered non-aromatic heterocyclic group containing one nitrogen atom and further containing one oxygen atom, sulfur atom or nitrogen atom, more preferably morpholinyl,
Pyrrolidinyl, piperidyl and piperazinyl. still,
The “heterocyclyl group containing at least one nitrogen atom” may have an oxo group and / or a thioxo group. Examples of such a group include groups such as 2-oxomorpholinyl and pyrrolidonyl. Can be mentioned.

The term "heterocyclyl group" in the definition of the substituent group γ means that 1 to 3 carbon atoms of a cycloalkyl or cycloalkenyl group having 5 to 7 carbon atoms are a sulfur atom, an oxygen atom and / or a nitrogen atom. Represents a non-aromatic heterocyclic group substituted with Preferably, morpholinyl,
Sulfur atoms such as thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
5 to 6 containing 1 to 3 oxygen atoms and / or nitrogen atoms
Membered non-aromatic heterocyclic group, more preferably contains one nitrogen atom such as morpholinyl, pyrrolidinyl, piperidyl, piperazinyl, and may further contain one oxygen atom or nitrogen atom. Membered non-aromatic heterocyclic group.

The above “heterocyclyl group” may be condensed with another cyclic group, and examples of such a group include groups such as chromanyl, indolinyl and isoindolinyl.

Among the groups defined as “substituent group α”, a preferable group of groups is “substituent group α ¹ ”, which includes a halogen atom, a lower alkoxy group, a halogeno lower alkoxy group, a lower alkylthio group. A more preferred set of groups consists of a group and a halogeno-lower alkylthio group, and is a “substituent group α ² ”, which comprises a halogen atom, a halogeno-lower alkoxy group and a lower alkylthio group.

In the definition of "substituent group α ¹ " and "substituent group α ² ": “halogen atom” has the same meaning as described above; “lower alkoxy group” means the above “lower alkyl group” Represents a group having an oxygen atom bonded thereto, and is preferably a linear or branched alkoxy group having 1 to 4 carbon atoms,
More preferably, it is methoxy, ethoxy, propoxy, isopropoxy, butoxy, even more preferably methoxy, ethoxy, propoxy, most preferably a methoxy group; "halogeno lower alkoxy group" The "halogeno lower alkyl group" represents a group bonded to an oxygen atom, preferably a halogenoalkoxy group having 1 to 4 carbon atoms, more preferably difluoromethoxy, trifluoromethoxy, 2,2,2 2-trifluoroethoxy, most preferably difluoromethoxy;
"Lower alkylthio group" refers to the above "lower alkyl group"
Represents a group bonded to a sulfur atom. Preferably, it is a linear or branched alkylthio group having 1 to 4 carbon atoms, and more preferably, methylthio, ethylthio, propylthio,
Isopropylthio, butylthio, even more preferably methylthio, ethylthio, propylthio, and most preferably methylthio; the “halogeno lower alkylthio group” means that the “halogeno lower alkyl group” Represents a bonded group, preferably having 1 to 4 carbon atoms
Halogenoalkylthio groups, more preferably difluoromethylthio, trifluoromethylthio, 2,
2,2-trifluoroethylthio.

Among the groups defined as “substituent group β”, a preferred group of groups is “substituent group β ¹ ”, which comprises a lower alkyl group and a halogeno lower alkyl group, and The group of groups is “substituent group β ² ”, which consists of lower alkyl groups.

"Ester" refers to the compound (I) of the present invention
Can be converted into an ester. An ester whose group is a “general protecting group” or a “protecting group that can be cleaved in vivo by a biological method such as hydrolysis”.

"General protecting group" refers to a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.

The “general protecting group” such as “ester of hydroxyl group” and “ester of mercapto group” is preferably formyl, acetyl, propionyl, butyryl,
Isobutyryl, pentanoyl, pivaloyl, valeryl,
Isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3
-Ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl,
Tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl,
Alkanoyl groups such as heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, henicosanoyl, chloroacetyl, dichloroacetyl,
Trichloroacetyl, a halogenated alkylcarbonyl group such as trifluoroacetyl, a lower alkoxyalkylcarbonyl group such as methoxyacetyl, acryloyl, propioyl, methacryloyl, crotonoyl,
"Aliphatic acyl group" such as an unsaturated alkylcarbonyl group such as isocrotonoyl and (E) -2-methyl-2-butenoyl (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms) Benzoyl, α-naphthoyl, β-
Arylcarbonyl groups such as naphthoyl; halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl; lower alkylated aryl groups such as 2,4,6-trimethylbenzoyl and 4-toluoyl. Carbonyl group, lower alkoxylated arylcarbonyl group such as 4-anisoyl, 4-nitrobenzoyl, 2-
A nitrated arylcarbonyl group such as nitrobenzoyl; a lower alkoxycarbonylated arylcarbonyl group such as 2- (methoxycarbonyl) benzoyl;
An "aromatic acyl group" such as an arylated arylcarbonyl group such as phenylbenzoyl; methoxycarbonyl,
Lower alkoxycarbonyl groups such as ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl, halogen such as 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl or "Alkoxycarbonyl group" such as lower alkoxycarbonyl group substituted with a tri-lower alkylsilyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methoxytetrahydropyran-4-yl, tetrahydrothio Pyran-2
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as -yl, 4-methoxytetrahydrothiopyran-4-yl; "tetrahydrofuranyl or tetrahydrothiolane such as tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl" Furanyl group "; tri-lower alkylsilyl groups such as trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, "Silyl group" such as tri-lower alkylsilyl group substituted with one or two aryl groups such as diphenylisopropylsilyl and phenyldiisopropylsilyl; methoxymethyl,
Lower alkoxymethyl groups such as 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl Groups, "alkoxymethyl groups" such as halogeno lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1- (isopropoxy) ethyl and the like Lower alkoxylated ethyl group,
A "substituted ethyl group" such as an ethyl halide group such as 2,2,2-trichloroethyl; the "aralkyl group"; an "alkenyloxycarbonyl group" such as vinyloxycarbonyl and allyloxycarbonyl; 4-methoxybenzyloxycarbonyl,
"Aralkyl" in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups such as 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl Oxycarbonyl group ".

The “general protecting group” for the “ester of a phosphono group” is preferably the aforementioned “halogeno lower alkyl”; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, Hydroxy "lower alkyl group" such as 1,4-dihydroxybutyl and 4-hydroxybutyl; "lower aliphatic acyl" such as acetylmethyl; "lower alkyl group"; and the aforementioned "silyl group".

The term "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" means that the compound is cleaved in a human body by a biological method such as hydrolysis and the compound (I) of the present invention or a compound thereof. A salt-protecting group is used to determine whether a derivative is such a derivative or not by intravenous injection into a laboratory animal such as a rat or mouse, and then examining the body fluid of the animal to determine whether the parent compound or its pharmacological Can be determined by being able to detect a salt acceptable to the `` ester of a hydroxyl group '' and `` ester of a mercapto group '' such `` protective group which can be cleaved by a biological method such as hydrolysis in a living body '' Preferably, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl,
Valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl,
1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 1- Formyloxypropyl, 1-acetoxypropyl, 1-
Propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-
Hexanoyloxypropyl, 1-acetoxybutyl,
1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, 1
1-("lower aliphatic acyl" oxy) "lower alkyl" such as -pivaloyloxyhexyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1
1-("cycloalkyl" such as -cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl
Carbonyloxy) 1-("aromatic acyl" oxy) such as "lower alkyl", benzoyloxymethyl
1- (acyloxy) "lower alkyl group" such as "lower alkyl group"; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, Pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1
-(Methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) ethyl, 1- (propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxy Carbonyloxy) ethyl,
1- (t-butoxycarbonyloxy) ethyl, 1-
(Pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1-
(Cyclohexyloxycarbonyloxy) propyl,
1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy)
Ethyl, 1- (ethoxycarbonyloxy) propyl,
1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (iso Butoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl,
(Propoxycarbonyloxy) butyl, 1- (isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy)
Pentyl, 1- (ethoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1-
(Lower alkoxycarbonyloxy) alkyl groups such as (ethoxycarbonyloxy) hexyl; (5-phenyl-2-oxo-1,3-dioxolen-4-yl)
Methyl, [5- (4-methylphenyl) -2-oxo-
1,3-dioxolen-4-yl] methyl, [5- (4
-Methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl]
Methyl, [5- (4-chlorophenyl) -2-oxo-
1,3-dioxolen-4-yl] methyl, (2-oxo-1,3-dioxolen-4-yl) methyl, (5-
Methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1, 3-dioxolen-4-yl) methyl, (5
-Isopropyl-2-oxo-1,3-dioxolene-
4-yl) methyl, (5-butyl-2-oxo-1,3)
"Carbonyldialkyl group" such as oxodioxenylmethyl group such as -dioxolen-4-yl) methyl; "phthalidyl group" such as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; "Acyl group": the "aromatic acyl group": "half ester salt residue of succinic acid": "phosphate ester salt residue": "ester forming residue such as amino acid": carbamoyl group: one or two lower groups Carbamoyl group substituted with an alkyl group:
And "1- (acyloxy) alkyloxycarbonyl group" such as pivaloyloxymethyloxycarbonyl, and preferably "carbonyloxyalkyl group".

On the other hand, the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” for the “ester of a phosphono group” is preferably methoxyethyl,
-Ethoxyethyl, 1-methyl-1-methoxyethyl,
1- (isopropoxy) ethyl, 2-methoxyethyl,
Lower alkoxy lower alkyl group such as 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, 2-methoxyethoxy Lower alkoxylated lower alkoxy lower alkyl group such as methyl, "aryl" oxy "lower alkyl group" such as phenoxymethyl, 2,2,2-
“Alkoxy lower alkyl groups” such as halogenated lower alkoxy lower alkyl groups such as trichloroethoxymethyl and bis (2-chloroethoxy) methyl; “lower alkoxy” carbonyl “lower alkyl groups” such as methoxycarbonylmethyl; "Cyano" lower alkyl group "such as cyanomethyl and 2-cyanoethyl;""loweralkyl" such as methylthiomethyl and ethylthiomethyl
"Thiomethyl group";"aryl" thiomethyl group such as phenylthiomethyl and naphthylthiomethyl; "lower alkyl optionally substituted by halogen" such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl Sulfonyl "lower alkyl group"; 2
-"Aryl" sulfonyl "lower alkyl group" such as benzenesulfonylethyl and 2-toluenesulfonylethyl; the "1- (acyloxy)" lower alkyl group ";the" phthalidyl group ";the" aryl group ";
The "lower alkyl group"; the "carboxyalkyl group" such as carboxymethyl; and the "amide-forming residue of amino acid" such as phenylalanine.

The "other derivative" means that when the compound (I) of the present invention has an amino group and / or a phosphono group,
The above “ester” and the following “the pharmaceutically acceptable salts thereof”
The derivative is shown because other derivatives can be used. Such derivatives include, for example, amide derivatives.

"Pharmacologically acceptable salt" means that the compound (I) of the present invention is reacted with an acid when it has a basic group such as a pyridine ring or an amino group.
When the compound has an acidic group such as a phosphono group, it can be converted to a salt by reacting with a base.

The salt based on a basic group is preferably
Inorganic acid salts such as hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates and phosphates; methanesulfonic acid Salts, lower alkane sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate,
aryl sulfonates such as p-toluenesulfonate, acetate, malate, fumarate, succinate,
Organic acid salts such as citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate. be able to.

On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an aluminum salt; Metal salts such as salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts,
Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) amino Amine salts such as organic salts such as methane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates.

The compound having the general formula (I) of the present invention is
An asymmetric carbon atom is present in the molecule and may have various isomers. In the compounds of the present invention, these isomers and mixtures of these isomers are all represented by a single formula, that is, the general formula (I). Accordingly, the present invention includes all these isomers and mixtures of these isomers.

The compound having the general formula (I) of the present invention is
By leaving in the air or recrystallizing,
In some cases, water may be absorbed, adsorbed water may be formed, or a hydrate may be formed. Such a hydrate is also included in the present invention.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Tables 1 to 7 below.

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TABLE 1 ----------------------------------- compound numbers Ar ¹ Ar ² m WR ⁴ R ¹ R ² −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 1-1 4-Pyr 4-F− Ph 0 (CH ₂ ) ₂ N ₃ HH 1-2 4-Pyr 4-F-Ph 0 (CH ₂ ) ₂ NO ₂ HH 1-3 4-Pyr 4-F-Ph 0 (CH ₂ ) ₂ ONO HH 1 -4 4-Pyr 4-F-Ph 0 (CH ₂ ) ₂ ONO ₂ HH 1-5 4-Pyr 4-F-Ph 0 (CH ₂ ) ₂ SCN HH 1-6 4-Pyr 4-F-Ph 0 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-7 4-Pyr 4-F-Ph 0 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-8 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₂ N ₃ HH 1-9 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₂ NO ₂ HH 1-10 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₂ ONO HH 1-11 4-Pyrm 4 -F-Ph 0 (CH ₂ ) ₂ ONO ₂ HH 1-12 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₂ SCN HH 1-13 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-14 4-Pyr 4-F-Ph 0 (CH ₂ ) ₃ N ₃ HH 1-15 4-Pyr 4-F-Ph 0 (CH ₂ ) ₃ NO ₂ HH 1-16 4- Pyr 4-F-Ph 0 (CH ₂ ) ₃ ONO HH 1-17 4-Pyr 4-F-Ph 0 (CH ₂ ) ₃ ONO ₂ HH 1-18 4-Pyr 4-F-Ph 0 (CH ₂ ) ₃ SCN HH 1-19 4-Pyr 4-F-Ph 0 (CH ₂ ) ₃ PO (OM e) ₂ HH 1-20 4-Pyr 4-F-Ph 0 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-21 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₃ N ₃ HH 1-22 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₃ NO ₂ HH 1-23 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₃ ONO HH 1-24 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₃ ONO ₂ HH 1-25 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₃ SCN HH 1-26 4-Pyrm 4-F-Ph 0 (CH ₂ ) ₃ PO (OMe) ₂ HH 1- 27 4-Pyr Ph 1 CH ₂ N ₃ HH 1-28 4-Pyr Ph 1 CH ₂ NO ₂ HH 1-29 4-Pyr Ph 1 CH ₂ ONO HH 1-30 4-Pyr Ph 1 CH ₂ ONO ₂ HH 1 -31 4-Pyr Ph 1 CH ₂ SCN HH 1-32 4-Pyr Ph 1 CH ₂ PO (OMe) ₂ HH 1-33 4-Pyr Ph 1 CH ₂ PO (OEt) ₂ HH 1-34 4-Pyrm Ph 1 CH ₂ N ₃ HH 1-35 4-Pyrm Ph 1 CH ₂ NO ₂ HH 1-36 4-Pyrm Ph 1 CH ₂ ONO HH 1-37 4-Pyrm Ph 1 CH ₂ ONO ₂ HH 1-38 4-Pyrm Ph 1 CH ₂ SCN HH 1-39 4-Pyrm Ph 1 CH ₂ PO (OMe) ₂ HH 1-40 4-Pyr Ph 1 (CH ₂ ) ₂ N ₃ HH 1-41 4-Pyr Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-42 4-Pyr Ph 1 (CH ₂ ) ₂ ONO HH 1-43 4-Pyr Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-44 4-Pyr Ph 1 (CH ₂ ) ₂ SCN HH 1-45 4-Pyr Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-46 4-Pyr Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-47 4-Pyrm Ph 1 (CH ₂ ) ₂ N ₃ HH 1-48 4-Pyrm Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-4 9 4-Pyrm Ph 1 (CH ₂ ) ₂ ONO HH 1-50 4-Pyrm Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-51 4-Pyrm Ph 1 (CH ₂ ) ₂ SCN HH 1-52 4-Pyrm Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-53 4-Pyr Ph 1 (CH ₂ ) ₃ N ₃ HH 1-54 4-Pyr Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-55 4- Pyr Ph 1 (CH ₂ ) ₃ ONO HH 1-56 4-Pyr Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-57 4-Pyr Ph 1 (CH ₂ ) ₃ SCN HH 1-58 4-Pyr Ph 1 ( CH ₂ ) ₃ PO (OMe) ₂ HH 1-59 4-Pyr Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-60 4-Pyrm Ph 1 (CH ₂ ) ₃ N ₃ HH 1-61 4- Pyrm Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-62 4-Pyrm Ph 1 (CH ₂ ) ₃ ONO HH 1-63 4-Pyrm Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-64 4-Pyrm Ph 1 (CH ₂ ) ₃ SCN HH 1-65 4-Pyrm Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-66 4-Pyr Ph 1 (CH ₂ ) ₄ N ₃ HH 1-67 4-Pyr Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-68 4-Pyr Ph 1 (CH ₂ ) ₄ ONO HH 1-69 4-Pyr Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-70 4-Pyr Ph 1 (CH ₂ ) ₄ SCN HH 1-71 4-Pyr Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-72 4-Pyr Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-73 4-Pyrm Ph 1 (CH ₂ ) ₄ N ₃ HH 1-74 4-Pyrm Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-75 4-Pyrm Ph 1 (CH ₂ ) ₄ ONO HH 1-76 4-Pyrm Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-77 4-Pyrm Ph 1 (CH ₂ ) ₄ SCN HH 1-78 4-Pyrm Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-79 4-Pyr 3-F-Ph 1 CH ₂ N ₃ HH 1-80 4-Pyr 3-F-Ph 1 CH ₂ NO ₂ HH 1-81 4-Pyr 3-F-Ph 1 CH ₂ ONO HH 1-82 4-Pyr 3-F-Ph 1 CH ₂ ONO ₂ HH 1-83 4-Pyr 3-F-Ph 1 CH ₂ SCN HH 1-84 4-Pyr 3-F-Ph 1 CH ₂ PO (OMe) ₂ HH 1-85 4-Pyr 3-F-Ph 1 CH ₂ PO (OEt) ₂ HH 1-86 4-Pyrm 3-F- Ph 1 CH 2 N 3 HH 1-87 4-Pyrm 3-F-Ph 1 CH 2 NO 2 HH 1-88 4-Pyrm 3-F-Ph 1 CH 2 ONO HH 1-89 4-Pyrm 3-F-Ph 1 CH ₂ ONO ₂ HH 1-90 4-Pyrm 3-F-Ph 1 CH ₂ SCN HH 1-91 4-Pyrm 3-F-Ph 1 CH ₂ PO (OMe ) ₂ HH 1-92 4-Pyr 3-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-93 4-Pyr 3-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-94 4-Pyr 3 -F-Ph 1 (CH ₂ ) ₂ ONO HH 1-95 4-Pyr 3-F-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-96 4-Pyr 3-F-Ph 1 (CH ₂ ) ₂ SCN HH 1-97 4-Pyr 3-F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-98 4-Pyr 3-F-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-99 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-100 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-101 4-Pyrm 3-F-Ph 1 ( CH ₂ ) ₂ ONO HH 1-102 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-103 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₂ SCN HH 1-104 4- Pyrm 3-F-Ph 1 (C H ₂ ) ₂ PO (OMe) ₂ HH 1-105 4-Pyr 3-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-106 4-Pyr 3-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-107 4-Pyr 3-F-Ph 1 (CH ₂ ) ₃ ONO HH 1-108 4-Pyr 3-F-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-109 4-Pyr 3-F-Ph 1 (CH ₂ ) ₃ SCN HH 1-110 4-Pyr 3-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-111 4-Pyr 3-F-Ph 1 (CH ₂ ) ₃ PO ( OEt) ₂ HH 1-112 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-113 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-114 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₃ ONO HH 1-115 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-116 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₃ SCN HH 1-117 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-118 4-Pyr 3-F-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-119 4- Pyr 3-F-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-120 4-Pyr 3-F-Ph 1 (CH ₂ ) ₄ ONO HH 1-121 4-Pyr 3-F-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-122 4-Pyr 3-F-Ph 1 (CH ₂ ) ₄ SCN HH 1-123 4-Pyr 3-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-124 4 -Pyr 3-F-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-125 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-126 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-127 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₄ ONO HH 1-128 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1- 129 4-Pyrm 3- F-Ph 1 (CH ₂ ) ₄ SCN HH 1-130 4-Pyrm 3-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-131 4-Pyr 4-F-Ph 1 CH ₂ N ₃ HH 1-132 4-Pyr 4-F-Ph 1 CH ₂ NO ₂ HH 1-133 4-Pyr 4-F-Ph 1 CH ₂ ONO HH 1-134 4-Pyr 4-F-Ph 1 CH ₂ ONO ₂ HH 1-135 4-Pyr 4-F-Ph 1 CH ₂ SCN HH 1-136 4-Pyr 4-F-Ph 1 CH ₂ PO (OMe) ₂ HH 1-137 4-Pyr 4-F-Ph 1 CH ₂ PO (OEt) ₂ HH 1-138 4-Pyrm 4-F-Ph 1 CH ₂ N ₃ HH 1-139 4-Pyrm 4-F-Ph 1 CH ₂ NO ₂ HH 1-140 4-Pyrm 4-F -Ph 1 CH ₂ ONO HH 1-141 4-Pyrm 4-F-Ph 1 CH ₂ ONO ₂ HH 1-142 4-Pyrm 4-F-Ph 1 CH ₂ SCN HH 1-143 4-Pyrm 4-F- Ph 1 CH ₂ PO (OMe) ₂ HH 1-144 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-145 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-146 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ ONO HH 1-147 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-148 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ SCN HH 1-149 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-150 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ PO ( OEt) ₂ HH 1-151 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-152 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-153 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ ONO HH 1-154 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-155 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ SCN HH 1-156 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-157 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-158 4- Pyr 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-159 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ ONO HH 1-160 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-161 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ SCN HH 1-162 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-163 4 -Pyr 4-F-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-164 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-165 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-166 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ ONO HH 1-167 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1- 168 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ SCN HH 1-169 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-170 4-Pyr 4-F- Ph 1 (CH ₂ ) ₄ N ₃ HH 1-171 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-172 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ ONO HH 1 -173 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-174 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ SCN HH 1-175 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-176 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-177 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-178 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-179 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ ONO HH 1-180 4-Pyrm 4 -F-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-181 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ SCN HH 1-182 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1- 183 4-Pyr 3-Cl-Ph 1 CH ₂ N ₃ HH 1-184 4-Pyr 3-Cl-Ph 1 CH ₂ NO ₂ HH 1-185 4-Pyr 3-Cl-Ph 1 CH ₂ ONO HH 1- 186 4-Pyr 3-Cl-Ph 1 CH ₂ ONO ₂ HH 1-187 4-Pyr 3-Cl-Ph 1 CH ₂ SCN HH 1-188 4-Pyr 3-Cl-Ph 1 CH ₂ PO (OMe) ₂ HH 1-189 4-Pyr 3-Cl-Ph 1 CH ₂ PO (OEt) ₂ HH 1-190 4-Pyrm 3-Cl-Ph 1 CH ₂ N ₃ HH 1-191 4-Pyrm 3-Cl-Ph 1 CH ₂ NO ₂ HH 1-192 4-Pyrm 3-Cl-Ph 1 CH ₂ ONO HH 1-193 4-Pyrm 3-Cl-Ph 1 CH ₂ ONO ₂ HH 1-194 4-Pyrm 3-Cl-Ph 1 CH ₂ SCN HH 1-195 4-Pyrm 3-Cl-Ph 1 CH ₂ PO (OMe) ₂ HH 1-196 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-197 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-198 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₂ ONO HH 1-199 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-200 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₂ SCN HH 1-201 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-202 4- Pyr 3-Cl-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-203 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-204 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-205 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₂ ONO HH 1-206 4-Pyrm 3-Cl-P h 1 (CH ₂ ) ₂ ONO ₂ HH 1-207 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₂ SCN HH 1-208 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-209 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-210 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-211 4-Pyr 3- Cl-Ph 1 (CH ₂ ) ₃ ONO HH 1-212 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-213 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₃ SCN HH 1-214 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-215 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-216 4 -Pyrm 3-Cl-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-217 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-218 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₃ ONO HH 1-219 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-220 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₃ SCN HH 1-221 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-222 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-223 4-Pyr 3-Cl-Ph 1 ( CH ₂ ) ₄ NO ₂ HH 1-224 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₄ ONO HH 1-225 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-226 4 -Pyr 3-Cl-Ph 1 (CH ₂ ) ₄ SCN HH 1-227 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-228 4-Pyr 3-Cl-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-229 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-230 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-231 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₄ ONO HH 1-232 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-233 4- Pyrm 3-Cl-Ph 1 (CH ₂ ) ₄ SCN HH 1-234 4-Pyrm 3-Cl-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-235 4-Pyr 3,4-diF-Ph 1 CH ₂ N ₃ HH 1-236 4-Pyr 3,4-diF-Ph 1 CH ₂ NO ₂ HH 1-237 4-Pyr 3,4-diF-Ph 1 CH ₂ ONO HH 1-238 4-Pyr 3 , 4-diF-Ph 1 CH ₂ ONO ₂ HH 1-239 4-Pyr 3,4-diF-Ph 1 CH ₂ SCN HH 1-240 4-Pyr 3,4-diF-Ph 1 CH ₂ PO (OMe) ₂ HH 1-241 4-Pyr 3,4-diF-Ph 1 CH ₂ PO (OEt) ₂ HH 1-242 4-Pyrm 3,4-diF-Ph 1 CH ₂ N ₃ HH 1-243 4-Pyrm 3 , 4-diF-Ph 1 CH ₂ NO ₂ HH 1-244 4-Pyrm 3,4-diF-Ph 1 CH ₂ ONO HH 1-245 4-Pyrm 3,4-diF-Ph 1 CH ₂ ONO ₂ HH 1 -246 4-Pyrm 3,4-diF-Ph 1 CH ₂ SCN HH 1-247 4-Pyrm 3,4-diF-Ph 1 CH ₂ PO (OMe) ₂ HH 1-248 4-Pyr 3,4-diF -Ph 1 (CH ₂ ) ₂ N ₃ HH 1-249 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-250 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₂ ONO HH 1-251 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-252 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₂ SCN HH 1-253 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-254 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-255 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-256 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-257 4- Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₂ ONO HH 1-258 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-259 4-Pyrm 3,4-diF- Ph 1 (CH ₂ ) ₂ SCN HH 1-260 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-261 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-262 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-263 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₃ ONO HH 1 -264 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-265 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₃ SCN HH 1-266 4-Pyr 3, 4-diF-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-267 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-268 4-Pyrm 3, 4-diF-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-269 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-270 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₃ ONO HH 1-271 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-272 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₃ SCN HH 1-273 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-274 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-275 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-276 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₄ ONO HH 1-277 4-Pyr 3,4- diF-Ph 1 (C H ₂ ) ₄ ONO ₂ HH 1-278 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₄ SCN HH 1-279 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₄ PO (OMe ) ₂ HH 1-280 4-Pyr 3,4-diF-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-281 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-282 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-283 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₄ ONO HH 1-284 4-Pyrm 3 , 4-diF-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-285 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₄ SCN HH 1-286 4-Pyrm 3,4-diF-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-287 4-Pyr 3,4-diCl-Ph 1 CH ₂ N ₃ HH 1-288 4-Pyr 3,4-diCl-Ph 1 CH ₂ NO ₂ HH 1 -289 4-Pyr 3,4-diCl-Ph 1 CH ₂ ONO HH 1-290 4-Pyr 3,4-diCl-Ph 1 CH ₂ ONO ₂ HH 1-291 4-Pyr 3,4-diCl-Ph 1 CH ₂ SCN HH 1-292 4-Pyr 3,4-diCl-Ph 1 CH ₂ PO (OMe) ₂ HH 1-293 4-Pyr 3,4-diCl-Ph 1 CH ₂ PO (OEt) ₂ HH 1- 294 4-Pyrm 3,4-diCl-Ph 1 CH ₂ N ₃ HH 1-295 4-Pyrm 3,4-diCl-Ph 1 CH ₂ NO ₂ HH 1-296 4-Pyrm 3,4-diCl-Ph 1 CH ₂ ONO HH 1-297 4-Pyrm 3,4-diCl-Ph 1 CH ₂ ONO ₂ HH 1-298 4-Pyrm 3,4-diCl-Ph 1 CH ₂ SCN HH 1-299 4-Pyrm 3,4 -diCl-Ph 1 CH ₂ PO (OMe) ₂ HH 1-300 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-301 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-302 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₂ ONO HH 1-303 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-304 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₂ SCN HH 1-305 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-306 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-307 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-308 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-309 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₂ ONO HH 1-310 4- Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-311 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₂ SCN HH 1-312 4-Pyrm 3,4-diCl- Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-313 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-314 4-Pyr 3,4-diCl-Ph 1 ( CH ₂ ) ₃ NO ₂ HH 1-315 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₃ ONO HH 1-316 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-317 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₃ SCN HH 1-318 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-319 4 -Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-320 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-321 4-Pyrm 3 , 4-diCl-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-322 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₃ ONO HH 1-323 4-Pyrm 3,4 -diCl-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-324 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₃ SCN HH 1-325 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-326 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-327 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-328 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₄ ONO HH 1-329 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-330 4 -Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₄ SCN HH 1-331 4-Pyr 3,4-diCl-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-332 4-Pyr 3, 4-diCl-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-333 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-334 4-Pyrm 3,4-diCl -Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-335 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₄ ONO HH 1-336 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-337 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₄ SCN HH 1-338 4-Pyrm 3,4-diCl-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-339 4-Pyr 3-Cl-4-F-Ph 1 CH ₂ N ₃ HH 1-340 4-Pyr 3-Cl-4-F-Ph 1 CH ₂ NO ₂ HH 1-341 4-Pyr 3- Cl-4-F-Ph 1 CH ₂ ONO HH 1-342 4-Pyr 3-Cl-4-F-Ph 1 CH ₂ ONO ₂ HH 1-343 4-Pyr 3-Cl-4-F-Ph 1 CH ₂ SCN HH 1-344 4-Pyr 3-Cl-4-F-Ph 1 CH ₂ PO (OMe) ₂ HH 1-345 4-Pyr 3-Cl-4-F-Ph 1 CH ₂ PO (OEt) ₂ HH 1-346 4-Pyrm 3-Cl-4-F-Ph 1 CH ₂ N ₃ HH 1-347 4-Pyrm 3-Cl-4-F-Ph 1 CH ₂ NO ₂ HH 1-348 4-Pyrm 3-Cl-4 -F-Ph 1 CH ₂ ONO HH 1-349 4-Pyrm 3-Cl-4-F-Ph 1 CH ₂ ONO ₂ HH 1-350 4-Pyrm 3-Cl-4-F-Ph 1 CH ₂ SCN HH 1-351 4-Pyrm 3-Cl-4-F-Ph 1 CH ₂ PO (OMe) ₂ HH 1-352 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1- 353 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-354 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ ONO HH 1-355 4- Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-356 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ SCN HH 1-357 4-Pyr 3- Cl-4-F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-358 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-359 4 -Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-360 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-361 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ ONO HH 1-362 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-363 4-Pyrm 3-Cl -4-F-Ph 1 (CH ₂ ) ₂ SCN HH 1-364 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-365 4-Pyr 3-Cl -4-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-366 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-367 4-Pyr 3-Cl-4 -F-Ph 1 (CH ₂ ) ₃ ONO HH 1-368 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-369 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ SCN HH 1-370 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-371 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-372 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-373 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-374 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ ONO HH 1- 375 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-376 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ SCN HH 1-377 4- Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-378 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-379 4 -Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-380 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ ONO HH 1-381 4-Pyr 3 -Cl-4-F-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-382 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ SCN HH 1-383 4-Pyr 3-Cl- 4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-384 4-Pyr 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-385 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-386 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-387 4-Pyrm 3- Cl-4-F-Ph 1 (CH ₂ ) ₄ ONO HH 1-388 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-389 4-Pyrm 3-Cl-4 -F-Ph 1 (CH ₂ ) ₄ SCN HH 1-390 4-Pyrm 3-Cl-4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-391 4-Pyr 3,4,5-triF-Ph 1 CH ₂ N ₃ HH 1-392 4-Pyr 3,4,5-triF-Ph 1 CH ₂ NO ₂ HH 1-393 4-Pyr 3 , 4,5-triF-Ph 1 CH ₂ ONO HH 1-394 4-Pyr 3,4,5-triF-Ph 1 CH ₂ ONO ₂ HH 1-395 4-Pyr 3,4,5-triF-Ph 1 CH ₂ SCN HH 1-396 4-Pyr 3,4,5-triF-Ph 1 CH ₂ PO (OMe) ₂ HH 1-397 4-Pyr 3,4,5-triF-Ph 1 CH ₂ PO (OEt) ₂ HH 1-398 4-Pyrm 3,4,5-triF-Ph 1 CH ₂ N ₃ HH 1-399 4-Pyrm 3,4,5-triF-Ph 1 CH ₂ NO ₂ HH 1-400 4-Pyrm 3,4,5-triF-Ph 1 CH ₂ ONO HH 1-401 4-Pyrm 3,4,5-triF-Ph 1 CH ₂ ONO ₂ HH 1-402 4-Pyrm 3,4,5-triF-Ph 1 CH ₂ SCN HH 1-403 4-Pyrm 3,4,5-triF-Ph 1 CH ₂ PO (OMe) ₂ HH 1-404 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-405 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-406 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₂ ONO HH 1-407 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-408 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₂ SCN HH 1-409 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-410 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-411 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-412 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1 -413 4-Pyrm 3,4,5-triF -Ph 1 (CH ₂ ) ₂ ONO HH 1-414 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₂ ONO ₂ HH 1-415 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₂ SCN HH 1-416 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-417 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-418 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-419 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₃ ONO HH 1-420 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-421 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₃ SCN HH 1-422 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-423 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-424 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-425 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-426 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₃ ONO HH 1-427 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₃ ONO ₂ HH 1-428 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₃ SCN HH 1-429 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-430 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-431 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1 -432 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₄ ONO HH 1-433 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-434 4 -Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₄ SCN HH 1-435 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-436 4-Pyr 3,4,5-triF-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-437 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₄ N ₃ HH 1-438 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₄ NO ₂ HH 1-439 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₄ ONO HH 1-440 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₄ ONO ₂ HH 1-441 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₄ SCN HH 1-442 4-Pyrm 3,4,5-triF-Ph 1 (CH ₂ ) ₄ PO (OMe ) ₂ HH-------------------------------

[0074]

[Table 2] (Continued from Table 1) --------------------------------------------------------- Compound No. Ar ¹ Ar ² m WR ⁴ R ¹ R ² ------------- Ph 2 CH ₂ N ₃ HH 1-444 4-Pyr Ph 2 CH ₂ NO ₂ HH 1-445 4-Pyr Ph 2 CH ₂ ONO HH 1-446 4-Pyr Ph 2 CH ₂ ONO ₂ HH 1-447 4- Pyr Ph 2 CH ₂ SCN HH 1-448 4-Pyr Ph 2 CH ₂ PO (OMe) ₂ HH 1-449 4-Pyr Ph 2 CH ₂ PO (OEt) ₂ HH 1-450 4-Pyrm Ph 2 CH ₂ N ₃ HH 1-451 4-Pyrm Ph 2 CH ₂ NO ₂ HH 1-452 4-Pyrm Ph 2 CH ₂ ONO HH 1-453 4-Pyrm Ph 2 CH ₂ ONO ₂ HH 1-454 4-Pyrm Ph 2 CH ₂ SCN HH 1-455 4-Pyrm Ph 2 CH ₂ PO (OMe) ₂ HH 1-456 4-Pyr Ph 2 (CH ₂ ) ₂ N ₃ HH 1-457 4-Pyr Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-458 4-Pyr Ph 2 (CH ₂ ) ₂ ONO HH 1-459 4-Pyr Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-460 4-Pyr Ph 2 (CH ₂ ) ₂ SCN HH 1-461 4 -Pyr Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-462 4-Pyr Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-463 4-Pyrm Ph 2 (CH ₂ ) ₂ N ₃ HH 1-464 4-Pyrm Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-465 4-Pyrm Ph 2 (CH ₂ ) ₂ ONO HH 1-466 4-Pyrm Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-467 4-Pyrm Ph 2 (CH ₂ ) ₂ SCN HH 1-468 4-Pyrm Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-469 4-Pyr Ph 2 (CH ₂ ) ₃ N ₃ HH 1-470 4-Pyr Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-471 4-Pyr Ph 2 (CH ₂ ) ₃ ONO HH 1-472 4-Pyr Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-473 4-Pyr Ph 2 (CH ₂ ) ₃ SCN HH 1-474 4-Pyr Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-475 4-Pyr Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-476 4-Pyrm Ph 2 (CH ₂ ) ₃ N ₃ HH 1-477 4-Pyrm Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-478 4-Pyrm Ph 2 (CH ₂ ) ₃ ONO HH 1-479 4-Pyrm Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-480 4-Pyrm Ph 2 (CH ₂ ) ₃ SCN HH 1-481 4-Pyrm Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-482 4-Pyr Ph 2 (CH ₂ ) ₄ N ₃ HH 1-483 4-Pyr Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-484 4-Pyr Ph 2 (CH ₂ ) ₄ ONO HH 1-485 4-Pyr Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-486 4-Pyr Ph 2 (CH ₂ ) ₄ SCN HH 1-487 4-Pyr Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-488 4-Pyr Ph 2 (CH ₂ ) ₄ PO (OEt ) ₂ HH 1-489 4-Pyrm Ph 2 (CH ₂ ) ₄ N ₃ HH 1-490 4-Pyrm Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-491 4-Pyrm Ph 2 (CH ₂ ) ₄ ONO HH 1-492 4-Pyrm Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-493 4-Pyrm Ph 2 (CH ₂ ) ₄ SCN HH 1-494 4-Pyrm Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-495 4-Pyr 3-F-Ph 2 CH ₂ N ₃ HH 1-496 4-Pyr 3-F-Ph 2 CH ₂ NO ₂ HH 1-497 4-Pyr 3-F-Ph 2 CH ₂ ONO HH 1-498 4-Pyr 3-F-Ph 2 CH ₂ ONO ₂ HH 1-499 4-Pyr 3-F-Ph 2 CH ₂ SCN HH 1-500 4-Pyr 3-F-Ph 2 CH ₂ PO (OMe ) ₂ HH 1-501 4-Pyr 3-F-Ph 2 CH ₂ PO (OEt) ₂ HH 1-502 4-Pyrm 3-F-Ph 2 CH ₂ N ₃ HH 1-503 4-Pyrm 3-F- Ph 2 CH ₂ NO ₂ HH 1-504 4-Pyrm 3-F-Ph 2 CH ₂ ONO HH 1-505 4-Pyrm 3-F-Ph 2 CH ₂ ONO ₂ HH 1-506 4-Pyrm 3-F- Ph 2 CH ₂ SCN HH 1-507 4-Pyrm 3-F-Ph 2 CH ₂ PO (OMe) ₂ HH 1-508 4-Pyr 3-F-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-509 4 -Pyr 3-F-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-510 4-Pyr 3-F-Ph 2 (CH ₂ ) ₂ ONO HH 1-511 4-Pyr 3-F-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-512 4-Pyr 3-F-Ph 2 (CH ₂ ) ₂ SCN HH 1-513 4-Pyr 3-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-514 4-Pyr 3-F-Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-515 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-516 4-Pyrm 3-F- Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-517 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₂ ONO HH 1-518 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-519 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₂ SCN HH 1-520 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-521 4 -Pyr 3-F-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-522 4-Pyr 3-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-523 4-Pyr 3-F-Ph 2 (CH ₂ ) ₃ ONO HH 1-524 4-Pyr 3-F-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-525 4-Pyr 3-F-Ph 2 (CH ₂ ) ₃ SCN HH 1-526 4-Pyr 3-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-527 4-Pyr 3-F-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-528 4-Pyrm 3-F- Ph 2 (CH ₂ ) ₃ N ₃ HH 1-529 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-530 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₃ ONO HH 1 -531 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1 -532 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₃ SCN HH 1-533 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-534 4-Pyr 3-F-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-535 4-Pyr 3-F-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-536 4-Pyr 3-F-Ph 2 (CH ₂ ) ₄ ONO HH 1-537 4-Pyr 3-F-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-538 4-Pyr 3-F- Ph 2 (CH ₂ ) ₄ SCN HH 1-539 4-Pyr 3-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-540 4-Pyr 3-F-Ph 2 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-541 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-542 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-543 4- Pyrm 3-F-Ph 2 (CH ₂ ) ₄ ONO HH 1-545 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-546 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₄ SCN HH 1-547 4-Pyrm 3-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-548 4-Pyr 4-F-Ph 2 CH ₂ N ₃ HH 1-549 4-Pyr 4-F-Ph 2 CH ₂ NO ₂ HH 1-550 4-Pyr 4-F-Ph 2 CH ₂ ONO HH 1-551 4-Pyr 4-F-Ph 2 CH ₂ ONO ₂ HH 1-552 4-Pyr 4-F-Ph 2 CH ₂ SCN HH 1-553 4-Pyr 4-F-Ph 2 CH ₂ PO (OMe) ₂ HH 1-554 4-Pyr 4-F-Ph 2 CH ₂ PO (OEt) ₂ HH 1-555 4-Pyrm 4 -F-Ph 2 CH ₂ N ₃ HH 1-556 4-Pyrm 4-F-Ph 2 CH ₂ NO ₂ HH 1-557 4-Pyrm 4-F-Ph 2 CH ₂ ONO HH 1-558 4-Pyrm 4 -F-Ph 2 CH ₂ ONO ₂ HH 1-559 4-Pyrm 4-F-Ph 2 CH ₂ SCN HH 1-560 4-Pyrm 4-F-Ph 2 CH ₂ PO (OMe) ₂ HH 1-561 4 -Pyr 4-F-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-562 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-563 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ ONO HH 1-564 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-565 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ SCN HH 1-566 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-567 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-568 4-Pyrm 4-F- Ph 2 (CH ₂ ) ₂ N ₃ HH 1-569 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-570 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ ONO H H 1-571 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-572 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ SCN HH 1-573 4-Pyrm 4-F- Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-574 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-575 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-576 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ ONO HH 1-577 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-578 4-Pyr 4- F-Ph 2 (CH ₂ ) ₃ SCN HH 1-579 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-580 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-581 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-582 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-583 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ ONO HH 1-584 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-585 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ SCN HH 1-586 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-587 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ N ₃ HH 1- 588 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-589 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ ONO HH 1-590 4-Pyr 4-F-Ph 2 ( CH ₂ ) ₄ ONO ₂ HH 1-591 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ SCN HH 1-592 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1 -593 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-594 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-595 4-Pyrm 4- F-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-596 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ ONO HH 1-597 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-598 4-Pyrm 4 -F-Ph 2 (CH ₂ ) ₄ SCN HH 1-599 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-600 4-Pyr 3-Cl-Ph 2 CH ₂ N ₃ HH 1-601 4-Pyr 3-Cl-Ph 2 CH ₂ NO ₂ HH 1-602 4-Pyr 3-Cl-Ph 2 CH ₂ ONO HH 1-603 4-Pyr 3-Cl-Ph 2 CH ₂ ONO ₂ HH 1-604 4-Pyr 3-Cl-Ph 2 CH ₂ SCN HH 1-605 4-Pyr 3-Cl-Ph 2 CH ₂ PO (OMe) ₂ HH 1-606 4-Pyr 3-Cl-Ph 2 CH ₂ PO (OEt) ₂ HH 1-607 4-Pyrm 3-Cl-Ph 2 CH ₂ N ₃ HH 1-608 4-Pyrm 3-Cl-Ph 2 CH ₂ NO ₂ HH 1-609 4-Pyrm 3- Cl-Ph 2 CH ₂ ONO HH 1-610 4-Pyrm 3-Cl-Ph 2 CH ₂ ONO ₂ HH 1-611 4-Pyrm 3-Cl-Ph 2 CH ₂ SCN HH 1-612 4-Pyrm 3-Cl -Ph 2 CH ₂ PO (OMe) ₂ HH 1-613 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-614 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-615 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₂ ONO HH 1-616 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-617 4-Pyr 3-Cl- Ph 2 (CH ₂ ) ₂ SCN HH 1-618 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-619 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-620 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-621 4-Pyrm 3-Cl-Ph 2 (C H ₂ ) ₂ NO ₂ HH 1-622 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₂ ONO HH 1-623 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-624 4 -Pyrm 3-Cl-Ph 2 (CH ₂ ) ₂ SCN HH 1-625 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-626 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-627 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-628 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₃ ONO HH 1-629 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-630 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₃ SCN HH 1-631 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-632 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-633 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-634 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-635 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₃ ONO HH 1-636 4-Pyrm 3-Cl -Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-637 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₃ SCN HH 1-638 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₃ PO (OMe ) ₂ HH 1-639 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-640 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-641 4-Pyr 3 -Cl-Ph 2 (CH ₂ ) ₄ ONO HH 1-642 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-643 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₄ SCN HH 1-644 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-645 4-Pyr 3-Cl-Ph 2 (CH ₂ ) ₄ PO (O Et) ₂ HH 1-646 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-647 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-648 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₄ ONO HH 1-649 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-650 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₄ SCN HH 1-651 4-Pyrm 3-Cl-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-652 4-Pyr 3,4-diF-Ph 2 CH ₂ N ₃ HH 1-653 4-Pyr 3,4-diF-Ph 2 CH ₂ NO ₂ HH 1-654 4-Pyr 3,4-diF-Ph 2 CH ₂ ONO HH 1-655 4-Pyr 3,4-diF-Ph 2 CH ₂ ONO ₂ HH 1-656 4-Pyr 3,4-diF-Ph 2 CH ₂ SCN HH 1-657 4-Pyr 3,4-diF-Ph 2 CH ₂ PO (OMe) ₂ HH 1-658 4-Pyr 3,4- diF-Ph 2 CH ₂ PO (OEt) ₂ HH 1-659 4-Pyrm 3,4-diF-Ph 2 CH ₂ N ₃ HH 1-660 4-Pyrm 3,4-diF-Ph 2 CH ₂ NO ₂ HH 1-661 4-Pyrm 3,4-diF-Ph 2 CH ₂ ONO HH 1-662 4-Pyrm 3,4-diF-Ph 2 CH ₂ ONO ₂ HH 1-663 4-Pyrm 3,4-diF-Ph 2 CH ₂ SCN HH 1-664 4-Pyrm 3,4-diF-Ph 2 CH ₂ PO (OMe) ₂ HH 1-665 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₂ N ₃ HH 1 -666 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-667 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₂ ONO HH 1-668 4-Pyr 3, 4-diF-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-669 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₂ SCN HH 1-670 4-Pyr 3,4-di F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-671 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-672 4-Pyrm 3,4- diF-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-673 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-674 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₂ ONO HH 1-675 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-676 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₂ SCN HH 1- 677 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-678 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-679 4- Pyr 3,4-diF-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-680 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₃ ONO HH 1-681 4-Pyr 3,4-diF- Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-682 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₃ SCN HH 1-683 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-684 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-685 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-686 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-687 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₃ ONO HH 1-688 4 -Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-689 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₃ SCN HH 1-690 4-Pyrm 3,4-diF -Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-691 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-692 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-693 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₄ ONO HH 1-694 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-695 4- Pyr 3,4-diF-Ph 2 (CH ₂ ) ₄ SCN HH 1-696 4-Pyr 3,4-diF-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-697 4-Pyr 3,4 -diF-Ph 2 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-698 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-699 4-Pyrm 3,4-diF- Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-700 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₄ ONO HH 1-701 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-702 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₄ SCN HH 1-703 4-Pyrm 3,4-diF-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1 -704 4-Pyr 3,4-diCl-Ph 2 CH ₂ N ₃ HH 1-705 4-Pyr 3,4-diCl-Ph 2 CH ₂ NO ₂ HH 1-706 4-Pyr 3,4-diCl-Ph 2 CH ₂ ONO HH 1-707 4-Pyr 3,4-diCl-Ph 2 CH ₂ ONO ₂ HH 1-708 4-Pyr 3,4-diCl-Ph 2 CH ₂ SCN HH 1-709 4-Pyr 3, 4-diCl-Ph 2 CH ₂ PO (OMe) ₂ HH 1-710 4-Pyr 3,4-diCl-Ph 2 CH ₂ PO (OEt) ₂ HH 1-711 4-Pyrm 3,4-diCl-Ph 2 CH ₂ N ₃ HH 1-712 4-Pyrm 3,4-diCl-Ph 2 CH ₂ NO ₂ HH 1-713 4-Pyrm 3,4-diCl-Ph 2 CH ₂ ONO HH 1-714 4-Pyrm 3, 4-diCl-Ph 2 CH ₂ ONO ₂ HH 1-715 4-Pyrm 3,4-diCl-Ph 2 CH ₂ SCN HH 1-716 4-Pyrm 3,4-diCl-Ph 2 CH ₂ PO (OMe) ₂ HH 1-717 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-718 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-719 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₂ ONO HH 1-720 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-721 4 -Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₂ SCN HH 1-722 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-723 4-Pyr 3, 4-diCl-Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-724 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-725 4-Pyrm 3,4-diCl -Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-726 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₂ ONO HH 1-727 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-728 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₂ SCN HH 1-729 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-730 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-731 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-732 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₃ ONO HH 1-733 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-734 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₃ SCN HH 1-735 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-736 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-737 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-738 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-739 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₃ ONO HH 1-740 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1 -741 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₃ SCN HH 1-742 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-743 4- Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-744 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-745 4-Pyr 3,4-diCl -Ph 2 (CH ₂ ) ₄ ONO HH 1-746 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-747 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₄ SCN HH 1-748 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-749 4-Pyr 3,4-diCl-Ph 2 (CH ₂ ) ₄ PO (OEt ) ₂ HH 1-750 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-751 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-752 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₄ ONO HH 1-753 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-754 4-Pyrm 3,4- diCl-Ph 2 (CH ₂ ) ₄ SCN HH 1-755 4-Pyrm 3,4-diCl-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-756 4-Pyr 3-Cl-4-F- Ph 2 CH ₂ N ₃ HH 1-757 4-Pyr 3-Cl-4-F-Ph 2 CH ₂ NO ₂ HH 1-758 4-Pyr 3-Cl-4-F-Ph 2 CH ₂ ONO HH 1- 759 4-Pyr 3-Cl-4-F-Ph 2 CH ₂ ONO ₂ HH 1-760 4-Pyr 3-Cl-4-F-Ph 2 CH ₂ SCN HH 1-761 4-Pyr 3-Cl-4 - F-Ph 2 CH ₂ PO (OMe) ₂ HH 1-762 4-Pyr 3-Cl-4-F-Ph 2 CH ₂ PO (OEt) ₂ HH 1-763 4-Pyrm 3-Cl-4-F- Ph 2 CH ₂ N ₃ HH 1-764 4-Pyrm 3-Cl-4-F-Ph 2 CH ₂ NO ₂ HH 1-765 4-Pyrm 3-Cl-4-F-Ph 2 CH ₂ ONO HH 1- 766 4-Pyrm 3-Cl-4-F-Ph 2 CH ₂ ONO ₂ HH 1-767 4-Pyrm 3-Cl-4-F-Ph 2 CH ₂ SCN HH 1-768 4-Pyrm 3-Cl-4 -F-Ph 2 CH ₂ PO (OMe) ₂ HH 1-769 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-770 4-Pyr 3-Cl-4-F -Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-771 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ ONO HH 1-772 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-773 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ SCN HH 1-774 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-775 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ HH 1-776 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-777 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-778 4-Pyrm 3-Cl-4-F-Ph 2 ( CH ₂ ) ₂ ONO HH 1-779 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ HH 1-780 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ SCN HH 1-781 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ HH 1-782 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-783 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-784 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ ONO HH 1-785 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-786 4-Pyr 3-Cl -4-F-Ph 2 (CH ₂ ) ₃ SCN HH 1-787 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-788 4-Pyr 3-Cl -4-F-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ HH 1-789 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-790 4-Pyrm 3- Cl-4-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-791 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ ONO HH 1-792 4-Pyrm 3-Cl-4 -F-Ph 2 (CH ₂ ) ₃ ONO ₂ HH 1-793 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₃ SCN HH 1-794 4-Pyrm 3-Cl-4-F- Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ HH 1-795 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-796 4-Pyr 3-Cl-4-F -Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-797 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ ONO HH 1-798 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-799 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ SCN HH 1-800 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-801 4-Pyr 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ PO (OEt) ₂ HH 1-802 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ N ₃ HH 1-803 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ NO ₂ HH 1-804 4-Pyrm 3-Cl-4-F-Ph 2 ( CH ₂ ) ₄ ONO HH 1-805 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ ONO ₂ HH 1-806 4-Pyrm 3- Cl-4-F-Ph 2 (CH ₂ ) ₄ SCN HH 1-807 4-Pyrm 3-Cl-4-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ HH 1-808 4-Pyr 4- F-Ph 1 CH (Me) CH ₂ NO ₂ HH 1-809 4-Pyr 4-F-Ph 1 CH ₂ CH (Me) NO ₂ HH 1-810 4-Pyr 4-F-Ph 1 C (Me) ₂ CH ₂ NO ₂ HH 1-811 4-Pyr 4-F-Ph 1 CH ₂ C (Me) ₂ NO ₂ HH 1-812 4-Pyr 4-F-Ph 1 CH (Me) (CH ₂ ) ₂ NO ₂ HH 1-813 4-Pyr 4-F-Ph 1 CH ₂ CH (Me) CH ₂ NO ₂ HH 1-814 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ CH (Me) NO ₂ HH 1 -815 4-Pyr 4-F-Ph 1 C (Me) ₂ (CH ₂ ) ₂ NO ₂ HH 1-816 4-Pyr 4-F-Ph 1 CH ₂ C (Me) ₂ CH ₂ NO ₂ HH 1- 817 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ C (Me) ₂ NO ₂ HH 1-818 4-Pyr 4-F-Ph 1 cHx-1,4-diyl NO ₂ HH 1-819 4- Pyr 4-F-Ph 1 CH = CH NO ₂ HH 1-820 4-Pyr 4-F-Ph 1 CH ₂ CH = CH NO ₂ HH 1-821 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ CH = CH NO ₂ HH 1-822 4-Pyr 4-F-Ph 2 CH (Me) CH ₂ NO ₂ HH 1-823 4-Pyr 4-F-Ph 2 CH ₂ CH (Me) NO ₂ HH 1- 824 4-Pyr 4-F-Ph 2 C (Me) ₂ CH ₂ NO ₂ HH 1-825 4-Pyr 4-F-Ph 2 CH ₂ C (Me) ₂ NO ₂ HH 1-826 4-Pyr 4- F-Ph 2 CH (Me) (CH ₂ ) ₂ NO ₂ HH 1-827 4-Pyr 4-F-Ph 2 CH ₂ CH (Me) CH ₂ NO ₂ HH 1-828 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ CH (Me) NO ₂ HH 1-829 4-Pyr 4-F- Ph 2 C (Me) ₂ (CH ₂ ) ₂ NO ₂ HH 1-830 4-Pyr 4-F-Ph 2 CH ₂ C (Me) ₂ CH ₂ NO ₂ HH 1-831 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ C (Me) ₂ NO ₂ HH 1-832 4-Pyr 4-F-Ph 2 cHx-1,4-diyl NO ₂ HH 1-833 4-Pyr 4-F-Ph 2 CH = CH NO ₂ HH 1-834 4-Pyr 4-F-Ph 2 CH ₂ CH = CH NO ₂ HH 1-835 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ CH = CH NO ₂ HH 1-836 4-Pyr 4-F-Ph 1 CH ₂ NO ₂ Me H 1-837 4-Pyr 4-F-Ph 1 CH ₂ NO ₂ H Me 1-838 4-Pyr 4-F-Ph 1 CH ₂ NO ₂ Me Me 1-839 4-Pyr 4-F-Ph 2 CH ₂ NO ₂ Me H 1-840 4-Pyr 4-F-Ph 2 CH ₂ NO ₂ H Me 1-841 4-Pyr 4-F-Ph 2 CH ₂ NO ₂ Me Me 1-842 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ Me H 1-843 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ H Me 1-844 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ Me Me 1-845 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ Me H 1-846 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ H Me 1-847 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ Me Me 1-848 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ Me H 1-849 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ H Me 1-850 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ Me Me 1-851 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ Me H 1-852 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ H Me 1-853 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ Me Me 1-854 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ NO ₂ Me H 1-855 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ NO ₂ H Me 1-856 4-Pyr 4- F-Ph 1 (CH ₂ ) ₄ NO ₂ Me Me 1-857 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ NO ₂ Me H 1-858 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ NO ₂ H Me 1-859 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ NO ₂ Me Me 1-860 4-Pyr 4-F-Ph 1 CH (Me) CH ₂ N ₃ HH 1-861 4-Pyr 4-F-Ph 1 CH ₂ CH (Me) N ₃ HH 1-862 4-Pyr 4-F-Ph 1 C (Me) ₂ CH ₂ N ₃ HH 1-863 4-Pyr 4-F- Ph 1 CH ₂ C (Me) ₂ N ₃ HH 1-864 4-Pyr 4-F-Ph 1 CH (Me) (CH ₂ ) ₂ N ₃ HH 1-865 4-Pyr 4-F-Ph 1 CH ₂ CH (Me) CH ₂ N ₃ HH 1-866 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ CH (Me) N ₃ HH 1-867 4-Pyr 4-F-Ph 1 C (Me) ₂ (CH ₂ ) ₂ N ₃ HH 1-868 4-Pyr 4-F-Ph 1 CH ₂ C (Me) ₂ CH ₂ N ₃ HH 1-869 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ C (Me) ₂ N ₃ HH 1-870 4-Pyr 4-F-Ph 1 cHx-1,4-diyl N ₃ HH 1-871 4-Pyr 4-F-Ph 1 CH = CH N ₃ HH 1-872 4-Pyr 4-F-Ph 1 CH ₂ CH = CH N ₃ HH 1-873 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ CH = CH N ₃ HH 1-874 4-Pyr 4-F- Ph 2 CH (Me) CH ₂ N ₃ HH 1-875 4-Pyr 4-F-Ph 2 CH ₂ CH (Me) N ₃ HH 1-876 4-Pyr 4-F-Ph 2 C (Me) ₂ CH ₂ N ₃ HH 1-877 4-Pyr 4-F-Ph 2 CH ₂ C (Me) ₂ N ₃ HH 1-878 4-Pyr 4-F-Ph 2 CH (Me) (CH ₂ ) ₂ N ₃ HH 1-879 4-Pyr 4-F-Ph 2 CH ₂ CH (Me) CH ₂ N ₃ HH 1-880 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ CH (Me) N ₃ HH 1-881 4-Pyr 4-F-Ph 2 C (Me) ₂ (CH ₂ ) ₂ N ₃ HH 1-882 4 -Pyr 4-F-Ph 2 CH ₂ C (Me) ₂ CH ₂ N ₃ HH 1-883 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ C (Me) ₂ N ₃ HH 1-884 4- Pyr 4-F-Ph 2 cHx-1,4-diyl N ₃ HH 1-885 4-Pyr 4-F-Ph 2 CH = CH N ₃ HH 1-886 4-Pyr 4-F-Ph 2 CH ₂ CH = CH N ₃ HH 1-887 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ CH = CH N ₃ HH 1-888 4-Pyr 4-F-Ph 1 CH ₂ N ₃ Me H 1-889 4 -Pyr 4-F-Ph 1 CH ₂ N ₃ H Me 1-890 4-Pyr 4-F-Ph 1 CH ₂ N ₃ Me Me 1-891 4-Pyr 4-F-Ph 2 CH ₂ N ₃ Me H 1-892 4-Pyr 4-F-Ph 2 CH ₂ N ₃ H Me 1-893 4-Pyr 4-F-Ph 2 CH ₂ N ₃ Me Me 1-894 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ N ₃ Me H 1-895 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ N ₃ H Me 1-896 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ N ₃ Me Me 1 -897 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ N ₃ Me H 1-898 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ N ₃ H Me 1-899 4-Pyr 4-F -Ph 2 (CH ₂ ) ₂ N ₃ Me Me 1-900 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ N ₃ Me H 1-901 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ N ₃ H Me 1-902 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ N ₃ Me Me 1-903 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ N ₃ Me H 1-904 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ N ₃ H Me 1-905 4-Pyr 4 -F-Ph 2 (CH ₂ ) ₃ N ₃ Me Me 1-906 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ N ₃ Me H 1-907 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ N ₃ H Me 1-908 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ N ₃ Me Me 1-909 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ N ₃ Me H 1- 910 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ N ₃ H Me 1-911 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ N ₃ Me Me 1-912 4-Pyr 4-Cl- Ph 1 (CH ₂ ) ₂ N ₃ HH 1-913 4-Pyr 4-Cl-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-914 4-Pyr 4-Cl-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-915 4-Pyr 4-Cl-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-916 2-NH ₂ -4-Pyrm 4-F-Ph 1 CH ₂ N ₃ HH 1-917 2-NH _2- 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-918 2-NH ₂ -4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-919 2-NH _2- 4-Pyrm 4-F-Ph 1 CH ₂ NO ₂ HH 1-920 2-NH ₂ -4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-921 2-NH ₂ -4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-922 2-NH ₂ -4-Pyrm 4-F-Ph 2 CH ₂ N ₃ HH 1-923 2-NH ₂ -4-Pyrm 4-F -Ph 2 (CH ₂ ) ₂ N ₃ HH 1-924 2-NH ₂ -4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-925 2-NH ₂ -4-Pyrm 4-F -Ph 2 CH ₂ NO ₂ HH 1-926 2-NH ₂ -4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-927 2-NH ₂ -4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH 1-928 2-MeNH-4-Pyrm 4 -F-Ph 1 CH ₂ N ₃ HH 1-929 2-MeNH-4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ N ₃ HH 1-930 2-MeNH-4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ N ₃ HH 1-931 2-MeNH-4-Pyrm 4-F-Ph 1 CH ₂ NO ₂ HH 1-932 2-MeNH-4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ HH 1-933 2-MeNH-4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ HH 1-934 2-MeNH-4-Pyrm 4-F-Ph 2 CH ₂ N ₃ HH 1- 935 2-MeNH-4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ N ₃ HH 1-936 2-MeNH-4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ N ₃ HH 1-937 2 -MeNH-4-Pyrm 4-F-Ph 2 CH ₂ NO ₂ HH 1-938 2-MeNH-4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ HH 1-939 2-MeNH-4- Pyrm 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ HH ------------------------------------------

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[Table 3] Table 2 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Compound No. Ar ¹ Ar ² WR ⁴ R ¹ R ² −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 2-1 4-Pyr 4-F-Ph CH ₂ N ₃ HH 2-2 4-Pyr 4-F-Ph CH ₂ NO ₂ HH 2-3 4-Pyr 4-F-Ph CH ₂ ONO HH 2-4 4-Pyr 4-F-Ph CH ₂ ONO ₂ HH 2-5 4-Pyr 4-F-Ph CH ₂ SCN HH 2-6 4-Pyr 4-F-Ph CH ₂ PO (OMe) ₂ HH 2-7 4-Pyr 4-F-Ph CH ₂ PO (OEt) ₂ HH 2-8 4-Pyrm 4-F-Ph CH ₂ N ₃ HH 2-9 4-Pyrm 4-F-Ph CH ₂ NO ₂ HH 2-10 4-Pyrm 4-F-Ph CH ₂ ONO HH 2-11 4-Pyrm 4-F-Ph CH ₂ ONO ₂ HH 2-12 4-Pyrm 4-F-Ph CH ₂ SCN HH 2-13 4-Pyrm 4-F-Ph CH ₂ PO (OMe) ₂ HH 2-14 4-Pyr 4-F-Ph (CH ₂ ) ₂ N ₃ HH 2-15 4-Pyr 4-F-Ph (CH ₂ ) ₂ NO ₂ HH 2-16 4-Pyr 4-F- Ph (CH ₂ ) ₂ ONO HH 2-17 4-Pyr 4-F-Ph (CH ₂ ) ₂ ONO ₂ HH 2-18 4-Pyr 4-F-Ph (CH ₂ ) ₂ SCN HH 2-19 4- Pyr 4-F-Ph (CH ₂ ) ₂ PO (OMe) ₂ HH 2-20 4-Pyr 4-F-Ph (CH ₂ ) ₂ PO (OEt) ₂ HH 2-21 4-Pyrm 4-F-Ph (CH ₂ ) ₂ N ₃ HH 2-22 4-Pyrm 4-F-Ph ( CH ₂ ) ₂ NO ₂ HH 2-23 4-Pyrm 4-F-Ph (CH ₂ ) ₂ ONO HH 2-24 4-Pyrm 4-F-Ph (CH ₂ ) ₂ ONO ₂ HH 2-25 4-Pyrm 4-F-Ph (CH ₂ ) ₂ SCN HH 2-26 4-Pyrm 4-F-Ph (CH ₂ ) ₂ PO (OMe) ₂ HH 2-27 4-Pyr 4-F-Ph (CH ₂ ) ₃ N ₃ HH 2-28 4-Pyr 4-F-Ph (CH ₂ ) ₃ NO ₂ HH 2-29 4-Pyr 4-F-Ph (CH ₂ ) ₃ ONO HH 2-30 4-Pyr 4-F- Ph (CH ₂ ) ₃ ONO ₂ HH 2-31 4-Pyr 4-F-Ph (CH ₂ ) ₃ SCN HH 2-32 4-Pyr 4-F-Ph (CH ₂ ) ₃ PO (OMe) ₂ HH 2 -33 4-Pyr 4-F-Ph (CH ₂ ) ₃ PO (OEt) ₂ HH 2-34 4-Pyrm 4-F-Ph (CH ₂ ) ₃ N ₃ HH 2-35 4-Pyrm 4-F- Ph (CH ₂ ) ₃ NO ₂ HH 2-36 4-Pyrm 4-F-Ph (CH ₂ ) ₃ ONO HH 2-37 4-Pyrm 4-F-Ph (CH ₂ ) ₃ ONO ₂ HH 2-38 4 -Pyrm 4-F-Ph (CH ₂ ) ₃ SCN HH 2-39 4-Pyrm 4-F-Ph (CH ₂ ) ₃ PO (OMe) ₂ HH 2-40 4-Pyr 4-F-Ph (CH ₂ ) ₄ N ₃ HH 2-41 4-Pyr 4-F-Ph (CH ₂ ) ₄ NO ₂ HH 2-42 4-Pyr 4-F-Ph (CH ₂ ) ₄ ONO HH 2-43 4-Pyr 4- F-Ph (CH ₂ ) ₄ ONO ₂ HH 2-44 4-Pyr 4-F-Ph (CH ₂ ) ₄ SCN HH 2-45 4-Pyr 4-F-Ph (CH ₂ ) ₄ PO (OMe) ₂ HH 2-46 4-Pyr 4-F-Ph (CH ₂ ) ₄ PO (OEt) ₂ HH 2-47 4-Pyrm 4-F-Ph (CH ₂ ) ₄ N ₃ HH 2-48 4-Pyrm 4- F-Ph (CH ₂ ) ₄ NO ₂ HH 2-49 4-Pyrm 4 -F-Ph (CH ₂ ) ₄ ONO HH 2-50 4-Pyrm 4-F-Ph (CH ₂ ) ₄ ONO ₂ HH 2-51 4-Pyrm 4-F-Ph (CH ₂ ) ₄ SCN HH 2- 52 4-Pyrm 4-F-Ph (CH ₂ ) ₄ PO (OMe) ₂ HH 2-53 4-Pyr 4-F-Ph (CH ₂ ) ₅ N ₃ HH 2-54 4-Pyr 4-F-Ph (CH ₂ ) ₅ NO ₂ HH 2-55 4-Pyr 4-F-Ph (CH ₂ ) ₅ ONO HH 2-56 4-Pyr 4-F-Ph (CH ₂ ) ₅ ONO ₂ HH 2-57 4- Pyr 4-F-Ph (CH ₂ ) ₅ SCN HH 2-58 4-Pyr 4-F-Ph (CH ₂ ) ₅ PO (OMe) ₂ HH 2-59 4-Pyr 4-F-Ph (CH ₂ ) ₅ PO (OEt) ₂ HH 2-60 4-Pyrm 4-F-Ph (CH ₂ ) ₅ N ₃ HH 2-61 4-Pyrm 4-F-Ph (CH ₂ ) ₅ NO ₂ HH 2-62 4- Pyrm 4-F-Ph (CH ₂ ) ₅ ONO HH 2-63 4-Pyrm 4-F-Ph (CH ₂ ) ₅ ONO ₂ HH 2-64 4-Pyrm 4-F-Ph (CH ₂ ) ₅ SCN HH 2-65 4-Pyrm 4-F-Ph (CH ₂ ) ₅ PO (OMe) ₂ HH −−−−−−−−−−−−−−−−−−−−−−−−−−−−− −−−−−−−−

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Table 4 Table 3 ----------------------------------- compound numbers Ar ¹ Ar ² WR ⁴ R ¹ R ² −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 3-1 4-Pyr 4-F-Ph CH ₂ N ₃ HH 3-2 4-Pyr 4-F-Ph CH ₂ NO ₂ HH 3-3 4-Pyr 4-F-Ph CH ₂ ONO HH 3-4 4-Pyr 4-F-Ph CH ₂ ONO ₂ HH 3-5 4-Pyr 4-F-Ph CH ₂ SCN HH 3-6 4-Pyr 4-F-Ph CH ₂ PO (OMe) ₂ HH 3-7 4-Pyr 4-F-Ph CH ₂ PO (OEt) ₂ HH 3-8 4-Pyrm 4-F-Ph CH ₂ N ₃ HH 3-9 4-Pyrm 4-F-Ph CH ₂ NO ₂ HH 3-10 4-Pyrm 4-F-Ph CH ₂ ONO HH 3-11 4-Pyrm 4-F-Ph CH ₂ ONO ₂ HH 3-12 4-Pyrm 4-F-Ph CH ₂ SCN HH 3-13 4-Pyrm 4-F-Ph CH ₂ PO (OMe) ₂ HH 3-14 4-Pyr 4-F-Ph (CH ₂ ) ₂ N ₃ HH 3-15 4-Pyr 4-F-Ph (CH ₂ ) ₂ NO ₂ HH 3-16 4-Pyr 4-F- Ph (CH ₂ ) ₂ ONO HH 3-17 4-Pyr 4-F-Ph (CH ₂ ) ₂ ONO ₂ HH 3-18 4-Pyr 4-F-Ph (CH ₂ ) ₂ SCN HH 3-19 4- Pyr 4-F-Ph (CH ₂ ) ₂ PO (OMe) ₂ HH 3-20 4-Pyr 4-F-Ph (CH ₂ ) ₂ PO (OEt) ₂ HH 3-21 4-Pyrm 4-F-Ph (CH ₂ ) ₂ N ₃ HH 3-22 4-Pyrm 4-F-Ph ( CH ₂ ) ₂ NO ₂ HH 3-23 4-Pyrm 4-F-Ph (CH ₂ ) ₂ ONO HH 3-24 4-Pyrm 4-F-Ph (CH ₂ ) ₂ ONO ₂ HH 3-25 4-Pyrm 4-F-Ph (CH ₂ ) ₂ SCN HH 3-26 4-Pyrm 4-F-Ph (CH ₂ ) ₂ PO (OMe) ₂ HH 3-27 4-Pyr 4-F-Ph (CH ₂ ) ₃ N ₃ HH 3-28 4-Pyr 4-F-Ph (CH ₂ ) ₃ NO ₂ HH 3-29 4-Pyr 4-F-Ph (CH ₂ ) ₃ ONO HH 3-30 4-Pyr 4-F- Ph (CH ₂ ) ₃ ONO ₂ HH 3-31 4-Pyr 4-F-Ph (CH ₂ ) ₃ SCN HH 3-32 4-Pyr 4-F-Ph (CH ₂ ) ₃ PO (OMe) ₂ HH 3 -33 4-Pyr 4-F-Ph (CH ₂ ) ₃ PO (OEt) ₂ HH 3-34 4-Pyrm 4-F-Ph (CH ₂ ) ₃ N ₃ HH 3-35 4-Pyrm 4-F- Ph (CH ₂ ) ₃ NO ₂ HH 3-36 4-Pyrm 4-F-Ph (CH ₂ ) ₃ ONO HH 3-37 4-Pyrm 4-F-Ph (CH ₂ ) ₃ ONO ₂ HH 3-38 4 -Pyrm 4-F-Ph (CH ₂ ) ₃ SCN HH 3-39 4-Pyrm 4-F-Ph (CH ₂ ) ₃ PO (OMe) ₂ HH 3-40 4-Pyr 4-F-Ph (CH ₂ ) ₄ N ₃ HH 3-41 4-Pyr 4-F-Ph (CH ₂ ) ₄ NO ₂ HH 3-42 4-Pyr 4-F-Ph (CH ₂ ) ₄ ONO HH 3-43 4-Pyr 4- F-Ph (CH ₂ ) ₄ ONO ₂ HH 3-44 4-Pyr 4-F-Ph (CH ₂ ) ₄ SCN HH 3-45 4-Pyr 4-F-Ph (CH ₂ ) ₄ PO (OMe) ₂ HH 3-46 4-Pyr 4-F-Ph (CH ₂ ) ₄ PO (OEt) ₂ HH 3-47 4-Pyrm 4-F-Ph (CH ₂ ) ₄ N ₃ HH 3-48 4-Pyrm 4- F-Ph (CH ₂ ) ₄ NO ₂ HH 3-49 4-Pyrm 4 -F-Ph (CH ₂ ) ₄ ONO HH 3-50 4-Pyrm 4-F-Ph (CH ₂ ) ₄ ONO ₂ HH 3-51 4-Pyrm 4-F-Ph (CH ₂ ) ₄ SCN HH 3- 52 4-Pyrm 4-F-Ph (CH ₂ ) ₄ PO (OMe) ₂ HH --- --------------------- −−−−−−

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TABLE 5 TABLE 4 ----------------------------------- compound numbers Ar ¹ Ar ² m WR ⁴ R ² −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 4-1 4-Pyr 4-F-Ph 1 CH ₂ N ₃ H 4-2 4-Pyr 4-F-Ph 1 CH ₂ NO ₂ H 4-3 4-Pyr 4-F-Ph 1 CH ₂ ONO H 4-4 4-Pyr 4-F-Ph 1 CH ₂ ONO ₂ H 4-5 4-Pyr 4-F-Ph 1 CH ₂ SCN H 4-6 4-Pyr 4-F-Ph 1 CH ₂ PO (OMe) ₂ H 4-7 4-Pyr 4-F -Ph 1 CH ₂ PO (OEt) ₂ H 4-8 4-Pyrm 4-F-Ph 1 CH ₂ N ₃ H 4-9 4-Pyrm 4-F-Ph 1 CH ₂ NO ₂ H 4-10 4- Pyrm 4-F-Ph 1 CH ₂ ONO H 4-11 4-Pyrm 4-F-Ph 1 CH ₂ ONO ₂ H 4-12 4-Pyrm 4-F-Ph 1 CH ₂ SCN H 4-13 4-Pyrm 4-F-Ph 1 CH ₂ PO (OMe) ₂ H 4-14 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ N ₃ H 4-15 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ H 4-16 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ ONO H 4-17 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ H 4-18 4-Pyr 4 -F-Ph 1 (CH ₂ ) ₂ SCN H 4-19 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ H 4-20 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ H 4-21 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ N ₃ H 4 -22 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ H 4-23 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ ONO H 4-24 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ H 4-25 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ SCN H 4-26 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ H 4-27 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ N ₃ H 4-28 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ H 4-29 4-Pyr 4-F- Ph 1 (CH ₂ ) ₃ ONO H 4-30 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ H 4-31 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ SCN H 4- 32 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ H 4-33 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ H 4-34 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ N ₃ H 4-35 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ H 4-36 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ ONO H 4-37 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ H 4-38 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ SCN H 4-39 4-Pyrm 4- F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ H 4-40 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ N ₃ H 4-41 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ NO ₂ H 4-42 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ ONO H 4-43 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ ONO ₂ H 4-44 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ SCN H 4-45 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ H 4-46 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ PO (OEt) ₂ H 4-47 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ N ₃ H 4-48 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ NO ₂ H 4-49 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ ONO H 4-50 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ ONO ₂ H 4-51 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ SCN H 4-52 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ H 4- 53 4-Pyr 4-F-Ph 2 CH ₂ N ₃ H 4-54 4-Pyr 4-F-Ph 2 CH ₂ NO ₂ H 4-55 4-Pyr 4-F-Ph 2 CH ₂ ONO H 4- 56 4-Pyr 4-F-Ph 2 CH ₂ ONO ₂ H 4-57 4-Pyr 4-F-Ph 2 CH ₂ SCN H 4-58 4-Pyr 4-F-Ph 2 CH ₂ PO (OMe) ₂ H 4-59 4-Pyr 4-F-Ph 2 CH ₂ PO (OEt) ₂ H 4-60 4-Pyrm 4-F-Ph 2 CH ₂ N ₃ H 4-61 4-Pyrm 4-F-Ph 2 CH ₂ NO ₂ H 4-62 4-Pyrm 4-F-Ph 2 CH ₂ ONO H 4-63 4-Pyrm 4-F-Ph 2 CH ₂ ONO ₂ H 4-64 4-Pyrm 4-F-Ph 2 CH ₂ SCN H 4-65 4-Pyrm 4-F-Ph 2 CH ₂ PO (OMe) ₂ H 4-66 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ N ₃ H 4-67 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ H 4-68 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ ONO H 4-69 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ H 4-70 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ SCN H 4-71 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ H 4-72 4- Pyr 4-F-Ph 2 (CH ₂ ) ₂ PO (OEt) ₂ H 4-73 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ N ₃ H 4-74 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ H 4-75 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ ONO H 4-76 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ H 4-77 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ SCN H 4-78 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ H 4-79 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ N ₃ H 4-80 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ H 4-81 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ ONO H 4-82 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ ONO ₂ H 4-83 4-Pyr 4-F -Ph 2 (CH ₂ ) ₃ SCN H 4-84 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ H 4-85 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ H 4-86 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ N ₃ H 4-87 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ H 4-88 4 -Pyrm 4-F-Ph 2 (CH ₂ ) ₃ ONO H 4-89 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ ONO ₂ H 4-90 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ SCN H 4-91 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ H 4-92 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ N ₃ H 4-93 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ NO ₂ H 4-94 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ ONO H 4-95 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ ONO ₂ H 4-96 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ SCN H 4-97 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ H 4- 98 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ PO (OEt) ₂ H 4-99 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ N ₃ H 4-100 4-Pyrm 4-F -Ph 2 (CH ₂ ) ₄ NO ₂ H 4-101 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ ONO H 4 -102 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ ONO ₂ H 4-103 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ SCN H 4-104 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ H −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−

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[Table 6] Table 5 -------------------------------------------------- Compound No.Ar ¹ Ar ² m WR ⁴ −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 5-1 4-Pyr 4-F-Ph 1 CH ₂ N ₃ 5-2 4-Pyr 4-F-Ph 1 CH ₂ NO ₂ 5-3 4-Pyr 4-F-Ph 1 CH ₂ ONO 5-4 4-Pyr 4-F-Ph 1 CH ₂ ONO ₂ 5 -5 4-Pyr 4-F-Ph 1 CH ₂ SCN 5-6 4-Pyr 4-F-Ph 1 CH ₂ PO (OMe) ₂ 5-7 4-Pyr 4-F-Ph 1 CH ₂ PO (OEt ) ₂ 5-8 4-Pyrm 4-F-Ph 1 CH ₂ N ₃ 5-9 4-Pyrm 4-F-Ph 1 CH ₂ NO ₂ 5-10 4-Pyrm 4-F-Ph 1 CH ₂ ONO 5 -11 4-Pyrm 4-F-Ph 1 CH ₂ ONO ₂ 5-12 4-Pyrm 4-F-Ph 1 CH ₂ SCN 5-13 4-Pyrm 4-F-Ph 1 CH ₂ PO (OMe) ₂ 5 -14 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ N _{3 5} -15 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ 5-16 4-Pyr 4-F-Ph 1 ( (CH ₂ ) ₂ ONO 5-17 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ 5-18 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ SCN 5-19 4-Pyr 4- F-Ph 1 (CH ₂ ) ₂ PO (OMe) ₂ 5-20 4-Pyr 4-F-Ph 1 (CH ₂ ) ₂ PO (OEt) ₂ 5-21 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ N ₃ 5-22 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ NO ₂ 5-23 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ ONO 5-24 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ ONO ₂ 5-25 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₂ SCN 5 -26 4-Pyrm 4-F- Ph 1 (CH 2) 2 PO (OMe) 2 5-27 4-Pyr 4-F-Ph 1 (CH 2) 3 N 3 5-28 4-Pyr 4-F- Ph 1 (CH ₂ ) ₃ NO ₂ 5-29 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ ONO 5-30 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ 5-31 4 -Pyr 4-F-Ph 1 (CH ₂ ) ₃ SCN 5-32 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ 5-33 4-Pyr 4-F-Ph 1 (CH ₂ ) ₃ PO (OEt) ₂ 5-34 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ N ₃ 5-35 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ NO ₂ 5-36 4 -Pyrm 4-F-Ph 1 (CH ₂ ) ₃ ONO 5-37 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ ONO ₂ 5-38 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ SCN 5-39 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₃ PO (OMe) ₂ 5-40 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ N ₃ 5-41 4-Pyr 4- _{F-Ph 1 (CH 2)} 4 NO 2 5-42 4-Pyr 4-F-Ph 1 (CH 2) 4 ONO 5-43 4-Pyr 4-F-Ph 1 (CH 2) 4 ONO 2 5- 44 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ SCN 5-45 4-Pyr 4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ 5-46 4-Pyr 4-F-Ph 1 _{(CH 2) 4 PO (OEt} ) 2 5-47 4-Pyrm 4-F-Ph 1 (CH 2) 4 N 3 5-48 4-Pyrm 4-F-Ph 1 (CH 2) 4 NO 2 5- 49 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ ONO 5-50 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ O NO ₂ 5-51 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ SCN 5-52 4-Pyrm 4-F-Ph 1 (CH ₂ ) ₄ PO (OMe) ₂ 5-53 4-Pyr 4- F-Ph 2 CH ₂ N ₃ 5-54 4-Pyr 4-F-Ph 2 CH ₂ NO ₂ 5-55 4-Pyr 4-F-Ph 2 CH ₂ ONO 5-56 4-Pyr 4-F-Ph 2 CH ₂ ONO ₂ 5-57 4-Pyr 4-F-Ph 2 CH ₂ SCN 5-58 4-Pyr 4-F-Ph 2 CH ₂ PO (OMe) ₂ 5-59 4-Pyr 4-F-Ph 2 CH ₂ PO (OEt) ₂ 5-60 4-Pyrm 4-F-Ph 2 CH ₂ N ₃ 5-61 4-Pyrm 4-F-Ph 2 CH ₂ NO ₂ 5-62 4-Pyrm 4-F- Ph 2 CH ₂ ONO 5-63 4-Pyrm 4-F-Ph 2 CH ₂ ONO ₂ 5-64 4-Pyrm 4-F-Ph 2 CH ₂ SCN 5-65 4-Pyrm 4-F-Ph 2 CH ₂ PO (OMe) ₂ 5-66 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ N ₃ 5-67 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ 5-68 4-Pyr 4 -F-Ph 2 (CH ₂ ) ₂ ONO 5-69 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ 5-70 4-Pyr 4-F-Ph 2 (CH ₂ ) ₂ SCN 5- 71 4-Pyr 4-F- Ph 2 (CH 2) 2 PO (OMe) 2 5-72 4-Pyr 4-F-Ph 2 (CH 2) 2 PO (OEt) 2 5-73 4-Pyrm 4- F-Ph 2 (CH ₂ ) ₂ N ₃ 5-74 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ NO ₂ 5-75 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ ONO 5- 76 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ ONO ₂ 5-77 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ SCN 5-78 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₂ PO (OMe) ₂ 5-79 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ N ₃ 5-80 4 -Pyr 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ 5-81 4-Pyr 4-F-Ph 2 (CH ₂ ) ₃ ONO 5-82 4-Pyr 4-F-Ph 2 (CH ₂ ) _{3 ONO 2 5-83 4-Pyr 4-} F-Ph 2 (CH 2) 3 SCN 5-84 4-Pyr 4-F-Ph 2 (CH 2) 3 PO (OMe) 2 5-85 4-Pyr 4- F-Ph 2 (CH ₂ ) ₃ PO (OEt) ₂ 5-86 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ N ₃ 5-87 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ NO ₂ 5-88 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ ONO 5-89 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ ONO ₂ 5-90 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ SCN 5-91 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₃ PO (OMe) ₂ 5-92 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ N ₃ 5- 93 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ NO ₂ 5-94 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ ONO 5-95 4-Pyr 4-F-Ph 2 (CH _{2 ) 4 ONO 2 5-96 4-Pyr} 4-F-Ph 2 (CH 2) 4 SCN 5-97 4-Pyr 4-F-Ph 2 (CH 2) 4 PO (OMe) 2 5-98 4-Pyr 4-F-Ph 2 (CH ₂ ) ₄ PO (OEt) ₂ 5-99 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ N ₃ 5-100 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ NO ₂ 5-101 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ ONO 5-102 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ ONO ₂ 5-103 4-Pyrm 4-F -Ph 2 (CH ₂ ) ₄ SCN 5-104 4-Pyrm 4-F-Ph 2 (CH ₂ ) ₄ PO (OMe) ₂ −−−−−−−−−−−−−−−−−−−−− −−−−−−−−−−−−− ----

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[Table 7] Table 6 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Compound No. Ar ¹ Ar ² R ³ R ¹ R ² − ----------------------------- 6-1 4-Pyr 4-F -Ph CH 2 N 3 HH 6-2 4- Pyr 4-F-Ph CH ₂ NO ₂ HH 6-3 4-Pyr 4-F-Ph CH ₂ ONO HH 6-4 4-Pyr 4-F-Ph CH ₂ ONO ₂ HH 6-5 4-Pyr 4- F-Ph CH ₂ SCN HH 6-6 4-Pyr 4-F-Ph CH ₂ PO (OMe) ₂ HH 6-7 4-Pyr 4-F-Ph CH ₂ PO (OEt) ₂ HH 6-8 4- Pyr 4-F-Ph COCH ₂ N ₃ HH 6-9 4-Pyr 4-F-Ph COCH ₂ NO ₂ HH 6-10 4-Pyr 4-F-Ph COCH ₂ ONO HH 6-11 4-Pyr 4- F-Ph COCH ₂ ONO ₂ HH 6-12 4-Pyr 4-F-Ph COCH ₂ SCN HH 6-13 4-Pyr 4-F-Ph COCH ₂ PO (OMe) ₂ HH 6-14 4-Pyr 4- F-Ph (CH ₂ ) ₂ N ₃ HH 6-15 4-Pyr 4-F-Ph (CH ₂ ) ₂ NO ₂ HH 6-16 4-Pyr 4-F-Ph (CH ₂ ) ₂ ONO HH 6- 17 4-Pyr 4-F-Ph (CH ₂ ) ₂ ONO ₂ HH 6-18 4-Pyr 4-F-Ph (CH ₂ ) ₂ SCN HH 6-19 4-Pyr 4-F-Ph (CH ₂ ) ₂ PO (OMe) ₂ HH 6-20 4-Pyr 4-F-Ph (CH ₂ ) ₂ PO (OEt) ₂ HH 6-21 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ N ₃ HH 6 -22 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ NO ₂ HH 6-23 4 -Pyr 4-F-Ph CO (CH ₂ ) ₂ ONO HH 6-24 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ ONO ₂ HH 6-25 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ SCN HH 6-26 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ PO (OMe) ₂ HH 6-27 4-Pyr 4-F-Ph (CH ₂ ) ₃ N ₃ HH 6-28 4 -Pyr 4-F-Ph (CH ₂ ) ₃ NO ₂ HH 6-29 4-Pyr 4-F-Ph (CH ₂ ) ₃ ONO HH 6-30 4-Pyr 4-F-Ph (CH ₂ ) ₃ ONO ₂ HH 6-31 4-Pyr 4-F-Ph (CH ₂ ) ₃ SCN HH 6-32 4-Pyr 4-F-Ph (CH ₂ ) ₃ PO (OMe) ₂ HH 6-33 4-Pyr 4- F-Ph (CH ₂ ) ₃ PO (OEt) ₂ HH 6-34 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ N ₃ HH 6-35 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ NO ₂ HH 6-36 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ ONO HH 6-37 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ ONO ₂ HH 6-38 4-Pyr 4 -F-Ph CO (CH ₂ ) ₃ SCN HH 6-39 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ PO (OMe) ₂ HH 6-40 4-Pyr 4-F-Ph PO (OMe) ₂ HH 6-41 4-Pyr 4-F-Ph PO (OEt) ₂ HH 6-42 4-Pyr 4-F-Ph SO ₂ CH ₂ N ₃ HH 6-43 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₂ N ₃ HH 6-44 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₃ N ₃ HH 6-45 4-Pyr 4-F-Ph SO ₂ CH ₂ NO ₂ HH 6-46 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₂ NO ₂ HH 6-47 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₃ NO ₂ HH −−−−−−−−−−−− −−−−−−−−−−−− --------

[0085]

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[0086]

[Table 8] Table 7 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Compound No. Ar ¹ Ar ² R ³ R ¹ R ² − −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 7-1 4-Pyr 4-F-Ph CH ₂ N ₃ HH 7-2 4- Pyr 4-F-Ph CH ₂ NO ₂ HH 7-3 4-Pyr 4-F-Ph CH ₂ ONO HH 7-4 4-Pyr 4-F-Ph CH ₂ ONO ₂ HH 7-5 4-Pyr 4- F-Ph CH ₂ SCN HH 7-6 4-Pyr 4-F-Ph CH ₂ PO (OMe) ₂ HH 7-7 4-Pyr 4-F-Ph CH ₂ PO (OEt) ₂ HH 7-8 4- Pyr 4-F-Ph COCH ₂ N ₃ HH 7-9 4-Pyr 4-F-Ph COCH ₂ NO ₂ HH 7-10 4-Pyr 4-F-Ph COCH ₂ ONO HH 7-11 4-Pyr 4- F-Ph COCH ₂ ONO ₂ HH 7-12 4-Pyr 4-F-Ph COCH ₂ SCN HH 7-13 4-Pyr 4-F-Ph COCH ₂ PO (OMe) ₂ HH 7-14 4-Pyr 4- F-Ph (CH ₂ ) ₂ N ₃ HH 7-15 4-Pyr 4-F-Ph (CH ₂ ) ₂ NO ₂ HH 7-16 4-Pyr 4-F-Ph (CH ₂ ) ₂ ONO HH 7- 17 4-Pyr 4-F-Ph (CH ₂ ) ₂ ONO ₂ HH 7-18 4-Pyr 4-F-Ph (CH ₂ ) ₂ SCN HH 7-19 4-Pyr 4-F-Ph (CH ₂ ) ₂ PO (OMe) ₂ HH 7-20 4-Pyr 4-F-Ph (CH ₂ ) ₂ PO (OEt) ₂ HH 7-21 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ N ₃ HH 7 -22 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ NO ₂ HH 7-23 4 -Pyr 4-F-Ph CO (CH ₂ ) ₂ ONO HH 7-24 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ ONO ₂ HH 7-25 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ SCN HH 7-26 4-Pyr 4-F-Ph CO (CH ₂ ) ₂ PO (OMe) ₂ HH 7-27 4-Pyr 4-F-Ph (CH ₂ ) ₃ N ₃ HH 7-28 4 -Pyr 4-F-Ph (CH ₂ ) ₃ NO ₂ HH 7-29 4-Pyr 4-F-Ph (CH ₂ ) ₃ ONO HH 7-30 4-Pyr 4-F-Ph (CH ₂ ) ₃ ONO ₂ HH 7-31 4-Pyr 4-F-Ph (CH ₂ ) ₃ SCN HH 7-32 4-Pyr 4-F-Ph (CH ₂ ) ₃ PO (OMe) ₂ HH 7-33 4-Pyr 4- F-Ph (CH ₂ ) ₃ PO (OEt) ₂ HH 7-34 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ N ₃ HH 7-35 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ NO ₂ HH 7-36 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ ONO HH 7-37 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ ONO ₂ HH 7-38 4-Pyr 4 -F-Ph CO (CH ₂ ) ₃ SCN HH 7-39 4-Pyr 4-F-Ph CO (CH ₂ ) ₃ PO (OMe) ₂ HH 7-40 4-Pyr 4-F-Ph PO (OMe) ₂ HH 7-41 4-Pyr 4-F-Ph PO (OEt) ₂ HH 7-42 4-Pyr 4-F-Ph SO ₂ CH ₂ N ₃ HH 7-43 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₂ N ₃ HH 7-44 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₃ N ₃ HH 7-45 4-Pyr 4-F-Ph SO ₂ CH ₂ NO ₂ HH 7-46 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₂ NO ₂ HH 7-47 4-Pyr 4-F-Ph SO ₂ (CH ₂ ) ₃ NO ₂ HH −−−−−−−−−−−− −−−−−−−−−−−− -------- In Tables 1 to 7, "Pyr" indicates pyridyl, "Ph" indicates phenyl, "Me" indicates methyl, "Et" indicates ethyl, and "Prym". "Represents pyrimidinyl.

In the above table, preferred compounds are exemplified compound Nos. 1-1, 1-5, 1-7, 1-14 to 1-1.
6, 1-18, 1-27, 1-28, 1-40, 1-4
1, 1-53, 1-54, 1-66, 1-67, 1-7
9, 1-80, 1-92, 1-93, 1-105, 1-
106, 1-118, 1-119, 1-131 to 1-
139, 1-144 to 1-152, 1-157 to 1
-165, 1-170 to 1-176, 1-183, 1
-184, 1-196, 1-197, 1-209, 1-
210, 1-222, 1-223, 1-235, 1-2
36, 1-248, 1-249, 1-261, 1-26
2, 1-274, 1-275, 1-287, 1-28
8, 1-300, 1-301, 1-313, 1-31
4, 1-326, 1-327, 1-339, 1-34
0, 1-352, 1-353, 1-365, 1-36
6, 1-378, 1-379, 1-391, 1-39
2, 1-404, 1-405, 1-417, 1-41
8, 1-430, 1-431, 1-443, 1-44
4, 1-456, 1-457, 1-469, 1-47
0, 1-482, 1-483, 1-495, 1-49
6, 1-508, 1-509, 1-521, 1-52
2, 1-534, 1-535, 1-548 to 1-55
6, 1-561 to 1-569, 1-574 to 1-5
82, 1-587 to 1-593, 1-600, 1-6
01, 1-613, 1-614, 1-626, 1-62
7, 1-639, 1-640, 1-652, 1-65
3, 1-665, 1-666, 1-678, 1-67
9, 1-691, 1-692, 1-704, 1-70
5, 1-717, 1-718, 1-730, 1-73
1, 1-743, 1-744, 1-756, 1-75
7, 1-769, 1-770, 1-782, 1-78
3, 1-795, 1-796, 1-808 to 1-81
1, 1-819, 1-820, 1-822 to 1-82
5, 1-833, 1-834, 1-860 to 1-86
3, 1-871, 1-872, 1-874 to 1-87
7, 1-885, 1-886, 1-916 to 1-93
9, 4-1, 4-2, 4-14, 4-15, 4-27,
4-28, 4-40, 4-41, 4-53, 4-54,
4-66, 4-67, 4-79, 4-80, 4-92,
4-93, 6-7, 6-15, 6-20, 6-22, 6
-34, 6-40 and 6-44. More preferred compounds are exemplified compound No. 1-
27, 1-28, 1-40, 1-41, 1-53, 1-
54, 1-66, 1-67, 1-79, 1-80, 1-
92, 1-93, 1-105, 1-106, 1-11
8, 1-119, 1-131 to 1-139, 1-14
4 to 1-152, 1-157 to 1-165, 1-1
70 to 1-176, 1-183, 1-184, 1-1
96, 1-197, 1-209, 1-210, 1-22
2, 1-223, 1-235, 1-236, 1-24
8, 1-249, 1-261, 1-262, 1-27
4, 1-275, 1-287, 1-288, 1-30
0, 1-301, 1-313, 1-314, 1-32
6, 1-327, 1-339, 1-340, 1-35
2,1-353,1-365,1-366,1-37
8, 1-379, 1-391, 1-392, 1-40
4, 1-405, 1-417, 1-418, 1-43
0, 1-431, 1-443, 1-444, 1-45
6, 1-457, 1-469, 1-470, 1-48
2, 1-483, 1-495, 1-496, 1-50
8, 1-509, 1-521, 1-522, 1-53
4, 1-535, 1-548 to 1-556, 1-56
1 to 1-569, 1-574 to 1-582, 1-5
87 to 1-593, 1-600, 1-601, 1-6
13, 1-614, 1-626, 1-627, 1-63
9, 1-640, 1-652, 1-653, 1-66
5, 1-666, 1-678, 1-679, 1-69
1, 1-692, 1-704, 1-705, 1-71
7, 1-718, 1-730, 1-731, 1-74
3, 1-744, 1-756, 1-757, 1-76
9, 1-770, 1-782, 1-783, 1-79
5, 1-796, 1-808 to 1-811, 1-81
9, 1-820, 1-822 to 1-825, 1-83
3, 1-834, 1-860 to 1-863, 1-87
1, 1-872, 1-874 to 1-877, 1-88
5, 1-886, 1-916 to 1-939, 4-1,
4-2, 4-14, 4-15, 4-27, 4-28, 4
-40, 4-41, 4-53, 4-54, 4-66, 4
-67, 4-79, 4-80, 4-92, 4-93, 6
-7, 6-15, 6-20, 6-22 and 6-40, and more preferred compounds are exemplified compound numbers 1-27, 1-28, 1-40, 1
-41, 1-53, 1-54, 1-79, 1-80, 1
-92, 1-93, 1-105, 1-106, 1-13
1, 1-132, 1-144, 1-145, 1-15
7, 1-158, 1-170, 1-171, 1-18
3, 1-184, 1-196, 1-197, 1-20
9, 1-210, 1-235, 1-236, 1-24
8, 1-249, 1-261, 1-262, 1-28
7, 1-288, 1-300, 1-301, 1-31
3, 1-314, 1-339, 1-340, 1-35
2,1-353,1-365,1-366,1-39
1, 1-392, 1-404, 1-405, 1-41
7, 1-418, 1-443, 1-444, 1-45
6, 1-457, 1-469, 1-470, 1-49
5, 1-496, 1-508, 1-509, 1-52
1, 1-522, 1-548, 1-549, 1-56
1, 1-562, 1-574, 1-575, 1-58
7, 1-588, 1-600, 1-601, 1-61
3, 1-614, 1-626, 1-627, 1-65
2, 1-653, 1-665, 1-666, 1-67
8, 1-679, 1-704, 1-705, 1-71
7, 1-718, 1-730, 1-731, 1-75
6, 1-757, 1-769, 1-770, 1-78
2, 1-783, 4-1 4-2, 4-14, 4-1
5, 4-27, 4-28, 4-53, 4-54, 4-6
6, 4-67, 4-79, 4-80, 6-7, 6-1
5, 6-20, 6-22 and 6-40.

Particularly preferred compounds are exemplified compound numbers 1-131, 1-132, 1-144, 1-145,
1-157, 1-158, 1-170, 1-171, 1
-210, 1-262, 1-548, 1-549, 1-
561, 1-562, 1-574, 1-575, 1-5
87, 1-588, 6-7, 6-15, 6-20, 6-
Compounds Nos. 22 and 6-40 can be mentioned.

[0089]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) is
For example, it is manufactured by the following method. [Method A] "Method A" is a method for preparing a compound having the general formula (I)
This is a method for producing a compound (I-Aa) and a compound (I-Ab) having the general formula (IA) and R ² is a hydrogen atom.

[0090]

Embedded image (In the formula, Ar ^1, Ar ^2, Q and R ³ have the same meanings as defined above, R ¹ a represents a group other than a hydrogen atom as defined as R ^1, R ¹² is a hydrogen atom or a " A silyl group ”, and R ¹³ represents the“ lower alkyl group ”, the“ lower alkenyl group ”or the“ aralkyl group ”.) In the first step, the keto alcohol compound (1) and the benzoyl acetate compound (3 ) In acetic acid in the presence of ammonium acetate to produce a pyrrolecarboxylic acid ester compound (4), which is described in the literature (D.
Davidson, J. Org. Chem., 3, 361 (1938)).

The second step is another method for producing the compound (4), in which the oxime compound (2) and the compound (3) are reacted by heating in acetic acid in the presence of zinc dust, followed by reductive condensation. This is the step of causing This step is carried out according to the method described in the literature (L, Knor
r, H. Lange, Chem. Ber., 35, 2998 (1902)).

In the third step, the pyrrole carboxylate compound (4) is hydrolyzed or hydrogenolyzed, followed by a decarboxylation reaction. In the compound (IA) of the present invention, R ¹ and R ² are hydrogen atoms. This is a step of producing a compound (I-Aa).

In the reaction preceding the present step, a hydrolysis reaction or a hydrogenolysis reaction using a common acid or alkali commonly used in organic synthetic chemistry is applied. In the subsequent decarboxylation reaction, an acid, alkali or heat is used. Is applied.

[0094] The fourth step is by modifying the 4-position of the pyrrole ring of a compound of the present invention (I-Aa) a group R ¹ a, is a step for preparing a compound of the present invention (I-Ab).

This step is performed according to WO97 / 5878 (particularly, S
CHEME VI to SCHEMEX).

[0096] Also, R ¹ a is a number from 1 to 15 alkyl group carbon, when the number 2 to 15 alkenyl groups or carbon atoms 2 to 15 alkynyl group carbon, this step in the literature Described method (BVGregorovich et al., Can.J.Che.
m., 46, 3291 (1968)).

In the compounds (1), (2) and (3), which are the starting materials of the above-mentioned method A, compounds in which the groups Ar ¹ , Ar ² and QR ³ are each arbitrarily substituted are used. As a result, compounds having different substitution positions of these three groups can be produced. [Method B] Method B is a compound (I-Ad) having the general formula (IA) among the compounds (I) of the present invention, wherein R ² is a group other than a hydrogen atom as defined above. It is a manufacturing method.

[0098]

Embedded image (In the ^{formula, Ar 1, Ar 2, Q} , R 1 and R ³ have the same meanings as defined above, R ² a represents a group other than a hydrogen atom as defined as R ^2.) The fifth step, The compound (I-Ac) [compound (I-Aa) or compound (I-Ab) produced by the above-mentioned Method A] is modified with the group R ² a at position 1 of the pyrrole ring, whereby the compound of the present invention ( This is a step of producing I-Ad). In this step, for example, the compound (I-Ac) is converted to a compound of the general formula: R ² aX (where R ² a has the same meaning as described above, X represents a halogen atom) in the presence of a phase transfer catalyst. Is achieved by reacting a compound having the formula: "The Chemistr
y of Heterocyclic Compounds, Vol. 48, Part 1, 432-4
36, John Wiley & Sons.

The compound (I) which is a starting material of the above method B is
-Ac) by using a compound in which the groups Ar ¹ , Ar ² and QR ³ are each optionally substituted,
Compounds having different substitution positions of these three groups can be produced. [Method C] The method C is a method according to the general formula (I), wherein ring A is imidazole and the following general formula (IB):

[0100]

Embedded image (Wherein Ar ¹ , Ar ² , Q, R ² and R ³ have the same meanings as described above).

[0101]

Embedded image (Shown in the above ^{formula, Ar 1, Ar 2, Q} , R 2 a, R 3 and R ¹² are as defined above.) The sixth step, the keto-alcohol compound (1) with the compound (5) and the reaction To form a compound in which R ² is a hydrogen atom in the general formula (IB) by forming an imidazole ring, and WO93 / 1408
It is performed according to the method detailed in 1.

[0102] The seventh step, by modifying the 1-position of the imidazole ring of the compound (I-Ba) a group R ² a, is a step for preparing a compound (I-Bb). This step is performed according to the “fourth step”.

By using a compound in which the groups Ar ¹ , Ar ² and QR ³ in the compound (1) and the compound (5) which are the starting materials of the above-mentioned Method C are each arbitrarily substituted, these compounds are used. Compounds having different substitution positions of the three groups can be produced. [Method D] Method D is a method for producing a compound having the following general formula (IC) in which ring A is oxazole in general formula (I).

[0104]

Embedded image (In the above formula, Ar ¹ , Ar ² , Q and R ³ have the same meanings as described above, L represents a leaving group, and M ¹ represents an alkali metal such as potassium or sodium.

The "leaving group" in the definition of L is usually
A group leaving as a nucleophilic residue, for example, a halogen atom such as fluorine, chlorine, bromine or iodine; a trihalogenomethyloxy group such as trichloromethyloxy; a lower atom such as methanesulfonyloxy or ethanesulfonyloxy Alkanesulfonyloxy groups; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy;
Examples include arylsulfonyloxy groups such as benzenesulfonyloxy, p-toluenesulfonyloxy, and p-nitrobenzenesulfonyloxy. It is preferably a halogen atom, particularly preferably a bromine atom. The eighth step is a step of producing compound (8) by condensing compound (6) and compound (7) in the presence of a solvent.

Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; N, N-dimethyl Aprotic polar solvents such as formamide, N, N-dimethylacetamide, dimethylsulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatics such as benzene, toluene and xylene Hydrocarbons; aliphatic hydrocarbons such as pentane, hexane and heptane; and mixed solvents thereof.

The reaction temperature is usually from -20 ° C to 150 ° C.
The temperature is preferably from room temperature to 100 ° C.

The reaction time depends mainly on the reaction temperature, the solvent used and the like, but is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.

In the ninth step, the compound (8) is subjected to a ring closure reaction to form an oxazole ring, thereby producing a compound (IC). This step is carried out in WO95
/ 13067 in accordance with the method detailed.

By using compounds in which the groups Ar ¹ , Ar ² and QR ³ in the compound (6) and compound (7), which are the starting materials for the above method D, are arbitrarily substituted, these compounds are used. Compounds having different substitution positions of the three groups can be produced. [Method E] Method E is a method for producing a compound having the following general formula (ID) in which ring A is pyrazole in general formula (I).

[0111]

Embedded image (In the ^{formula, Ar 1, Ar 2, Q} , R 1 a and R ³ are as defined above.) 10th step, the compound (9) with the compound (10) is reacted with with pyrazole ring A step of producing a compound (11) by forming
This is performed according to the method detailed in 5/31451.

The eleventh step is a step of producing a compound (I-Da) by removing the amino group of the compound (11),
For example, it is carried out by adding sodium nitrate in the presence of hydrochloric acid.

[0113] 12 step is a step of producing the compound (I-Db) by modifying the fifth position of the pyrazole ring of the compound (I-Da) a group R ¹ a, the "fourth step" It is implemented according to.

By using a compound in which the groups Ar ¹ , Ar ² and QR ³ in the compound (9) and compound (10) which are the starting materials of the above-mentioned Method E are arbitrarily substituted, these compounds are used. Compounds having different substitution positions of the three groups can be produced.

In the above methods A to D, the method for producing a compound in which ring A is pyrrole, imidazole, oxazole or pyrazole in the general formula (I) has been described. For example, `` The Chemistry of Heterocyclic Compounds, V
ol.34, Vol.37, Vol.39, Vol.44 and Vol.49, John Wi
ley & Sons ”), a compound in which ring A is a 5-membered heteroaryl ring other than the above can also be produced. [Method F] The method F is a method according to the general formula (I), wherein R ³ is
General formula: -S (O) _m -WR ⁴ (wherein R ⁴ , m and W
Is as defined above. This is a method for producing a compound that is a group having

[0116]

Embedded image (In the above formula, ring A, Ar ¹ , Ar ² , Q, L, R ¹ , R ² ,
R ⁴ , W and m are as defined above, and M ⁺ is a cation.

The “cation” in the definition of M ⁺ includes monovalent metal ions such as potassium ion, sodium ion and silver ion; and quaternary ammonium ions such as ammonium ion and tetrabutylammonium ion. it can. ) In the thirteenth step, compound (1)
Reacting 2) with compound (13) in the presence of a solvent,
The leaving group L of the compound (12) and (R ⁴ ) ⁻ of the compound (14)
By substituting an anion, the compound (I-
This is the step of manufacturing E).

Examples of the solvent used include halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; N, N-dimethyl Aprotic polar solvents such as formamide, N, N-dimethylacetamide and dimethylsulfoxide; nitriles such as acetonitrile; esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene And aliphatic hydrocarbons such as pentane, hexane and heptane; or a mixed solvent thereof.

The reaction temperature is usually from -20 ° C to 150 ° C.
The temperature is preferably from room temperature to 100 ° C.

The reaction time depends mainly on the reaction temperature, the solvent used and the like, but is usually from 10 minutes to 48 hours, preferably from 30 minutes to 24 hours.

R ³ is a group represented by the general formula: —S (O) _m —WR
⁴ (wherein, R ⁴ , m and W have the same meanings as described above), and the compound in which S (O) _m is sulfoxide or sulfone is a corresponding sulfide compound or sulfoxide, respectively. It can also be produced by oxidizing a compound.

In the oxidation reaction, an inert solvent (for example, an aliphatic hydrocarbon such as hexane, heptane or petroleum ether; an aromatic hydrocarbon such as benzene, toluene or xylene; Halogenated hydrocarbons such as chloroform, carbon tetrachloride and dichloroethane; alcohols such as methanol, ethanol, propanol and butanol; esters such as ethyl acetate, propyl acetate, butyl acetate and ethyl propionate; Carboxylic acids such as propionic acid; water; or a mixed solvent thereof can be mentioned, preferably a halogenated hydrocarbon or carboxylic acid, particularly preferably dichloromethane, chloroform, dichloroethane or acetic acid. ), An oxidizing agent (for example, peroxidic acid, Peracids such as benzoic acid and m-chloroperbenzoic acid; hydrogen peroxide; alkali metal perhalates such as sodium metaperchlorate, sodium metaperiodate and potassium metaperiodate. Preferably, they are peracids or hydrogen peroxide, particularly preferably m-chloroperbenzoic acid.) And a sulfide compound or a sulfoxide compound at -20 ° C to 150 ° C.
° C (preferably 0 ° C to 100 ° C) for 10 minutes to 1
The reaction is carried out for 0 hour (preferably 30 minutes to 5 hours).

When one oxygen atom is added by the above oxidation reaction, 0.6 to 1.4 equivalents (preferably 0.8 to 1.2 equivalents) are added to 1 equivalent of the substrate. An oxidizing agent is used. Further, by using a sulfide compound as a substrate and performing the above oxidation reaction using 1.5 to 3 equivalents (preferably 1.8 to 2.5 equivalents) of an oxidizing agent with respect to 1 equivalent of the substrate, A sulfone compound can be produced.

Further, this oxidation reaction can be carried out after any of the above-mentioned steps, if necessary. [Method G] "Method G" is a method for preparing a compound having the general formula (I)
This is a method for producing a compound having the general formula (IA).

[0125]

Embedded image (Wherein Ar ¹ , Ar ² , Q, R ¹ , R ² , R ³ and X
Is as defined above. The fourteenth step is a step of producing a 1,4-diketone compound (16) by reacting the ketone compound (14) with the α-haloketone compound (15).
In this step, a 4-diketone compound (16) is reacted with an amine compound (17) to form a pyrrole ring, thereby producing a compound (IA).

These steps are performed according to the method described in detail in WO 97/5878. [Method H] "Method H" is a group represented by the formula -QR in the general formula (I).
³ is a step for preparing a compound which is a group having the general formula (II).

[0127]

Embedded image [Wherein ring A, cyclic group E, Ar ¹ , Ar ² , R ¹ , R ²
And X represents the same meanings as defined above, R ³ a have the general formula -W
R ⁴ , —S (O) _m WR ⁴ , —SO ₂ N (WR ⁴ ) R ⁵ , —C
ON (WR ⁴ ) R ⁵ , -COWR ⁴ or -PO (OR ⁶ )
A group having (OR ⁷ ) (wherein, R ⁴ , R ⁵ , R ⁶ , R ⁷ , W
And m are as defined above. ). In a sixteenth step, the compound (18) is reacted with the compound (19) to form a nitrogen atom on the ring E of the compound (18) (this ring corresponds to the cyclic group E) into a group R ³ a) producing a compound in which the group -QR ³ in the general formula (I) is a group having the general formula (II).

In this step, an alkylation reaction, an acylation reaction, a sulfonylation reaction, or a phosphorylation reaction of a secondary amine, which is widely used in organic synthetic chemistry, can be employed. It is performed in the presence or absence.

Examples of the solvent used include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane; aprotic polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfoxide; and nitriles such as acetonitrile. Esters such as methyl acetate and ethyl acetate; aromatic hydrocarbons such as benzene, toluene and xylene; and aliphatic hydrocarbons such as pentane, hexane and heptane.

Examples of the base used include, for example, sodium methoxide, sodium ethoxide, potassium-t
Alkali metal alkoxides such as butoxide; alkali metal hydroxides such as sodium hydroxide and lithium hydroxide; alkali metal carbonates such as sodium carbonate and potassium carbonate; triethylamine, tributylamine, pyridine, picoline, 1, Examples thereof include amines such as 8-diazabicyclo [5.4.0] -7-undecene.

Compounds serving as starting materials for the above-mentioned Method A and Method C to Method H, that is, compounds (1), (2), (3),
(5), (6), (7), (9), (10), (1)
2), (13), (14), (15), (17), (1)
8) and (19) are compounds known per se,
From a known compound, a known method (for example, WO97 / 5)
878) and a compound which can be easily obtained by treating according to the above-mentioned "Method F".

After completion of each of the above reactions, the target compound is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration. Then, an immiscible organic solvent such as water and ethyl acetate is added. An organic layer containing the compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method.
For example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, and magnesium-silica gel type florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm and Haas),
A method using a synthetic adsorbent such as distribution column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), a method using ion exchange chromatography,
Alternatively, separation and purification can be performed by appropriately combining a normal phase / reverse phase column chromatography method with silica gel or alkylated silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent. .

The 5-membered heteroaryl compounds of the present invention exhibit excellent inflammatory cytokine production inhibitory effects and are therefore effective as pharmaceuticals. Such drugs include, for example, analgesic / anti-inflammatory agents, antiviral agents, and rheumatoid arthritis,
Preventive agent for osteoarthritis, allergic disease, asthma, sepsis, psoriasis, osteoporosis, autoimmune diseases (eg, systemic lupus erythematosus, ulcerative colitis, Crohn's disease, etc.), diabetes, glomerulonephritis, arteriosclerosis or Therapeutic agents can be mentioned, in particular, analgesic / anti-inflammatory agents, and agents for preventing rheumatoid arthritis, osteoarthritis, allergic diseases, sepsis, psoriasis, osteoporosis, ulcerative colitis, diabetes, arteriosclerosis or Therapeutic agents can be mentioned.

The administration form of the compound having the general formula (I) of the present invention, a pharmaceutically acceptable salt or derivative thereof includes:
For example, oral administration such as tablets, capsules, granules, powders or syrups, or parenteral administration such as injections or suppositories can be mentioned. These preparations are manufactured by a known method using additives such as excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, and diluents.

Here, as the excipient, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol and sorbitol; corn starch, potato starch, α-
Starch derivatives such as starch, dextrin, carboxymethyl starch; cellulose derivatives such as crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; Organic excipients such as pullulan; and silicate derivatives such as light silicic anhydride, synthetic aluminum silicate, magnesium metasilicate aluminate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; And inorganic excipients such as sulfates.

Examples of the lubricant include metal stearates such as stearic acid, calcium stearate and magnesium stearate; talc; colloidal silica; waxes such as veegum and gay wax; boric acid: adipic acid; Sodium sulfate, DL-leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate, magnesium lauryl sulfate; silicic acids such as silicic anhydride, silicic acid hydrate; And the above-mentioned starch derivatives.

Examples of the binder include polyvinylpyrrolidone, macrogol and the same compounds as the above-mentioned excipients.

Examples of the disintegrant include the same compounds as the above-mentioned excipients and chemically modified starch and cellulose such as croscarmellose sodium, sodium carboxymethyl starch and crosslinked polyvinylpyrrolidone.

As the stabilizer, for example, methyl paraben,
Paraoxybenzoic acid esters such as propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid. be able to.

Examples of the flavoring agents include, for example, commonly used sweeteners, acidulants, flavors and the like.

The amount of the compound having the general formula (I) of the present invention, or a pharmaceutically acceptable salt or derivative thereof, varies depending on the condition, age, administration method and the like. 0.1m per day
g (preferably 0.5 mg), with an upper limit of 2000 m
g (preferably 500 mg) is desirably administered once or several times depending on the condition. In the case of intravenous administration, the lower limit is 0.1 per day for adults.
01 mg (preferably 0.05 mg), with an upper limit of 2 mg
It is desirable to administer 00 mg (preferably 50 mg) once or in several divided doses according to the symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples, Preparation Examples and Test Examples, but the present invention is not limited thereto.

[0145]

【Example】

[0146]

Example 1 5- [4- (2-azidoethylthio) fe
Nil] -2- (4-fluorophenyl) -3- (pyridi
N-4-yl) -1H-pyrrole (exemplary compound number 1-
1) 1) 2- (t-butyldimethylsilyloxy) -4 ′
-Fluoro-2- (pyridin-4-yl) acetopheno
Was dissolved in emissions anhydrous tetrahydrofuran 130ml diisopropylamine 12.13 g (0.120 mol), under a nitrogen atmosphere, it was added dropwise 1.68M n-butyllithium / hexane solution 74.78ml (0.125mol) at -40 ° C.. Then, 25.51 g (0.114 mol) of 4- (t-butyldimethylsilyloxymethyl) pyridine
Of 25 ml of anhydrous tetrahydrofuran was added dropwise. −
After stirring at 40 ° C. for 1 hour, N-methoxy-N-methyl-4 was added.
-Fluorobenzamide 20.92 g (0.114 mo
1) A solution of 45 ml of anhydrous tetrahydrofuran was added dropwise,
After stirring at the same temperature for 2 hours, the cooling bath was removed and the temperature was returned to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1).
To give 33.43 g of the title compound as an orange oil (yield 85%).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.60 (2H, d, J = 6 Hz), 8.04 (2
H, dd, J = 9Hz, 5Hz), 7.46 (2H, d, J = 6Hz), 7.04 (2H, t, J = 9H
z), 5.61 (1H, s), 0.91 (9H, s), 0.12 (6H, s). 2) 4- (2-hydroxyethylthio) benzonitrile
Le N, N-dimethylformamide 250 ml 2-mercaptoethanol 14.45ml (206mmol) and potassium t- butoxide 23.12 g (206 mmol)
After stirring for 30 minutes under ice cooling, 25.00 g (206 mmol) of 4-fluorobenzonitrile was added, and the mixture was stirred at 75 ° C for 2 hours. After cooling to room temperature, 200 ml of water
And extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 36.90 g of the title compound as a yellow oil (yield; quantitative).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 7.55 (2H, d, J = 8 Hz), 7.39 (2
(H, d, J = 8Hz), 3.86 (2H, q, J = 7Hz), 3.21 (2H, t, J = 7Hz), 1.9
8 (1H, t, J = 7Hz). 3) 36.00 g (201 mmol) of 4- (2-hydroxyethylthio) benzonitrile obtained in 4- (2-hydroxyethylthio ) benzoic acid 2) was treated with 270 m of acetic acid.
l, 80 ml of concentrated sulfuric acid and 190 ml of water, and stirred at 130 ° C for 4 hours. After cooling to room temperature, 28% aqueous ammonia was added to adjust the pH to around 3, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 38.46 g of the title compound as a white powder (yield 99%). 4) 4- (2-acetoxyethyl thio) was obtained benzoic acid 3) 4- (2-hydroxyethyl) benzoic acid 38.00 g (197 mmol) of pyridine 50ml and acetic anhydride 37.14Ml (394 mmol) was added, 7
Stirred at 0 ° C. for 1 hour. After cooling to room temperature, the reaction solution was made acidic by adding water and acetic acid, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 30.88 g of the title compound as a white powder (yield 65).
%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.02 (2H, d, J = 8 Hz), 7.40 (2
H, d, J = 8Hz), 4.28 (2H, t, J = 7Hz), 3.23 (2H, t, J = 7Hz), 2.0
5 (3H, s). 5) 4- (2-acetoxyethylthio) benzoyl vinegar
30.78 g (128 mmol) of 4- (2-acetoxyethylthio) benzoic acid obtained in acid p-nitrobenzyl ester 4) was suspended in 300 ml of anhydrous tetrahydrofuran, and 22.85 g (141 mmol) of 1,1′-carbonyldiimidazole was obtained. At room temperature
The mixture was stirred for an hour to obtain a homogeneous solution.

Separately, mono (p-nitrobenzyl) malonate
67.30 g of ester magnesium salt (134 mmo
l), 37.5 ml of triethylamine (269 mmol)
l) and magnesium chloride 13.43 g (141 mm
ol), 300 ml of anhydrous tetrahydrofuran was added, and the mixture was stirred at room temperature for 3 hours. The above solution was added dropwise to this reaction mixture at 0 to 5 ° C.
The mixture was acidified with N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure.
51.70 g of the title compound were obtained as an orange oil (96% yield).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.23 (2H, d, J = 8 Hz), 7.87 (2
H, d, J = 8Hz), 7.51 (2H, d, J = 8Hz), 7.42 (2H, d, J = 8Hz), 5.2
0 (2H, s,), 4.21 (2H, t, J = 7Hz), 4.02 (2H, s), 3.19 (2H, t, J
= 7Hz), 2.05 (3H, s). 6) 5- [4- (2-acetoxyethylthio) phenyl
Ru] -2- (4-fluorophenyl) -4- (p-nitro
Robenzyloxycarbonyl) -3- (pyridine-4-
Yl) -1H-pyrrole 2- (t-butyldimethylsilyloxy) -obtained in 1)
4- (4-fluoro-2- (pyridin-4-yl) acetophenone, obtained from 26.25 g (76 mmol), 5).
(2-acetoxyethylthio) benzoylacetic acid p-nitrobenzyl ester 31.72 g (76 mmol) and ammonium acetate 23.43 g (304 mmol)
To the mixture was added 130 ml of acetic acid, and the mixture was stirred at 130 ° C for 1 hour.
After cooling to room temperature, 28% aqueous ammonia was added under ice cooling to make the mixture alkaline, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 5) to give 9.55 g of the title compound as an orange amorphous solid (20% yield).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 9.82 (1H, br.s), 8.54 (2H, d,
J = 6Hz), 8.43 (2H, d, J = 8Hz), 8.06 (2H, d, J = 8Hz), 7.51 (2H
(H, d, J = 8Hz), 7.34 (2H, d, J = 8Hz), 7.28-7.17 (2H, m), 7.15
-7.08 (2H, m), 6.98 (2H, d, J = 8Hz), 5.08 (2H, s), 4.23 (2H,
t, J = 7Hz), 3.18 (2H, t, J = 7Hz), 2.04 (3H, s). 7) 2- (4-fluorophenyl) -5- [4- (2
-Hydroxyethylthio) phenyl] -3- (pyridine
-4-yl) -1H-pyrrole 6- (4- (2-acetoxyethylthio) phenyl) -2- (4-fluorophenyl) -4- (p-
Nitrobenzyloxycarbonyl) -3- (pyridine-
9.55 g of 4-yl) -1H-pyrrole (15.6 mm)
ol) was dissolved in a mixed solvent of 200 ml of methanol and 15 ml of tetrahydrofuran, 7.2 g of 10% palladium on carbon was added, and the mixture was stirred at 50 ° C for 6 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a free carboxylic acid compound. This was dissolved in 70 ml of glycerol, heated under reflux for 5 hours, cooled to room temperature, added with water,
Extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 4) to give 1.89 g of the title compound as a yellow powder. (Yield 32%).

¹ H-nuclear magnetic resonance spectrum (270 MH
_{z, CDCl 3 -DMSO-d 6} ) δppm: 10.70-10.6
0 (1H, br.s), 8.43 (2H, dd, J = 5Hz, 2Hz), 7.62 (2H, d, J = 8H
z), 7.44 (2H, dd, J = 8Hz, 5Hz), 7.40 (2H, d, J = 8Hz), 7.23 (2H
H, dd, J = 5Hz, 2Hz), 7.07 (2H, t, J = 9Hz), 6.72 (1H, d, J = 3H
z), 3.84-3.74 (2H, m), 3.50-3.35 (1H, m), 3.12 (2H, t, J = 6
Hz). 8) 5- [4- (2-chloroethylthio) phenyl]
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H-pyrrole 2- (4-fluorophenyl) -5- [4-
(2-hydroxyethylthio) phenyl] -3- (pyridin-4-yl) -1H-pyrrole 1.80 g (4.6
1 mmol), 36 ml of thionyl chloride was added, and
Stirred for hours. Thionyl chloride was distilled off under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 4: 1) to give 1.0 g of the title compound as yellow. Obtained as a powder (53% yield).

¹ H-nuclear magnetic resonance spectrum (270 MH
_{z, DMSO-d 6) δppm} : 11.70 (1H, s), 8.40 (2H,
d, J = 5Hz), 7.77 (2H, d, J = 8Hz), 7.47-7.44 (2H, m), 7.28 (2H
(H, t, J = 9Hz), 7.23 (2H, d, J = 5Hz), 6.97 (1H, d, J = 2Hz), 3.7
6 (2H, t, J = 7Hz), 3.41-3.34 (2H, m). 9) 5- [4- (2-azidoethylthio) phenyl]
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H -pyrrole 300 mg of 5- [4- (2-chloroethylthio) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole obtained in 8). (0.73m
mol) was dissolved in 6 ml of N, N-dimethylformamide, 143 mg (2.2 mmol) of sodium azide was added, and the mixture was stirred at 50 to 80 ° C. for 9 hours. Water was added to the reaction solution, extracted with ethyl acetate, the organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 300 mg of the title compound as a yellow powder (yield 98%).

¹ H-nuclear magnetic resonance spectrum (270 MH
_{z, DMSO-d 6) δppm} : 11.70 (1H, s), 8.44 (2H,
d, J = 6Hz), 7.81 (2H, d, J = 8Hz), 7.50 (2H, m), 7.45 (2H, d, J
= 8Hz), 7.32 (2H, t, J = 9Hz), 7.26 (2H, d, J = 6Hz), 7.00 (1H,
d, J = 2 Hz), 3.57 (2H, t, J = 6 Hz), 3.27 (2H, t, J = 6 Hz).

[0156]

Example 2 5- [4- (2-azidoethylsulfini)
Ru) phenyl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-144) 5- [4- (2-azidoethylthio) phenyl] -2- (4-fluorophenyl) -3- (obtained in Example 1) 300 mg (0.7 mg of pyridin-4-yl) -1H-pyrrole
2 mmol) in 12 ml of tetrahydrofuran,
Under ice-cooling and stirring, 125 mg of 70% m-chloroperbenzoic acid
(0.72 mmol) was added little by little.
The mixture was further stirred at the same temperature for 30 minutes. Ethyl acetate and a 10% aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was vigorously shaken and separated.
Then washed with water. The solvent was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 4).
To give 210 mg of the title compound as pale yellow powder (67% yield).

Melting point: 163-165 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 9.66 (1H, br.s), 8.44 (2H, d, J = 6 Hz), 7.
73 (2H, d, J = 8Hz), 7.60 (2H, d, J = 8Hz), 7.42 (2H, dd, J = 9Hz,
5Hz), 7.23 (2H, d, J = 6Hz), 7.09 (2H, d, J = 9Hz), 6.84 (2H,
d, J = 3Hz), 3.81-3.71 (1H, m), 3.63-3.51 (1H, m), 3.00-2.
95 (2H, m).

[0158]

Example 3 2- (4-fluorophenyl) -5- [4
-(3-nitropropylthio) phenyl-3- (pyridi
N-4-yl) -1H-pyrrole (exemplary compound number 1-
15) 1) 4- (3-hydroxypropylthio) benzonit
The reaction was carried out in the same manner as in Example 1-2) using 3-mercaptopropanol instead of lyl 2-mercaptoethanol, to give the title compound as a pale-yellow oil (yield 97).
%). 2) 4- (3-hydroxypropylthio) benzoic acid The reaction was carried out in the same manner as in Example 1-3) using 4- (3-hydroxypropylthio) benzonitrile obtained in 1),
The title compound was obtained as a white powder (96% yield). 3) 4- (3-acetoxypropylthio) benzoic acid An acetylation reaction was carried out using 4- (3-hydroxypropylthio) benzoic acid obtained in 2) in the same manner as in Example 1-4) to give the title compound. Was obtained as a white powder (yield 85
%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.00 (2H, d, J = 8 Hz), 7.32 (2
(H, d, J = 8Hz), 4.21 (2H, t, J = 6Hz), 3.08 (2H, t, J = 7Hz), 2.0
8 (3H, s), 2.06-1.98 (2H, m). 4) 4- (3-acetoxypropylthio) benzoyl
Acetic acid p-nitrobenzyl ester Using 4- (3-acetoxypropylthio) benzoic acid obtained in 3) instead of 4- (2-acetoxyethylthio) benzoic acid, the reaction was carried out in the same manner as in Example 1-5). The title compound was obtained as a pale yellow powder (yield; quantitative).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.19 (2H, d, = 9 Hz), 7.83 (2H,
d, J = 9Hz), 7.48 (2H, d, J = 9Hz), 7.30 (2H, d, J = 9Hz), 5.29
(2H, s), 4.20 (2H, t, J = 6Hz), 3.08 (2H, t, J = 7Hz), 2.08 (3
H, s), 2.07-2.01 (2H, m). 5) 5- [4- (3-acetoxypropylthio) fe
Nil] -2- (4-fluorophenyl) -4- (p-di
Trobenzyloxycarbonyl) -3- (pyridine-4
-Yl) -1H-pyrrole 4- (2-acetoxyethylthio) benzoylacetic acid p
4- obtained in 4) instead of -nitrobenzyl ester
The reaction was carried out in the same manner as in Example 1-6) using (3-acetoxypropylthio) benzoylacetic acid p-nitrobenzyl ester to obtain the title compound as a yellow amorphous solid (yield: 21%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 9.32 (1H, br.s), 8.45 (2H, d,
J = 6Hz), 8.05 (2H, d, J = 9Hz), 7.51 (2H, d, J = 8Hz), 7.20 (2
(H, d, J = 9Hz), 7.17-7.11 (2H, m), 7.00-6.94 (4H, m), 5.09
(2H, s), 4.18-4.10 (2H, m), 3.02 (2H, t, J = 7Hz), 2.08-1.9
5 (2H, m), 2.04 (3H, s). 6) 5- [4- (3-acetoxypropylthio) fe
Nil] -2- (4-fluorophenyl) -3- (pyridi
N-4-yl) -1H-pyrrole 5- [4- (2-acetoxyethylthio) phenyl]-
2- (4-fluorophenyl) -4- (p-nitrobenzyloxycarbonyl) -3- (pyridin-4-yl)
5- [4- (3) obtained in 5) instead of -1H-pyrrole
-Acetoxypropylthio) phenyl] -2- (4-fluorophenyl) -4- (p-nitrobenzyloxycarbonyl) -3- (pyridin-4-yl) -1H-pyrrole; The title compound was obtained as a yellow powder (yield 63%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.71 (1H, br.s), 8.44 (2H.d.
J = 6Hz), 7.47 (2H, d, J = 8Hz), 7.37 (2H, dd, J = 9Hz, 5Hz), 7.
22 (2H, d, J = 6Hz), 7.08 (2H, t, J = 9Hz), 6.72 (1H, d, J = 3Hz),
4.19 (2H, t, = 6Hz), 3.01 (2H, d, J = 7Hz), 2.05 (3H, s), 2.0
3-1.93 (2H, m). 7) 2- (4-fluorophenyl) -5- [4- (3
-Hydroxypropylthio) phenyl] -3- (pyridi
Down-4-yl)-1H-obtained in pyrrole 6) 5- [4- (3-acetoxymethyl-propyl thio)
Phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole 2.60 g (5.
82 mmol) is dissolved in a mixture of 48 ml of methanol and 12 ml of water, and 6.3 ml of a 1N aqueous sodium hydroxide solution is dissolved.
(6.3 mmol) and stirred at 80 ° C. for 1 hour.
The solvent was distilled off under reduced pressure, and the precipitated solid was washed with water to obtain 2.13 g of the title compound as a yellow powder (yield: 90).
%).

¹ H-nuclear magnetic resonance spectrum (270 MH
_{z, CDCl 3 -DMSO-d 6} ) δppm: 10.90 (1H,
s), 8.42 (2H, d, J = 6Hz), 7.63 (2H, d, J = 8Hz), 7.44 (2H, dd,
J = 9Hz, 5Hz), 7.35 (2H, d, J = 8Hz), 7.22 (2Hd, J = 6Hz), 7.07
(2H, t, J = 9Hz), 6.71 (1H, d, J = 3Hz), 3.72 (2H, t, J = 7Hz),
3.53 (1H, br.s), 3.06 (2H, t, J = 7Hz), 1.89 (2H, m). 8) 5- [4- (3-bromopropylthio) phenyl
L] -2- (4-Fluorophenyl) -3- (pyridine
-4-yl) -1H-pyrrole N-bromosuccinimide (660 mg, 3.71 mmol)
l) was dissolved in 15 ml of tetrahydrofuran, and 1.02 g (3.89 mmol) of triphenylphosphine was added, followed by stirring for 30 minutes. The reaction mixture was added with 2-
750 mg (1.85 mmol) of (4-fluorophenyl) -5- [4- (3-hydroxypropylthio) phenyl] -3- (pyridin-4-yl) -1H-pyrrole
Was added, and the mixture was stirred at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogen carbonate and water were sequentially added, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1) to obtain 750 mg of the title compound as a pale brown powder. (Yield 86
%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.82 (1H, br.s), 8.43 (2H, b
rs), 7.49 (2H, d, J = 8Hz), 7.39 (2H, d, J = 8Hz), 7.40-7.35
(2H, m), 7.24 (2H, d, J = 6Hz), 7.08 (2H, t, J = 9Hz), 6.73 (1
H, d, J = 3Hz), 3.54 (2H, t, J = 7Hz), 3.10 (2H, t, J = 7Hz), 2.2
3-2.13 (2H, m). 9) 2- (4-fluorophenyl) -5- [4- (3
-Nitropropylthio) phenyl] -3- (pyridine-
5- [4- (3-Bromopropylthio) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole obtained in 4-yl) -1H-pyrrole 8). 750 mg (1.61
mmol) in 15 ml of dimethyl sulfoxide,
After adding 221 mg (3.21 mmol) of sodium nitrite and stirring at room temperature for 2 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1) to give the title compound (400 mg).
Was obtained as a yellow powder (yield 57%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.72 (1H, br.s), 8.44 (2H, d,
J = 6Hz), 7.49 (2H, d, J = 8Hz), 7.40 (2H, d, J = 8Hz), 7.37 (2H
H, dd, J = 9Hz, 6Hz), 7.22 (2H, d, J = 6Hz), 7.09 (2H, t, J = 9H
z), 6.74 (2H, d, J = 3Hz), 4.55 (2H, t, J = 7Hz), 3.04 (2H, t, J
= 7Hz), 2.37-2.27 (2H, m).

Infrared absorption spectrum (KBr) νmax
(Cm ^-1 ): 1552, 1379.

[0167]

Example 4 2- (4-fluorophenyl) -5- [4
-(3-nitrosooxypropylthio) phenyl] -3
-(Pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-16) The title compound was used as a fraction eluted earlier than the compound of Example 3 in silica gel column chromatography of Example 3-9). Was obtained as a yellow powder (yield 33
%).

Melting point: 153-155 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 8.59 (1H, br.s), 8.45 (2H, d, J = 6 Hz), 7.
48 (2H, d, J = 8Hz), 7.38 (2H, d, J = 8Hz), 7.41-7.36 (2H, m),
7.23 (2H, d, J = 6Hz), 7.09 (2H, t, J = 9Hz), 6.73 (1H, d, J = 3H
z), 4.83 (2H, t, J = 6Hz), 3.02 (2H, t, J = 7Hz), 2.14-2.04 (2
H, m).

Infrared absorption spectrum (KBr) νmax
(Cm ^-1 ): 1646.

[0170]

Example 5 2- (4-fluorophenyl) -5- [4
-(3-nitropropylsulfinyl) phenyl] -3
-(Pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-158) 2- (4-fluorophenyl) -5 obtained in Example 3
[Oxidation reaction was carried out in the same manner as in Example 2 using 4- (3-nitropropylthio) phenyl-3- (pyridin-4-yl) -1H-pyrrole as a starting material to obtain the title compound as a yellow powder. (Yield 71%).

Melting point: 183-185 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl _{3
-DMSO-d 6) δppm: 11.20} (1H, s), 8.63-8.52
(2H, br.s), 7.98 (2H, d, J = 8Hz), 6.98 (2H, d, J = 8Hz), 7.55
-7.50 (2H, m), 7.29 (2H, d, J = 5Hz), 7.16 (2H, t, J = 9Hz), 6.
92 (1H, d, J = 3Hz), 4.70-4.59 (2H, m), 3.15-3.04 (1H, m),
2.99-2.88 (1H, m), 2.62-2.51 (1H, m), 2.48-2.32 (1H, m).

[0172]

Example 6 2- (4-fluorophenyl) -5- [4
-(3-Nitropropylsulfonyl) phenyl] -3-
(Pyridin-4-yl) -1H-pyrrole (Exemplified Compound No. 1-575) The reaction of Example 5 was carried out using 2 equivalents of m-chloroperbenzoic acid (oxidation) based on 1 equivalent of the starting material (sulfide). The title compound was obtained as a pale yellow powder (yield: 74%).

Melting point: 228-230 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDCl _{3
-DMSO-d 6) δppm: 11.40} (1H, br.s), 8.45 (2
(H, d, J = 6Hz), 7.95 (2H, d, J = 9Hz), 7.87 (2H, d, J = 9Hz), 7.4
6 (2H, dd, J = 9Hz, 5Hz), 7.22 (2H, d, J = 6Hz), 7.10 (2H, t, J = 9
Hz), 6.92 (1H, d, J = 3Hz), 4.62 (2H, t, J = 7Hz), 3.28 (2H, t,
J = 7Hz), 2.52-2.42 (2H, m).

[0174]

Example 7 2- (4-fluorophenyl) -5- [4
-(3-Nitrooxypropylsulfinyl) phenyl]
-3- (pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-160) 1) 5- [4- (3-bromopropylsulfinyl)
Phenyl] -2- (4-fluorophenyl) -3- (pi
Lysin-4-yl) -1H-pyrrole 5- [4- (3-bromopropylthio) phenyl] -2- (4-fluorophenyl) -3 obtained in Example 3-8).
Using-(pyridin-4-yl) -1H-pyrrole,
The oxidation reaction was carried out in the same manner as in Example 2 to obtain the title compound as a yellow amorphous solid (yield: 71%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 9.29 (1H, br.s), 8.46 (2H, d,
J = 6Hz), 7.73 (2H, d, J = 8Hz), 7.61 (2H, d, J = 8Hz), 7.42 (2H
H, dd, J = 9Hz, 5Hz), 7.24 (2H, d, J = 6Hz), 7.10 (2H, t, J = 9H
z), 6.84 (1H, d, J = 2Hz), 3.53-3.43 (2H, m), 3.08-2.85 (2
H, m), 2.39-2.23 (1H, m), 2.21-2.09 (1H, m). 2) 2- (4-fluorophenyl) -5- [4- (3
-Nitroxypropylsulfinyl) phenyl] -3-
5- [4- (3-Bromopropylsulfinyl) phenyl] -2- (4-fluorophenyl) -3- obtained by (pyridin-4-yl) -1H-pyrrole 1)
(Pyridin-4-yl) -1H-pyrrole 180 mg
(0.37 mmol) was dissolved in a mixture of 15 ml of acetonitrile and 5 ml of dimethyl sulfoxide.
26 mg (0.74 mmol) was added, and the mixture was stirred at room temperature overnight and filtered. Water was added to the filtrate and extracted with ethyl acetate.
After washing the organic layer with water and drying over anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 1) to give the title compound (40 mg) as a pale-yellow powder (yield 23%).

Melting point: 225 ° C. (decomposition) ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
_{l 3) δppm: 9.04 (1H} , br.s), 8.47-8.43 (2H, m), 7.7
3 (2H, d, J = 8Hz), 7.64 (2H, d, J = 8Hz), 7.45-7.40 (2H, m),
7.36-7.34 (2H, m), 7.13 (2H, t, J = 9Hz), 6.88 (1H, d, J = 2H
z), 4.58-4.52 (2H, m), 3.02-2.94 (1H, m), 2.91-2.82 (1H,
m), 2.35-1.86 (2H, m).

[0177]

Example 8 5- [4- (2-diethylphosphonoethyl)
Thio) phenyl] -2- (4-fluorophenyl) -3
-(Pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-7) 1) 4- (2-diethylphosphonoethylthio) benzoic acid
Acid 0.50 g (3.25 mmol ) of 4-mercaptobenzoic acid
l) was changed to 5 ml of N, N-dimethylformamide and 5 ml of water.
and stirred at room temperature for 15 minutes.
Bromoethylphosphonic acid diethyl ester 0.59 ml
(3.25 mmol) and stirred at 50 ° C. for 1 hour. After cooling the reaction solution to room temperature, 20 ml of water was added,
The pH was adjusted to about 3 with concentrated hydrochloric acid and extracted with ethyl acetate.
The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.04 g) as a pale-yellow oil (yield; quantitative).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 7.98 (2H, d, J = 8 Hz), 7.33 (2
(H, d, J = 8Hz), 4.22-4.05 (4H, m), 3.28-3.17 (2H, m), 2.20-
2.08 (2H, m), 1.39-1.28 (6H, m). 2) 4- (2-diethylphosphonoethylthio) benzo
Example 1-5) using 4- (2-diethylphosphonoethylthio) benzoic acid obtained in 1) in place of 4- (2-acetoxyethylthio) benzoic acid instead of p-nitrobenzyl ylacetic acid 4- (2-acetoxyethylthio) benzoic acid The reaction was carried out in the same manner to give the title compound as a pale yellow oil (yield; quantitative).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.12 (2H, d, J = 9 Hz), 7.85 (2
(H, d, J = 9Hz), 7.50 (2H, d, J = 9Hz), 7.33 (2H, d, J = 9Hz), 5.3
0 (2H, s), 4.22-4.05 (4H, m), 4.06 (2H, s), 3.30-3.15 (2H,
m), 2.20-2.02 (2H, m), 1.40-1.28 (6H, m). 3) 5- [4- (2-diethylphosphonoethylthio)
Phenyl] -2- (4-fluorophenyl) -4- (p
-Nitrobenzyloxycarbonyl) -3- (pyridine
-4-yl) -1H-pyrrole 4- (2-acetoxyethylthio) benzoylacetic acid p
Instead of -nitrobenzyl ester, 4-
(2-Diethylphosphonoethylthio) benzoylacetic acid
Example 1-6) using p-nitrobenzyl ester
The title compound was obtained as a pale brown oil (yield 31%).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 9.15-9.00 (1H, br.s), 8.51
(2H, d, J = 6Hz), 8.06 (2H, d, J = 9Hz), 7.54 (2H, d, J = 8Hz),
7.32 (2H, d, J = 8Hz), 7.22 (2H, d, J = 6Hz), 7.16 (2H, dd, J = 9H)
z, 5Hz), 6.98 (2H, t, J = 9Hz), 6.97 (2H, d, J = 9Hz), 5.09 (2H
H, s), 4.20-4.00 (4H, m), 3.21-3.06 (2H, m), 2.17-1.98
(2H, m), 1.33 (6H, t, J = 7Hz). 4) 5- [4- (2-diethylphosphonoethylthio)
Phenyl] -2- (4-fluorophenyl) -3- (pi
5- [4- (2-Diethylphosphonoethylthio) phenyl] -2- (4-fluorophenyl) -4- obtained by 3) -lysin-4-yl) -1H-pyrrole
Example 3 was prepared using (p-nitrobenzyloxycarbonyl) -3- (pyridin-4-yl) -1H-pyrrole.
In the same manner as in -6), the ester was subjected to hydrogenolysis and decarboxylation to give the title compound as a brown oil (yield 27%). ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 8.76 to 8.63 (1H, br.s), 8.47 (2H, d, J = 6H
z), 7.51 (2H, d, J = 9Hz), 7.45-7.32 (4H, m), 7.24 (2H, d, J =
6Hz), 7.09 (2H, t, J = 9Hz), 6.75 (1H, d, J = 3Hz), 4.18-3.99
(4H, m), 3.20-3.08 (2H, m), 2.17-1.99 (2H, m), 1.32 (6H,
t, J = 7Hz).

[0181]

Embodiment 95- [4- (2-diethylphosphonoethyl)
Sulfinyl) phenyl] -2- (4-fluorophenyl
) -3- (pyridin-4-yl) -1H-pyrrole
(Exemplified Compound No. 1-150) 5- [4- (2-diethylphosphonoethyl) obtained in Example 8
Ruthio) phenyl] -2- (4-fluorophenyl)-
Starting from 3- (pyridin-4-yl) -1H-pyrrole
Oxidation reaction was carried out in the same manner as in Example 2 using
The title compound was obtained as a light brown powder (yield 50%).

Melting point: 160-162 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 9.93-9.63 (1H, br.s), 8.46 (2H, d, J = 6H
z), 7.77 (2H, d, J = 8Hz), 7.55 (2H, d, J = 8Hz), 7.43 (2H, dd,
J = 9Hz, 5Hz), 7.23 (2H, d, J = 6Hz), 7.09 (2H, t, J = 9Hz), 6.8
5 (1H, d, J = 3Hz), 4.00-3.92 (4H, m), 3.21-3.04 (1H, m), 2.
96-2.78 (1H, m), 2.28-2.04 (1H, m), 1.90-1.67 (1H, m), 1.
28 (3H, t, J = 7Hz), 1.27 (3H, t, J = 7Hz).

[0183]

Embodiment 105- [4- (2-diethylphosphonoethyl)
Rusulfonyl) phenyl] -2- (4-fluorophenyl
) -3- (pyridin-4-yl) -1H-pyrrole
(Exemplified Compound No. 1-567) 5- [4- (2-diethylphosphonoethyl) obtained in Example 9
Rusulfinyl) phenyl] -2- (4-fluorophene
Nyl) -3- (pyridin-4-yl) -1H-pyrrole
Using as a starting material, an oxidation reaction was carried out in the same manner as in Example 2.
The title compound was obtained as a pale yellow powder (yield 70
%).

Melting point: 212-214 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 9.26-9.09 (1H, br.s), 8.48 (2H, d, J = 6H
z), 7.99 (2H, d, J = 9Hz), 7.75 (2H, d, J = 9Hz), 7.42 (2H, dd,
J = 9Hz, 5Hz), 7.24 (2H, d, J = 6Hz), 7.11 (2H, t, J = 9Hz), 6.9
3 (1H, d, J = 3Hz), 4.15-3.98 (4H, m), 3.37-3.22 (2H, m), 2.
23-2.05 (2H, m), 1.30 (6H, t, J = 7Hz).

[0185]

Example 11 2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -5- [4- (2-thiocyana
Tolethylthio) phenyl] -1H-pyrrole (Exemplary Compound No. 1-5) 1) 5- [4- (2-bromoethylthio) phenyl]
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H-pyrrole 2- (4-fluorophenyl) -5- [4- (3-hydroxypropylthio) phenyl] -3- (pyridine-4
Example 1-7) Instead of -yl) -1H-pyrrole
2- (4-fluorophenyl) -5- [4- (2
Example 3-8) using (-hydroxyethylthio) phenyl] -3- (pyridin-4-yl) -1H-pyrrole
The title compound was obtained as a pale brown powder (yield 89%).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.55-8.45 (1H, br.s), 8.47
(2H, d, J = 6Hz), 7.50 (2H, d, J = 9Hz), 7.43 (2H, d, J = 9Hz),
7.39 (2H, dd, J = 9Hz, 5Hz), 7.25 (2H, d, J = 6Hz), 7.10 (2H, t,
J = 7Hz), 6.76 (1H, d, J = 3Hz), 3.54-3.43 (2H, m), 3.37-3.2
7 (2H, m). 2) 2- (4-fluorophenyl) -3- (pyridine
-4-yl) -5- [4- (2-thiocyanatoethyl
Thio) phenyl] -1H-pyrrole 5- [4- (2-bromoethylthio) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole obtained in 1). 1.00g (2.32m
mol) was dissolved in a mixture of 20 ml of N, N-dimethylformamide and 5 ml of dimethylsulfoxide, 2.14 g (13.42 mmol) of potassium thiocyanate was added, and the mixture was stirred at 80 ° C for 1 hour. After cooling the reaction solution to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain the title compound (0.91 g) as a pale yellow powder (yield; quantitative).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δppm: 8.62-8.52 (1H, br.s), 8.47
(2H, d, J = 6Hz), 7.53 (2H, d, J = 9Hz), 7.46 (2H, d, J = 9Hz),
7.39 (2H, dd, J = 9Hz, 5Hz), 7.25 (2H, d, J = 6Hz), 7.10 (2H, t,
J = 9Hz), 6.77 (1H, d, J = 3Hz), 3.36-3.27 (2H, m), 3.18-3.0
8 (2H, m).

[0188]

Example 12 2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -5- [4- (2-thiocyana
-Ethylsulfinyl ) phenyl] -1H-pyrrole (Exemplary Compound No. 1-148) 2- (4-fluorophenyl) -3- obtained in Example 11
Using (pyridin-4-yl) -5- [4- (2-thiocyanatoethylthio) phenyl] -1H-pyrrole as a starting material, an oxidation reaction was carried out in the same manner as in Example 2 to give the title compound Obtained as a white powder (yield 73%).

Melting point: 195-196 ° C. (decomposition) ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 8.88-8.68 (1H, br.s), 8.47 (2H, d, J = 6H
z), 7.74 (2H, d, J = 9Hz), 7.66 (2H, d, J = 9Hz), 7.41 (2H, dd,
J = 9Hz, 5Hz), 7.24 (2H, d, J = 6Hz), 7.11 (2H, t, J = 9Hz), 6.8
8 (1H, d, J = 3Hz), 3.43-3.26 (2H, m), 3.24-3.09 (2H, m).

[0190]

Embodiment 132- (4-fluorophenyl) -3-
(Pyridin-4-yl) -5- [4- (2-thiocyana
-Ethylsulfonyl) phenyl] -1H-pyrrole
(Exemplified Compound No. 1-565) 2- (4-fluorophenyl) -3- obtained in Example 11
(Pyridin-4-yl) -5- [4- (2-thiocyana
Starting ethylthio) phenyl] -1H-pyrrole
Oxidation reaction was carried out in the same manner as in Example 6 using
The title compound was obtained as a yellow powder (yield 79%).

Melting point: 230-232 ° C. (decomposition) ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 11.42-11.25 (1H, br.s), 8.46 (2H, d, J = 6
Hz), 7.96 (2H, d, J = 9Hz), 7.89 (2H, d, J = 9Hz), 7.47 (2H, d
d, J = 9Hz, 5Hz), 7.22 (2H, d, J = 6Hz), 7.10 (2H, t, J = 9Hz),
6.94 (1H, d, J = 3Hz), 3.63-3.55 (2H, m), 3.36-3.27 (2H,
m).

[0192]

Example 14 5- [4- (3-azidopropylthio)
Phenyl] -2- (4-fluorophenyl) -3- (pi
Lysin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-14) 5- [4- (2-chloroethylthio) phenyl] -2-
5- [4- (3-bromopropylthio) phenyl]-obtained in Example 3-8) instead of (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole
2- (4-fluorophenyl) -3- (pyridine-4-
The reaction was carried out in the same manner as in Example 1-9) using yl) -1H-pyrrole to give the title compound as a pale-yellow powder (yield 92%).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.58 (1H, br.s), 8.45 (2H, d,
J = 6Hz), 7.48 (2H, d, J = 9Hz), 7.38 (2H, d, J = 9Hz), 7.37-7.
35 (2H, m), 7.23 (2H, d, J = 6Hz), 7.07 (2H, t, J = 9Hz), 6.73
(1H, d, J = 3Hz), 3.46 (2H, t, J = 7Hz), 3.03 (2H, t, J = 7Hz),
1.97-1.87 (2H, m).

[0194]

Example 15 5- [4- (3-azidopropylsulfur)
Ynyl) phenyl] -2- (4-fluorophenyl)-
3- (pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-157) 5- [4- (3-azidopropylthio) phenyl] -2- (4-fluorophenyl) obtained in Example 14 -3-
An oxidation reaction was carried out in the same manner as in Example 2 using (pyridin-4-yl) -1H-pyrrole as a starting material to obtain the title compound as a white powder (yield 73%). Melting point: 158-160 ° C ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 9.79 (1H, br.s), 8.44 (2H, br.s), 7.74
(2H, d, J = 8Hz), 7.58 (2H, d, J = 8Hz), 7.45-7.40 (2H, m), 7.
24 (2H, d, J = 6Hz), 7.08 (2H, t, J = 9Hz), 6.83 (1H, d, J = 2Hz),
3.48-3.28 (2H, m), 2.93-2.77 (2H, m), 2.00-1.90 (2H, m
m).

[0195]

Example 16 5- [4- (3-azidopropylsulfo)
Nyl) phenyl] -2- (4-fluorophenyl) -3
-(Pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 1-574) 5- [4- (3-Azidopropylthio) phenyl] -2- (4-fluorophenyl)-obtained in Example 14 3-
Using (pyridin-4-yl) -1H-pyrrole as a starting material, an oxidation reaction was carried out in the same manner as in Example 6 to obtain the title compound as a pale yellow powder (yield: 82%).

Melting point: 188-190 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δppm: 9.41 (1H, br.s), 8.45 (2H, br.s), 7.87
(2H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz), 7.41 (2H, dd, J = 8Hz, 6H
z), 7.23 (2H, d, J = 5Hz), 7.09 (2H, t, J = 8Hz), 6.91 (1H, d, J
= 3Hz), 3.44 (2H, t, J = 6Hz), 3.19 (2H, t, J = 7Hz), 2.06-1.9
6 (2H, m).

[0197]

Example 17 2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -5- [4- (2-thiocyana
Propylthio) phenyl] -1H-pyrrole (Exemplified Compound No. 1-18) 5- [4- (2-bromoethylthio) phenyl] -2-
5- [4- (3-bromopropylthio) phenyl]-obtained in Example 3-8) instead of (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole
2- (4-fluorophenyl) -3- (pyridine-4-
The reaction was carried out in the same manner as in Example 11-2) using yl) -1H-pyrrole to obtain the title compound as a pale yellow powder (96% yield).

¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.61 (1H, br.s), 8.46 (2H, d,
J = 6Hz), 7.50 (2H, d, J = 9Hz), 7.41 (2H, d, J = 9Hz), 7.41-7.
36 (2H, m), 7.24 (2H, d, J = 6Hz), 7.09 (2H, t, J = 9Hz), 6.74
(1H, d, J = 3Hz), 3.14-3.08 (4H, m), 2.20-2.14 (2H, m).

[0199]

Example 18 2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -5- [4- (3-thiocyanana
Propylsulfinyl) phenyl] -1H-pillow
Le obtained in (Compound No. 1-161) Example 17 2- (4-fluorophenyl) -3-
Using (pyridin-4-yl) -5- [4- (2-thiocyanatopropylthio) phenyl] -1H-pyrrole as a starting material, an oxidation reaction was carried out in the same manner as in Example 2.
The title compound was obtained as a white powder (67% yield).

Melting point: 108-110 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 8.82 (1H, br.s), 8.48 (2H, d, J = 6 Hz), 7.
72 (2H, d, J = 9Hz), 7.66 (2H, d, J = 9Hz), 7.43-7.38 (2H, m),
7.24 (2H, d, J = 6Hz), 7.11 (2H, t, J = 9Hz), 6.85 (1H, d, J = 3H
z), 3.12-2.86 (4H, m), 2.34-2.15 (2H, m).

[0201]

Example 19 2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -5- [4- (3-thiocyanana
Propylsulfonyl ) phenyl] -1H-pyrrole (Exemplary Compound No. 1-578) 2- (4-fluorophenyl) -3- obtained in Example 17
Using (pyridin-4-yl) -5- [4- (2-thiocyanatopropylthio) phenyl] -1H-pyrrole as a starting material, an oxidation reaction was carried out in the same manner as in Example 6.
The title compound was obtained as a pale yellow powder (81% yield).

Melting point: 210-214 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 8.84 (1H, br.s), 8.48 (2H, d, J = 5 Hz), 7.
93 (2H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz), 7.40 (2H, dd, J = 9Hz,
6Hz), 7.23 (2H, d, J = 5Hz), 7.11 (2H, t, J = 9Hz), 6.93 (1H,
d, J = 3Hz), 3.23 (2H, t, J = 7Hz), 3.16 (2H, t, J = 7Hz), 2.38-
2.31 (2H, m).

[0203]

Example 20 5- [4- (2-azidoethylsulfoni)
Ru) phenyl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole (Exemplified Compound No. 1-561) 5- [4- (2-azidoethylthio) phenyl] -2- (4-fluorophenyl) -3- (obtained in Example 1) An oxidation reaction was carried out in the same manner as in Example 6 using (pyridin-4-yl) -1H-pyrrole as a starting material to obtain the title compound as a white powder (yield 73%).

Melting point: 207-208 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CDC
l ₃ ) δ ppm: 8.75 to 8.64 (1H, br.s), 8.49 (2H, d, J = 5H
z), 7.95 (2H, d, J = 9Hz), 7.73 (2H, d, J = 9Hz), 7.41 (2H, dd,
J = 9Hz, 5Hz), 7.24 (2H, d, J = 5Hz), 7.12 (2H, t, J = 9Hz), 6.9
4 (1H, d, J = 3Hz), 3.74 (2H, t, J = 7Hz), 3.37 (2H, t, J = 7Hz).

[0205]

Example 21 5- (4-azidomethylsulfinyl LF)
Enyl) -2- (4-fluorophenyl) -3- (pyri
Zin-4-yl) -1H-pyrrole (Exemplary Compound No. 1)
-131) 1) 1- (4-Fluorophenyl) -4- (4-methyl
Rusulfinylphenyl) -2- (pyridine-4-i
L) butane-1,4-dione 1- (4-fluorophenyl) -4- (4-methylthiophenyl) -2- (pyridin-4-yl) butane-1,
An oxidation reaction was carried out in the same manner as in Example 2 using 4-dione,
The title compound was obtained as a light brown powder (76% yield).

The ¹ H-nuclear magnetic resonance spectrum (400 MH
z, CDCl ₃ ) δ ppm: 8.58 (2H, d, J = 6 Hz), 8.13 (2
H, d, J = 8Hz), 8.04 (2H, dd, J = 9Hz, 5Hz), 7.75 (2H, d, J = 8H
z), 7.30 (2H, d, J = 6Hz), 7.12 (2H, t, J = 9Hz), 5.28 (1H, dd,
J = 10Hz, 4Hz), 4.27-4.14 (1H, m), 3.31 (1H, dd, J = 18Hz, 3
Hz), 2.76 (3H, s). 2) 4- (4-chloromethylthiophenyl) -1-
(4-Fluorophenyl) -2- (pyridine-4-i
L) butane-1,4-dione 1- (4-fluorophenyl) -4- (4-
Methylsulfinylphenyl) -2- (pyridine-4-
Il) Butane-1,4-dione 0.82 g (2.1 mm
ol) was dissolved in 8 ml of dichloromethane, and 0.18 ml (2.5 mmol) of thionyl chloride was added thereto.
Stirred for 0 minutes. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. (Yield 9
4%).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.56-8.55 (2H, m), 8.05-8.0
2 (2H, m), 7.96-7.94 (2H, m), 7.52-7.50 (2H, m), 7.29-7.2
7 (2H, m), 7.11 (2H, t, J = 8Hz), 5.27-5.24 (1H, m), 5.04 (2
H, s), 4.19-4.11 (1H, m), 3.32-3.26 (1H, m). 3) 4- (4-azidomethylthiophenyl) -1-
(4-Fluorophenyl) -2- (pyridine-4-i
Ru) butane-1,4-dione 4- (4-chloromethylthiophenyl) -1 obtained in 2)
0.97 g of-(4-fluorophenyl) -2- (pyridin-4-yl) butane-1,4-dione (2.3 mmol
l) was dissolved in 20 ml of N, N-dimethylformamide, and 0.45 g (7.0 mmol) of sodium azide was added, followed by stirring at 40 ° C for 3 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 1: 2) to give the title compound 0.6
0 g was obtained as a yellow amorphous solid (62% yield).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.56-8.55 (2H, m), 8.05-8.0
4 (2H, m), 7.93-7.91 (2H, m), 7.50-7.48 (2H, m), 7.29-7.2
5 (2H, m), 7.11 (2H, t, J = 8Hz), 5.28-5.24 (1H, m), 4.64 (2
H, s), 4.19-4.11 (1H, m), 3.31-3.26 (1H, m). 4) 5- (4-azidomethylthiophenyl) -2-
(4-Fluorophenyl) -3- (pyridine-4-i
4 -H-pyrrole 4- (4-azidomethylthiophenyl) -1 obtained in 3)
0.60 g (1.4 mmol) of-(4-fluorophenyl) -2- (pyridin-4-yl) butane-1,4-dione
l) was dissolved in 6 ml of acetic acid, and 0.44 of ammonium acetate was dissolved.
g (5.7 mmol) was added and the mixture was stirred at 125 ° C. for 2 hours. The mixture was cooled to room temperature, poured into ice water, made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1) to obtain 0.40 g of the title compound as a white powder. (Yield 71%).

The ¹ H-nuclear magnetic resonance spectrum (270 MH
z, CDCl ₃ ) δ ppm: 8.83 (1H, br.s), 8.44-8.43
(2H, m), 7.54-7.23 (8H, m), 7.09 (2H, t, J = 9Hz), 6.77 (1H,
d, J = 3 Hz), 4.56 (2H, s). 5) 5- (4-azidomethylsulfinylphenyl)
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H-pyrrole 5- (4-azidomethylthiophenyl) -2 obtained in 4)
An oxidation reaction was carried out using-(4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole in the same manner as in Example 2 to obtain the title compound as a white powder (yield 1).
7%).

Melting point: 188-190 ° C. ¹ H-nuclear magnetic resonance spectrum (270 MHz, CD ₃ O
D) δ ppm: 8.32 (2H, d, J = 5 Hz), 7.93 (2H, d, J = 9 Hz),
7.72 (2H, d, J = 9Hz), 7.47-7.43 (2H, m), 7.33-7.32 (2H, m),
7.15 (2H, t, J = 9Hz), 7.02 (1H, s), 4.60-4.26 (2H, m).

[0211]

Example 22 5- (4-azidomethylsulfonylfe)
Nil) -2- (4-fluorophenyl) -3- (pyridi
N-4-yl) -1H-pyrrole (exemplary compound number 1-
548) Example 6 was repeated using 5- (4-azidomethylthiophenyl) -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole obtained in Example 21-4). Similarly, an oxidation reaction was performed to obtain the title compound as a white powder (yield: 58%).

Melting point: 217-220 ° C. (decomposition) ¹ H-nuclear magnetic resonance spectrum (270 MHz, DMSO
−d ₆ ) δppm: 12.00 (1H, br.s), 8.44-8.42 (2H, m),
8.09 (2H, d, J = 8Hz), 7.91 (2H, d, J = 8Hz), 7.60-7.47 (2H,
m), 7.34-7.17 (5H, m), 4.98 (2H, s).

The compounds of Examples 23 to 45 were synthesized according to the method of Examples 1, 2, 3, 5, 6, or 20.

[0214]

Embedded image

[0215]

Embedded image

[0216]

Embedded image

[0219]

Working Example 46 5- [4- (2-azidoethylsulfyi)
Nyl) phenyl] -2- (4-fluorophenyl) -3
-(Pyridin-4-yl) -1H-pyrrole (Example
2. Optical Resolution of Exemplary Compound No. 1-144) The compound of Example 2 was fractionated by HPLC using an optically active column. <HPLC conditions> Column: CHIRALCEL OJ (manufactured by Daicel Chemical Industries, Ltd., inner diameter: 0.46 cm, length: 25 cm) Mobile phase: hexane / ethanol = 40/60 (vol /
vol) Flow rate: 1.0 ml / min Temperature: 40 ° C Detection: UV 330 nm <Retention time> First peak: 9.23 minutes (Example 46a) Second peak: 12.96 minutes (Example 46b) The ¹ H-nuclear magnetic resonance spectrum of each optically active compound was identical to that of the compound of Example 2.

[0218]

Example 47 5- (4-azidomethylsulfinyl lf)
Enyl) -2- (4-fluorophenyl) -3- (pyri
Zin-4-yl) -1H-pyrrole (Example 21, illustrative)
Optical Resolution of Compound No. 1-131) HPLC of Compound of Example 21 Using Optically Active Column
Was collected. <HPLC conditions> Column: CHIRALCEL OC (manufactured by Daicel Chemical Industries, Ltd., inner diameter: 0.46 cm, length: 25 cm) Mobile phase: hexane / ethanol = 60/40 (vol /
vol) Flow rate: 1.0 ml / min Temperature: 40 ° C. Detection: UV 330 nm <Retention time> First peak: 11.78 minutes (Example 47a) Second peak: 15.09 minutes (Example 47b) The ¹ H-nuclear magnetic resonance spectrum of each optically active compound was consistent with that of the compound of Example 21.

[0219]

Working Example 48 5- (1-Dimethylphosphorylpiperidi )
N-4-yl) -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole (Exemplary Compound No. 6-40) 2- (4-fluorophenyl) -5- (piperidine-4)
-Yl) -3- (pyridin-4-yl) -1H-pyrrole dihydrochloride (500 mg, 1.27 mmol) was dissolved in tetrahydrofuran (5 ml), and triethylamine 0.5
4 ml (3.87 mmol) was added and stirred for 30 minutes. Then, dimethyl phosphoryl chloride 0.1 under ice cooling.
4 ml (1.27 mmol) was added, and the mixture was stirred at room temperature for 1 hour. After adding a saturated aqueous sodium hydrogen carbonate solution, the mixture was extracted with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (solvent; ethyl acetate: methanol = 9: 1) to give the title compound (299).
mg was obtained as a yellow powder (55% yield).

Melting point: 177-179 ° C. ¹ H-nuclear magnetic resonance spectrum (500 MHz, CDC
l ₃ ) δ ppm: 8.42 (2H, d, J = 6 Hz), 8.19-8.08 (1H, br.
s), 7.31 (2H, dd, J = 9Hz, 5Hz), 7.19 (2H, d, J = 6Hz), 7.05 (2
(H, t, J = 9Hz), 6.19 (1H, d, J = 3Hz), 3.72 (3H, s), 3.72-3.63
(2H, m), 3.70 (3H, s), 2.92-2.83 (2H, m), 2.81-2.73 (1H,
m), 2.05-1.97 (2H, m), 1.73-1.62 (2H, m).

[0221]

[Formulation Examples] The preparations of the present invention containing the compound having the above general formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof as an active ingredient can be produced, for example, by the following method.

[0222]

Formulation Example 1 Powder 5 g of the compound of Example 2, 895 g of lactose and 100 g of corn starch were mixed with a blender.
A powder is obtained.

[0223]

Formulation Example 2 Granules 5 g of the compound of Example 5, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose were mixed, and then mixed with 10% aqueous solution of hydroxypropylcellulose 30
Add 0 g and knead. This is granulated using an extrusion granulator and dried to obtain a granule.

[0224]

Formulation Example 3 Capsule 5 g of the compound of Example 6, lactose 115 g, corn starch 58 g and magnesium stearate
After mixing 2 g using a V-type mixer, 180 mg is filled into No. 3 capsules to obtain capsules.

[0225]

Formulation Example 4 Tablets 5 g of the compound of Example 20, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender, and the mixture is compressed with a tablet machine to give tablets.

[0226]

[Test example]

[0227]

[Test Example 1] Human whole blood IL-1β and TNFα production
Inhibition test (in vitro) The method of Hartman et al. (DAHartman, SJ Ochalski a
nd RPCarlson; Theeffects of antiinflammatory and
antiallergic drugs on cytokine release after stim
ulation of human whole blood bylipopolysaccharide
and zymosan A: Inflamm. Res., 44, 269 (1995)).

Peripheral blood was collected from healthy volunteers in the presence of heparin. 1000 μl of whole blood is added to an eppendorf tube to which 2 μl of a dimethyl sulfoxide solution of a test compound has been added in advance, and lipopolysaccharide (LPS) (derived from E. coli O26: B6, Dif
After adding 10 μl (final concentration: 10 μg / ml), the mixture was mixed well and cultured at 37 ° C. for 6 hours under the conditions of 5% CO ₂ . After completion of the culture, the reaction was stopped by cooling to 4 ° C., and immediately centrifuged at 14,000 rpm for 5 minutes to separate and collect the supernatant plasma. IL- produced and released in plasma
1β and TNFα were measured with an enzyme-linked immunosorbent assay (ELISA) kit (Cayman and Genzyme). The inhibition rate was determined from the amount of cytokine production in the presence and absence of the test compound.

In this test, the compound of the present invention showed an excellent inhibitory effect on cytokine production.

[0230]

Test Example 2 TNFα Production Inhibition Test (in Vivo) The method of Ochalski et al. (SJ Ochalski, DAHartma)
n, MTBelfast, TLWalter, KBGlaser and RPCar
lson; Inhibition of endotoxin-induced hypothermia
and serum TNF-α levels in CD-1 mice by various ph
armacologicalagents: Agents Actions 39, C52-C54 (199
3) Performed according to).

LPS production was induced by intravenous injection of LPS into mice. Balb / c mice (male, 5 to 7 weeks old, weighing 22) fasted overnight from the day before the experiment.
g of LPS (derived from E. coli O26: B6, Difc) using a physiological saline solution to adjust to 0.045 mg / ml in the tail vein of Charles River Japan
o company) was administered at a rate of 10 ml / kg body weight. One hour later, the mouse was opened under anesthesia with ether, and blood was collected from the abdominal vena cava. For blood collection, a 1 ml disposable syringe with a 23G needle attached and an inner wall wetted with heparin was used. After blood collection, the blood was immediately transferred to a 1.5 ml Eppendorf tube, and centrifuged at 14,000 rpm at 4 ° C. to separate plasma. This plasma is TNF
Stored at −20 ° C. until measurement of α.

The amount of TNFα was measured by enzyme immunoassay (ELI).
SA) kit (mouse TNFα ELISA KI
T, Genzyme).

The test compound was suspended in 0.5% tragacanth solution and orally administered at a ratio of 10 ml / kg of body weight 30 minutes before the injection of LPS. A minimum of 3 doses per test compound were administered to 5 mice each. The average inhibition rate for the control group was calculated for each dose.

In this test, the compound of the present invention showed an excellent inhibitory action on TNFα production.

[0235]

[Test Example 3] IL-1β production inhibition test (in vivo
o) The method of Griffith et al. (Richard J. Griffiths, Ethan J. Sta
m, James T. Downs and Ivan G. Otterness; ATPInduces t
he Release of IL-1 from LPS-Primed Cells InVivo:
J. Immunol., 154, 2821-2828 (1995)).

By intraperitoneally injecting LPS and adenosine triphosphate (ATP) into mice, IL-
Induction of 1β was induced. Ba fasted overnight from the day before the experiment
LPS prepared in abdominal cavity of a lb / c mouse (male, 5 to 7 weeks old, around 22 g, Charles River Japan) using a physiological saline solution to a concentration of 0.0045 mg / ml.
(E. coli O26: derived from B6, Difco) was administered at a rate of 10 ml / kg body weight. Two hours later, 0.5 ml of ATP adjusted to 6.03 mg / ml using a physiological saline solution was intraperitoneally administered. 0.5 hours after ATP administration, 3 ml of washing PBS (heparin:
10 U / ml, PMSF: 0.25 mM, leupep
sin: 1 μg / ml, pepstatin: 1 μg /
ml, containing 1 mM EDTA) was injected intraperitoneally and the peritoneal cavity was washed. A 1 ml disposable syringe equipped with a 21G needle was used for collecting the washing solution. After the collection, the washing solution from the peritoneal cavity was immediately transferred to a 1.5 ml Eppendorf tube, and centrifuged at 4 ° C. and 7,500 rpm to separate the supernatant. This supernatant is
Stored at -20 ° C until measurement of L-1β.

The amount of IL-1β was measured by enzyme immunoassay (EL
ISA) kit (mouse ELISA KIT, G
test compound was suspended in 0.5% tragacanth solution, and 10 ml 30 minutes before LPS injection.
Oral administration was performed at a rate of 1 kg / body weight. A minimum of 3 doses per test compound were administered to 5 mice each. The average inhibition rate for the control group was calculated for each dose.

In this test, the compound of the present invention showed an excellent inhibitory action on IL-1β production.

[0239]

The compound containing the "prophylactic or therapeutic agent for diseases involving inflammatory cytokines" of the present invention as an active ingredient has excellent inhibitory action on inflammatory cytokine production (in particular, suppression of IL-1β and TNFα production). Action), good oral absorption, and low toxicity.
For example, analgesic / anti-inflammatory agents, antiviral agents, and rheumatoid arthritis, osteoarthritis, allergic diseases, asthma, sepsis, psoriasis, osteoporosis, autoimmune diseases (eg, systemic lupus erythematosus, ulcerative colitis, clones) Disease)
It is useful as a prophylactic or therapeutic agent for diabetes, glomerulonephritis, and arteriosclerosis, especially for analgesic and anti-inflammatory drugs, and rheumatoid arthritis, osteoarthritis, allergic diseases, sepsis,
It is useful as a preventive or therapeutic agent for psoriasis, osteoporosis, ulcerative colitis, diabetes, and arteriosclerosis.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 101 A61P 9/10 101 19/10 19/10 25/04 25/04 29/00 29 / 00 101 101 31/00 31/00 37/02 37/02 37/08 37/08 43/00 111 43/00 111 // C07D 401/04 C07D 401/04 403/04 403/04 (72) Inventor Akira Nakao 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Shigeru Ushiyama 1-2-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Shimozato, inventor Ryuichi 1-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Keisuke Suzuki 1-2-58, Hiromachi, Shinagawa-ku, Tokyo F-term (reference) 4C063 AA01 AA03 BB01 CC12 CC25 CC29 CC52 DD04 DD12 DD25 DD29 EE01 4C086 AA01 BC17 BC38 BC42 BC69 DA34 GA07 GA08 GA09 MA01 MA04 NA14 ZA08 ZA45 ZA66 ZA89 ZA96 ZA97 ZB11 ZB13 ZB15 ZC35

Claims (47)

[Claims] A compound having the following general formula (I) or a compound thereof
Pharmacologically acceptable salts, esters or other derivatives
Involve inflammatory cytokines containing as an active ingredient
Prophylactic or therapeutic agent for illness:Wherein ring A represents a 5-membered heteroaryl ring;¹And Ar^TwoAre the same or different,
Aryl group, heteroaryl group, substituent group α and substituent
An aryl group substituted with a group selected from the group β, or
Substituted with a group selected from substituent group α and substituent group β
Q represents an arylene group, a heteroarylene group, a substituent group α or
And arylene substituted with a group selected from the substituent group β
Group, substituted with a group selected from the substituent group α and the substituent group β
Heteroarylene group or at least one nitrogen
A divalent 3- to 8-membered saturated heterocyclic group containing an atom,¹Is a group bonded to a carbon atom on the ring,
, An alkyl group having 1 to 15 carbon atoms, 2 to 1 carbon atoms
5 alkenyl groups, alkynyl having 2 to 15 carbon atoms
1 to 3 selected from a group, a substituent group α and a substituent group γ
Alkyl groups having 1 to 15 carbon atoms substituted with
1 to 3 groups selected from the substituent group α and the substituent group γ
An alkenyl group having 2 to 15 carbon atoms,
1 to 3 groups selected from the substituent group α and the substituent group γ
An alkynyl group having 2 to 15 carbon atoms substituted with
A gen atom or a nitro group;^TwoIs a group attached to the nitrogen atom on the ring,
, An alkyl group having 1 to 15 carbon atoms, 2 to 1 carbon atoms
5 alkenyl groups, alkynyl having 2 to 15 carbon atoms
1 to 3 selected from a group, a substituent group α and a substituent group γ
Alkyl groups having 1 to 15 carbon atoms substituted with
1 to 3 groups selected from the substituent group α and the substituent group γ
An alkenyl group having 2 to 15 carbon atoms,
Is one to three selected from the substituent group α and the substituent group γ
An alkynyl group having 2 to 15 carbon atoms substituted by a group of
Indicates, R^ThreeIs the general formula -WR^Four, -OWR^Four, -S (O)_mW
R^Four, -N (WR^Four) R^Five, -SO_TwoN (WR^Four) R^Five, -C
ON (WR^Four) R^Five, -COWR^FourOr -PO (OR ⁶)
(OR⁷Wherein m represents 0, 1 or 2, W is an alkylene group, a lower alkenylene group, a cycloalkyl group;
Kylene group, cycloalkenylene group or lower alkynylene
R represents a group^FourStands for azide, nitro, nitrosooxy, nitro
Roxy, thiocyanate, PO (OR⁶) (O
R⁷), Group C (= NOR⁸) R⁹Or the group CON (OR ⁸) R
⁹And R^Five, R⁸And R⁹Are the same or different
A hydrogen atom, an alkyl group having 1 to 15 carbon atoms,
2 to 15 alkenyl groups, 2 to 15 carbon atoms
Alkynyl, aryl, aralkyl, heteroaryl
R, a heteroarylalkyl group or a protecting group;⁶And R⁷Are the same or different and are each hydrogen
Atom, alkyl group having 1 to 15 carbon atoms, 2 to carbon atoms
15 alkenyl groups, alkynyl having 2 to 15 carbon atoms
Or an aralkyl group. Wherein (a) ring A is an oxygen atom, a sulfur atom and a nitrogen atom
Containing three atoms selected from: and (b)
Ring A is selected from an oxygen atom, a sulfur atom and a nitrogen atom
Contains two atoms, one of which is oxygen or sulfur
If it is a yellow atom, R¹And R^TwoIs not present; (c) when ring A contains two nitrogen atoms, R¹Passing
And R^TwoIs not present, and (d) ring A is nitrogen
When no atom is contained, R^TwoDoes not exist. ｝ [Substituent group α] halogen atom, cyano group, nitro group, N
R^TenR¹¹(Where R^TenAnd R¹¹Are the same or different,
A hydrogen atom and an alkyl group having 1 to 15 carbon atoms, respectively
Or a halogeno lower alkyl group, or
Together with the nitrogen atom to which they are attached
To form a heterocyclyl group containing two nitrogen atoms
You. ), OR^Ten(Where R^TenHas the same meaning as above.
You. ) And SR^Ten(Where R^TenHas the same meaning as above.
You. ), [Substituent group β] lower alkyl group, and the above-mentioned substituent group α
Lower alkyl group substituted with one to three groups selected from [substituent group γ] aryl group, heteroaryl group, and
Terocyclyl groups (these groups are the substituent group α and the substituent
May be substituted with 1 to 3 groups selected from the group β.
No. ) 2. The compound according to claim 1, wherein ring A is a 5-membered aromatic heterocyclic ring containing at least one nitrogen atom and further containing an oxygen atom or a nitrogen atom, or a pharmacologically acceptable compound thereof. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a salt, ester or other derivative as an active ingredient. 3. The disease according to claim 1, wherein Ring A contains pyrrole, imidazole or oxazole, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient, wherein the inflammatory cytokine is involved. Prophylactic or therapeutic agents. 4. The method according to claim 1, wherein the following general formula (I-
A): embedded image A prophylactic or therapeutic agent for a disease associated with an inflammatory cytokine, comprising a compound having the formula: or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 5. The method according to claim 1, wherein Ar ¹ is a heteroaryl group or a heteroaryl group substituted with a group selected from the group of substituents α and β. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a compound that is an aryl group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 6. The method according to claim 1, wherein Ar ¹ is a 5- to 6-membered aromatic heterocyclic group containing one or two nitrogen atoms, or a substituent group α and A nitrogen atom substituted with a group selected from substituent group β
Or a prophylactic or therapeutic agent for diseases involving inflammatory cytokines, comprising as an active ingredient a compound which is a 5- or 6-membered aromatic heterocyclic group containing two or a pharmacologically acceptable salt, ester or other derivative thereof. . 7. The pyridyl according to claim 1, wherein Ar ¹ is substituted with a group selected from pyridyl, pyrimidinyl, a substituent group α and a substituent group β. Or a compound that is pyrimidinyl substituted with a group selected from the substituent group α and the substituent group β, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient, and involves an inflammatory cytokine. An agent for preventing or treating a disease. 8. The method according to claim 1, wherein Ar ¹ is substituted with 4-pyridyl or a group selected from a substituent group α and a substituent group β.
-A compound which is pyridyl or a pharmaceutically acceptable salt thereof,
An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising an ester or another derivative as an active ingredient. 9. The method according to claim 1, wherein Ar ² is substituted with an aryl group, a heteroaryl group, or a group selected from a substituent group α and a substituent group β. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a compound which is an aryl group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 10. An aryl group according to any one of claims 1 to 8, wherein Ar ² is substituted with an aryl group or a group selected from a substituent group α and a substituent group β. Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient, a prophylactic or therapeutic agent for a disease associated with an inflammatory cytokine. 11. The method according to claim 1, wherein Q is substituted by an arylene group, a heteroarylene group, or a group selected from a substituent group α and a substituent group β. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a compound having an arylene group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 12. The method according to claim 1, wherein Q is an arylene group or an arylene group substituted with a group selected from a substituent group α and a substituent group β. A compound or a pharmacologically acceptable salt thereof,
An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising an ester or another derivative as an active ingredient. 13. The method according to claim 1, wherein Q is substituted with 1,4-phenylene or a group selected from the group of substituents α and β. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a compound which is 1,4-phenylene or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 14. The method according to claim 11, wherein R ³ is a group represented by the general formula —WR ⁴ , —O
A preventive or therapeutic agent for a disease involving an inflammatory cytokine, comprising as an active ingredient a compound which is a group having WR ⁴ or —S (O) _m WR ⁴ , or a pharmacologically acceptable salt, ester or other derivative thereof. Agent. 15. The method according to claim 11, wherein R ³ is a group represented by the general formula —S (O) _m W.
An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a compound which is a group having R ⁴ or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. 16. The method according to claim 11, wherein R ³ is a group represented by the general formula: —S (O) _m W
A preventive or therapeutic agent for a disease involving inflammatory cytokines, comprising a compound having R ⁴ and m is 1 or 2, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. Agent. 17. The compound according to claim 1, wherein Q is a divalent 3- to 8-membered saturated heterocyclic group containing at least one nitrogen atom, or a compound thereof. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a pharmacologically acceptable salt, ester or other derivative as an active ingredient. 18. The method according to claim 1, wherein Q is azetidinediyl, pyrrolidinediyl, imidazolidinediyl, oxazolidindiyl, thiazolidinediyl, piperidinediyl, piperazindiyl, morpholinediyl or thioline. Containing a compound that is morpholinediyl or a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient,
An agent for preventing or treating a disease associated with an inflammatory cytokine. 19. The compound according to claim 1, wherein Q is azetidindiyl, pyrrolidinediyl, piperidinediyl or piperazinediyl, or a pharmaceutically acceptable salt, ester or other compound thereof. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a derivative of the above as an active ingredient. 20. The compound according to claim 17, wherein the group —QR ³ is represented by the following general formula (II): 中 wherein the cyclic group: Is in the definition of Q, a divalent 3-8 membered saturated heterocyclic group containing at least one nitrogen atom, R ³ a
Is a general formula -WR ⁴ , -S (O) _m in the definition of R ^3.
WR ⁴ , -SO ₂ N (WR ⁴ ) R ⁵ , -CON (WR ⁴ )
R ^5, a group having a -COWR ⁴ or ^{-PO (OR 6) (OR 7} ). A prophylactic or therapeutic agent for a disease associated with an inflammatory cytokine, comprising as an active ingredient a compound which is a group having｝ or a pharmacologically acceptable salt, ester or other derivative thereof. 21. The method of claim 20, R ³ a is Formula _{^{-WR 4, -S (O) m}} WR 4 or a compound or a pharmacologically acceptable salt thereof is a group having -COWR ^4, ester or An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising another derivative as an active ingredient. 22. The method of claim 20, R ³ a is, contain general formula -WR ^4, or a group, compound or a pharmacologically acceptable salt thereof having a -COWR ^4, ester or other derivative as an active ingredient And prophylactic or therapeutic agents for diseases involving inflammatory cytokines. 23. The method of claim 20, R ³ a is contains general compound formula -WR ⁴ is a group having the or a pharmacologically acceptable salt, ester or other derivative as an active ingredient, inflammatory cytokines Or a prophylactic or therapeutic agent for a disease associated with. 24. The compound according to claim 1, wherein W is an alkylene group, a lower alkenylene group or a lower alkynylene group, or a pharmaceutically acceptable salt, ester or other compound thereof. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a derivative of the above as an active ingredient. 25. The method according to any one of claims 1 to 23, wherein W is an alkylene group or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. And prophylactic or therapeutic agents for diseases involving inflammatory cytokines. 26. The compound according to claim 1, wherein W is a linear or branched alkylene group having 1 to 4 carbon atoms, or a pharmaceutically acceptable compound thereof. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a salt, ester or other derivative as an active ingredient. 27. The compound according to any one of claims 1 to 23, wherein W is a linear or branched alkylene group having 1 to 3 carbon atoms, or a pharmaceutically acceptable compound thereof. An agent for preventing or treating a disease associated with an inflammatory cytokine, comprising a salt, ester or other derivative as an active ingredient. 28. The compound according to any one of claims 1 to 23, wherein W is methylene, ethylene or trimethylene, or a pharmaceutically acceptable salt, ester or other derivative thereof as an active ingredient. A prophylactic or therapeutic agent for a disease associated with an inflammatory cytokine. 29. The method according to any one of claims 1 to 23, wherein W is methylene or ethylene, or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. A prophylactic or therapeutic agent for a disease involving inflammatory cytokines. 30. The method according to claim 1, wherein R ⁴ is an azide group, a nitro group,
Thiocyanate group or group PO (OR ⁶ ) (OR ⁷ ) [wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ have the same meaning as described above. ]
Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient, a prophylactic or therapeutic agent for a disease associated with an inflammatory cytokine. 31. The compound according to claim 1, wherein R ⁴ is an azido group or a nitro group, or a pharmaceutically acceptable salt, ester or other derivative thereof. An agent for preventing or treating a disease associated with an inflammatory cytokine, which is contained as a component. 32. The method according to any one of claims 1 to 31, wherein R ¹ is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or a substituent group α and a substituent group γ.
An inflammatory cytokine containing, as an active ingredient, a compound which is an alkyl group having 1 to 15 carbon atoms and substituted with 1 to 3 groups selected from the group consisting of: and a pharmacologically acceptable salt, ester or other derivative thereof. Or a prophylactic or therapeutic agent for a disease associated with. 33. The method according to claim ¹ , wherein R ¹ is a hydrogen atom or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. A prophylactic or therapeutic agent for a disease involving inflammatory cytokines. 34. The method according to any one of claims 1 to 33, wherein R ² is a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or a substituent group α and a substituent group γ.
An inflammatory cytokine containing, as an active ingredient, a compound which is an alkyl group having 1 to 15 carbon atoms and substituted with 1 to 3 groups selected from the group consisting of: and a pharmacologically acceptable salt, ester or other derivative thereof. Or a prophylactic or therapeutic agent for a disease associated with. 35. The compound according to any one of claims 1 to 33, wherein R ² is a hydrogen atom or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. A prophylactic or therapeutic agent for a disease involving inflammatory cytokines. 36. The preventive or therapeutic agent for a disease associated with an inflammatory cytokine according to claim 1, comprising a compound selected from the following or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. : 5- [4- (2-azidoethylsulfinyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl)- 5- [4- (3-nitropropylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (3-nitropropylsulfonyl) ) Phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (3-nitroxypropylsulfinyl) Phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (2-diethylphosphonoethylsulfinyl) phenyl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 5- [4- (2-diethylphosphonoethylsulfonyl) phenyl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -5- [4- (2-thiocyanatoethylsulfinyl) phenyl] -1H-pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4)
-Yl) -5- [4- (2-thiocyanatoethylsulfonyl) phenyl] -1H-pyrrole, 5- [4- (3-azidopropylsulfinyl) phenyl] -2- (4-fluorophenyl)- 3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (3-azidopropylsulfonyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H -Pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -5- [4- (3-thiocyanatopropylsulfinyl) phenyl] -1H-pyrrole, 2- (4-fluorophenyl) -3- (pyridine-4)
-Yl) -5- [4- (3-thiocyanatopropylsulfonyl) phenyl] -1H-pyrrole, 5- [4- (2-azidoethylsulfonyl) phenyl] -2- (4-fluorophenyl)- 3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (azidomethylsulfinyl) phenyl]
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H-pyrrole, 5- [4- (azidomethylsulfonyl) phenyl]-
2- (4-fluorophenyl) -3- (pyridine-4-
Yl) -1H-pyrrole, 5- [1- (2-diethylphosphonoethyl) piperidin-4-yl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (2-nitroethyl) piperidin-4-yl] -3- (pyridin-4-yl) -1H -Pyrrole, -5- [1- (diethylphosphonomethyl) piperidine-
4-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (3-nitropropionyl) piperidine -4-yl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (dimethylphosphoryl) piperidin-4-yl] -3- (pyridine -2-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (4-nitrobutylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (3-chlorophenyl) -5- [4- (3-nitropropylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole; and 2- (3,4-difluorophenyl)- 5- [ -
(3-Nitropropylsulfinyl) phenyl] -3-
(Pyridin-4-yl) -1H-pyrrole. 37. The preventive or therapeutic agent for a disease associated with inflammatory cytokines according to claim 1, comprising a compound selected from the following or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient. : 5- [4- (2-azidoethylsulfinyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl)- 5- [4- (3-nitropropylsulfinyl) phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [4- (3-nitropropylsulfonyl) ) Phenyl] -3- (pyridin-4-yl) -1H-pyrrole, 5- [4- (3-azidopropylsulfinyl) phenyl] -2- (4-fluorophene) Nyl) -3- (pyridin-4-yl) -1H-pyrrole, * 5- [4- (3-azidopropylsulfonyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) ) -1H-pyrrole, 5- [4- (2-azidoethylsulfonyl) phenyl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, -(Azidomethylsulfinyl) phenyl]
-2- (4-fluorophenyl) -3- (pyridine-4
-Yl) -1H-pyrrole, 5- [1- (2-diethylphosphonoethyl) piperidin-4-yl] -2- (4-fluorophenyl) -3-
(Pyridin-4-yl) -1H-pyrrole, 2- (4-fluorophenyl) -5- [1- (2-nitroethyl) piperidin-4-yl] -3- (pyridin-4-yl) -1H -Pyrrole, -5- [1- (diethylphosphonomethyl) piperidine-
4-yl] -2- (4-fluorophenyl) -3- (pyridin-4-yl) -1H-pyrrole, and 2- (4-fluorophenyl) -5- [1- (3-nitropropionyl) Piperidin-4-yl] -3- (pyridin-4-yl) -1H-pyrrole. 38. An agent for preventing or treating a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as an analgesic and / or an anti-inflammatory agent. 39. The preventive or therapeutic agent for a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as a preventive or therapeutic agent for rheumatoid arthritis. 40. A prophylactic or therapeutic agent for a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as a prophylactic or therapeutic agent for osteoarthritis. . 41. A preventive or therapeutic agent for a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as a preventive or therapeutic agent for an allergic disease. 42. An agent for preventing or treating a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as an agent for preventing or treating sepsis. 43. An agent for preventing or treating a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as an agent for preventing or treating psoriasis. 44. An agent for preventing or treating a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as an agent for preventing or treating osteoporosis. 45. A prophylactic or therapeutic agent for a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as a prophylactic or therapeutic agent for ulcerative colitis. . 46. The preventive or therapeutic agent for a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as a preventive or therapeutic agent for diabetes. 47. An agent for preventing or treating a disease associated with an inflammatory cytokine according to any one of claims 1 to 37, which is used as a preventive or therapeutic agent for arteriosclerosis.