DESCRIPTION
PYRIDAZINONE COMPOUNDS AND P2X7 RECEPTOR INHIBITORS
BACKGROUND OF THE INVENTION TECHNICAL FIELD
The present invention relates to novel heterocyclic compounds which inhibit the P2X7 receptor.
BACKGROUND ART
The purinergic P2X7 receptor is a ligand-gated ion channel which becomes permeable to ions such as Ca2+ upon the binding of purine nucleotides and is expressed in macrophages, mast cells, T-lymphocytes, B-lymphocytes, antigen presenting cells, osteoclasts, keratinocytes and the like. It is associated with inflammatory and immunological diseases by mediating production of inflammatory cytokines, in particular IL-1|3 (interleukin-1(3) (Non-patent documents 1 and 2) . It is also expressed in microglia and associated with pain (Non-patent document 3).
Therefore, P2X7 receptor inhibitors can be useful for treatment of these diseases, and actually, it is known that P2X7 knockout mice are resistant to the development of experimental arthritis and pain and that P2X7 receptor inhibitors attenuate neuropathic pain (Nonpatent documents 3 to 5).
Although several P2X7 receptor inhibitors have been
known from the following reports (such as Patent
documents 1 and 2), further development of such drugs is
demanded.
Patent document 1: WO99/29660
Patent document 2: WO2007/109192
Non-patent document 1: Physiol. Rev. 2002: 82, p.1013-1067
Non-patent document 2 : J. Immunol. 2 0 06: 176, p.3877-3883
Non-patent document 3: Pain 200δ: 114, p.386-396
Non-patent document 4 : J. Immunol. 2 0 02: 16 8, p.6436-6445
Non-patent document δ: J. Pharmacol. Exp. Ther. 2006: 319, p.1376-1385
DISCLOSURE OF THE INVENTION
The object of the present invention is to provide novel pyridazinone compounds which inhibit the P2X7 receptor and are useful for inflammatory and immunological diseases.
The present inventors conducted extensive research to find novel low molecular weight compounds having antagonistic action on the P2X7 receptor, and as a result, found that the compounds of the present invention have strong antagonistic action. The present invention was accomplished on the basis of this discovery. Namely,
the present invention provides:
(1) A compound represented by the formula (I):
(Formula Removed)
wherein R means a hydrogen atom, a hydroxy group, a nitro group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C1-6 alkoxy group (the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or more halogen atoms),
R2 means a hydrogen atom, a hydroxy group, a nitro group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a mono-C1-6 alkylamino group, a di-C1-6 alkylamino group, a C1-6 alkylthio group or a C1-6 alkylsulfonyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the mono-C1-6 alkylamino group, the di-C1-6 alkylamino group, the C1-6 alkylthio group and the C1-6 alkyl sulfonyl group are unsubstituted or substituted with one or more halogen atoms), Q means any of the structures represented by the formula II) :
(Formula Removed)
(wherein each of R3 and R5 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group (the C1-6 alkyl group, the C2-6 alkenyl group and the C2-6 alkynyl group are unsubstituted or substituted with one or more halogen atoms), R4 means a C1-20 alkyl group, a C2-20 alkenyl group or a C2-19 heterocyclyl group (the C1-20 alkyl group, the C2-20 alkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from a substituent set V1) , or
R3 and R4 mean, together with each other, a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1 or one or more C1-20 alkyl groups),
m means 0, 1 or 2, and
T means an oxygen atom or a sulfur atom), X means a single bond or a C1-6 alkylene group (the C1-6 alkylene group is unsubstituted or substituted with one or more identical or different substituents selected from
the substituent set V1) ,
Y means a single bond, a C2-14 arylene group, a C2-9 heterocyclylene group (the C2-14 arylene group and the C2-. heterocyclylene group are unsubstituted or substituted with one or more identical or different substituents selected from a substituent set V2) or any of the structures represented by the formula (III) :
(Formula Removed)
(wherein each of R6 and R7 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group (the C1-6 alkyl group and the C2-6 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) or a C1-3 haloalkyl group, each of U and W independently means an oxygen atom, a sulfur atom or NOR10 (wherein R10 means a hydrogen atom, a C1-3 alkyl group or a C1-3 haloalkyl group), and n means 0, 1 or 2) , Z means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl
group, a C1-6 alkoxy group, a C3-12 cycloalkyl group, a C3-
12 cycloalkenyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C3-12 cycloalkyl group and the C3-12 cycloalkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a fused C2-14 aryl group, a C2-14 aryloxy group or a C2-9 heterocyclyl group (the C2-14 aryl group, the fused C2-14 aryl group, the C2-14 aryloxy group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , the substituent set V1 consists of carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, sulfo groups, tetrazolyl groups, formyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C2-6 alkenyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups and C1-6 alkylsulfonyl groups (the mono-C1-6 alkylamino groups, the di-C1-6 alkylamino groups, the C1-6 alkyl groups, the C2-6 alkenyl groups, the C1-6 alkoxy groups, the C2-9 heterocyclyl groups, the C1-6 alkylthio groups and the C1-6 alkylsulfonyl groups are unsubstituted or substituted with one or more carboxy groups, one or more carbamoyl groups, one or more sulfamoyl groups, one or more phosphono groups, one or more sulfo groups, one
or more tetrazolyl groups, one or more formyl groups, one
or more nitro groups, one or more cyano groups, one or more halogen atoms, one or more C1-6 alkyl groups, one or more C1-3 haloalkyl groups, one or more C1-6 alkoxy groups, one or more C1-3 haloalkoxy groups, one or more hydroxy groups, one or more amino groups, one or more mono-C1-6 alkylamino groups, one or more di-C1-6 alkylamino groups, one or more C1-6 alkylthio groups or one or more C1-6 alkylsulfonyl groups), and
the substituent set V2 consists of the substituent set V1, C2-14 aryl groups and fused C2-14 aryl groups (the C2-14 aryl groups and the fused C2-14 aryl groups are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. (2) A compound represented by the formula (I):
(Formula Removed)
wherein R means a hydrogen atom, a hydroxy group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C1-6 alkoxy group (the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group
and the C1-6 alkoxy group are unsubstituted or substituted with one or more halogen atoms),
R2 means a hydrogen atom, a hydroxy group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C1-6 alkylthio group or a C1-6 alkylsulfonyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C1-6 alkyl thio group and the C1-6 alkylsulfonyl group are unsubstituted or substituted with one or more halogen atoms), Q means any of the structures represented by the formula (IV) :
(Formula Removed)
(wherein each of R3 and R5 independently means a hydrogen
atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6
alkynyl group (the C1-6 alkyl group, the C2-6 alkenyl group
and the C2-6 alkynyl group are unsubstituted or
substituted with one or more halogen atoms),
R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the
C1-20 alkyl group and the C2-20 alkenyl group are
unsubstituted or substituted with one or more identical
or different substituents selected from a substituent set
V1) , or
R3 and R4 mean, together with each other, a nitrogen-
containing heterocyclyl group (the nitrogen-containing
heterocyclyl group is unsubstituted or substituted with
one or more identical or different substituents selected
from the substituent set V1 or one or more C1-20 alkyl
groups), and
T means an oxygen atom or a sulfur atom),
X means a single bond or a C1-6 alkylene group (the C1-6
alkylene group is unsubstituted or substituted with one
or more identical or different substituents selected from
the substituent set V1) ,
Y means a single bond, a C2-14 arylene group, a C2-9
heterocyclylene group (the C2-14 arylene group and the C2-9
heterocyclylene group are unsubstituted or substituted
with one or more identical or different substituents
selected from a substituent set V2) or any of the
structures represented by the formula (V):
(Formula Removed)
(wherein each of R6 and R7 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C1-3 haloalkyl group, U means an oxygen atom, a sulfur atom or NOR10 (wherein R10 means a hydrogen atom, a C1-3 alkyl
group or a C1-3 haloalkyl group), and n means 0, 1 or 2),
Z means a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C3-12 cycloalkyl group and the C3-12 cycloalkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a fused C2-14 aryl group, a C2-14 aryloxy group or a C2-9 heterocyclyl group (the C2-14 aryl group, the fused C2-14 aryl group, the C2-14 aryloxy group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , the substituent set V1 consists of carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, sulfo groups, tetrazolyl groups, formyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C2-6 alkenyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups and C1-6 alkylsulfonyl groups (the mono-C1-6 alkylamino groups, the di-C1-6 alkylamino groups, the C1-6 alkyl groups, the C2-6 alkenyl groups, the C1-6 alkoxy groups, the C2-9 heterocyclyl groups, the C1-6 alkylthio groups and the C1-6 alkylsulfonyl groups are unsubstituted or substituted with one or more carboxy groups, one or
more carbamoyl groups, one or more sulfamoyl groups, one or more phosphono groups, one or more sulfo groups, one or more tetrazolyl groups, one or more formyl groups, one or more nitro groups, one or more cyano groups, one or more halogen atoms, one or more C1-6 alkyl groups, one or more C1-3 haloalkyl groups, one or more C1-6 alkoxy groups, one or more C1-3 haloalkoxy groups, one or more hydroxy groups, one or more amino groups, one or more mono-C1-6 alkylamino groups, one or more di-C1-6 alkylamino groups, one or more C1-6 alkylthio groups or one or more C1-6 alkylsulfonyl groups), and
the substituent set V2 consists of the substituent set V1, C2-14 aryl groups and fused C2-14 aryl groups (the C2-14 aryl groups and the fused C2-14 aryl groups are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(3) The compound according to (1) or (2), wherein R1 is a hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(4) The compound according to (1) or (2), wherein R1 is a hydrogen atom or an ethoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(5) The compound according to any one of (1) to (4),
wherein R2 is a hydrogen atom, a halogen atom, a C1-3
alkoxy group, a C1-3 alkyl group, a C1-3 alkylthio group or
a C1-3 alkylsulfonyl group (the C1-3 alkoxy group, the C1-3
alkyl group, the C1-3 alkylthio group and the C1-3
alkylsulfonyl group are unsubstituted or substituted with
one or more halogen atoms), a tautomer, prodrug or
pharmaceutically acceptable salt of the compound or a
solvate thereof.
(6) The compound according to (5), wherein R2 is a halogen atom, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(7) The compound according to any one of (1) to (6), wherein Q is represented by the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms) , and R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the C1-20 alkyl group and the C2-20 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) , a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(8) The compound according to any one of (1) and (3) to
(6), wherein Q is represented by the formula (VII):
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the C1-20 alkyl group and the C2-20 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) , a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(9) The compound according to (7) or (8), wherein R3
means a hydrogen atom, and R4 means a C3-12 cycloalkyl
group or a C3-12 cycloalkenyl group (the C3-12 cycloalkyl
group and the C3-12 cycloalkenyl group are unsubstituted
or substituted with one to three identical or different
substituents selected from the substituent set V1) , a
tautomer, prodrug or pharmaceutically acceptable salt of
the compound or a solvate thereof.
(10) The compound according to any one of (1) and (3) to
(6), wherein R3 means a hydrogen atom, and R4 means a C2-19
heterocyclyl group (the C2-19 heterocyclyl group is unsubstituted or substituted with one to three identical or different substituents selected from the substituent set V1), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(11) The compound according to (10), wherein R3 means a
hydrogen atom, and R4 means a C2-11 heterocyclyl group
(the C2-11 heterocyclyl group is unsubstituted or
substituted with one to three identical or different
substituents selected from the substituent set V1) , a
tautomer, prodrug or pharmaceutically acceptable salt of
the compound or a solvate thereof.
(12) The compound according to any one of (1) to (11),
wherein X means a C1-6 alkylene group (the C1-6 alkylene
group is unsubstituted or substituted with one or two
identical or different substituents selected from the
substituent set V1) ,
Y means a single bond or any of the structures
represented by the formula (VIII):
(Formula Removed)
(wherein R6 means a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms), and U means an oxygen atom or a sulfur atom), and
Z means a C1-6 alkyl group, a C1-6 alkoxy group (the C1-6 alkyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a C2-14 aryloxy group or a C2-9 heterocyclyl group (the C2-14 aryl group, the C2-14 aryloxy group and the C2-9 heterocyclyl group are unsubstituted or
substituted with one substituent selected from the
substituent set V2) , a tautomer, prodrug or
pharmaceutically acceptable salt of the compound or a
solvate thereof.
(13) The compound according to any one of (1) to (12),
wherein Z means a C1-6 alkyl group (the C1-6 alkyl group is
substituted with a C2-9 heteroaryl group (the C2-9
heteroaryl group is unsubstituted or substituted with one
or two identical or different substituents selected from
the substituent set V1) ) , a tautomer, prodrug or
pharmaceutically acceptable salt of the compound or a
solvate thereof.
(14) A compound represented by the formula (I):
(Formula Removed)
wherein R means a hydrogen atom, a hydroxy group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C1-6 alkoxy group (the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or more halogen atoms),
R2 means a C2-14 aryl group (the C2-14 aryl group is unsubstituted or substituted with one or more identical
or different substituents selected from a substituent set
V2),
Q means any of the structures represented by the formula
(II) :
(Formula Removed)
(wherein each of R3 and R5 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group (the C1-6 alkyl group, the C2-6 alkenyl group and the C2-6 alkynyl group are unsubstituted or substituted with one or more halogen atoms), R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the C1-20 alkyl group and the C2-20 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from a substituent set V1) , or
R3 and R4 mean, together with each other, a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1 or one or more C1-20 alkyl groups),
m means 0, 1 or 2, and
T means an oxygen atom or a sulfur atom), X means a C1-6 alkylene group (the C1-6 alkylene group is
unsubstituted or substituted with one or more identical
or different substituents selected from the substituent
set V1) ,
Y means a structure represented by the formula (IX):
(Formula Removed)
(wherein R6 means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C1-3 haloalkyl group, and U means an oxygen atom, a sulfur atom or NOR10 (wherein R10 means a hydrogen atom, a C1-3 alkyl group or a C1-3 haloalkyl group)),
Z means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C3-12 cycloalkyl group and the C3-12 cycloalkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a fused C2-14 aryl group or a C2-9 heterocyclyl group (the C2-14 aryl group, the fused C2-14 aryl group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , the substituent set V1 consists of carboxy groups,
carbamoyl groups, sulfamoyl groups, phosphono groups,
sulfo groups, tetrazolyl groups, formyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C2-6 alkenyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups and C1-6 alkylsulfonyl groups (the mono-C1-6 alkylamino groups, the di-C1-6 alkylamino groups, the C1-6 alkyl groups, the C2-6 alkenyl groups, the C1-6 alkoxy groups, the C2-9 heterocyclyl groups, the C1-6 alkyl thio groups and the C1-6 alkylsulfonyl groups are unsubstituted or substituted with one or more carboxy groups, one or more carbamoyl groups, one or more sulfamoyl groups, one or more phosphono groups, one or more sulfo groups, one or more tetrazolyl groups, one or more formyl groups, one or more nitro groups, one or more cyano groups, one or more halogen atoms, one or more C1-6 alkyl groups, one or more C1-3 haloalkyl groups, one or more C1-6 alkoxy groups, one or more C1-3 haloalkoxy groups, one or more hydroxy groups, one or more amino groups, one or more mono-C1-6 alkylamino groups, one or more di-C1-6 alkylamino groups, one or more C1-6 alkylthio groups or one or more C1-6 alkylsulfonyl groups), and
the substituent set V2 consists of the substituent set V1, C2-14 aryl groups and fused C2-14 aryl groups (the C2-14 aryl groups and the fused C2-14 aryl groups are unsubstituted or substituted with one or more identical
or different substituents selected from the substituent
set V1), a tautomer, prodrug or pharmaceutically
acceptable salt of the compound or a solvate thereof.
(15) The compound according to (14), wherein R1 is a
hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy
group,
R2 is a C2-14 aryl group,
Q is represented by the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms),
R4 means a C1-20 alkyl group (the C1-20 alkyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) , and
Z means a C1-6 alkyl group (the C1-6 alkyl group is substituted with a C2-9 heteroaryl group (the C2-9 heteroaryl group is unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V1) ) , a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(16) The compound according to (14), wherein R1 is a hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy
group,
R2 is a C2-14 aryl group,
Q means any of the structures represented by the formula
(VII):
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C1-20 alkyl group (the C1-20 alkyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) , and Z means a C1-6 alkyl group (the C1-6 alkyl group is substituted with a C2-9 heteroaryl group (the C2-9 heteroaryl group is unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V1) ) , a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
(17) A P2X7 receptor inhibitor containing the compound according to any one of (1) to (16), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient.
(18) A preventive, therapeutic or improving agent for diseases against which inhibition of the P2X7 receptor is effective, which contains the P2X7 receptor inhibitor according to (17), as an active ingredient.
(19) A therapeutic agent for rheumatoid arthritis, which
contains the P2X7 receptor inhibitor according to (17),
as an active ingredient.
(2 0) Medicament containing the compound according to any
one of (1) to (16), a tautomer, prodrug or
pharmaceutically acceptable salt of the compound or a
solvate thereof, as an active ingredient.
EFFECTS OF THE INVENTION
The present invention provides novel pyridazinone compounds which have excellent inhibitory action on the P2X7 receptor and are useful for inflammatory and immunological diseases.
BEST MODE FOR CARRYING OUT THE INVENTION
Now, the present invention will be described in detail.
In the present invention, "n" denotes normal, "i" denotes iso, "s" denotes secondary, "t" denotes tertiary, "c" denotes cyclo, "o" denotes ortho, "m" denotes meta, "p" denotes para, "rac" denotes racemate, "Ph" denotes phenyl, "Py" denotes pyridyl, "Me" denotes methyl, "Et" denotes ethyl, "Pr" denotes propyl, "Bu" denotes butyl, "Boc" denotes tertiary-butoxycarbonyl, "Ms" denotes methanesulfonyl, "Tf" denotes trifluoromethanesulfonyl, and "MOM" denotes methoxymethyl.
First, the terms in the respective substituents R1 to R10 will be explained.
As a halogen atom, fluorine, chlorine, bromine or
iodine may be mentioned.
A C1-3 alkyl group is an alkyl group containing one to three carbon atoms and may be linear, branched or a C3 cycloalkyl group. As specific examples, methyl, ethyl, n-propyl, i-propyl and c-propyl may be mentioned.
A C1-6 alkyl group is an alkyl group containing one to six carbon atoms and may be linear, branched or a C3-6 cycloalkyl group. As specific examples, in addition to those mentioned above, n-butyl, i-butyl, s-butyl, t-butyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, n-pentyl, 1-methyl-n-butyl, 2-methyl-n-butyl, 3-methyl-n-butyl, 1,1-dimethyl-n-propyl, 1,2-dimethyl-n-propyl, 2,2-dimethyl-n-propyl, 1-ethyl-n-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2 - ethyl-c-propyl, n-hexyl, 1-methyl-n-pentyl, 2-methyl-n-pentyl, 3-methyl-n-pentyl, 4-methyl-n-pentyl, 1,1-dimethyl-n-butyl, 1,2-dimethyl-n-butyl, 1,3-dimethyl-n-butyl, 2,2-dimethyl-n-butyl, 2,3-dimethyl-n-butyl, 3,3-dimethyl-n-butyl, 1-ethyl-n-butyl, 2-ethyl-n-butyl, 1,1,2-trimethyl-n-propyl, 1,2,2-trimethyl-n-propyl, 1-ethyl-1-methyl-n-propyl, 1-ethyl-2-methyl-n-propyl, c-hexyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1- ethyl-c-butyl, 2 -ethyl-c-butyl, 3 -ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2-dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4-dimethyl-c-
butyl, 3,3-dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-
propyl-c-propyl, 1-i-propyl-c-propyl, 2-i-propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl-c-propyl, l-ethyl-2-methyl-c-propyl, 2 - ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl, 2-ethyl-3-methyl-c-propyl and the like may be mentioned.
A C3-12 cycloalkyl group is a cycloalkyl group containing 3 to 12 carbon atoms and may have a fused polycyclic structure, a bridged cyclic structure or a spirocyclic structure. As specific examples, c-propyl, c-butyl, 1-methyl-c-propyl, 2-methyl-c-propyl, c-pentyl, 1-methyl-c-butyl, 2-methyl-c-butyl, 3-methyl-c-butyl, 1,2-dimethyl-c-propyl, 2,3-dimethyl-c-propyl, 1-ethyl-c-propyl, 2-ethyl-c-propyl, c-hexyl, 1-methyl-c-pentyl, 2-methyl-c-pentyl, 3-methyl-c-pentyl, 1-ethyl-c-butyl, 2-ethyl-c-butyl, 3 -ethyl-c-butyl, 1,2-dimethyl-c-butyl, 1,3-dimethyl-c-butyl, 2,2-dimethyl-c-butyl, 2,3-dimethyl-c-butyl, 2,4-dimethyl-c-butyl, 3,3 -dimethyl-c-butyl, 1-n-propyl-c-propyl, 2-n-propyl-c-propyl, 1-i-propyl-c-propyl, 2-i-propyl-c-propyl, 1,2,2-trimethyl-c-propyl, 1,2,3-trimethyl-c-propyl, 2,2,3-trimethyl-c-propyl, 1-ethyl-2-methyl-c-propyl, 2 -ethyl-1-methyl-c-propyl, 2-ethyl-2-methyl-c-propyl, 2-ethyl-3-methyl-c-propyl, c-heptyl, c-octyl, c-nonyl, c-decyl, c-undecyl, c-dodecyl, the structures shown below and the like may be mentioned.
(Formula Removed)
A C7-12 cycloalkyl group is a cycloalkyl group containing seven to twelve carbon atoms and may have a fused polycyclic structure, a bridged cyclic structure or a spirocyclic structure. As specific examples, the structures shown below and the like may be mentioned.
(Formula Removed)
A C8-12 cycloalkyl group is a cycloalkyl group containing eight to twelve carbon atoms and may have a fused polycyclic structure, a bridged cyclic structure or a spirocyclic structure. As specific examples, the structures shown below and the like may be mentioned.
(Formula Removed)
A C1-20 alkyl group is an alkyl group containing one to twenty carbon atoms and may be linear, branched or a C3-20 cycloalkyl group. Herein, a C3-20 cycloalkyl group is a cycloalkyl group containing three to twenty carbon atoms and may have a fused polycyclic structure, a bridged cyclic structure or a spirocyclic structure. As specific examples of C1-20 alkyl groups, in addition to those mentioned above, 1-methyl-1-ethyl-n-pentyl, 1-heptyl, 2-heptyl, 1-ethyl-l,2-dimethyl-n-propyl, 1-ethyl-2,2-dimethyl-n-propyl, 1-octyl, 3-octyl, 4-methyl-3-n-heptyl, 6-methyl-2-n-heptyl, 2-propyl-1-n-heptyl, 2,4,4,-trimethyl-1-n-pentyl, 1-nonyl, 2-nonyl, 2,6-dimethyl-4-n-heptyl, 3-ethyl-2,2-dimethyl-3-n-pentyl, 3,5,5-trimethyl-1-n-hexyl, 1-decyl, 2-decyl, 4-decyl, 3,7-dimethyl-1-n-
octyl, 3,7-dimethyl-3-n-octyl, n-nonyl, n-undecyl, n-
dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-
hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-
icosanyl, c-heptyl, c-octyl, c-nonyl, c-decyl, c-undecyl,
c-dodecyl, c-tridecyl, c-tetradecyl, c-pentadecyl, c-
hexadecyl, c-heptadecyl, c-octadecyl, c-nonadecyl, c-
icosanyl, the structures shown below and the like may be
mentioned.
(Formula Removed)
A C2-6 alkenyl group means a group obtained by converting arbitrary one, two or three bonds in the above-mentioned C1-6 alkyl group (other than a methyl group) to double bonds, and may be linear, branched or a C3-6 cycloalkenyl group. As specific examples, ethenyl, 1-propenyl, 2-propenyl, 1-methyl-1-ethenyl, 1-butenyl, 2-
butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-
propenyl, 1-ethylethenyl, 1-methyl-1-propenyl, 1-methyl-
2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4 -
pentenyl, 1-n-propylethenyl, 1-methyl-1-butenyl, 1-
methyl-2-butenyl, 1-methyl-3-butenyl, 2-ethyl-2-propenyl,
2-methyl-1-butenyl, 2-methyl-2-butenyl, 2-methyl-3-
butenyl, 3-methyl-1-butenyl, 3-methyl-2-butenyl, 3-
methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1-i-
propylethenyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-
propenyl, 1-c-pentenyl, 2 -c-pentenyl, 3 -c-pentenyl, 1-
hexeny1, 2 -hexeny1, 3 -hexeny1, 4 -hexeny1, 5-hexeny1, 1-
methyl-1-pentenyl, 1-methyl-2-pentenyl, l-methyl-3-
pentenyl, 1-methyl-4-pentenyl, 1-n-butylethenyl, 2-
methyl-1-pentenyl, 2-methyl-2-pentenyl, 2-methyl-3-
pentenyl, 2-methyl-4-pentenyl, 2-n-propyl-2-propenyl, 3-
methyl-1-pentenyl, 3-methyl-2-pentenyl, 3-methyl-3-
pentenyl, 3-methyl-4-pentenyl, 3 -ethyl- 3-butenyl, 4 -
methyl-1-pentenyl, 4-methyl-2-pentenyl, 4-methyl-3-
pentenyl, 4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl,
1,1-dimethyl-3-butenyl, 1,2-dimethyl-1-butenyl, 1,2-
dimethyl-2-butenyl, 1,2-dimethyl- 3-butenyl, 1-methyl-2 -
ethyl-2-propenyl, 1-s-butylethenyl, 1,3-dimethyl-1-
butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,
1-i-butylethenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-
butenyl, 2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl,
2-i-propyl-2-propenyl, 3,3 -dimethyl-1-butenyl, 1-ethyl-1-
butenyl, 1-ethyl-2-butenyl, 1-ethyl- 3-butenyl, 1-n-
propyl-1-propenyl, l-n-propyl-2-propenyl, 2-ethyl-1-
butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-2-propenyl, 1-t-butylethenyl, 1-methyl-1-ethyl-2-propenyl, 1-ethyl-2-methyl-1-propenyl, l-ethyl-2-methyl-2-propenyl, 1-i-propyl-1-propenyl, l-i-propyl-2-propenyl, l-methyl-2-c-pentenyl, l-methyl-3-c-pentenyl, 2-methyl-1-c-pentenyl, 2-methyl-2-c-pentenyl, 2-methyl-3-c-pentenyl, 2-methyl-4-c-pentenyl, 2-methyl-5-c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentenyl, 3-methyl-2-c-pentenyl, 3-methyl-3-c-pentenyl, 3-methyl-4-c-pentenyl, 3-methyl-5-c-pentenyl, 3-methylene-c-pentyl, 1-c-hexenyl, 2-c-hexenyl, 3-c-hexenyl and the like may be mentioned.
A C2-20 alkenyl group means a group obtained by converting arbitrary one, two or three bonds in the above-mentioned C1-20 alkyl group (other than a methyl group) to double bonds, and may be linear, branched or a C3-20 cycloalkenyl group. Herein, a C3-20 cycloalkenyl group means a group obtained by converting arbitrary one, two or three bonds in the above-mentioned C3-20 cycloalkyl group to double bonds and may have a fused polycyclic structure, a bridged cyclic structure or a spirocyclic structure. As specific examples of C2-20 alkenyl groups, in addition to those mentioned above, 1-methyl-n-hexenyl, 1,2-dimethyl-n-hexenyl, 1-ethyl-n-hexenyl, 1-n-heptenyl, 2-n-heptenyl, 3-n-heptenyl, 4-n-heptenyl, 1-n-octenyl, 2-n-octenyl, 3-n-octenyl, 1-methyl-c-hexenyl, 1,2-dimethyl-c-hexeny1, 1-ethy1-c-hexeny1, 1-c-hep teny1, 2 -c-hep teny1,
3 -c-hepteny1, 4 -c-heptenyl, 1-c-oc tenyl, 2 -c-oc tenyl, 3 -
c-octenyl, 4-c-octenyl, 1-decenyl, 2-decenyl, 4-decenyl,
3,7-dimethyl-1-n-octenyl, 3,7-dimethyl-3-n-octenyl, 2-n-
nonenyl, 3-n-undecenyl, 1-n-dodecenyl, 3-n-tridecenyl, 2-
n-tetradecenyl, 4,6-n-pentadecadienyl, 2-n-nonadecenyl,
4-n-icosenyl, 2-c-nonenyl, 4-c-decenyl, 2-c-undecenyl, 5-
c-dodecenyl, 3-c-tridecenyl, 6-c-tetradecenyl, 1-c-
pentadecenyl, 5-c-hexadecenyl, 4 -c-heptadecenyl, 1-c-
octadecenyl, 3-c-nonadecenyl, 2-c-icosenyl, the
structures shown below and the like may be mentioned.
(Formula Removed)
A C3-12 cycloalkenyl group means a group obtained by converting arbitrary one, two or three bonds in the above-mentioned C3-12 cycloalkyl group to double bonds and
may have a fused polycyclic structure, a bridged cyclic
structure or a spirocyclic structure. As specific examples, 1-c-pentenyl, 2-c-pentenyl, 3-c-pentenyl, 1-methyl-2 -c-pentenyl, 1-methyl- 3 -c-pentenyl, 2-methyl-1-c-pentenyl , 2-methyl-2 -c-pentenyl, 2-methyl- 3 -c-pentenyl, 2-methyl-4-c-pentenyl, 2-methyl-5-c-pentenyl, 2-methylene-c-pentyl, 3-methyl-1-c-pentenyl, 3-methyl-2-c-pentenyl, 3-methyl- 3 -c-pentenyl, 3-methyl-4 -c-pentenyl, 3-methyl-5-c-pentenyl, 3-methylene-c-pentyl, 1-c-hexenyl, 2-c-hexenyl, 3-c-hexenyl, 1-methyl-c-hexenyl, 1,2-dimethyl-c-hexenyl, 1-ethyl-c-hexenyl, 1-c-heptenyl, 2 -c-heptenyl, 3 -c-heptenyl, 4 -c-heptenyl, 1-c-oc tenyl, 2 -c-octenyl, 3-c-octenyl, 4-c-octenyl, 1-c-decenyl, 2-c-decenyl, 4-c-decenyl, 3,7-dimethyl-1-c-octenyl, 3,7-dime thy1- 3 -c-oc tenyl, 2 -c-noneny1, 3 -c-undec eny1, 1-c-dodecenyl, 3-c-tridecenyl, 2-c-tetradecenyl, 4,6-c-pentadecadienyl, 2 -c-hexadecenyl, 5-c-heptadecenyl, 1-c-oc tadecenyl, 2 -c-nonadecenyl, 2 -c-undecenyl, 5-c-dodecenyl, the structures shown below and the like may be mentioned.
(Formula Removed)
A C7-12 cycloalkenyl group means a group obtained by converting arbitrary one, two or three bonds in the above-mentioned C7-12 cycloalkyl group to double bonds and may have a fused polycyclic structure, a bridged cyclic structure or a spirocyclic structure. As specific examples, the structures shown below and the like may be mentioned.
(Formula Removed)
A C2-6 alkynyl group means an alkynyl group containing two to six carbon atoms and may be linear, branched or a C6 cycloalkynyl group. As specific examples, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl, 1-methyl- 3-butynyl, 2-methyl- 3-butynyl, 3-methyl-1-butynyl, 1,1-dimethyl-2-propynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, l-methyl-3-pentynyl, 1-methyl-4-pentynyl, 2-methyl-3-pentynyl, 2-methyl-4-pentynyl, 3-methyl-1-pentynyl, 3-methyl-4-pentynyl, 4-methyl-1-pentynyl, 4-methyl-2-pentynyl, 1,1-dimethyl-2-butynyl, 1,1-dimethyl-3-butynyl, 1,2-dimethyl-
3-butynyl, 2,2-dimethyl-3-butynyl, 3,3-dimethyl-1-
butynyl, 1-ethyl-2-butynyl, 1-ethyl- 3-butynyl, 1-n-propyl-2-propynyl, 2-ethyl-3-butynyl, l-methyl-1-ethyl-2-propynyl, l-c-propyl-2-propynyl, l-i-propyl-2-propynyl and the like may be mentioned.
A C1-3 haloalkyl group is a C1-3 alkyl group such as those mentioned above which is substituted with one or more halogen atoms such as fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms. As specific examples, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a chlorofluoromethyl group, a chlorodifluoromethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, a bromomethyl group, a dibromomethyl group, a tribromomethyl group, a iodomethyl group, a diiodomethyl group, a triiodomethyl group, a fluoroethyl group, a difluoroethyl group, a trifluoroethyl group, a tetrafluoroethyl group, a pentafluoroethyl group, a chloroethyl group, a dichloroethyl group, a trichloroethyl group, a tetrachloroethyl group, a pentachloroethyl group, a bromoethyl group, a dibromoethyl group, a tribromoethyl group, a tetrabromoethyl group, a pentabromoethyl group, a perfluoro-n-propyl group, a 2,2-difluoro-n-propyl group, a 2,2,3,3,3-pentafluoro-n-propyl group, a perfluoro-i-propyl group, a 2-fluoro-i-propyl group, a 2,2,2,2,2,2-hexafluoro-i-propyl group, a 2,2-difluoro-c-propyl group,
2,2,3,3-tetrafluoro-c-propyl group and the like may be
mentioned.
A C1-6 alkoxy group may be linear, branched or a C3-6
cycloalkoxy group. As specific examples, methoxy,
ethoxy, n-propoxy, i-propoxy, c-propoxy, n-butoxy, i-
butoxy, s-butoxy, t-butoxy, c-butoxy, 1-methyl-c-propoxy,
2-methyl-c-propoxy, n-pentyloxy, 1-methyl-n-butoxy, 2-
methyl-n-butoxy, 3-methyl-n-butoxy, 1,1-dimethyl-n-
propoxy, 1,2-dimethyl-n-propoxy, 2,2-dimethyl-n-propoxy,
1-ethyl-n-propoxy, c-pentyloxy, 1-methyl-c-butoxy, 2-
methyl-c-butoxy, 3-methyl-c-butoxy, 1,2-dimethyl-c-
propoxy, 2,3-dimethyl-c-propoxy, 1-ethyl-c-propoxy, 2-
ethyl-c-propoxy, n-hexyloxy, 1-methyl-n-pentyloxy, 2-
methyl-n-pentyloxy, 3-methyl-n-pentyloxy, 4-methyl-n-
pentyloxy, 1,1-dimethyl-n-butoxy, 1,2-dimethyl-n-butoxy,
1,3-dimethyl-n-butoxy, 2,2-dimethyl-n-butoxy, 2,3-
dimethyl-n-butoxy, 3,3-dimethyl-n-butoxy, 1-ethyl-n-
butoxy, 2-ethyl-n-butoxy, 1,1,2-trimethyl-n-propoxy,
1,2,2-trimethyl-n-propoxy, 1-ethyl-1-methyl-n-propoxy, 1-
ethyl-2-methyl-n-propoxy, c-hexyloxy, 1-methyl-c-
pentyloxy, 2-methyl-c-pentyloxy, 3-methyl-c-pentyloxy, 1-
ethyl-c-butoxy, 2-ethyl-c-butoxy, 3-ethyl-c-butoxy, 1,2-
dimethyl-c-butoxy, 1,3-dimethyl-c-butoxy, 2,2-dimethyl-c-
butoxy, 2,3-dimethyl-c-butoxy, 2,4-dimethyl-c-butoxy,
3,3-dimethyl-c-butoxy, 1-n-propyl-c-propoxy, 2-n-propyl-
c-propoxy, 1-i-propyl-c-propoxy, 2-i-propyl-c-propoxy,
1,2,2-trimethyl-c-propoxy, 1,2,3-trimethyl-c-propoxy,
2,2,3-trimethyl-c-propoxy, l-ethyl-2-methyl-c-propoxy, 2-
ethyl-1-methyl-c-propoxy, 2-ethyl-2-methyl-c-propoxy, 2-
ethyl-3-methyl-c-propoxy and the like may be mentioned.
A C1-3 alkoxy group is an alkoxy group containing one to three carbon atoms and may be linear, branched or a C3 cycloalkoxy group. As specific examples, methoxy, ethoxy, n-propoxy, i-propoxy, c-propoxy and the like may be mentioned.
A C1-3 haloalkoxy group is a C1-3 alkoxy group such as those mentioned above in which the alkoxy group is substituted with one or more halogen atoms such as fluorine atoms, chlorine atoms, bromine atoms and/or iodine atoms. As specific examples, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a chlorofluoromethoxy group, a chlorodifluoromethoxy group, a chloromethoxy group, a dichloromethoxy group, a trichloromethoxy group, a bromomethoxy group, a dibromomethoxy group, a tribromomethoxy group, a iodomethoxy group, a diiodomethoxy group, a triiodomethoxy group, a fluoroethoxy group, a difluoroethoxy group, a trifluoroethoxy group, a tetrafluoroethoxy group, a pentafluoroethoxy group, a chloroethoxy group, a dichloroethoxy group, a trichloroethoxy group, a tetrachloroethoxy group, a pentachloroethoxy group, a bromoethoxy group, a dibromoethoxy group, a tribromoethoxy group, a tetrabromoethoxy group, a pentabromoethoxy group, a
perfluoro-n-propoxy group, a 2,2-difluoro-n-propoxy
group, a 2,2,3,3,3-pentafluoro-n-propoxy group, a
perfluoro-i-propoxy group, a 2-fluoro-i-propoxy group, a
2,2,2,2,2,2-hexafluoro-i-propoxy group, a 2,2-difluoro-c-
propoxy group, 2,2,3,3-tetrafluoro-c-propoxy group and
the like may be mentioned.
A C1-3 alkylene group is a linear, branched or cyclic alkylene group having one to three carbon atoms and may be, for example, a methylene group, an ethylene group, a propylene group, an isopropylene group or a c-propylene group.
A C1-6 alkylene group is a linear, branched or cyclic alkylene group having one to six carbon atoms and may be, for example, a methylene group, an ethylene group, a propylene group, an isopropylene group, a c-propylene group, an ethylpropylene group, a butylenes group, an isobutylene group, a c-butylene group, an ethylbutylene group, a pentylene group, a c-pentylene group, a hexylene group or a c-hexylene group.
A C2-14 aryl group means a C6-14 aryl group containing no hetero atoms as ring constituting atoms or a C2-9 aromatic heterocyclic group.
A C6-14 aryl group containing no hetero atoms is an aryl group containing six to fourteen carbon atoms, and as specific examples, a phenyl group, a 1-indenyl group, a 2 -indenyl group, a 3 -indenyl group, a 4 -indenyl group, a 5-indenyl group, a 6 -indenyl group, a 7-indenyl group,
an α - naphthyl group, a ß - naphthyl group, a 1 -
tetrahydronaphthyl group, a 2 -tetrahydronaphthyl group, a
5-tetrahydronaphthyl group, a 6 -tetrahydronaphthyl group,
an o-biphenylyl group, a m-biphenylyl group, a p-
biphenylyl group, a 1-anthryl group, a 2 -anthryl group, a
9-anthryl group, a 1-phenanthryl group, a 2-phenanthryl
group, a 3-phenanthryl group, a 4-phenanthryl group, a 9-
phenanthryl group and the like may be mentioned.
A C2-9 aromatic heterocyclic group means a 5 to 7-membered C2-6 heteromonocyclic group or a 8 to 10-membered C5-9 fused heterobicyclic group containing from 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms singly or in combination, and, if contains one or more nitrogen atoms, may be in the form of an N-oxide.
As specific examples of 5 to 7-membered C2-6 heteromonocyclic groups, 2-thienyl group, a 3-thienyl group, a 2 -furyl group, a 3 -furyl group, a 2-pyranyl group, a 3-pyranyl group, a 4-pyranyl group, a 1-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, a 1-imidazolyl group, a 2 -imidazolyl group, a 4 -imidazolyl group, a 1-pyrazolyl group, a 3-pyrazolyl group, a 4 -pyrazolyl group, a 2 -thiazolyl group, a 4 -thiazolyl group, a 5-thiazolyl group, a 3 -isothiazolyl group, a 4 -isothiazolyl group, a 5-isothiazolyl group, a 2-oxazolyl group, a 4 -oxazolyl group, a 5-oxazolyl group, a 3 -isoxazolyl group, a 4-isoxazolyl group, a 5-isoxazolyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl
group, a 2-pyrazinyl group, a 2-pyrimidinyl group, a 4-
pyrimidinyl group, a 5-pyrimidinyl group, a 3-pyridazinyl
group, a 4-pyridazinyl group, a 2-1,3,4-oxadiazolyl
group, a 2-1,3,4-thiadiazolyl group, a 3-1,2,4-
oxadiazolyl group, a 5-1,2,4-oxadiazolyl group, a 3-
1,2,4-thiadiazolyl group, a 5-1,2,4-thiadiazolyl group, a
3-1,2,5-oxadiazolyl group, a 3-1,2,5-thiadiazolyl group,
3-4H-1,2,4-triazolyl group, 3-1H-1,2,4-triazolyl group,
5-1H-1,2,4-triazolyl group, 4-2H-1,2,3-triazolyl group,
5-2H-1,2,3-triazolyl group, 4-1H-1,2,3-triazolyl group
and 5-1H-1,2,3-triazolyl group and the like may be
mentioned.
A 8 to 10-membered C5-9 fused heterobicyclic group
may be a 2-benzofuranyl group, a 3-benzofuranyl group, a
4-benzofuranyl group, a 5-benzofuranyl group, a 6 -
benzofuranyl group, a 7-benzofuranyl group, a 1-
isobenzofuranyl group, a 4 -isobenzofuranyl group, a 5-
isobenzofuranyl group, a 2-benzothienyl group, a 3-
benzothienyl group, a 4-benzothienyl group, a 5-
benzothienyl group, a 6-benzothienyl group, a 7 -
benzothienyl group, a 1-isobenzothienyl group, a 4 -
isobenzothienyl group, a 5-isobenzothienyl group, a 2-
chromenyl group, a 3 -chromenyl group, a 4 -chromenyl
group, a 5-chromenyl group, a 6 -chromenyl group, a 7-
chromenyl group, a 8-chromenyl group, a 1-indoli z inyl
group, a 2 -indolizinyl group, a 3 -indolizinyl group, a 5-
indolizinyl group, a 6-indolizinyl group, a 7-indolizinyl
group, a 8-indolizinyl group, a 1-isoindolyl group, a 2-isoindolyl group, a 4-isoindolyl group, a 5-isoindolyl group, a 1-indolyl group, a 2-indolyl group, a 3-indolyl group, a 4-indolyl group, a 5-indolyl group, a 6-indolyl group, a 7-indolyl group, a 1-indazolyl group, a 2-indazolyl group, a 3-indazolyl group, a 4-indazolyl group, a 5-indazolyl group, a 6-indazolyl group, a 7-indazolyl group, a 2-(7-aza)indazolyl group, a 3-(7-aza)indazolyl group, a 4-(7-aza)indazolyl group, a 5-(7-aza)indazolyl group, a 6-(7-aza)indazolyl group, a 2-(4-aza)indazolyl group, a 3-(4-aza)indazolyl group, a 5-(4-aza)indazolyl group, a 6-(4-aza)indazolyl group, a 7-(4-aza)indazolyl group, a 1-purinyl group, a 2-purinyl group, a 3-purinyl group, a 6-purinyl group, a 7-purinyl group, a 8-purinyl group, a 2-quinolyl group, a 3-quinolyl group, a 4-quinolyl group, a 5-quinolyl group, a 6-quinolyl group, a 7-quinolyl group, a 8-quinolyl group, a 1-isoquinolyl group, a 3-isoquinolyl group, a 4-isoquinolyl group, a 5-isoquinolyl group, a 6-isoquinolyl group, a 7-isoquinolyl group, a 8-isoquinolyl group, a 1-phthalazinyl group, a 5-phthalazinyl group, a 6-phthalazinyl group, a 1-2,7-naphthyridinyl group, a 3-2,7-naphthyridinyl group, a 4-2,7-naphthyridinyl group, a 1-2,6-naphthyridinyl group, a 3-2,6-naphthyridinyl group, a 4-2,6-naphthyridinyl group, a 2-1,8-naphthyridinyl group, a 3-1,8-naphthyridinyl group, a 4-1,8-naphthyridinyl group, a 2-1,7-naphthyridinyl group, a 3-
1,7-naphthyridinyl group, a 4-1,7-naphthyridinyl group, a 5-1,7-naphthyridinyl group, a 6-1,7-naphthyridinyl group, a 8-1,7-naphthyridinyl group, 2-1,6-naphthyridinyl group, a 3-1,6-naphthyridinyl group, a 4-1,6-naphthyridinyl group, a 5-1,6-naphthyridinyl group, a 7-1,6-naphthyridinyl group, a 8-1,6-naphthyridinyl group, a 2-1,5-naphthyridinyl group, a 3-1,5-naphthyridinyl group, a 4-1,5-naphthyridinyl group, a 6-1,5-naphthyridinyl group, a 7-1,5-naphthyridinyl group, a 8-1,5-naphthyridinyl group, a 2-quinoxalinyl group, a 5-quinoxalinyl group, a 6 -quinoxalinyl group, a 2 -quinazolinyl group, a 4 -quinazolinyl group, a 5-quinazolinyl group, a 6-quinazolinyl group, a 7-quinazolinyl group, a 8-quinazolinyl group, a 3-cinnolinyl group, a 4-cinnolinyl group, a 5-cinnolinyl group, a 6-cinnolinyl group, a 7-cinnolinyl group, a 8-cinnolinyl group, a 2-pteridinyl group, a 4-pteridinyl group, a 6-pteridinyl group, a 7-pteridinyl group or the like.
A C2-9 heteroaryl group means a 5 to 7-membered C2-6 heteromonocyclic group or a 8 to 10-membered C5-9 fused heterobicyclic group containing from 1 to 3 oxygen atoms, nitrogen atoms or sulfur atoms singly or in combination, and, if contains one or more nitrogen atoms, may be in the form of an N-oxide.
As specific examples of 5 to 7-membered C2-6 heteromonocyclic groups, 2-thienyl group, a 3-thienyl group, a 2-fury1 group, a 3-fury1 group, a 2-pyranyl
group, a 3-pyranyl group, a 4-pyranyl group, a 1-pyrrolyl
group, a 2-pyrrolyl group, a 3-pyrrolyl group, a 1-imidazolyl group, a 2 -imidazolyl group, a 4 -imidazolyl group, a 1-pyrazolyl group, a 3-pyrazolyl group, a 4 -pyrazolyl group, a 2 -thiazolyl group, a 4 -thiazolyl group, a 5-thiazolyl group, a 3 -isothiazolyl group, a 4 -isothiazolyl group, a 5-isothiazolyl group, a 2-oxazolyl group, a 4 -oxazolyl group, a 5-oxazolyl group, a 3 -isoxazolyl group, a 4-isoxazolyl group, a 5-isoxazolyl group, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl group, a 2-pyrazinyl group, a 2-pyrimidinyl group, a 4-pyrimidinyl group, a 5-pyrimidinyl group, a 3-pyridazinyl group, a 4-pyridazinyl group, a 2-1,3,4-oxadiazolyl group, a 2-1,3,4-thiadiazolyl group, a 3-1,2,4-oxadiazolyl group, a 5-1,2,4-oxadiazolyl group, a 3-1,2,4-thiadiazolyl group, a 5-1,2,4-thiadiazolyl group, a 3-1,2,5-oxadiazolyl group, a 3-1,2,5-thiadiazolyl group and the like may be mentioned.
As specific examples of 8 to 10-membered C5-9 fused heterobicyclie groups, a 2-benzofuranyl group, a 3-benzofuranyl group, a 4-benzofuranyl group, a 5-benzofuranyl group, a 6-benzofuranyl group, a 7 -benzofuranyl group, a 1-isobenzofuranyl group, a 4 -isobenzofuranyl group, a 5-isobenzofuranyl group, a 2-benzothienyl group, a 3-benzothienyl group, a 4 -benzothienyl group, a 5-benzothienyl group, a 6 -benzothienyl group, a 7-benzothienyl group, a 1-
isobenzothienyl group, a 4-isobenzothienyl group, a 5-
isobenzothienyl group, a 2 -chromenyl group, a 3 -chromenyl
group, a 4 -chromenyl group, a 5-chromenyl group, a 6 -
chromenyl group, a 7-chromenyl group, a 8-chromenyl
group, a 1-indoli zinyl group, a 2 -indolizinyl group, a 3 -
indolizinyl group, a 5-indolizinyl group, a 6-indolizinyl
group, a 7-indoli z inyl group, a 8-indolizinyl group, a 1-
isoindolyl group, a 2-isoindolyl group, a 4-isoindolyl
group, a 5-isoindolyl group, a 1-indolyl group, a 2 -
indolyl group, a 3 -indolyl group, a 4 -indolyl group, a 5-
indolyl group, a 6 -indolyl group, a 7-indolyl group, a 3 -
(7-aza)indazolyl group, a 4-(7-aza)indazolyl group, a 5-
(7-aza)indazolyl group, a 6-(7-aza)indazolyl group, a 2-
(4-aza)indazolyl group, a 3-(4-aza)indazolyl group, a 5-
(4-aza)indazolyl group, a 6-(4-aza)indazolyl group, a 7-
(4-aza)indazolyl group, a 1-indazolyl group, a 2-
indazolyl group, a 3 -indazolyl group, a 4 -indazolyl
group, a 5-indazolyl group, a 6 -indazolyl group, a 7-
indazolyl group, a 1-purinyl group, a 2-purinyl group, a
3-purinyl group, a 6-purinyl group, a 7-purinyl group, a
8-purinyl group, a 2-quinolyl group, a 3-quinolyl group,
a 4 -quinolyl group, a 5-quinolyl group, a 6 -quinolyl
group, a 7-quinolyl group, a 8-quinolyl group, a 1-
isoquinolyl group, a 3-isoquinolyl group, a 4-isoquinolyl
group, a 5-isoquinolyl group, a 6-isoquinolyl group, a 7-
isoquinolyl group, a 8-isoquinolyl group, a 1-
phthalazinyl group, a 5-phthalazinyl group, a 6-
phthalazinyl group, a 1-2,7-naphthyridinyl group, a 3-2,7-naphthyridinyl group, a 4-2,7-naphthyridinyl group, a 1-2,6-naphthyridinyl group, a 3-2,6-naphthyridinyl group, a 4-2,6-naphthyridinyl group, a 2-1,8-naphthyridinyl group, a 3-1,8-naphthyridinyl group, a 4-1,8-naphthyridinyl group, a 2-1,7-naphthyridinyl group, a 3-1,7-naphthyridinyl group, a 4-1,7-naphthyridinyl group, a 5-1,7-naphthyridinyl group, a 6-1,7-naphthyridinyl group, a 8-1,7-naphthyridinyl group, 2-1,6-naphthyridinyl group, a 3-1,6-naphthyridinyl group, a 4-1,6-naphthyridinyl group, a 5-1,6-naphthyridinyl group, a 7-1,6-naphthyridinyl group, a 8-1,6-naphthyridinyl group, a 2-1,5-naphthyridinyl group, a 3-1,5-naphthyridinyl group, a 4-1,5-naphthyridinyl group, a 6-1,5-naphthyridinyl group, a 7-1,5-naphthyridinyl group, a 8-1,5-naphthyridinyl group, a 2-quinoxalinyl group, a 5-quinoxalinyl group, a 6 -quinoxalinyl group, a 2 -quinazolinyl group, a 4 -quinazolinyl group, a 5-quinazolinyl group, a 6-quinazolinyl group, a 7-quinazolinyl group, a 8-quinazolinyl group, a 3-cinnolinyl group, a 4-cinnolinyl group, a 5-cinnolinyl group, a 6-cinnolinyl group, a 7-cinnolinyl group, a 8-cinnolinyl group, a 2-pteridinyl group, a 4-pteridinyl group, a 6-pteridinyl group, a 7-pteridinyl group and the like may be mentioned.
A C2-14 arylene group is a bivalent group obtained by removing one hydrogen atom from a ring-constituting atom in the above-mentioned C2-14 aryl group and may, for
example, be a phenylene group, an indenylene group, a
naphthylene group, a tetrahydronaphthylene group, a biphenylene group, a thienylene group, a furylene group, a pyranylene group, a pyrrolylene group, an imdazolylene group, a pyrazolylene group, a thiazolylene group, an isothiazolylene group, an oxazolylene group, a pyridylene group, a pyrazinylene group, a pyrimidinylene group, a pyridazinylene group, an oxadiazolylene group, a thiadiazolylene group, a triazolylene group, a benzofuranylene group, an isobenzofuranylene group, a benzothienylene group, an isobenzothienylene group, a chromenylene group, an indolizinylene group, an isoindolylene group, an indolylene group, an indazolylene group, a purinylene group, a quinolylene group, an isoquinolylene group, a phthalazinylene group, a naphthyridinylene group, a quinoxalinylene group, a quinazolinylene group, a cinnolinylene group, a pteridinylene group or the like.
A C2-19 heterocyclyl group means a group derived from the above-mentioned C3-20 cycloalkyl group or the above-mentioned C3-20 cycloalkenyl groups by replacing one or more arbitrary carbon atoms with atoms arbitrarily selected from nitrogen atoms, oxygen atoms and sulfur atoms, and carbon atoms constituting the ring may be carbonyl or thiocarbonyl. As specific examples,
(Formula Removed)
may be mentioned.
A C2-n heterocyclyl group means a group derived from the above-mentioned C3-12 cycloalkyl group or the above-mentioned C3-12 cycloalkenyl group by replacing one or
more arbitrary carbon atoms with atoms arbitrarily
selected from nitrogen atoms, oxygen atoms and sulfur
atoms, and carbon atoms constituting the ring may be
carbonyl or thiocarbonyl. As specific examples,
(Formula Removed)
may be mentioned.
A C2-9 heterocyclyl group is a heteromonocyclic or heterobicyclic group consisting of at least one atom arbitrarily selected from nitrogen atoms, oxygen atoms and sulfur atoms and two to nine carbon atoms, and carbon atoms constituting the ring may be carbonyl or thiocarbonyl. As specific examples,
(Formula Removed)
may be mentioned.
A C2-9 heterocyclylene group is a bivalent group obtained by removing one hydrogen atom from a ring-constituting atom in the above-mentioned C2-9 heterocyclyl group and, for example,
(Formula Removed)
may be mentioned.
A nitrogen-containing heterocyclyl group is a heteromonocyclic or heterobicyclic group containing at least one nitrogen atom and two to nine carbon atoms which may further contain at least one atoms arbitrary selected from oxygen atoms and sulfur atoms, and carbon atoms constituting the ring may be carbonyl or thiocarbonyl. As specific examples,
(Formula Removed)
may be mentioned.
A fused C2-14 aryl group is a fused bicyclic or tricyclic group consisting of the above-mentioned C2-14 aryl group fused with the above-mentioned C2-9 heterocyclyl group or the above-mentioned C3-6 cycloalkyl group, and as specific examples,
(Formula Removed)
may be mentioned.
A C2-14 aryloxy group may be a C6-14 aryloxy group
containing no hetero atoms as ring constituting atoms or
a C2-9 aromatic heterocyclyloxy group, and a C2-9 aromatic
heterocyclyloxy group may be a 5 to 7-membered C2-6
heteromonocyclyloxy group or a 8 to 10-membered C5-9 fused
heterobicyclyloxy group containing from 1 to 3 oxygen
atoms, nitrogen atoms or sulfur atoms singly or in
combination.
As a C6-14 aryloxy group containing no hetero atoms, a phenyloxy group, a 1-indenyloxy group, a 2-indenyloxy group, a 3-indenyloxy group, a 4-indenyloxy group, a 5-indenyloxy group, a 6-indenyloxy group, a 7-indenyloxy group, an a-naphthyloxy group, a |3-naphthyloxy group, a 1-tetrahydronaphthyloxy group, a 2 -tetrahydronaphthyloxy group, a 5-tetrahydronaphthyloxy group, a 6 -tetrahydronaphthyloxy group, an o-biphenylyloxy group, a m-biphenylyloxy group, a p-biphenylyloxy group, a 1-anthryloxy group, a 2-anthryloxy group, a 9-anthryloxy group, a 1-phenanthryloxy group, a 2-phenanthryloxy group, a 3-phenanthryloxy group, a 4-phenanthryloxy group, a 9-phenanthryloxy group or the like may be mentioned.
A 5 to 7-membered C2-6 heteromonocyclyloxy group may be a 2-thienyloxy group, a 3-thienyloxy group, a 2-furyloxy group, a 3-furyloxy group, a 2-pyranyloxy group, a 3-pyranyloxy group, a 4-pyranyloxy group, a 1-pyrrolyloxy group, a 2-pyrrolyloxy group, a 3-pyrrolyloxy
group, a 1-imidazolyloxy group, a 2-imidazolyloxy group,
a 4-imidazolyloxy group, a 1-pyrazolyloxy group, a 3-pyrazolyloxy group, a 4-pyrazolyloxy group, a 2-thiazolyloxy group, a 4-thiazolyloxy group, a 5-thiazolyloxy group, a 3-isothiazolyloxy group, a 4-isothiazolyloxy group, a 5-isothiazolyloxy group, a 2-oxazolyloxy group, a 4-oxazolyloxy group, a 5-oxazolyloxy group, a 3-isoxazolyloxy group, a 4-isoxazolyloxy group, a 5-isoxazolyloxy group, a 2-pyridyloxy group, a 3-pyridyloxy group, a 4-pyridyloxy group, a 2-pyrazinyloxy group, a 2-pyrimidinyloxy group, a 4-pyrimidinyloxy group, a 5-pyrimidinyloxy group, a 3-pyridazinyloxy group, a 4-pyridazinyloxy group, a 2-1,3,4-oxadiazolyloxy group, a 2-1,3,4-thiadiazolyloxy group, a 3-1,2,4-oxadiazolyloxy group, a 5-1,2,4-oxadiazolyloxy group, a 3-1,2,4-thiadiazolyloxy group, a 5-1,2,4-thiadiazolyloxy group, a 3-1,2,5-oxadiazolyloxy group, a 3-1,2,5-thiadiazolyloxy group or the like.
A 8 to 10-membered C5-9 fused heterobicyclyloxy group may be a 2-benzofuranyloxy group, a 3-benzofuranyloxy group, a 4-benzofuranyloxy group, a 5-benzofuranyloxy group, a 6-benzofuranyloxy group, a 7-benzofuranyloxy group, a 1-isobenzofuranyloxy group, a 4-
isobenzofuranyloxy group, a 5-isobenzofuranyloxy group, a 2-benzothienyloxy group, a 3-benzothienyloxy group, a 4-benzothienyloxy group, a 5-benzothienyloxy group, a 6-benzothienyloxy group, a 7-benzothienyloxy group, a 1-
isobenzothienyloxy group, a 4-isobenzothienyloxy group, a
5-isobenzothienyloxy group, a 2-chromenyloxy group, a 3-chromenyloxy group, a 4-chromenyloxy group, a 5-chromenyloxy group, a 6-chromenyloxy group, a 7-chromenyloxy group, a 8-chromenyloxy group, a 1-indolizinyloxy group, a 2-indolizinyloxy group, a 3-indolizinyloxy group, a 5-indolizinyloxy group, a 6-indolizinyloxy group, a 7-indolizinyloxy group, a 8-indolizinyloxy group, a 1-isoindolyloxy group, a 2-isoindolyloxy group, a 4-isoindolyloxy group, a 5-isoindolyloxy group, a 1-indolyloxy group, a 2-indolyloxy group, a 3-indolyloxy group, a 4-indolyloxy group, a 5-indolyloxy group, a 6-indolyloxy group, a 7-indolyloxy group, a 1-indazolyloxy group, a 2-indazolyloxy group, a 3-indazolyloxy group, a 4-indazolyloxy group, a 5-indazolyloxy group, a 6-indazolyloxy group, a 7-indazolyloxy group, a 1-purinyloxy group, a 2-purinyloxy group, a 3-purinyloxy group, a 6-purinyloxy group, a 7-purinyloxy group, a 8-purinyloxy group, a 2-quinolyloxy group, a 3-quinolyloxy group, a 4-quinolyloxy group, a 5-quinolyloxy group, a 6-quinolyloxy group, a 7-quinolyloxy group, a 8-quinolyloxy group, a 1-isoquinolyloxy group, a 3-isoquinolyloxy group, a 4-isoquinolyloxy group, a 5-isoquinolyloxy group, a 6-isoquinolyloxy group, a 7-isoquinolyloxy group, a 8-isoquinolyloxy group, a 1-phthalazinyloxy group, a 5-phthalazinyloxy group, a 6-phthalazinyloxy group, a 1-2,7-naphthyridinyloxy group, a
3-2,7-naphthyridinyloxy group, a 4-2,7-naphthyridinyloxy
group, a 1-2,6-naphthyridinyloxy group, a 3-2,6-naphthyridinyloxy group, a 4-2,6-naphthyridinyloxy group, a 2-1,8-naphthyridinyloxy group, a 3-1,8-
naphthyridinyloxy group, a 4-1,8-naphthyridinyloxy group, a 2-1,7-naphthyridinyloxy group, a 3-1,7-
naphthyridinyloxy group, a 4-1,7-naphthyridinyloxy group, a 5-1,7-naphthyridinyloxy group, a 6-1,7-
naphthyridinyloxy group, a 8-1,7-naphthyridinyloxy group, 2-1,6-naphthyridinyloxy group, a 3-1,6-naphthyridinyloxy group, a 4-1,6-naphthyridinyloxy group, a 5-1,6-naphthyridinyloxy group, a 7-1,6-naphthyridinyloxy group, a 8-1,6-naphthyridinyloxy group, a 2-1,5-
naphthyridinyloxy group, a 3-1,5-naphthyridinyloxy group, a 4-1,5-naphthyridinyloxy group, a 6-1,5-
naphthyridinyloxy group, a 7-1,5-naphthyridinyloxy group, a 8-1,5-naphthyridinyloxy group, a 2-quinoxalinyloxy group, a 5-quinoxalinyloxy group, a 6-quinoxalinyloxy group, a 2-quinazolinyloxy group, a 4-quinazolinyloxy group, a 5-quinazolinyloxy group, a 6-quinazolinyloxy group, a 7-quinazolinyloxy group, a 8-quinazolinyloxy group, a 3-cinnolinyloxy group, a 4-cinnolinyloxy group, a 5-cinnolinyloxy group, a 6-cinnolinyloxy group, a 7-cinnolinyloxy group, a 8-cinnolinyloxy group, a 2-pteridinyloxy group, a 4-pteridinyloxy group, a 6-pteridinyloxy group, a 7-pteridinyloxy group or the like. A C1-6 monoalkylamino group is an amino group
containing one C1-6 alkyl group and may be linear,
branched or C3-6 cycloalkylamino group, and as specific
examples, methylamino, ethylamino, n-propylamino, i-
propylamino, c-propylamino, n-butylamino, i-butylamino,
s-butylamino, t-butylamino, c-butylamino, 1-methyl-c-
propylamino, 2-methyl-c-propylamino, n-pentylamino, 1-
methyl-n-butylamino, 2-methyl-n-butylamino, 3-methyl-n-
butylamino, 1,1-dimethyl-n-propylamino, 1,2-dimethyl-n-
propylamino, 2,2-dimethyl-n-propylamino, 1-ethyl-n-
propylamino, c-pentylamino, 1-methyl-c-butylamino, 2-
methyl-c-butylamino, 3-methyl-c-butylamino, 1,2-dimethyl-
c-propylamino, 2,3-dimethyl-c-propylamino, 1-ethyl-c-
propylamino, 2-ethyl-c-propylamino, n-hexylamino, 1-
methyl-n-pentylamino, 2-methyl-n-pentylamino, 3-methyl-n-
pentylamino, 4-methyl-n-pentylamino, 1,1-dimethyl-n-
butylamino, 1,2-dimethyl-n-butylamino, 1,3-dimethyl-n-
butylamino, 2,2-dimethyl-n-butylamino, 2,3-dimethyl-n-
butylamino, 3,3-dimethyl-n-butylamino, 1-ethyl-n-
butylamino, 2-ethyl-n-butylamino, 1,1,2-trimethyl-n-
propylamino, 1,2,2-trimethyl-n-propylamino, 1-ethyl-1-
methyl-n-propylamino, 1-ethyl-2-methyl-n-propylamino, c-
hexylamino, 1-methyl-c-pentylamino, 2-methyl-c-
pentylamino, 3-methyl-c-pentylamino, 1-ethyl-c-
butylamino, 2-ethyl-c-butylamino, 3-ethyl-c-butylamino,
1,2-dimethyl-c-butylamino, 1,3-dimethyl-c-butylamino,
2,2-dimethyl-c-butylamino, 2,3-dimethyl-c-butylamino,
2,4-dimethyl-c-butylamino, 3,3-dimethyl-c-butylamino, 1-
n-propyl-c-propylamino, 2-n-propyl-c-propylamino, 1-i-
propyl-c-propylamino, 2-i-propyl-c-propylamino, 1,2,2-
trimethyl-c-propylamino, 1,2,3-trimethyl-c-propylamino,
2,2,3-trimethyl-c-propylamino, l-ethyl-2-methyl-c-
propylamino, 2-ethyl-1-methyl-c-propylamino, 2-ethyl-2-
methyl-c-propylamino, 2-ethyl-3-methyl-c-propylamino or
the like may be mentioned.
A C1-6 dialkylamino group is an amino group having
two C1-6 alkyl groups and may be symmetric or asymmetric.
A symmetric C1-6 dialkylamino group may be linear,
branched or a C3-6 cycloalkylamino group, and as specific
examples, dimethylamino, diethylamino, di-n-propylamino,
di-i-propylamino, di-c-propylamino, di-n-butylamino, di-
i-butylamino, di-s-butylamino, di-t-butylamino, di-c-
butylamino, di-(1-methyl-c-propyl)amino, di-(2-methyl-c-
propyl)amino, di-n-pentylamino, di-(1-methyl-n-
butyl)amino, di-(2-methyl-n-butyl)amino, di-(3-methyl-n-
butyl)amino, di-(1,1-dimethyl-n-propyl)amino, di-(1,2-
dimethyl-n-propyl)amino, di-(2,2-dimethyl-n-propyl)amino,
di-(1-ethyl-n-propyl)amino, di-c-pentylamino, di-(1-
methyl-c-butyl)amino, di-(2-methyl-c-butyl)amino, di-(3-
methyl-c-butyl)amino, di-(1,2-dimethyl-c-propyl)amino,
di-(2,3-dimethyl-c-propyl)amino, di-(1-ethyl-c-
propyl)amino, di-(2-ethyl-c-propyl)amino, di-n-
hexylamino, di-(1-methyl-n-pentyl)amino, di-(2-methyl-n-
pentyl)amino, di-(3-methyl-n-pentyl)amino, di-(4-methyl-
n-pentyl)amino, di-(1,1-dimethyl-n-butyl)amino, di-(1,2-
dimethyl-n-butyl)amino, di-(1,3-dimethyl-n-butyl)amino,
di-(2,2-dimethyl-n-butyl)amino, di-(2,3-dimethyl-n-butyl) amino, di-(3,3-dimethyl-n-butyl)amino, di-(1-ethyl-n-butyl)amino, di-(2-ethyl-n-butyl)amino, di-(1,1,2-trimethyl-n-propyl)amino, di-(1,2,2-trimethyl-n-propyl)amino, di-(1-ethyl-1-methyl-n-propyl)amino, di-(1-ethyl-2-methyl-n-propyl)amino, di-c-hexylamino, di-time thyl-c-pentyl) amino, di-(2-methyl-c-pentyl)amino, di-(3-methyl-c-pentyl)amino, di-(1-ethyl-c-butyl)amino, di-(2-ethyl-c-butyl)amino, di-(3-ethyl-c-butyl)amino, di-(1,2-dimethyl-c-butyl)amino, di-(1,3-dimethyl-c-butyl)amino, di-(2,2-dimethyl-c-butyl)amino, di-(2,3-dimethyl-c-butyl)amino, di-(2,4-dimethyl-c-butyl)amino, di-(3,3-dimethyl-c-butyl)amino, di-(1-n-propyl-c-propyl)amino, di-(2-n-propyl-c-propyl)amino, di-(1-i-propyl-c-propyl)amino, di-(2-i-propyl-c-propyl)amino, di-(1,2,2-trimethyl-c-propyl)amino, di-(1,2,3-trimethyl-c-propyl)amino, di-(2,2,3-trimethyl-c-propyl)amino, di-(1-ethyl-2-methyl-c-propyl)amino, di-(2-ethyl-1-methyl-c-propyl)amino, di-(2-ethyl-2-methyl-c-propyl)amino, di-(2-ethyl-3-methyl-c-propyl)amino and the like may be mentioned.
An asymmetric C1-6 dialkylamino group may be linear, branched or a C3-6 cycloalkylamino group, and as specific examples, (methyl, ethyl)amino, (methyl, n-propyl)amino, (methyl, i-propyl)amino, (methyl, c-propyl)amino, (methyl, n-butyl)amino, (methyl, i-butyl)amino, (methyl,
s-butyl)amino, (methyl, t-butyl)amino, (methyl, n-
pentyl)amino, (methyl, c-pentyl)amino, (methyl, n-
hexyl)amino, (methyl, c-hexyl)amino, (ethyl, n-
propyl)amino, (ethyl, i-propyl)amino, (ethyl, c-
propyl)amino, (ethyl, n-butyl)amino, (ethyl, i-
butyl)amino, (ethyl, s-butyl)amino, (ethyl, t-
butyl)amino, (ethyl, n-pentyl)amino, (ethyl, c-
pentyl)amino, (ethyl, n-hexyl)amino, (ethyl, c-
hexyl)amino, (n-propyl, i-propyl)amino, (n-propyl, c-
propyl)amino, (n-propyl, n-butyl)amino, (n-propyl, i-
butyl)amino, (n-propyl, s-butyl)amino, (n-propyl, t-
butyl)amino, (n-propyl, n-pentyl)amino, (n-propyl, c-
pentyl)amino, (n-propyl, n-hexyl)amino, (n-propyl, c-
hexyl)amino, (i-propyl, c-propyl)amino, (i-propyl, n-
butyl)amino, (i-propyl, i-butyl)amino, (i-propyl, s-
butyl)amino, (i-propyl, t-butyl)amino, (i-propyl, n-
pentyl)amino, (i-propyl, c-pentyl)amino, (i-propyl, n-
hexyl)amino, (i-propyl, c-hexyl)amino, (c-propyl, n-
butyl)amino, (c-propyl, i-butyl)amino, (c-propyl, s-
butyl)amino, (c-propyl, t-butyl)amino, (c-propyl, n-
pentyl)amino, (c-propyl, c-pentyl)amino, (c-propyl, n-
hexyl)amino, (c-propyl, c-hexyl)amino, (n-butyl, i-
butyl)amino, (n-butyl, s-butyl)amino, (n-butyl, t-
butyl)amino, (n-butyl, n-pentyl)amino, (n-butyl, c-
pentyl)amino, (n-butyl, n-hexyl)amino, (n-butyl, c-
hexyl)amino, (i-butyl, s-butyl)amino, (i-butyl, t-
butyl)amino, (i-butyl, n-pentyl)amino, (i-butyl, c-
pentyl)amino, (i-butyl, n-hexyl)amino, (i-butyl, c-
hexyl)amino, (s-butyl, t-butyl)amino, (s-butyl, n-pentyl)amino, (s-butyl, c-pentyl)amino, (s-butyl, n-hexyl)amino, (s-butyl, c-hexyl)amino, (t-butyl, n-pentyl)amino, (t-butyl, c-pentyl)amino, (t-butyl, n-hexyl)amino, (t-butyl, c-hexyl)amino, (n-pentyl, c-pentyl)amino, (n-pentyl, n-hexyl)amino, (n-pentyl, c-hexyl)amino, (c-pentyl, n-hexyl)amino, (c-pentyl, c-hexyl)amino, (n-hexyl, c-hexyl)amino and the like may be mentioned.
A C1-6 alkylthio group is a thio group having a C1-6 alkyl group and may be linear, branched or a C3-6 cycloalkylthio group. As specific examples, methylthio, ethylthio, n-propylthio, i-propylthio, c-propylthio, n-butylthio, i-butylthio, s-butylthio, t-butylthio, c-butylthio, 1-methyl-c-propylthio, 2-methyl-c-propylthio, n-pentylthio, 1-methyl-n-butylthio, 2-methyl-n-butylthio, 3-methyl-n-butylthio, 1,1-dimethyl-n-propylthio, 1,2-dimethyl-n-propylthio, 2,2-dimethyl-n-propylthio, 1-ethyl-n-propylthio, c-pentylthio, 1-methyl-c-butylthio, 2-methyl-c-butylthio, 3-methyl-c-butylthio, 1,2-dimethyl-c-propylthio, 2,3-dimethyl-c-propylthio, 1-ethyl-c-propylthio, 2-ethyl-c-propylthio, n-hexylthio, 1-methyl-n-pentylthio, 2-methyl-n-pentylthio, 3-methyl-n-pentylthio, 4-methyl-n-pentylthio, 1,1-dimethyl-n-butylthio, 1,2-dimethyl-n-butylthio, 1,3-dimethyl-n-butylthio, 2,2-dimethyl-n-butylthio, 2,3-dimethyl-n-
butylthio, 3,3-dimethyl-n-butylthio, 1-ethyl-n-butylthio,
2-ethyl-n-butylthio, 1,1,2-trimethyl-n-propylthio, 1,2,2-
trimethyl-n-propylthio, 1-ethyl-1-methyl-n-propylthio, 1-
ethyl-2-methyl-n-propylthio, c-hexylthio, 1-methyl-c-
pentylthio, 2-methyl-c-pentylthio, 3-methyl-c-pentylthio,
1-ethyl-c-butylthio, 2-ethyl-c-butylthio, 3-ethyl-c-
butylthio, 1,2-dimethyl-c-butylthio, 1,3-dimethyl-c-
butylthio, 2,2-dimethyl-c-butylthio, 2,3-dimethyl-c-
butylthio, 2,4-dimethyl-c-butylthio, 3,3-dimethyl-c-
butylthio, 1-n-propyl-c-propylthio, 2-n-propyl-c-
propylthio, 1-i-propyl-c-propylthio, 2-i-propyl-c-
propylthio, 1,2,2-trimethyl-c-propylthio, 1,2,3-
trimethyl-c-propylthio, 2,2,3-trimethyl-c-propylthio, 1-
ethyl-2-methyl-c-propylthio, 2-ethyl-1-methyl-c-
propylthio, 2 -ethyl-2-methyl-c-propylthio, 2-ethyl-3-
methyl-c-propylthio and the like may be mentioned.
A C1-3 alkylthio group is an alkylthio group containing one to three carbon atoms and may be linear, branched or a C3 cycloalkyl group, and as specific examples, methylthio, ethylthio, n-propylthio, i-propylthio, c-propylthio and the like may be mentioned.
A C1-6 alkylsulfonyl is a sulfonyl group having a C1-6 alkyl group and may be linear, branched or a C3-6 cycloalkylsulfonyl group. As specific examples, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl, c-propylsulfonyl, n-butylsulfonyl, i-butylsulfonyl, s-butylsulfonyl, t-butylsulfonyl, c-
butylsulfonyl, 1-methyl-c-propylsulfonyl, 2-methyl-c-
propylsulfonyl, n-pentylsulfonyl, 1-methyl-n-
butylsulfonyl, 2-methyl-n-butylsulfonyl, 3-methyl-n-
butylsulfonyl, 1,1-dimethyl-n-propylsulfonyl, 1,2-
dimethyl-n-propylsulfonyl, 2,2-dimethyl-n-propylsulfonyl,
1-ethyl-n-propylsulfonyl, c-pentylsulfonyl, 1-methyl-c-
butylsulfonyl, 2-methyl-c-butylsulfonyl, 3-methyl-c-
butylsulfonyl, 1,2 -dimethyl-c-propylsulfonyl, 2,3-
dimethyl-c-propylsulfonyl, 1-ethyl-c-propylsulfonyl, 2 -
ethyl-c-propylsulfonyl, n-hexylsulfonyl, 1-methyl-n-
pentylsulfonyl, 2-methyl-n-pentylsulfonyl, 3-methyl-n-
pentylsulfonyl, 4-methyl-n-pentylsulfonyl, 1,1-dimethyl-
n-butylsulfonyl, 1,2-dimethyl-n-butylsulfonyl, 1,3-
dimethyl-n-butylsulfonyl, 2,2-dimethyl-n-butylsulfonyl,
2,3-dimethyl-n-butylsulfonyl, 3,3-dimethyl-n-
butylsulfonyl, 1-ethyl-n-butylsulfonyl, 2-ethyl-n-
butylsulfonyl, 1,1,2-trimethyl-n-propylsulfonyl, 1,2,2-
trimethyl-n-propylsulfonyl, 1-ethyl-1-methyl-n-
propylsulfonyl, 1-ethyl-2-methyl-n-propylsulfonyl, c-
hexylsulfonyl, 1-methyl-c-pentylsulfonyl, 2-methyl-c-
pentylsulfonyl, 3-methyl-c-pentylsulfonyl, 1-ethyl-c-
butylsulfonyl, 2 -ethyl-c-butylsulfonyl, 3 -ethyl-c-
butylsulfonyl, 1,2 -dimethyl-c-butylsulfonyl, 1,3-
dimethyl-c-butylsulfonyl, 2,2 -dimethyl-c-butylsulfonyl,
2,3-dimethyl-c-butylsulfonyl, 2,4-dimethyl-c-
butylsulfonyl, 3,3-dimethyl-c-butylsulfonyl, 1-n-propyl-
c-propylsulfonyl, 2-n-propyl-c-propylsulfonyl, 1-i-
propyl-c-propylsulfonyl, 2-i-propyl-c-propylsulfonyl,
1,2,2-trimethyl-c-propylsulfonyl, 1,2,3-trimethyl-c-
propylsulfonyl, 2,2,3-trimethyl-c-propylsulfonyl, 1-
ethyl-2-methyl-c-propylsulfonyl, 2-ethyl-1-methyl-c-
propylsulfonyl, 2-ethyl-2-methyl-c-propylsulfonyl, 2-
ethyl-3-methyl-c-propylsulfonyl and the like may be
mentioned.
A C1-3 alkylsulfonyl group is an alkylsulfonyl group containing one to three carbon atoms and may be linear, branched or a C3 cycloalkylsulfonyl group. As specific examples, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, i-propylsulfonyl, c-propylsulfonyl and the like may be mentioned.
Next, preferred structures of the respective substituents will be mentioned.
The substituent R1 is preferably a hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy group.
The substituent R1 is more preferably a hydrogen atom or an ethoxy group, and further preferably a hydrogen atom.
The substituent R2 is preferably a hydrogen atom, a halogen atom, a C1-3 alkoxy group, a C1-3 alkyl group, a C1-3 alkylthio group or a C1-3 alkylsulfonyl group (the C1-3 alkoxy group, the C1-3 alkyl group, the C1-3 alkyl thio group and the C1-3 alkylsulfonyl group are unsubstituted or substituted with one or more halogen atoms).
The substituent R2 is more preferably a halogen atom,
a methyl group, a trifluoromethyl group, a difluoromethyl
group, a fluoromethyl group, a trifluoromethoxy group or
a difluoromethoxy group, further preferably a halogen
atom.
The substituent Q is preferably any of the
structures represented by the formula (X):
(Formula Removed)
(wherein R3 and R5 mean hydrogen atoms, R4 means a C7-12 cycloalkyl group or a C7-12 cycloalkenyl group, and T means an oxygen atom), the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms) , and R4 means a C1-20 alkyl group, a C2-20 alkenyl group or a C2-19 heterocyclyl group (the C1-20 alkyl group, the C2-20 alkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C1-20 alkyl
group, a C2-20 alkenyl group or a C2-19 heterocyclyl group (the C1-20 alkyl group, the C2-20 alkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) .
The substituent Q is more preferably any of the structures represented by the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group or a C2-19 heterocyclyl group (the C3-12 cycloalkyl group, the C3-12 cycloalkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1)), and the formula (VII):
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group or a C2-19 heterocyclyl group (the C3-12 cycloalkyl group, the C3-12 cycloalkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one to three identical or different substituents selected from the substituent
set V1) ) .
The substituent Q is further preferably any of the
structures represented by the formula (VI):

(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means a C7-12 cycloalkyl group or a C7-12 cycloalkenyl group (the C7-12 cycloalkyl group and the C7-12 cycloalkenyl group are unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of halogen atoms, carboxy groups, carbamoyl groups, sulfamoyl groups, nitro groups, cyano groups, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups, C1-6 alkylsulfonyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups) ) , and the formula (VII):
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C7-12 cycloalkyl group or a C7-12 cycloalkenyl group (the C7-12 cycloalkyl group and the C7-12 cycloalkenyl group are unsubstituted or substituted with one to two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, sulfamoyl groups,
nitro groups, cyano groups, halogen atoms, hydroxy
groups, amino groups, mono-C1-6 alkylamino groups, di-C1-(
alkylamino groups, C1-6 alkoxy groups, C2-9 heterocyclyl
groups, C1-6 alkylthio groups, C1-6 alkylsulfonyl groups,
C1-3 haloalkyl groups and C1-3 haloalkoxy groups) ) .
The substituent Q is particularly preferably
represented by the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means a C8-12 cycloalkyl group (the C8-12 cycloalkyl group is unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylsulf onyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)).
The substituent Q is more particularly preferably any of the structures represented by the formula (IV):
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means any of the structures shown below):

(Formula Removed)
and the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means any of the structures shown below).
(Structure Removed)
The substituent X is preferably a C1-6 alkylene group (the C1-6 alkylene group is unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V1) .
The substituent X is more preferably a C1-3 alkylene group, further preferably a methylene group, a 1,2-ethylene group or a 1,1-ethylene group, particularly preferably a methylene group.
The substituent Y is preferably a single bond or any of the structures represented by the formula (VIII):
(Formula Removed)
(wherein R6 means a hydrogen atom or a C1-3 alkyl group (the C1-3 alkyl group is unsubstituted or substituted with one or more halogen atoms), and U means an oxygen atom or a sulfur atom).
The substituent Y is more preferably any of the structures represented by the formula (VIII):
(Formula Removed)
(wherein R6 means a hydrogen atom, and U means an oxygen atom).
The substituent Z is preferably a C1-6 alkyl group, a C1-6 alkoxy group (the C1-6 alkyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a C2-14 aryloxy group or a C2-9 heterocyclyl group (the C2-14 aryl group, the C2-14 aryloxy group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V2) .
The substituent Z is more preferably a C1-6 alkyl
group (the C1-6 alkyl group is substituted with one C2-9
heteroaryl group, one C2-9 heterocyclyl group (the C2-9
heteroaryl group and the C2-9 heterocyclyl group are
unsubstituted or substituted or one or two identical or
different substituents selected from the substituent set
V1)) .
The substituent Z is further preferably a C1-6 alkyl group (the C1-6 alkyl group is substituted with one C2-9 heteroaryl group or one C2-9 heterocyclyl group (the C2-9 heteroaryl group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, sulfamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, C1-6 alkyl groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups, C1-6 alkylsulfonyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)).
The substituent Z is particularly preferably a C1-3 alkyl group (the C1-3 alkyl group is substituted with one substituent selected from the substituent set (XI):
(Formula Removed)
(wherein each substituent is unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylsulfonyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)) or a C1-3 alkyl group (the C1-3 alkyl group is substituted with one substituent selected from the substituent set (XII):
(Formula Removed)
(wherein each substituent is unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino
groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C1-6
alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylsulfonyl
groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)).
The substituent Z is more particularly preferably a (3-methylpyridyl)methyl group, a (3-methylpyridyl)ethyl group, a pyridylmethyl group, a pyridylethyl group, a (2-fluoropyridyl)ethyl group, a (3 -chloropyridyl)ethyl group, a (3 -dimethylaminopyridyl)methyl group, a pyridazinylethyl group, a pyridazinylpropyl group, a pyrimidinylethyl group, a pyrimidinylpropyl group, a (4 -methylpyridazinyl)methyl group, a (3-dimethylaminopyridazinyl)methyl group, a (3-methylpyridazinyl)ethyl group, a (3-chloropyridazinyl)ethyl group, a (3-methoxypyridazinyl)ethyl group, a (3 -chloro-6 -methylpyridazinyl)ethyl group or a (3-methanesulfonylpyridyl)methyl group.
Favorable compounds as the P2X7 receptor inhibitor, the preventive, therapeutic or improving agent for diseases against which inhibition of the P2X7 receptor is effective and the therapeutic agent for rheumatoid arthritis of the present invention are as follows:
1) Compounds represented by the formula (I), wherein R1 is a hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy group,
R2 is a hydrogen atom, a halogen atom, a C1-3 alkoxy group, a C1-3 alkyl group, a C1-3 alkylthio group or a C1-3
alkylsulfonyl group (the C1-3 alkoxy group, the C1-3 alkyl
group, the C1-3 alkylthio group and the C1-3 alkylsulfonyl
group are unsubstituted or substituted with one or more
halogen atoms),
Q is any of the structures represented by the formula
(Formula Removed)
(wherein R3 and R5 mean hydrogen atoms, and R4 means a C7-12 cycloalkyl group or a C7-12 cycloalkenyl group, and T means an oxygen atom of a sulfur atom), the formula (VI):

(Formula Removed)
(wherein R3 means a hydrogen atom or a C1-6 alkyl group
(the C1-6 alkyl group is unsubstituted or substituted with
one or more halogen atoms) , and R4 means a C1-20 alkyl
group, a C2-20 alkenyl group or a C2-19 heterocyclyl group
(the C1-20 alkyl group, the C2-20 alkenyl group and the C2-19
heterocyclyl group are unsubstituted or substituted with
one or more identical or different substituents selected
from the substituent set V1) ) , and the formula (VII) :
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C1-20 alkyl
group, a C2-20 alkenyl group or a C2-19 heterocyclyl group (the C1-20 alkyl group, the C2-20 alkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) ,
X is a C1-6 alkylene group (the C1-6 alkylene group is unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V1),
Y is a bond or any of the structure represented by the formula (VIII):
(Formula Removed)
(wherein R6 is a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms), and U means an oxygen atom), and Z is a C1-6 alkyl group, a C1-6 alkoxy group (the C1-6 alkyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V2) , a C2-14 aryl group or a C2-9 heterocyclyl group (the C2-14 aryl group and the C2-9 heterocyclyl group are unsubstituted or substituted with one substituent selected from the substituent set V2) , tautomers, prodrugs or
pharmaceutically acceptable salts of the compounds or
solvates thereof.
2) The compounds according to 1), wherein R1 is a hydrogen atom or an ethoxy group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
3) The compound according to 1) or 2), wherein R2 is a halogen atom, a methyl group, a trifluoromethyl group, a difluoromethyl group, a fluoromethyl group, a
trifluoromethoxy group or a difluoromethoxy group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
4) The compounds according to any of 1) to 3),
wherein Q is any of the structures represented by the
formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group or a C2-19 heterocyclyl group (the C3-12 cycloalkyl group, the C3-12 cycloalkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one to three identical or different substituents selected from the substituent set V1)) and the formula (VII):

(Formula Removed)
(wherein m means 0, 1 or 2, R4 means a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group or a C2-19 heterocyclyl group (the C3-12 cycloalkyl group, the C3-12 cycloalkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one to three identical or different substituents selected from the substituent set V1) ) , tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
5) The compounds according to any of 1) to 4), wherein X is a C1-3 alkylene group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
6) The compounds according to any of 1) to 5) , wherein the substituent Y is any of the structures represented by represented by the formula (VIII):
(Formula Removed)
(wherein R6 means a hydrogen atom, and U means an oxygen atom), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
7) The compounds according to any of 1) to 6), wherein the substituent Z is a C1-6 alkyl group (the C1-6
alkyl group is substituted with one C2-9 heteroaryl group
(the C2-9 heteroaryl group is unsubstituted or substituted
with one or two identical or different substituents
selected from the substituent set V1)), tautomers,
prodrugs or pharmaceutically acceptable salts of the
compounds or solvates thereof.
8) The compound according to any of 1) to 7), wherein R1 is a hydrogen atom, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
9) The compound according to any of 1) to 8), wherein R2 is a halogen atom, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
10) The compound according to any of 1) to 9),
wherein Q is any of the structures represented by the
formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means a C7-12 cycloalkyl group or a C7-12 cycloalkenyl group (the C7-12 cycloalkyl group and the C7-12 cycloalkenyl group are unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, sulfamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy
groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6
alkylamino groups, C1-6 alkoxy groups, C2-9 heterocyclyl
groups, C1-6 alkylthio groups, C1-6 alkylsulfonyl groups,
C1-3 haloalkyl groups and C1-3 haloalkoxy groups) ) , and the
formula (VII):
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C7-12 cycloalkyl group or a C7-12 cycloalkenyl group (the C7-12 cycloalkyl group and the C7-12 cycloalkenyl group are unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, sulfamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups, C1-6 alkylsulf onyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups) ) , tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
11) The compounds according to any of 1) to 10), wherein X is a methylene group, a 1,2-ethylene group or a 1,1-ethylene group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
12) The compounds according to any of 1) to 11),
wherein the substituent Z is a C1-6 alkyl group (the C1-6
alkyl group is substituted with one C2-9 heteroaryl group or one C2-9 heterocyclyl group (the C2-9 heteroaryl group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, sulfamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, C1-6 alkyl groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups, C1-6 alkylsulfonyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
13) The compounds according to any of 1) to 12), wherein the substituent Q is represented by the formula (VI) :
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 means a C8-12 cycloalkyl group (the C8-12 cycloalkyl group is unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups,
mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6
alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylsulfonyl
groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)),
tautomers, prodrugs or pharmaceutically acceptable salts
of the compounds or solvates thereof.
14) The compounds according to any of 1) to 13),
wherein the substituent Z is a C1-3 alkyl group (the C1-3
alkyl group is substituted with one substituent selected
from the substituent set (XI):
(Formula Removed)
(wherein each substituent is unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylsulf onyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)) or a C1-3 alkyl group (the C1-3 alkyl group is substituted with one substituent selected from the substituent set
(Formula Removed)
(wherein each substituent is unsubstituted or substituted with one or two identical or different substituents selected from the group consisting of carboxy groups, carbamoyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylsulfonyl groups, C1-3 haloalkyl groups and C1-3 haloalkoxy groups)), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
15) The compounds according to any of 1) to 14), wherein Q is represented by the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 is any of the structures shown below):
(Formula Removed)
or the formula (VI

(Formula Removed)
(wherein R3 means a hydrogen atom, and R4 is any of the structures shown below),
(Formula Removed)
tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
16) The compounds according to any of 1) to 15), wherein Z is a (3-methylpyridyl)methyl group, a pyridylmethyl group, a (3-methylpyridyl)ethyl group, a pyridylethyl group, a (2 -fluoropyridyl)ethyl group, a (3 -chloropyridyl)ethyl group, a (3 -
dimethylaminopyridyl)methyl group, a pyridazinylethyl group, a pyridazinylpropyl group, a pyrimidinylethyl group, a pyrimidinylpropyl group, a (4-methylpyridazinyl)methyl group, a (3-dimethylaminopyridazinyl)methyl group, a (3-methylpyridazinyl)ethyl group, a (3-chloropyridazinyl)ethyl group, a (3-methoxypyridazinyl)ethyl group, a (3 -chloro-6 -methylpyridazinyl)ethyl group or a (3-
methanesulfonylpyridyl)methyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or
solvates thereof.
17) The compounds wherein R1 is a hydrogen atom, R2
is bromine, X is a methylene group, Y is -CONH-, and Q
and Z are any of the following combinations in Table 1,
tautomers, prodrugs or pharmaceutically acceptable salts
of the compounds or solvates thereof. The symbols in
Table 1 denote the flowing substituents.
(Formula Removed)
TABLE 1
(Table Removed)
18) The compounds wherein R1 is a hydrogen atom, R2 is bromine, X is a methylene group, Y is -CONH-, and Q and Z are any of the above combinations in Table 1, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof (provided that in the case of 18), Q1 to Q10 and Zl to Z30 in Table 1 denote the following substituents).
(Formula Removed)
19) The compounds wherein R1 is a hydrogen atom, R2 is bromine, X is a methylene group, Y is -CONH-, and Q and Z are any of the above combinations in Table 1, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof (provided that in the case of 19), Q1 to Q10 and Zl to Z30 in Table 1
denote the following substituents).
(Formula Removed)
20) The compounds wherein R1 is a hydrogen atom, R2 is bromine, X is a methylene group, Y is -CONH-, and Q and Z are any of the above combinations in Table 1, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof (provided that in
the case of 20), Q1 to Q10 and Zl to Z30 in Table 1
denote the following substituents).
(Formula Removed)
21) The compounds according to any of 17) to 20), wherein R1 is converted to an ethoxy group, tautomers, prodrugs or pharmaceutically acceptable salts of the
compounds or solvates thereof.
22) The compounds according to any of 17) to 20) , wherein R1 is converted to a trifluoromethyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
23) The compounds according to any of 17) to 20), wherein R1 is converted to a trifluoromethoxy group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
24) The compounds according to any of 17) to 23), wherein R2 is converted to chlorine, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
25) The compounds according to any of 17) to 23), wherein R2 is converted to iodine, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
26) The compounds according to any of 17) to 23), wherein R2 is converted to fluorine, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
27) The compounds according to any of 17) to 23), wherein R2 is converted to a trifluoromethyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
28) The compounds according to any of 17) to 23), wherein R2 is converted to a methyl group, tautomers,
prodrugs or pharmaceutically acceptable salts of the
compounds or solvates thereof.
29) The compounds according to any of 17) to 23), wherein R2 is converted to a methylthio group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
30) The compounds according to any of 17) to 23), wherein R2 is converted to a methylsulfonyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
31) The compounds according to any of 17) to 23), wherein R2 is converted to an ethylthio group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
32) The compounds according to any of 17) to 23), wherein R2 is converted to an ethylsulfonyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
33) The compounds according to any of 17) to 23) , wherein R2 is converted to a cyclopropyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
34) The compounds according to any of 17) to 23), wherein R2 is converted to a cyclohexyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
35) The compounds according to any of 17) to 23),
wherein R2 is converted to a trifluoromethoxy group,
tautomers, prodrugs or pharmaceutically acceptable salts
of the compounds or solvates thereof.
36) The compounds according to any of 17) to 23), wherein R2 is converted to a difluoromethoxy group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
37) The compounds according to any of 17) to 36), wherein X is converted to an ethylene group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
38) The compounds according to any of 17) to 36), wherein X is converted to the following structure, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
39) The compounds according to any of 17) to 36), wherein X is converted to the following structure, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
40) The compounds according to any of 17) to 36),
(Formula Removed)
wherein X is converted to the following structure,
tautomers, prodrugs or pharmaceutically acceptable salts
of the compounds or solvates thereof.
(Formula Removed)
41) The compounds according to any of 17) to 36), wherein X is converted to a single bond, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
42) The compounds according to any of 17) to 41), wherein Y is converted to -CSNH-, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
43) The compounds according to any of 17) to 41), wherein Y is converted to -CO-, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
44) The compounds according to any of 17) to 41), wherein Y is converted to -CS-, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
45) The compounds according to any of 17) to 41), wherein Y is converted to a methylene group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
46) The compounds according to any of 17) to 41),
wherein Y is converted to -NH-, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
47) The compounds according to any of 17) to 41),
wherein Y is converted to the following structure,
tautomers, prodrugs or pharmaceutically acceptable salts
of the compounds or solvates thereof.
(Formula Removed)
48) The compounds according to any of 17) to 41),
wherein Y is converted to the following structure,
tautomers, prodrugs or pharmaceutically acceptable salts
of the compounds or solvates thereof.
(Formula Removed)
49) The compounds according to any of 17) to 41), wherein Y is converted to the following structure, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
(Formula Removed)
50) The compounds according to any of 17) to 41),
wherein Y is converted to -NHCO-, tautomers, prodrugs or
pharmaceutically acceptable salts of the compounds or
solvates thereof.
51) The compounds according to any of 17) to 41), wherein Y is converted to -0-, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
52) The compounds according to any of 17) to 41), wherein Y is converted to -S-, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
53) The compounds according to any of 17) to 41), wherein Y is converted to a single bond, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
54) The compounds according to any of 17) to 20), wherein R1 is converted to an ethoxy group, and R2 is converted to a phenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
55) The compounds according to any of 17) to 20), wherein R1 is converted to a trifluoromethyl group, and R2 is converted to a phenyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
56) The compounds according to any of 17) to 20), wherein R2 is converted to a phenyl group, tautomers,
prodrugs or pharmaceutically acceptable salts of the
compounds or solvates thereof.
57) The compounds according to any of 54) to 56), wherein R2 is converted to a 4-pyridyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
58) The compounds according to any of 54) to 56), wherein R2 is converted to a 5-pyrimidyl group, tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof.
59) P2X7 receptor inhibitors containing the compounds according to any of 1) to 58), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof, as an active ingredient.
60) Preventive, therapeutic and improving agents for diseases against which inhibition of the P2X7 receptor is effective, which contain the P2X7 receptor inhibitors according to 59) as an active ingredient.
61) Therapeutic agent for rheumatoid arthritis containing the P2X7 receptor inhibitors according to 59) as an active ingredient.
62) Medicament containing the compound according to any of 1) to 58), tautomers, prodrugs or pharmaceutically acceptable salts of the compounds or solvates thereof, as an active ingredient.
In the present invention, the compounds of the
present invention represented by the formula (I) may be present in the form of tautomers or geometrical isomers which undergo endocyclic or exocyclic isomerization, mixtures of tautomers or geometric isomers or mixtures of thereof. When the compounds of the present invention have an asymmetric center, whether or not resulting from an isomerization, the compounds of the present invention may be in the form of resolved optical isomers or in the form of mixtures containing them in certain ratios. Further, when the compounds of the present invention have two or more asymmetric centers, the compounds of the present invention can be in the form of diastereomers dues to optical isomerism about them. The compounds of the present invention may be in the form of a mixture of all these isomers in certain ratios. For example, diastereomer can be separated by techniques known well to those skilled in the art such as fractional crystallization, and optical isomers can be obtained by techniques well known in the field of organic chemistry for this purpose.
The compounds of the present invention represented by the formula (I) or pharmaceutically acceptable salts thereof may be in the form of arbitrary crystals or arbitrary hydrates, depending on the production conditions. The present invention covers these crystals, hydrates and mixtures. They may be in the form of
solvates with organic solvents such as acetone, ethanol
and tetrahydrofuran, and the present invention covers any
of these forms.
The compounds of the present invention represented by the formula (I) may be converted to pharmaceutically acceptable salts or may be liberated from the resulting salts, if necessary. The pharmaceutically acceptable salts of the present invention may be, for example, salts with alkali metals (such as lithium, sodium and potassium), alkaline earth metals (such as magnesium and calcium), ammonium, organic bases and amino acids. They may be salts with inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid) and organic acids (such as acetic acid, citric acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid and p-toluenesulfonic acid).
The compounds which serve as prodrugs are derivatives of the present invention having chemically or metabolically degradable groups which give pharmacologically active compounds of the present invention upon solvolysis or under physiological conditions in vivo. Methods for selecting or producing appropriate prodrugs are disclosed, for example, in Design of Prodrugs (Elsevier, Amsterdam 1985) .
In the present invention, when the compound has a hydroxy group, acyloxy derivatives obtained by reacting
the compound with appropriate acyl halides or appropriate
acid anhydrides may, for example, be mentioned as
prodrugs. Acyloxys particularly preferred as prodrugs
include -OCOC2H5, -OCO(t-Bu) , -OCOC15H31, -OCO (m-CO2Na-Ph) ,
-OCOCH2CH2CO2Na, -OCOCH (NH2) CH3, -OCOCH2N (CH3) 2 and the
like. When the compound of the present invention has an
amino group, amide derivatives obtained by reacting the
compound having an amino group with appropriate acid
halides or appropriate mixed acid anhydrides may, for
example, be mentioned as prodrugs. Amides particularly
preferred as prodrugs include -NHCO (CH2) 20OCH3,
-NHCOCH(NH2)CH3 and the like.
The preventive, therapeutic and improving agents for
diseases against which inhibition of the P2X7 receptor is
effective which contain the P2X7 receptor inhibitors of
the present invention, as an active ingredient may
usually be administered as oral medicines such as
tablets, capsules, powder, granules, pills and syrup, as
rectal medicines, percutaneous medicines or inj ections.
The agents of the present invention may be administered
as a single therapeutic agent or as a mixture with other
therapeutic agents. Though they may be administered as
they are, they are usually administered in the form of
medical compositions. These pharmaceutical preparations
can be obtained by adding pharmacologically and
pharmaceutically acceptable additives by conventional
methods. Namely, for oral medicines, ordinary additives
such as excipients, lubricants, binders, disintegrants,
humectants, plasticizers and coating agents may be used.
Oral liquid preparations may be in the form of aqueous or
oily suspensions, solutions, emulsions, syrups or elixirs
or may be supplied as dry syrups to be mixed with water
or other appropriate solvents before use. Such liquid
preparations may contain ordinary additives such as
suspending agents, perfumes, diluents and emulsifiers.
In the case of rectal administration, they may be
administered as suppositories. Suppositories may use an
appropriate substance such as cacao butter, laurin
tallow, Macrogol, glycerogelatin, Witepsol, sodium
stearate and mixtures thereof as the base and may, if
necessary, contain an emulsifier, a suspending agent, a
preservative and the like. For inj ections,
pharmaceutical ingredients such as distilled water for
injection, physiological saline, 5% glucose solution,
propylene glycol and other solvents or solubilizing
agents, a pH regulator, an isotonizing agent and a
stabilizer may be used to form aqueous dosage forms or
dosage forms which need dissolution before use.
The dose of the agents of the present invention for
administration to human is usually about from 0.1 to 1000
mg/human/day in the case of oral drugs or rectal
administration and about from 0.05 mg to 500 mg/human/day
in the case of inj ections, though it depends on the age
and conditions of the patient. The above-mentioned
ranges are mere examples, and the dose should be
determined from the conditions of the patient.
The present invention is used when the use of
compounds which inhibit the P2X7 receptor are expected to
improve pathological conditions. Such cases include, for
example, prevention and therapy of swelling, exacerbation
of pain and bone metabolism in rheumatoid arthritis,
prevention and therapy of inflammatory bowel diseases,
chronic obstructive pulmonary disease (COPD) and
osteoarthritis, prevention and therapy of inflammatory
pain and cancer pain and IL-1ß-associated diseases such
as Crohn's disease, emphysema, acute respiratory distress
syndrome, adult respiratory distress syndrome, asthma,
bronchitis, chronic pulmonary inflammatory diseases,
silicosis, pulmonary sarcoidosis, allergic reactions,
allergic contact hypersensitivity, eczema, contact
dermatitis, psoriasis, sunburn, cancer, tissue
ulceration, restenosis, periodontal disease,
epidermolysis bullosa, osteoporosis, bone resorption
disease, loosening of artificial joint implants,
atherosclerosis, aortic aneurysm, congestive heart
failure, myocardial infarction, stroke, cerebral
ischemia, head trauma, neurotrauma, spinal cord injury,
neurodegenerative disorder, Alzheimer's disease,
Parkinson's disease, migraine, depression, peripheral
neuropathy, pain, cerebral amyloid angiopathy, nootropic
or cognition enhancement, amyotrophic lateral sclerosis,
multiple sclerosis, ocular angiogenesis, corneal injury,
macular degeneration, corneal scarring, scleritis,
abnormal wound healing, burns, autoimmune diseases,
Huntington's disease, diabetes, AIDS, cachexia, sepsis,
septic shock, endotoxin shock, conjunctivitis shock,
gram-negative sepsis, toxic shock syndrome, cerebral
malaria, cardiac and renal reperfusion injury,
thrombosis, glomerulonephritis, graft-versus-host
reaction, homograft rejection, organ transplant toxicity,
ulcerative colitis or muscle degeneration, but there is
no restriction.
The compounds of the present invention can be prepared generally, but not restrietively, by the processes described below.
The compounds of the present invention can usually be purified by column chromatography, thin layer chromatography, high performance liquid chromatography (HPLC) or high performance liquid chromatography-mass spectrometry (LC-MS) and, if necessary, they may be obtained with high purity by recrystallization or washing with solvents.
As the base mentioned in the general processes for producing the compounds of the present invention, an alkali metal salt such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, potassium hydroxide, sodium hydroxide, sodium hydride, lithium hydride, sodium amide,
potassium t-butoxide, sodium t-butoxide, n-butyllithium
or lithium diisopropylamide, an amine such as pyridine,
triethylamine, diisopropylethylamine, pyrrolidine or N-
methylpiperidine, a silane reagent represented by
hexamethyldisilazane, sodium acetate or potassium acetate
may be mentioned.
In the general processes for producing the compounds
of the present invention, any solvent that is stable
under the reaction conditions and inert enough not to
hinder the reaction may be used without any particular
restrictions, and for example, a sulfoxide solvent
represented by dimethyl sulfoxide, an amide solvent
represented by N,N-dimethylformamide or N,N-
dimethylacetamide, an ether solvent represented by
diethyl ether, dimethoxyethane, tetrahydrofuran, 1,4-
dioxane or cyclopentyl methyl ether, a halogenated
solvent represented by dichloromethane, chloroform or
dichloroethane, a nitrile solvent represented by
acetonitrile or propionitrile, an aromatic hydrocarbon
solvent represented by benzene or toluene, a hydrocarbon
solvent represented by hexane or heptane, an ester
solvent represented by ethyl acetate, an alcohol solvent
represented by methanol, ethanol, 1-propanol, 2-propanol
or ethylene glycol or water may be mentioned. The
reactions may be carried out in an arbitrary mixture of
the above-mentioned solvents or in the absence of a
solvent.
In the general process for producing the compounds
of the present invention, the reaction temperature is
selected appropriately from the range between -78°C and the boiling point of the solvent used in the reaction, and the processes can be carried out under ordinary pressure or with application of pressure or microwave irradiation.
In the following description of the processes for producing the compounds of the present invention, the general formulae for the intermediates obtained in the respective steps of the processes for producing the compounds of the present invention and the end products of the processes cover precursors thereof. Herein, precursors mean compounds which can be converted to the desired products, if necessary, by hydrolysis, deprotection, reduction, oxidation, alkylation or the like, and for example, cover compounds protected by protecting groups acceptable in the field of organic chemistry. Protection and deprotection can be carried out by generally known protection and deprotection reactions (Protective Groups in Organic Synthesis, Fourth edition, written by T.W. Green, John Wiley & Sons Inc. (2006)) .
For generally known syntheses of pyridazinone compounds, the following may be referred to:
New Heterocyclic Compounds (Shinpen Heterokan-Kagoubutsu) Basics (Kodansha 20 04) pp.1-14, 69-132, 176-
207
Journal of Heterocyclic Chemistry, 33 (6) , 1579-1582; 1996
Comprehensive Heterocyclic Chemistry., Vol. 3, Part 2B, Pergamon Press
Journal of Heterocyclic Chemistry, 42, 427-43δ: 2005
WO9501343 and the like.
The compounds represented by the formula (I) wherein Q is represented by the following structure are prepared, for example, by the process represented by the following scheme (1).
(Scheme Removed)
The reaction of (1)-I with an amine (l)-II, (l)-IV
or (1)-V in a solvent with stirring, if necessary in the
presence of a catalyst and/or a base such as potassium
carbonate or triethylamine, if necessary under heating,
gives (l)-III, (l)-VIII, (1)-IX or a precursor thereof
(steps (1)-1 and (l)-2).
The subsequent reaction of (1)-VIII with (1)-VI or reaction of (l)-IX with (l)-VII in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine, if necessary under heating, gives (l)-III or a precursor thereof (step (l)-3).
The compounds of the formula (I) wherein Q is either of the following structures are prepared, for example, by the process represented by the following scheme (2).
(Scheme Removed)
The reaction with compound (2)-I and (2)-II in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine, if necessary under heating, gives (2)-III or a precursor thereof (step (2)-l). The reaction of the compound (2)-III in a solvent with stirring in the presence of an acid such as hydrochloric acid, if necessary under heating, gives (2)-IV or a precursor thereof (step (2)-2) . The reaction of the compound (2)-IV with a compound (2)-V in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine and/or by
using a condensation agent such as water soluble
carbodiimide (WSC), if necessary under heating, gives
(2)-VI or a precursor thereof (step (2)-3) . The reaction
of (2)-IV with a compound represented by R4NCS or R4NCO
in a solvent with stirring, if necessary in the presence
of a catalyst, if necessary under heating, gives (2)-VII
or a precursor thereof (step (2)-4) . The compound (2)-IV
is treated with thiophosgene, phosgene or their
equivalent in a solvent with stirring, if necessary under
heating, to give (2)-VIII or a precursor thereof (step
(2)-5) . The subsequent reaction of the compound (2)-VIII
with a compound (2)-IX in a solvent with stirring, if
necessary in the presence of a catalyst and/or a base
such as potassium carbonate or triethylamine, if
necessary under heating, gives (2)-X or a precursor
thereof (step (2)-6) .
The compounds shown in the scheme (2) wherein T is a sulfur atom are also obtainable from the compounds wherein T is an oxygen atom by using Lawesson's reagent or its equivalent in a solvent with stirring, if necessary under heating.
The compounds of the formula (I) wherein Q is any of the following structures are prepared, for example, by the process represented by the following scheme (3).
(Scheme Removed)
The reaction of compound (3)-I and (3)-II in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine, if necessary under heating, gives (3)-III (step (3)-l) . The reaction of the compound (3)-III with a compound (3)-IV in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine and/or by using a condensation agent such as WSC, if necessary under heating, gives (3)-VI or a precursor thereof (step (3)-2) . The compound (3)-III is treated with phosgene, thiophosgene or their equivalent in a solvent with stirring, if necessary under heating, and then reacted with (3)-V to give (3)-VII or a precursor thereof (step
(3)-3).
The compounds shown in the scheme (3) wherein T is a sulfur atom are also obtainable from the compounds wherein T is an oxygen atom by using Lawesson's reagent or its equivalent in a solvent with stirring, if necessary under heating.
The compounds of the formula (I) wherein X is a C1-6 alkylene group are prepared, for example, by the process represented by the following scheme (4).

(Scheme Removed)
The reaction of compounds (4)-I and (4)-II in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine, if necessary under heating, gives (4)-III or a precursor thereof.
The compounds of the formula (I) wherein X is a single bond or a C1-6 alkylene group, and each of Y and Z is either of the following structures: U
(Structure Removed)
or X is a single bond or C1-6 alkylene group, Y is either

of the following structures:
(Formula Removed)
and Z is a heterocyclyl group are prepared, for example, by the process represented by the following scheme (5).
(Formula Removed)
The reaction of a compound (5)-I or (5)-II with a compound (5) -III in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine, and/or by using a condensation agent such as WSC, if necessary under heating, gives (5)-IV or (5)-V or a precursor thereof (step (5)-l).
The reaction of a compound (5)-I or (5)-II with a compound ZH (wherein Z means a heterocyclyl group) in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine and/or by using a condensation agent such as WSC, if necessary under heating, gives (5)-VI or (5)-
VII or a precursor thereof (step (5)-2).
The compounds shown in the scheme (5) wherein U is a sulfur atom are also obtainable from the compounds wherein U is an oxygen atom by using Lawesson's reagent or its equivalent in a solvent with stirring, if necessary under heating.
The compounds shown in the scheme (5) wherein U is NOR10 are also obtainable from the compounds wherein U is an oxygen atom in a solvent with stirring by using H2NOR10 or its equivalent, if necessary in the presence of an acid or a base if necessary under heating.
The compounds of the formula (I) wherein X is a C1-6 alkylene, and each of Y and Z is any of the following structures:
(Structure Removed)
are prepared, for example, by the process represented by the following scheme (6).
(Structure Removed)
The reaction of a compound (6)-I with compounds (6)-
II to (6)-VI in a solvent with stirring, if necessary in
the presence of a catalyst and/or a base such as
potassium carbonate or triethylamine and/or under
Mitsunobu reaction conditions, if necessary under
heating, gives (6)-VII to (6)-XI or precursors thereof
(step (6)-1) .
The compounds shown in the scheme (6) wherein U is a sulfur atom are also obtainable from the compounds wherein U is an oxygen atom by using Lawesson's reagent or its equivalent in a solvent with stirring, if necessary under heating.
In the compounds (6)-IX, -S- can be converted to -SO- or -S02- in a solvent with stirring by using an oxidizing agent such as m-chloroperbenzoic acid, if necessary under heating.
The compounds of the formula (I) wherein R2 is a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group or a C2-14 aryl group are prepared, for example, by the process represented by the following scheme (7).
(Scheme Removed)
The reaction of (7)-I or (7)-II with an organic metal compounds (7)-III such as organic boronic acid, an
organic boronate, an organic tin compound or an organic
magnesium compound in a solvent with stirring, if
necessary by using a transition metal catalyst such as
tetrakistriphenylphosphinopalladium or (1,1'-
bis(diphenylphosphino)ferrocene)dichloropalladium and/or
a base such as potassium carbonate, triethylamine or
sodium carbonate, if necessary under heating, gives (7)-
IV or (7)-V or a precursor thereof (step (7)-l).
(Organic Synthesis Guided by Transition Metals
(Senikinzoku-ga Maneku Yuuki Gosei), written by Jiro
Tsuji, 1997, Kagakudojin, and Cross-Coupling Reactions: A
Practical Guide (Topics in Current Chemistry, vol. 219),
edited by Norio Miyaura, Springer).
The compounds of the formula (I) wherein R2 is a C1-6
alkoxy group or a C1-6 alkylthio group are prepared, for
example, by the process represented by the following
scheme (8).
(Scheme Removed)
The reaction of (8)-I or (8)-II with a corresponding
alcohol or thiol in a solvent with stirring, if necessary
in the presence of a catalyst and/or a base such as
sodium hydride, triethylamine or sodium carbonate, if
necessary under heating, gives (8)-III or (8)-IV or a
precursor thereof (step (8)-l) .
The reaction of (8)-V or (8)-VI with a corresponding alkyl halide, alkyl triflate or alcohol in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine and/or under Mitsunobu reaction conditions, if necessary under heating, gives (8)-III or (8)-IV or a precursor thereof (step (8)-2) .
The compounds of the formula (I) wherein R2 is a C1-6 alkylsulfonyl group are prepared, for example, from the compound (8)-III or (8)-IV wherein R2 is a C1-6 alkylthio group in a solvent with stirring by using an oxidizing agent such as m-chloroperbenzoic acid, if necessary under heating.
The amine compounds of the formula (1)-II, (1)-IV, (1)-V, 2-IX, 3-II, 3-V, 5-III and (6)-II are prepared from the corresponding nitrile compounds, acid amide compounds, oxime compounds, halides, ketone compounds, aldehyde compounds, alcohol compounds, boron compounds, epoxide compounds, acid imide compounds, carbamate compound and the like (Jikken Kagaku Koza 4th Edition, vol. 20, Organic Syntheses II, edited by the Chemical
Society of Japan, Maruzen, Bioorganic & Medicinal
Chemistry, 13, 4022, 2005, Kuramoti T. et al., Journal of
Medicinal Chemistry, 50, 149, 2007, Journal of Organic
Chemistry, 44, 2081, 1979, Acta Chemica Scandinavica, 19,
1741, 1965, Organic Letter, 5, 4497, 2003) .
The compound of the formula (I) wherein Q is either
of the following structures are prepared, for example, by
the process represented by the following scheme (9).
(Scheme Removed)
The reaction of (9)-I with an alcohol (9)-II or a thiol (9)-IV in a solvent with stirring, if necessary in the presence of a catalyst and/or a base such as potassium carbonate or triethylamine, if necessary under heating, gives (9)-III or (9)-V or a precursor thereof
(steps (9)-l and (9)-2).
The subsequent reaction of (9)-V in a solvent with stirring using an oxidizing agent such as m-chloroperbenzoic acid, if necessary under heating, can convert -S- to -SO- or -S02- (step (9)-3).
Now, the present invention will be described in further detail with reference to Reference Synthetic Examples, Synthetic Examples, Assay Examples and Formulation Examples. However, it should be understood that the present invention is by no means restricted by these specific Examples.
The 1H-NMR analysis was carried out at 300 MHz, and LC/MS was measured under the following conditions.
The compositions of the eluents used in silica gel column chromatography are represented on a volume basis. LC/MS condition 1
Column: Waters SunFire C18 (3.5 µm, 4.6x30 mm) Eluent: acetonitrile/0.1 volume% aqueous formic acid
(10/90 → 30/70)
LC/MS condition 2
Column: Waters SunFire C18 (3.5 µm, 4.6x30 mm)
Eluent: acetonitrile/0.1 volume% aqueous formic acid
(10/90 → 85/15)
LC/MS conditions 3
Column: Waters Xterra MSC18 (3.5 µm, 2.1x2 0 mm)
Eluent: acetonitrile/0.2 volurne% aqueous formic acid
(20/80 → 90/10)
LC/MS conditions 4
Column: Waters Xterra MSC18 (3.5 urn, 4.6x30 mm) Eluent: acetonitrile/0.2 volume% aqueous formic acid (15/85 → 85/15) LC/MS condition 5
Column: Waters SunFire C18 (3.5 µm, 2.1x2 0 mm) Eluent: acetonitrile/0.1 volume% aqueous formic acid
(10/90 → 30/70)
LC/MS condition 6
Column: Waters SunFire C18 (3.5 µm, 2.1x2 0 mm)
Eluent: acetonitrile/0.1 volume% aqueous formic acid
(10/90 → 60/40)
LC/MS condition 7
Column: Waters SunFire C18 (3.5 µm, 2.1x2 0 mm)
Eluent: acetonitrile/0.1 volume% aqueous formic acid
(10/90 → 85/15)
LC/MS condition 8
Column: Waters SunFire C18 (3.5 µm, 2.1x2 0 mm)
Eluent: acetonitrile/0.1 volume% aqueous formic acid
(20/80 → 100/0)
LC/MS condition 9
Column: Waters SunFire C18 (3.5 µm, 2.1x2 0 mm)
Eluent: acetonitrile/0.1 volume% aqueous formic acid
(40/60 → 100/0)
REFERENCE SYNTHETIC EXAMPLE 1 N- (Pyridin-4-ylmethyl)cyclopropanamine
(Formula Removed)
Cyclopropylamine (69 uL, 0.99 mmol) in ethanol (1 mL) was mixed with 4-pyridinecarbaldehyde (86 uL, 0.99
mmol) at room temperature and refluxed at 9 0°C for 2 hours. After completion of the reaction, the ethanol was evaporated azeotropically. The resulting reaction product in methanol (1 mL) was mixed with sodium borohydride (2 04 mg, 5.40 mmol) under cooling with ice and stirred at room temperature for 24 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (185 mg, quant.).
REFERENCE SYNTHETIC EXAMPLE 2 1-(Pyridin-4-yl)ethanamine
Me 1-(Pyridin-4-yl)ethanol
(Formula Removed)
4-Pyridinecarbaldehyde (1.00 ml, 10.5 mmol) in
tetrahydrofuran (10 mL) was mixed with methylmagnesium
bromide (0.97 M in tetrahydrofuran, 19.5 mL, 18.9 mmol)
under cooling with ice and stirred at room temperature
for 5 hours. After quenching by adding water under
cooling with ice, the reaction solution was mixed with
ethyl acetate, and the organic layer was washed with
saturated aqueous ammonium chloride, dried over anhydrous
sodium sulfate and evaporated under reduced pressure to
give the desired product (283 mg, 22% yield).
Morphology: pale yellow solid
1H-NMR(CDCl3)
8:1.56 (s, 3H), 4.73 (s, 1H), 7.29-7.33 (m, 1H), 7.42 (dd,
J = 4.5, 1.5 Hz, 1H) , 8.42-8.44 (m, 2H) .
2-[1-(Pyridin-4-yl)ethyl]isoindoline-1,3-dione
(Formula Removed)
A tetrahydrofuran solution (10 mL) of 1-(pyridin-4-yDethanol (283 mg, 2.32 mmol), phthalimide (375 mg, 2.55 mmol) and triphenylphosphine (686 mg, 2.55 mmol) was mixed with diisopropyl azodicarboxylate (4 0% in toluene, 1.34 mL, 2.55 mmol) and stirred at room temperature for 29 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride,
dried over anhydrous sodium sulfate and evaporated under
reduced pressure. The resulting residue was purified by
silica gel column chromatography (chloroform/ethyl
acetate = 10/1) to give the desired product (283 mg, 48%
yield).
LC/MS: Condition 2, retention time 1.24 min
LC/MS(ESI+ (Electrospray Ionization)) m/z; 253 [M+l]+
1-(Pyridin-4-yl)ethanamine
2-[1-(Pyridin-4-yl)ethyl]isoindoline-1,3-dione (283
mg, 1.12 mmol) in methanol (3 mL) was mixed with
hydrazine monohydrate (272 µL, 5.61 mmol) and stirred at
room temperature for 16 hours. After completion of the
reaction, the solid was filtered off with chloroform, and
the filtrate was evaporated under reduced pressure
repeatedly to give the desired product.
LC/MS: Condition 2, retention time 1.03 min
LC/MS (ESI + ) m/z; 123 [M+l] +
REFERENCE SYNTHETIC EXAMPLE 3
{1R, 2R, 3R, 5S) -N-Methylisopinocampheylamine
(Formula Removed)
Methyl (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3. l.l]hept-3-ylcarbamate
(Formula Removed)
A tetrahydrofuran solution (10 mL) of (1R, 2R, 3R, 5S) -isopinocampheylamine (1.0 mL, 5.89 mmol) and triethylamine (1.23 mL, 8.82 mmol) was mixed with methyl chloroformate (0.56 8 mL, 7.35 mmol) and stirred at room temperature for 15 minutes. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (1.11 g, 89% yield). Morphology: colorless oil {1R, 2R, 3R, 5S) -N-Methylisopinocampheylamine
Methyl (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylcarbamate (555 mg, 2.63 mmol) in tetrahydrofuran (10 mL) was mixed with lithium
aluminum hydride (501 mg, 13.2 mmol) and refluxed at 90°C for 3 hours. After cooling, the reaction solution was mixed with saturated aqueous sodium sulfate, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography to give the desired product (180 mg, 41% yield). Morphology: colorless oil
REFERENCE SYNTHETIC EXAMPLE 4
(li?,2i?,3,S,51S) -Isopinocampheylamine

(Formula Removed)
A tetrahydrofuran solution (10 mL) of {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ol (500 mg, 3.24 mmol), phthalimide (525 mg, 3.57 mmol) and triphenylphosphine (93 6 mg, 3.57 mmol) was mixed with diisopropyl azodicarboxylate (1.9 M in toluene, 1.88 mL) and stirred at room temperature for 22 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was mixed with water and extracted with ethyl acetate. From the resulting organic layer, the solvent was removed by vacuum distillation, and the residue was dissolved in methanol (10 mL) and stirred with hydrazine monohydrate (1.00 mL, 32 .1 mmol) for 15 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel chromatography (ethyl acetate) to give the desired product.
Morphology: light brown oil
LC/MS: condition 2, retention time 0.80 min LC/MS (ESI + ) m/z; 154 [M+l] + REFERENCE SYNTHETIC EXAMPLE 5
{1S,2S,3R,SR)-Isopinocampheylamine
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 4 by using {1S,1S, 3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol. Morphology: light brown oil
LC/MS: condition 2, retention time 0.81 min LC/MS (ESI + ) m/z; 154 [M+l] + REFERENCE SYNTHETIC EXAMPLE 6 3,4,4-Trimethylcyclohex-2-enamine
(Formula Removed)
An ethanol-water solution (1:3, 4 mL) of 3,4,4-trimethylcyclohex-2-enone (500 mg, 3.62 mmol) and sodium acetate (356 mg, 4.35 mmol) was stirred with
hydroxylamine sulfate (475 mg, 2.89 mmol) at 70°C for 40 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate, and the resulting organic layer was evaporated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (5 mL), mixed with lithium aluminum
hydride (412 mg, 10.9 mmol) at 0°C and stirred at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium sulfate, dried over anhydrous magnesium sulfate and filtered through celite, and the solvent was removed by vacuum distillation to give the desired product.
Morphology: colorless oil
N-Methoxy-N-methylpyridazine-4-carboxamide
LC/MS: condition 3, retention time 0.40 min LC/MS (ESI + ) m/z; 140 [M+l] + REFERENCE SYNTHETIC EXAMPLE 7 1-(Pyridazin-4-yl)ethanamine hydrochloride
(Formula Removed)
A N,N-dimethylformamide solution (16 mL) of 4-pydirazincarboxylic acid (1.61 g, 13.0 mmol), N-methyl-N-methoxyamine hydrochloride (2 .54 g, 26.0 mmol) , 1-(3-dimethylaminopropyl)- 3 -ethylcarbodiimide hydrochloride (6.23 g, 32.5 mmol), 1-hydroxybenzotriazole hydrate (catalytic amount) and triethylamine (9.06 mL, 65.0 mmol
was stirred at room temperature for 3 days. After
completion of the reaction, the solvent was removed by vacuum distillation, and the residue was mixed with water and chloroform and filtered through celite. The filtrate was extracted with chloroform, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (94% yield). Morphology: light brown oil
LC/MS: Condition 7, retention time 0.71 min LC/MS (ESI + ) m/z; 168 [M+l] + 1H-NMR(CDCl3)
δ :3.42 (s, 3H), 3.58 (s, 3H), 7.76 (dd, J = 5.4 and 2.0 Hz, 1H) , 9.35 (d, J = 5.4 Hz, 1H) , 9.45 (d, J = 2.0 Hz, 1H) . 1-(Pyridazin-4-yl)ethanone
(Formula Removed)
To N-methoxy-N-methylpyridazine-4-carboxamide (1.13 g, 6.76 mmol) in tetrahydrofuran (22 mL), methylmagnesium bromide (10.1 mL, 10.1 mmol, 1M in diethyl ether) was added dropwise at 0°C in a nitrogen stream, and the resulting solution was stirred for 1 hour. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and
extracted with chloroform, and the extract was dried over
anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate= 1/2 → 0/1) to give the desired product (42% yield). Morphology: pale yellow solid LC/MS: Condition 7, retention time 0.75 min LC/MS (ESI + ) m/z; 123 [M+l] + 1H-NMRtCDCl3)
δ:2.70 (s, 3H), 7.86 (dd, J = 0.8 and 5.4 Hz, 1H), 9.48 (d, J = 5.4 Hz, 1H), 9.61 (d, J = 0.8 Hz, 1H). N-Hydroxy-1-(pyridazin-4-yl)ethanimine hydrochloride
(Formula Removed)
1-(Pyridazin-4-yl)ethanone (1.00 g, 8.19 mmol) and hydroxylamine hydrochloride (598 mg, 8.60 mmol) were
stirred in ethanol (20 mL) at 90°C for 10 minutes. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting crude reaction product was used for the next step. Morphology: brown solid
LC/MS: Condition 7, retention time 0.75 min LC/MS (ESI + ) m/z; 138 [M+l] + 1H-NMRtCDCl3) δ:2.69 (s, 3H) , 7.86 (dd, J = 0.8 and 5.3Hz, 1H) , 9.46
(d, J = 5.3Hz, 1H), 7.61 (d, J = 0.8Hz, 1H).
1-(Pyridazin-4-yl)ethanamine hydrochloride
N-Hydroxy-1-(Pyridazin-4-yl)ethanimine hydrochloride
(1.48 g, 8.53 mmol) and 10% palladium-carbon (0.15 g) were stirred in ethanol (30 mL) in a hydrogen stream at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was evaporated under reduced pressure. The resulting crude reaction product was used for the next step. Morphology: brown amorphous
LC/MS: Condition 5, retention time 0.71 min LC/MS (ESI + ) m/z; 124 [M+l] + 1H-NMRtCDCl3)
δ:1.56 (d, J = 7.0Hz, 3H), 4.52 (br d, J = 7.0Hz, 1H), 7.89 (dd, J = 2.5 and 5.4Hz, 1H) , 8.8-9.1 (br s, 3H) , 9.31 (d, J = 5.4 Hz, 1H), 9.43 (d, J = 2.5Hz, 1H). REFERENCE SYNTHETIC EXAMPLE 8 rac-2-[(Methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]heptan-3-amine
(Formula Removed)
rac-2-[(Methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]hept-2-ene
(Formula Removed)
(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methanol (10.0 g, 65.7 mmol), diisopropylethylamine
(17.0 mL, 97.6 mmol) and chloromethyl methyl ether (6.5 mL, 85.6 mmol) were stirred in dichloromethane (100 mL) at room temperature for 1 day. After completion of the reaction, the reaction solution was mixed with saturated sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography
(hexane-ethyl acetate = 10/1) to give the desired product
(100% yield).
Morphology: colorless oil 1H-NMRtCDCl3)
δ:0.84 (s, 3H) , 1.18 (d, J = 8.7 Hz, 1H) , 1.29 (s, 3H) , 2.09-2.44 (m, 5H), 3.37 (s, 3H), 3. 92 (s, 2H), 4.61 (s, 2H) , 5.51 (s, 1H)
(Formula Removed)
rac-2-[(Methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]heptan-3-ol
(Formula Removed)
2-[(methoxymethoxy)methyl]-6,6-
dimethylbicyclo[3.1.1]hept-2-ene (3 . 00 g, 15.3 mmol) in
tetrahydrofuran (25 mL), a borane-tetrahydrofuran complex
(0.99 M in tetrahydrofuran, 12 mL) was added gradually
dropwise at 0°C, and then the resulting reaction solution was warmed to room temperature and stirred for 1 days.
The reaction solution was cooled to 0°C, and 28 mass% aqueous ammonia (2 mL) and about 8 mass% aqueous sodium hypochlorite (28 g) were added gradually dropwise successively. The reaction solution was warmed to room temperature and stirred for 1 day. After completion of the reaction, the reaction solution was mixed with 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate = 10/1 → 4/1) to give rac-2-[(methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]heptan-3-ol.
Separately, the aqueous layer was brought to pH = 10 with 1 M aqueous sodium hydroxide and extracted with chloroform twice. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude reaction product containing rac-2-[(methoxymethoxy)methyl]-6,6-
dimethylbicyclo[3.1.1]heptan-3-amine, which was used for the next step. rac-2-[(Methoxymethoxy)methyl]-6,6-
dimethylbicyclo[3.1.1]heptan-3-ol
Yield: 64%
Morphology: pale yellow oil 1H-NMRtCDCl3)
δ:0.90 (s, 3H) , 1.14 (d, J = 9.6 Hz, 1H) , 1.21 (s, 3H) , 1.70-1.81 (m, 1H), 1.86-1.91 (m, 1H), 1.93-2.00 (m, 1H), 2.15-2.27 (m, 1H), 2.40-2.60 (m, 2H), 3.38 (s, 3H), 3.50-3.65 (m, 2H), 4.25-4.35 (m, 1H), 4.65 (s, 2H) rac-2-[(Methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]heptan-3-amine Yield: 9%
Morphology: yellow oil REFERENCE SYNTHETIC EXAMPLE 9 1-[3-(Morpholin-4-yl)pyridin-4-yl]methanamine
(Formula Removed)
3-Chloro-5-(morpholin-4-yl)pyridin-4-ylcarbonitrile (103 mg, 0.462 mmol)in methanol (6 mL) was mixed with 10 mass% palladium-carbon (20 mg) in a nitrogen stream and stirred at room temperature in a hydrogen atmosphere for 6 hours. After completion of the reaction, the reaction solution was filtered through celite and evaporated under reduced pressure. The resulting crude reaction product was used for the next reaction without further
purification (99% yield).
Morphology: ocher amorphous
1H--NMR (CD3OD)

δ:3.02-3.06 (m, 4H), 3.84-3.89(m, 4H), 4.31(s, 2H), 7.49 (d, J = 5.2Hz, 1H), 8.41 (d, J = 5.2Hz, 1H), 8.5l(s, 1H)
REFERENCE SYNTHETIC EXAMPLE 10
rac-(6,6-Dimethylbicyclo[3.1.1]hept-2-en-2-yl)methyl
methyl ether
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 8 by using methyl iodide (56% yield).
Morphology: pale yellow oil 1H-NMRtCDCl3)
δ:0.84 (s, 3H) , 1.18 (d, J = 8.4 Hz, 1H) , 1.29 (s, 3H) , 2.09-2.44 (m, 5H), 3.29 (s, 3H), 3.77-3.79 (m, 2H), 5.48-5.50 (m, 1H)
REFERENCE SYNTHETIC EXAMPLE 11
4-(Methoxymethoxy)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene
(Formula Removed)
Synthesis was carried out in the same manner as in
Reference Synthetic Example 8 by using 4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-ol (79% yield). Morphology: colorless oil 1H-NMRtCDCl3)
δ:0.84 (s, 3H), 1.18 (d, J = 5.7 Hz, 1H), 1.34 (s, 3H), 1.73 (t, J = 1.5 Hz, 3H), 1.94-1.98 (m, 1H), 2.33-2.48
(m, 2H), 3.38 (s, 3H), 4.35 (brs, 1H), 4.70 ( dd, J = 6.6, 8.7 Hz, 2H), 5.37 (brs, 1H) REFERENCE SYNTHETIC EXAMPLE 12 5-Methoxytricyclo [3.3.1.13,7] decan-2-one
55% sodium hydride (40 mg, 0.917 mmol) in N,N-dimethylformamide (1 mL) was mixed with 5-hydroxy-2-adamantanone (100 mg, 0.602 mmol) and methyl iodide (750
µL, 12 mmol) at 0°C and stirred at 50°C for 8 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step.
Morphology: colorless oil REFERENCE SYNTHETIC EXAMPLE 13
(Formula Removed)
(Methoxymethoxy)tricyclo[3.3.1.1 ' ]decan-2-one

(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 12 by using chloromethyl methyl ether, and the resulting crude product containing the desired product was used for the next step. Morphology: colorless oil REFERENCE SYNTHETIC EXAMPLE 14
2-(1,3-Dioxolan-2-yl)-1-(pyridin-4-yl)ethanol OH
(Formula Removed)
4-Pyridinecarbaldehyde (0.5 ml, 5.25 mmol) in tetrahydrofuran (10 mL) was refluxed with (1,3-dioxolan-2-ylmethyl)magnesium bromide (0.5 M, 12.6 ml, 6.30 mmol) for 7 hours. After cooling, the reaction solution was quenched with saturated aqueous ammonium chloride and mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product was used for the next step without further purification (124 mg, 13%). Morphology: pale yellow oil
1H-NMRtCDCl3)
δ : 2 .00-2 .10 (m, 2H), 3.70-4.06 (m, 4H), 4.15-4.25 (m, 1H), 4.90-5.06 (m,lH), 7.32 (d, J = 5.9 Hz, 2H), 8.52 (d, J = 5.9 Hz, 2H). REFERENCE SYNTHETIC EXAMPLES 15 TO 16
Compounds were synthesized in the same manner as in Reference Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 2. "Crude" in the remarks column means that the crude reaction product was used for the next step without purification.
TABLE 2
(Table Removed)
The structures of the compounds obtained are shown
below.
(Formula Removed)
REFERENCE SYNTHETIC EXAMPLES 17 to 24
Amines were synthesized in the same manner as in Reference Synthetic Example 2, and the yields and morphology of the resulting amines, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 3. "Crude" in the remarks column means that the crude reaction product was used for the next step without purification.
TABLE 3
(Table Removed)
The structures of the compounds obtained are shown
below.
(Formula Removed)
REFERENCE SYNTHETIC EXAMPLES 25 to 28
Amines were synthesized in the same manner as in Reference Synthetic Example 4 by using ketones or aldehydes, and the yields and morphology of the resulting amines, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 4. "Crude" in the remarks column means that the crude reaction product was used for the next step without purification.
TABLE 4
(Table Removed)
The structures of the compounds obtained are shown
below.
(Formula Removed)
REFERENCE SYNTHETIC EXAMPLES 2 9 TO 3 0
Amines were synthesized in the same manner as in Reference Synthetic Example 7 by using ketones or aldehydes, and the yields and morphology of the resulting amines, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 5. "Crude" in the remarks column means that the crude reaction product was used for the next step without purification.
TABLE 5
(Table Removed)
The structures of the compounds obtained are shown
below.
(Formula Removed)
REFERENCE SYNTHETIC EXAMPLES 31 TO 33
Amines were synthesized in the same manner as in Reference Synthetic Example 8, and the yields and morphology of the resulting amines, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 6. "Crude" in the remarks column means that the crude reaction product was used for the next step without purification.
TABLE 6
(Table Removed)
The structures of the compounds obtained are shown
below.
(Formula Removed)
REFERENCE SYNTHETIC EXAMPLES 34 TO 3 5
Amines were synthesized in the same manner as in Reference Synthetic Example 9, and the yields and morphology of the resulting amines, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 7. "Crude" in the remarks column means that the crude reaction product was used for the next step without purification.
TABLE 7
(Table Removed)
The structures of the compounds obtained are shown
(Formula Removed)
REFERENCE SYNTHETIC EXAMPLE 3 6
1-(Pyridin-4-yl)cyclopropanamine
below.
(Formula Removed)
To 4-cyanopyridine (1.04 g, 10 mmol) in diethyl ether (50 mL), tetraisopropoxytitanium (3.27 mL, 11 mmol) and ethylmagnesium bromide (6.3 mL, 22 mmol, 3 M in diethyl ether) were added dropwise in a nitrogen stream
at -78°C, and after 10 minutes, the reaction solution was warmed to room temperature and stirred for 1.5 hours and then stirred with a borane-tetrahydrofuran complex (21.5 mL, 2 0 mmol. 0.93 M in tetrahydrofuran) for 1 hour. After completion of the reaction, the reaction solution was diluted with diethyl ether (10 mL), and dilute hydrochloric acid (30 mL, 1 M) was added dropwise. After addition of aqueous sodium hydroxide (100 mL, 10% w/v), the reaction solution was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol = 9/1) to give the desired product
(2 .6% yield) .
Morphology: ocher amorphous 1H-NMRtCDCl3)
δ:1.19-1.24 (m, 2H), 1.37-1.41 (m, 2H), 7.31 (d, J = 6.9 Hz, 2H), 8.42 (d, J = 6.9 Hz, 2H) REFERENCE SYNTHETIC EXAMPLE 3 7 Ethyl 3-amino-3-(pyridin-4-yl)prop-2-enoate
(Formula Removed)
Ethyl isonicotinoylacetate (1.00 g, 5.17 mmol) and ammonium formate (1.63 g, 25.8 mmol) were stirred in
methanol (10 mL) at 7 0°C for 18 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product was used for the next step without further purification. Morphology: pale yellow solid 1H-NMR (CDCl3)
δ :1.31 (t, J = 7.2 Hz, 3H) , 4.20 (q, J = 7.2 Hz, 2H) , 5.03 (s, 1H), 7.42 (d, J = 6.2 Hz, 2H), 8.69 (d, J = 6.2 Hz, 2H) REFERENCE SYNTHETIC EXAMPLE 3 8
Ethyl 3 -amino-3 -(pyridin-4-yl)propanoate
(Formula Removed)
To ethyl 3-amino-3-(pyridin-4-yl)prop-2-enoate (0.98 g) in methanol (30 mL), 10% palladium-carbon (50 mg) was added in a nitrogen stream, and the reaction solution was stirred in a hydrogen atmosphere at room temperature for 3 days. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was evaporated. The resulting crude reaction product was used for the next step without further purification (42% yield, two steps). Morphology: ocher amorphous 1H-NMR (DMSO-d6)
δ : 1.09-1.12 (m, 3H), 2.58-2.65 (m, 2H), 3.93-4.08 (m, 2H), 4.13-4.17 (m, 1H), 7.32-7.38 (m, 2H), 8.45-8.48 (m, 2H)
REFERENCE SYNTHETIC EXAMPLE 3 9
rac-2-[(Methoxymethoxy)methyl]-6,6-
rac-3-Amino-6,6-dimethylbicyclo[3.1.1]heptane-2-carbonitrile
(Formula Removed)
dimethylbicyclo[3.1.1]heptan-3-ol
(Formula Removed)
rac-2-[(Methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]heptan-3-ol (2.00 g, 9.33 mmol) prepared in Reference Synthetic Example 8, silica gel (2 g) and pyridinium chlorochromate (4.00 g, 18.5 mmol) were stirred in dichloromethane (4 0 mL) at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography (hexane/ethyl acetate = 10/1 → 4/1) to give a crude reaction product. To lithium aluminum hydride (590 mg, 15.5 mmol) in tetrahydrofuran (50 mL), the crude product (1.64 g) in tetrahydrofuran (5
mL) was added dropwise at -10°C, and the resulting solution was stirred for 2 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate and a small amount of saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and filtered through celite, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1 → 5/1) to give the desired product (52% yield, two steps).
Morphology: colorless oil
1H-NMRtCDCl3)
δ :l.01-1.04 (m, 4H) , 1.16 (s, 3H) , 1.83-1.89 (m, 1H) , 1.89-1.92 (m, 2H), 2.24-2.30 (m, 1H), 2.44-2.52 (m, 1H), 2.60-2.70 (m, 1H), 2.90 (m, 1H), 3.38 (s, 3H), 3.40-3.47
(m, 1H) , 4.12 (t, J = 10.8 Hz, 1H) , 4.47-4.58 (m, 1H) , 4.65 (s, 2H)
rac-2-{2-[(Methoxymethoxy)methyl]-6,6-
dimethylbicyclo[3.1.1]hept-3-yl}-1H-isoindole-1,3(2H)-dione
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 2 by using rac-2-
[(methoxyme thoxy)me thy1]-6,6-
dimethylbicyclo[3.1.1]heptan-3-ol (59% yield). Morphology: colorless oil
δ:1.13 (s, 3H), 1.29 (s, 3H), 1.90-2.60 (m, 6H), 2.80-2.95 (m, 1H), 3.26 (s, 6H), 3.40-3.60 (m, 2H), 4.40-4.60
(m, 2H), 4.70-4.85 (m, 1H), 7.65-7.80 (m, 2H), 7.80-7.90
(m, 2H)
rac-2-[2-(Hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-
3-yl]-1H-isoindole-1,3(2H)-dione
(Formula Removed)
rac-2-{2-[(Methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]hept-3-yl}-1H-isoindole-1,3(2H)-dione (0.97 g, 2.82 mmol) was stirred with hydrogen chloride-methanol (2 0 mL, 10 %w/v) at room temperature for 1 day. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the residue was mixed with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (100% yield). Morphology: colorless oil 1H-NMRtCDCl3)
δ:1.11 (s, 3H), 1.29 (s, 3H), 2.00-2.15 (m, 3H), 2.30-2.40 (m, 2H), 2.40-2.50 (m, 1H), 2.65-2.80 (m, 1H), 3.50-3.80 (m, 2H), 4.73 (q, J = 9.0 Hz, 1H), 7.65-7.80 (m, 2H), 7.80-7.90 (m, 2H)
3-(1,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-6,6-dimethylbicyclo[3.1.1]heptane-2-carbaldehyde
(Formula Removed)
rac-2-[2-(Hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]-1H-isoindole-1,3(2H)-dione (75 0 mg, 2.51 mmol), silica gel (0.75 g) and pyridinium chlorochromate (1. 08 g, 5 . 01 mmol) were stirred in dichloromethane (2 0 mL) at room temperature for 2 hours. After completion of the reaction, the reaction solution was filtered through celite, and the filtrate was evaporated. The resulting residue was purified by column chromatography (hexane/ethyl acetate = 5/1 → 3/1) to give the desired product (61% yield) . Morphology: colorless solid
δ:0. 94 (s, 3H), 1.31 (s, 3H), 2.05-2.21 (m, 3H), 2.45-2.60 (m, 2H), 2.60-2.70 (m, 1H), 3.48 (dd, J = 7.5, 2.1 Hz, 1H), 5.40-5.55 (m, 1H), 7.65-7.80 (m, 2H), 7.80-7.90
(m, 2H), 9.71 (s, 1H)
rac-3-Amino-6,6-dimethylbicyclo[3.1.1]heptane-2-
carbonitrile
rac-3-(1,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-6,6-dimethylbicyclo[3.1.1]heptane-2-carbaldehyde (100 mg, 0.336 mmol) and hydroxylamine hydrochloride (28 mg, 0.403
mmol) were stirred in formic acid (0.5 mL) at 110°C for 3 hours. After completion of the reaction, the reaction
solution was mixed with water and extracted with ethyl
acetate. The organic layer was dried over anhydrous
sodium sulfate to give a crude product. The crude
product in methanol (3 mL) was stirred with hydrazine
monohydrate (52 µL, 1.67 mmol) at room temperature for 1
day. The reaction solution was evaporated under reduced
pressure, and the residue was mixed with ethanol (10 mL)
and refluxed for 7 hours. After completion of the
reaction, the reaction solution was evaporated under
reduced pressure, and the resulting solid was filtered
off with diisopropyl ether. The filtrate was evaporated
under reduced pressure. The resulting crude reaction
product containing the desired product was used for the
next step.
Morphology: yellow oil
REFERENCE SYNTHETIC EXAMPLE 4 0
rac-2-(Difluoromethyl)-6,6-dimethylbicyclo[3.1.1]heptan-
3-amine
(Formula Removed)
rac-3-(1,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)-6,6-dimethylbicyclo[3.1.1]heptane-2-carbaldehyde (122 mg, 0.41 mmol) prepared in Reference Synthetic Example 3 9 in dichloromethane (3 mL) was mixed with (diethylamino)sulfur trifluoride (180 uL, 1.36 mmol) at -
78°C and stirred at -78°C for 1 hour and then at room temperatuer for 1 hour. After completion of the reaction, the reaction solution was mixed with saturated aqeuous sodium hydrogen carbonate and extracted with ethyl aetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude reaction product. The crude reaction product in ethanol (5 mL) was mixed with hydrazine monohydrate (100 µL, 1.87 mmol) and refluxed for 1 day. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting solid was filtered off with chloroform. The filtrate was evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step. Morphology: orange oil REFERENCE SYNTHETIC EXAMPLE 41 2-Aminotricyclo [3 .3 .1 .l3,7] decan-1-ol
(Formula Removed)
Tricyclo [3.3.1.13'7] dec-1-yl carbamate
(Formula Removed)
1-Adamantanol (1.52 g, 10.0 mmol) in dichloromethane
(30 mL) was mixed with trichloroacetyl isocyanate (1.40
mL, 11.8 mmol) at 0°C, then warmed to room temperature and stirred for 2 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting crude reaction product was mixed with methanol (15 mL) and saturated
aqueous potassium carbonate and stirred at 5 0°C for 1 day. After completion of the reaction, the methanol was removed by vacuum distillation, and the residue was filtered. The resulting solid was washed with water and dried under reduced pressure to give the desired product (74% yield, 2 steps). Morphology: colorless solid 1H-NMR (CDCl3)
δ:1.60 (s, 6H) , 2.02 (s, 6H) , 2.09 (s, 3H), 6.14 (bs, 2H) 2-Oxa-4-azatetracyclo [6 . 3 .1.16'10. 01'5] tridecan-3-one
(Formula Removed)
Tricyclo [3 .3 .1 .l3'7] dec-1-yl carbamate (100 mg, 0.512 mmol), iodobenzenediacetate (220 mg, 0.683 mmol), magnesium oxide ( 5 0 mg, 1.24 mmol) and rhodium (II) acetate dimer (22 mg, 0.050 mmol) were stirred in
dichloromethane (3 mL) at 5 0°C for 5 hours. After completion of the reaction, the reaction solution was filtered, and the solid was washed with chloroform and
the filtrate was evaporated under reduced pressure. The
resulting residue was purified by silica gel column
chromatography (hexane/ethyl aetate =10/1 -> 2/1) to give
the desired product (77% yield).
Morphology: colorless solid
LC/MS: Condition 7, retention time 3.18 min
LC/MS(ESI + ) m/z; 194 [M+l] +
2-Aminotricyclo [3 .3 .1 .l3'7] decan-1-ol
2-Oxa-4-azatetracyclo [6 .3 .1 .l6,10. O1,5] tridecan-3-one
(76 mg, 0.395 mmol) in 1,4-dioxane (1 mL) was stirred
with 5 M aqueous potassium hydroxide at 7 0°C for 1 day.
After completion of the reaction, the reaction solution
was extracted with chloroform, and the organic layer was
dried over anhydrous sodium sulfate and evaporated under
reduced pressure to give the desired product (70% yield).
Morphology: colorless solid
LC/MS: Condition 7, retention time 0.53 min
LC/MS(ESI+) m/z; 168[M+l]+
REFERENCE SYNTHETIC EXAMPLE 42
2- (Aminomethyl) tricyclo [3.3.1.13'7] decan-2-ol
(Formula Removed)
2-Adamantanone (1.50 g, 10.0 mmol), zinc iodide (96 0 mg, 3.01 mmol) and trimethylsilyl cyanide (1.20 g, 12.1 mmol) were stirred in dichloromethane (30 mL) at room
temperature for 1 day. After completion of the reaction,
the reaction solution was mixed with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give a crude reaction product. To lithium aluminum hydride (750 mg, 19.8 mmol) in tetrahydrofuran (50 mL), the crude reaction product (2.31 g) in tetrahydrofuran (5 mL) was added dropwise at room temperature, and the resulting solution was stirred at 70°C for 5 hours. After completion of the reaction, the reaction solution was mixed with chloroform and a small amount of saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and filtered through celite, and the filtrate was evaporated under reduced pressure. The resulting crude product containing the desired product was used for the next step.
Morphology: colorless solid 1H-NMR (CDCl3)
δ:1.50-1.60 (m, 2H), 1.60-1.90(m, 10H), 2.20-2.30 (m, 2H), 2.87 (s, 2H)
REFERENCE SYNTHETIC EXAMPLE 4 3 2- (Aminomethyl) tricyclo [3.3.1.13'7] decan-2-ol

(Formula Removed)
Synthesis was carried out in the same manner as in
Reference Synthetic Example 42 by using {1R, 2R, 5S) -3-
(aminomethyl)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol.
Morphology: colorless oil
LC/MS: Condition 7, retention time 0.90 min
LC/MS(ESI + ) m/z; 184 [M+l] +
REFERENCE SYNTHETIC EXAMPLE 44
2-Methyl-1-(pyridin-4-yl)propan-1-amine
(Formula Removed)
4-Pyridinecarbaldehyde (0.5 mL, 5.25 mmol) in tetrahydrofuran (10 mL) was mixed with lithium hexamethyldisilazide in tetrahydrofuran (1 M, 6.3 mL, 6.3
mmol) and stirred at 0°C for 4 hours and then stirred with isopropylmagnesium bromide in tetrahydrofuran (0.98 M, 6.3 mL, 6.3 mmol) at room temperature for 16 hours. After completion of the reaction, 1 M aqueous hydrochloric acid was added, and the reaction solution was washed with ethyl acetate. After addition of 1 M aqueous sodium hydroxide, the combined aqueous layer was extracted with chloroform. The resulting organic layer was filtered through celite, and the filtrate was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step.
Morphology: brown oil
1H-NMR (CDCl3)
δ:0.69 (d, J = 6.9 Hz, 3H), 0.80 (d, J = 6.6 Hz, 3H),1.74(ddd, J = 6.9, 6.6, 6.3 Hz, 1H), 3.53 (d, J = 6.3 Hz, 1H), 7.10 (d, J = 4.8 Hz, 2H), 8.39 (d, J = 4.8 Hz, 2H)
REFERENCE SYNTHETIC EXAMPLE 4 5 1-(Pyrimidin-4-yl)propan-1-amine
1-(5-Bromopyrimidin-4-yl)propan-1-ol
(Formula Removed)
To 5-bromopyrimidine (2 .39 g, 15.0 mmol) and propionaldehyde (1.05 g, 18.0 mmol) in diethyl ether (80 mL), lithium diisopropylamide (18 mmol) in diethyl ether (20 mL) was gradually added dropwise at 0°C. After the dropwise addition, the reaction mixture was warmed to room temperature and stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was extracted by adding water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The
resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 2.5/1) to give a
mixture (colorless oil) containing the desired product,
which was used for the next step (427 mg, 13% yield).
2-[1-(5-Bromopyrimidin-4-yl)propyl]isoindoline-1,3-dione
(Formula Removed)
A tetrahydrofuran solution (10 mL) of 1-(5-bromopyrimidin-4-yl)propan-1-ol (427 mg, 1.97 mmol), phthalimide (3 53 mg, 2.40 mmol) and triphenylphosphine (629 mg, 2.40 mmol) was mixed with diisopropyl azodicarboxylate (4 0% in toluene, 1.04 mL, 2.40 mmol) under cooling with ice and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 10/1) to give the desired product (568 mg, 83% yield). Morphology: colorless oil 1H-NMR (CDCl3) δ:1.11 (t, J = 7.5 Hz, 3H), 2.30-2.50 (m, 1H), 2.5-2.8
(m, 1H), 5.50 (dd, J = 5.7 Hz, J = 10.8 Hz, 1H), 7.71-
7.78 (m, 2H), 7.84-7.89 (m, 2H), 8.75 (s, 1H), 9.07 (s,
1H)
2-[1-(Pyrimidin-4-yl)propyl]isoindoline-1,3-dione
(Formula Removed)
2-[1-(5-Bromopyrimidin-4-yl)propyl]isoindoline-1,3-dione (568 mg, 1.64 mmol), triethylamine (0.228 mL, 1.64 mmol) and 10% palladium-carbon (50 wt%, 100 mg) were stirred in methanol (10 mL) in a hydrogen atmosphere at room temperature for 1 day. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give the desired product (292 mg, 66% yield). Morphology: colorless oil 1H-NMR (CDCl3)
δ:1.05 (t, J = 7.5 Hz, 3H), 2.30-2.70 (m, 2H), 5.34 (dd, J = 5.7 Hz, J = 10.8 Hz, 1H), 7.41 (d, J = 5.4 Hz, 1H), 7.71-7.78 (m, 2H), 7.84-7.89 (m, 2H), 8.69 (d, J = 5.4 Hz, 1H), 9.13 (s, 1H) 1-(Pyrimidin-4-yl)propan-1-amine
2-[1-(Pyrimidin-4-yl)propyl]isoindoline-1,3-dione
(292 mg, 1.09 mmol) in methanol (2 mL) was stirred with
hydrazine monohydrate (153 µL, 3.15 mmol) at room
temperature for 16 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product (84% yield). Morphology: colorless oil 1H-NMR (CDCl3)
δ: 0.93 (t, J = 7.5 Hz, 3H), 1.60-1.90 (m, 2H), 3.86 (m, 1H), 7.34 (d, J = 5.4 Hz, 1H), 8.67 (d, J = 5.4 Hz, 1H), 9.16 (s, 1H)
REFERENCE SYNTHETIC EXAMPLE 4 6 1-(Pyrimidin-4-yl)ethanol
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 45 by using acetaldehyde. Morphology: colorless oil 1H-NMR (CDCl3)
δ:1.44 (d, J = 6.9 Hz, 3H), 4.12 (q, J = 6.9 Hz, 1H), 7.38 (d, J = 5.4 Hz, 1H), 8.68 (d, J = 5.4 Hz, 1H), 9.16
(s, 1H) REFERENCE SYNTHETIC EXAMPLE 4 7
(1-Methyl-1H-tetrazol-5-yl)methanamine
(Formula Removed)
2-[(l-Methyl-1H-tetrazol-5-yl)methyl]isoindoline-1,3-dione
(Formula Removed)
5-(Chloromethyl)-1-methyl-1H-tetrazole (a crude product 6.9 g prepared in accordance with Chemical & Pharmaceutical Bulletin, 37(2), 322-6:1989), was dissolved in 5 0 mL of dimethylformamide and stirred with potassium phthalimide (5.00 g, 27.0 mmol) and sodium iodide (391 mg, 2.60 mmol) at room temperature for 17 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give the desired product (550 mg, 4% yield, two steps). Morphology: colorless solid
LC/MS: Condition 7, retention time 1.98 min LC/MS (ESI + ) m/z; 244 [M+l] +
1H-NMR (CDCl3)
δ:4.23 (s, 3H), 5.12 (s, 2H), 7.74-7.80 (m, 2H), 7.85-7.92 (m, 2H)
(1-Methyl-1H-tetrazol-5-yl)methanamine
2-[(l-Methyl-1H-tetrazol-5-yl)methyl]isoindoline-1,3-dione (122 mg, 0.50 mmol) in methanol (1 mL) was mixed with hydrazine monohydrate (122 µL, 2.50 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, the solid was filtered off with chloroform. The filtrate was evaporated under reduced pressure repeatedly to give the desired product
(98% yield).
Morphology: colorless oil 1H-NMR (CDCl3)
δ :4 .10 (s, 3H) , 4.17 (s, 2H) REFERENCE SYNTHETIC EXAMPLE 4 8
5-Bromo-4-methylpyrimidine
(5-Bromopyrimidin-4-yl)methanamine
(Formula Removed)
To 5-bromopyrimidine (17.3 g, 109 mmol) in diethyl ether (100 mL), methyllithium in diethyl ether (109 mmol, 1.09 M, 100 mL) was gradually added dropwise at room temperature, and the resulting reaction mixture was stirred at room temperature for 1 hour. After completion of the reaction, the reaction mixture was stirred with water (1.96 mL, 109 mmol) and 2,3-dichloro-5,6-dicyano-p-benzoquinone (24.7 g, 109 mmol) in tetrahydrofuran (150 mL) at room temperature for 16 hours. After completion of the reaction, water and ethyl acetate were added, and the organic layer was separated. The organic layer was washed with 1M aqueous sodium hydroxide, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography(hexane/ethyl acetate = 1/1) to give the desired product (2.9 g, 15% yield). Morphology: yellow oil 1H-NMR (CDCl3)
δ:2.65 (s, 3H), 8.72 (s, 1H), 8.98 (s, 1H) 2-[(5-Bromopyrimidin-4-yl)methyl]isoindoline-1,3-dione
(Formula Removed)
5-Bromo-4-methylpyrimidine (2 .90 g, 16.8 mmol) in acetic acid (40 mL) was stirred with bromine (3.18 g, 20.2 mmol) at 8 0°C for 4 0 minutes. After completion of
the reaction, the reaction solution was cooled, diluted with ethyl acetate and neutralized with water and 1 M aqueous sodium hydroxide, and the organic layer was separated, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 7/1) . The resulting product
(3.69 g) was dissolved in 60 mL of dimethylformamide and heated with potassium phthalimide (2.84 g, 15.3 mmol) at 80°C for 1 hour with stirring. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform) to give the desired product (4.3 g, 80% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 3.71 min LC/MS(ESI + ) m/z; 317, 319 [M+l] + 1H-NMR (CDCl3)
δ :5.06 (s, 2H), 7.74-7.80 (m, 2H), 7.85-7.94 (m, 2H), 8.77 (s, 1H), 8.90 (s, 1H)
(5-Bromopyrimidin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 47 by using 2-[(5-bromopyrimidin-4-yl)methyl]isoindoline-1,3-dione (100% yield).
Morphology: colorless oil
1H-NMR (CDCl3)
δ:4.06 (s, 2H), 8.72 (s, 1H), 9.09 (s, IK] REFERENCE SYNTHETIC EXAMPLE 4 9
(5-Methylpyirimidin-4-yl)methanamine

(Formula Removed)
2-[(5-Methylpyirimidin-4-yl)methyl]isoindoline-1,3-dione
(Formula Removed)
2-[(5-Bromopyrimidin-4-yl)methyl]isoindoline-1,3-dione (318 mg, 1.00 mmol), trimethylboroxine (12 6 mg, 1.32 mmol), [1,1'-
bis(diphenylphosphono)ferrocene]dichloropalladium (II) dichloromethane complex (40.8 mg, 0.05 mmol) and potassium carbonate (276 mg, 2.00 mmol) were mixed with water (0.2 mL) and 1,4-dioxane (1.8 mL) and stirred at
110°C for 1 hour. After completion of the reaction, the reaction solution was allowed to cool, and the solvent was removed by vacuum distillation. The resulting residue was mixed with 4 M hydrogen chloride/1,4-dioxane (10 mL) and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 1/2) to give the desired product
(154 mg, 61% yield). Morphology: dark brown solid
LC/MS: Condition 7, retention time 3.20 min LC/MS (ESI + ) m/z; 254 [M+l] + 1H-NMR (CDCl3)
δ:2.41 (s, 3H), 4.94 (s, 2H), 7.74-7.80 (m, 2H), 7.85-7.94 (m, 2H), 8.4 6 (s, 1H), 8.85 (s, IH)
(5-Methylpyrimidin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 45 by using 2-[(5-methylpyrimidin-4-yl)methyl]isoindoline-1,3-dione (100% yield).
Morphology: colorless oil 1H-NMR (CDCl3)
δ:2.26 (s, 3H), 3.96 (s, 2H), 8.42 (s, 1H), 9.03 (s, IH) REFERENCE SYNTHETIC EXAMPLE 5 0
{S)-1-Amino-2-methylpropan-2-ol
Isobutylene oxide (415 mg, 5.76 mmol) and 28 mass% aqueous ammonia were sealed in a reaction tube and heated
at 12 0°C for 3 0 minutes with stirring and microwave irradiation. The solvent was removed by vacuum distillation to give the desired product (44% yield). Morphology: colorless oil 1H-NMR (CDCl3)
δ:1.16 (s, 3H), 1.21 (s, 3H), 2.60 (s, 2H) REFERENCE SYNTHETIC EXAMPLE 51
(S)-1-Amino-3-methoxypropan-2-ol
(Formula Removed)
(R)-(-)-Glycidyl methyl ether (252 mg, 2.86 mmol) and 28 mass% aqueous ammonia were sealed in a reaction
tube and heated at 12 0°C for 3 0 minutes with stirring and microwave irradiation. The solvent was removed by vacuum distillation to give the desired product (75% yield). Morphology: colorless oil 1H-NMR (CDCl3)
δ:2.65-2.89 (m, 2H), 3.35-3.50 (m, 3H), 3.40 (s, 3H), 3.70-3.90 (m, 1H) REFERENCE SYNTHETIC EXAMPLE 52
(S)-1-Methoxy-3-(methylamino)propan-2-ol
(Formula Removed)
(R) - (-)-Glycidyl methyl ether (321 mg, 3.65 mmol) and 4 0 mass% methylamine-methanol (1 mL) were sealed in a
reaction tube and heated at 12 0°C for 3 0 minutes with stirring and microwave irradiation. The solvent was removed by vacuum distillation to give the desired product (88% yield). Morphology: colorless oil 1H-NMR (CDCl3)
δ:2.44 (s, 3H), 2.55-2.70 (m, 2H), 3.35-3.50 (m, 3H), 3.40 (s, 3H) , 3 .82-3 .92 (m, 1H) REFERENCE SYNTHETIC EXAMPLE 53
(S)-1-Methoxy-3-(pyridin-4-ylmethylamino)propan-2-ol
(Formula Removed)
(R) -(-) -Glycidyl methyl ether (88 mg, 1 mmol) and 4-picolylamine (108 mg, 1 mmol) in methanol (1 mL) were
sealed in a reaction tube and heated at 12 0°C for 3 0 minutes with stirring and microwave irradiation. The solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired
product (17% yield). Morphology: colorless oil 1H-NMR (CDCl3)
δ:2.60-2.80 (m, 2H), 3.35-3.50 (m, 2H), 3.40 (s, 3H), 3.87 (s, 2H), 3.87-3.92 (m, 1H), 7.26 (d, J = 4.5 Hz, 2H), 8.55 (d, J = 4.5 Hz, 2H) REFERENCE SYNTHETIC EXAMPLE 54 1-(Pyridazin-4-yl)propan-1-amine

(Formula Removed)
2-[1-(3,6-Dichloropyridazin-4-yl)propyl]isoindoline-1,3-dione CI
(Formula Removed)
3,6-Dichloropyridazine (5 96 mg, 4 mmol) , 2- (1,3-dioxoisoindolin-2-yl)butanoic acid (1.59 g, 6.8 mmol), silver nitrate (67.9 mg, 0.4 mmol), trifluoroacetic acid (91.2 mg, 0.8 mmol) and water (10 mL) were heated at 70°C with stirring, and to the resulting mixture, diammonium peroxodisulfate (1.64 g, 7.2 mmol) in water (2 mL) was added dropwise over 3 0 minutes. After the dropwise
addition, the resulting reaction mixture was stirred at
70°C for 30 minutes, then mixed with 10 mL of ethyl acetate and allowed to cool to room temperature. The reaction mixture was cooled with ice, then basified with 28% aqueous ammonia (to pH 9) and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/ethyl acetate = 1/1) to give a crude product, which was used for the next reaction. Morphology: colorless oil
LC/MS: Condition 7, retention time 4.30 min LC/MS(ESI + ) m/z; 336, 338 [M+l] + 2-[1-(Pyridazin-4-yl)propyl]isoindoline-1,3-dione
(Formula Removed)
2-[1-(3,6-Dichloropyridazin-4-yl)propyl]isoindoline-1,3-dione, triethylamine (1.11 mL, 8 mmol) and 10% palladium-carbon (50 wt%, 100 mg) were stirred in tetrahydrofuran in a hydrogen atmosphere (1 atm) at room temperature for 4 days. The reaction solution was filtered through celite and concentrated under reduced
pressure, and the resulting residue was dissolved in chloroform, and the resulting organic layer was washed with water and saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 1/3) to give the desired product
(294 mg, 28% yield, two steps). Morphology: colorless oil
LC/MS: Condition 7, retention time 4.30 min LC/MS (ESI + ) m/z; 268 [M+l] + 1H-NMR (CDCl3)
δ:1.00 (t, J = 7.5 Hz, 3H), 2.20-2.40 (m, 1H), 2.50-2.70
(m, 1H), 5.25 (dd, J = 5.7 Hz, J = 10.8 Hz, 1H), 7.76 (d, J = 5.4 Hz, 1H), 7.71-7.78 (m, 2H), 7.84-7.89 (m, 2H), 9.18 (d, J = 5.4 Hz, 1H), 9.29 (s, 1H) 1-(Pyridazin-4-yl)propan-1-amine
2-[1-(Pyridazin-4-yl)propyl]isoindoline-1,3-dione
(91.8 mg, 0.34 mmol) in methanol (1 mL) was mixed with hydrazine monohydrate (83 uL, 1.7 mmol) at room temperature and stirred at 6 0°C for 3 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product
(100% yield).
Morphology: colorless oil 1H-NMR (CDCl3)
δ: 0.92 (t, J = 7.5 Hz, 3H), 1.60-2.05 (m, 2H), 3.91 (m, 1H), 7.47 (d, J = 5.1 Hz, 1H), 9.11 (d, J = 5.1 Hz, 1H), 9.18 (s, 1H) REFERENCE SYNTHETIC EXAMPLE 55
(3-Methoxypyridazin-4-yl)methanamine
(Formula Removed)
2-[(3-Methoxypyridazin-4-yl)methyl]isoindoline-1,3-dione
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 3-chloro-6-methoxypyridazine and 2-(1,3-dioxoindolin-2-yl)acetic acid (33% yield, two steps). Morphology: colorless solid 1H-NMR (CDCl3)
δ:4.20 (s, 3H), 4.86 (s, 2H), 7.09 (d, J = 4.8 Hz, 1H), 7.71-7.81 (m, 2H), 7.89-7.94 (m, 2H), 8.75 (d, J = 4.8 Hz, 1H) (3-Methoxypyridazin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-[(3-
methoxypyridazin-4-yl)methyl]isoindoline-1,3-dione (96% yield).
Morphology: colorless solid 1H-NMR (CDCl3)
δ:3.84 (s, 2H) , 4.17 (s, 3H), 7.39 (d, J = 4.8 Hz, 1H), 8.79 (d, J = 4.8 Hz, 1H) REFERENCE SYNTHETIC EXAMPLE 56 4-(Aminomethyl)pyridazin-3[2H]-one
(Formula Removed)
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione
(Formula Removed)
2-[(3-Methoxypridazin-4-yl)methyl]isoindoline-1,3-dione (1.15 g, 4.27 mmol) in 1,4-dioxane (90 mL) was refluxed with 12 M hydrochloric acid (2 mL) for 1 hour. After completion of the reaction, the solvent was removed by vacuum distillation to give the desired product (1.1 g, 100% yield). Morphology: colorless solid 1H-NMR (DMSO-d6)

δ:4.58 (s, 2H), 7.24 (d, J = 3.6 Hz, 1H), 7.7; 3.6 Hz, 1H), 7.80-7.95 (m, 4H), 13.2 (s, 1H) 4-(Aminomethyl)pyridazin-3[2H]-one
(Formula Removed)
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione (2 55 mg, 1.00 mmol) in methanol (2 mL) was mixed with hydrazine monohydrate (250
mg, 5.00 mmol) at room temperature and stirred at 60°C for 3 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give a crude reaction product containing the desired product, which was used for the next step. REFERENCE SYNTHETIC EXAMPLE 57 4-(Aminomethyl)-2-methylpyridazin-3(2H)-one
(Formula Removed)
2-[(2-Methyl-3-oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione
(Formula Removed)
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione (2 55 mg, 1.00 mmol) in dimethylformamide (3 mL) was heated with potassium carbonate (14 5 mg, 1.05 mmol) and methyl iodide (42 6 mg, 3 .00 mmol) at 70°C for 2 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was stirred with 4 M hydrogen chloride/1,4-dioxane (10 mL) at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (233 mg, 86% yield). Morphology: yellow solid
LC/MS: Condition 7, retention time 3.05 min LC/MS (ESI + ) m/z; 270 [M+l] + 1H-NMR (CDCl3)
δ:3.80 (s, 3H), 4.85 (s, 2H), 6.91 (d, J = 3.9 Hz, 1H), 7.66 (d, J = 3.9 Hz, 1H), 7.71-7.81 (m, 2H), 7.85-7.94 (m, 2H) 4-(Aminomethyl)-2-methylpyridazin-3(2H)-one
Synthesis was carried out in the same manner as in Reference Synthetic Example 56 by using 2-[(2-methyl-3-oxo-2,3-dihydropyridazin-4-yl)methyl]isoindoline-1,3-dione (100% yield).
Morphology: colorless amorphous
1H-NMR (CDCl3)
δ:3.80 (s, 3H), 3.82 (s, 2H) , 7.22 (d, J = 3.9 Hz, 1H), 7.74 (d, J = 3.9 Hz, 1H) REFERENCE SYNTHETIC EXAMPLE 58
[5-Bromo-4-(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)-6-oxopyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Ethyl [5-bromo-4-(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)-6-oxopyridazin-1(6H)-yl]acetate
(Formula Removed)
Ethyl 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetate (1.50 g, 4.41 mmol), 1-noradamantamine hydrochloride (1.15 g, 6.62 mmol) and triethylamine (1.83 mL, 13.2 mmol) were stirred in a 1,4-dioxane-water mixed solvent (1/1) at 90°C for 1 day. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium
chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate = 1/1 → 0/1) to give the desired product (50% yield).
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.76 min LC/MS(ESI + ) m/z; 3 96, 3 98 [M+l] + LC/MS (ESI") m/z; 3 94, 3 96 [M-l] "
[5-Bromo-4-(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)-6-oxopyridazin-1(6H)-yl]acetic acid
Synthesis was carried out in the same manner as in Reference Synthetic Example 1 by using ethyl [5-bromo-4-
(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)-6-
oxopyridazin-1(6H)-yl]acetate.
Yield: 100%
Morphology: colorless amorphous
REFERENCE SYNTHETIC EXAMPLE 5 9
Synthesis was carried out in the same manner as in Reference Synthetic Example 58 by using ethyl 2- (4,5-
[5-Chloro-4-(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)-6-oxopyridazin-1(6H)-yl]acetic acid
(Formula Removed)
dichloro-6-oxopyridazin-1(6H)-yl)acetate. Yield: 61% (two steps) Morphology: colorless solid
LC/MS: Condition 7, retention time 4.2 0 min LC/MS(ESI + ) m/z; 324, 32 6 [M+l] + LC/MS(ESI") m/z; 322, 324 [M-l]" REFERENCE SYNTHETIC EXAMPLE 6 0
[5-Chloro-4-(1-adamantanamino)-6-oxopyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 59 by using 1-adamantamine. Yield: 23% (two steps) Morphology: colorless solid REFERENCE SYNTHETIC EXAMPLE 61
[5-Chloro-4-(2-adamantanamino)-6-oxopyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 59 by using 2-adamantamine. Yield: 6 5% (two steps)
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.2 0 min LC/MS(ESI + ) m/z; 338, 34 0 [M+l] + LC/MS(ESI") m/z; 336, 338 [M-l] ~ REFERENCE SYNTHETIC EXAMPLE 62 [5-Chloro-4-{[(1S,2S,3R,5S)-2-hydroxy-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-6-oxopyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 59 by using (1S,2S,3R,5S)-3-amino-2,6,6-trimethylbicyclo[3.1.1]heptan-2-ol. Yield: 51% (two steps) Morphology: colorless amorphous LC/MS: Condition 7, retention time 3.85 min LC/MS(ESI+) m/z; 3 56, 3 58 [M+l] + LC/MS(ESI") m/z; 3 54, 3 56 [M-l]" REFERENCE SYNTHETIC EXAMPLE 6 3
[4-(Bicyclo[3.3.1]non-9-ylamino)-5-chloro-6-oxopyridazin-1(6H)-yl]acetic acid o
(Formula Removed)
Synthesis was carried out in the same manner as in
Reference Synthetic Example 59 by using bicyclo[3.3.1]nonan-9-amine. Yield: 49% (two steps) Morphology: colorless solid
LC/MS: Condition 7, retention time 4.08 min LC/MS(ESI + ) m/z; 32 6, 32 8 [M+l] + LC/MS(ESI") m/z; 324, 32 6 [M-l] ~ REFERENCE SYNTHETIC EXAMPLE 64
[4-(Bicyclo[3.3.1]non-9-ylamino)-5-bromo-6-oxopyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 58 by using bicyclo[3.3.1]nonan-9-amine. Yield: 58% (two steps) Morphology: colorless solid
LC/MS: Condition 7, retention time 4.08 min LC/MS(ESI+) m/z; 370, 3 72 [M+l] + LC/MS(ESI") m/z; 368, 370 [M-l]" REFERENCE SYNTHETIC EXAMPLE 6 5
2-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4-yl)propyl]acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 48 by using 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetic acid. Yield: 36%
Morphology: brown amorphous
LC/MS: Condition 7, retention time 0.90 min LC/MS(ESI+) m/z; 42 9, 431, 433 [M+l]+ LC/MS(ESI") m/z; 42 7, 42 9, 431 [M-l] ~ REFERENCE SYNTHETIC EXAMPLE 6 6
2-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)-N- [1- (3-methylpyridin-4-yl)methyl]acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 48 by using (3-methylpyridin-4-yl)methanamine. Yield: 25%
Morphology: brown solid
LC/MS: Condition 7, retention time 0.90 min LC/MS(ESI+) m/z; 415, 417, 419 [M+l] + LC/MS(ESI") m/z; 413, 415, 417 [M-l]"
REFERENCE SYNTHETIC EXAMPLE 67
2-(4,5-Dichloro-6-oxopyridazin-1(6H)-yl)-N-(pyridin-4 ylmethyl)acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 48 by using 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)acetic acid. Yield: 9%
Morphology: light brown solid LC/MS: Condition 7, retention time 0.90 min LC/MS(ESI + ) m/z; 313, 315 [M+l] + LC/MS(ESI") m/z; 311, 313 [M-l]" REFERENCE SYNTHETIC EXAMPLE 6 8
2-(4,5-Dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4 yl)propyl]acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 67 by using 1-(pyridin-4-yl)propan-1-amine. Yield: 45% Morphology: brown amorphous
LC/MS: Condition 7, retention time 0.87 min LC/MS(ESI + ) m/z; 341, 34 3 [M+l] + LC/MS (ESI") m/z; 33 9, 341 [M-l] " REFERENCE SYNTHETIC EXAMPLE 6 9
2-(4,5-Dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(3 methylpyridin-4-yl)methyl]acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 66 by using 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)acetic acid. Yield: 39%
Morphology: brown solid
LC/MS: Condition 7, retention time 0.84 min LC/MS (ESI + ) m/z; 32 7, 32 9 [M+l] + LC/MS(ESI") m/z; 32 5, 32 7 [M-l]" REFERENCE SYNTHETIC EXAMPLE 7 0
2-(4,5-Dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4 yl)ethyl]acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 67 by using 1-(pyridin-4-
yl)ethanamine. Yield: 59%
Morphology: colorless solid
LC/MS: Condition 7, retention time 0.64 min LC/MS(ESI+) m/z; 32 7, 32 9, 331 [M+l]+ LC/MS(ESI") m/z; 32 5, 32 7, 32 9 [M-l] " REFERENCE SYNTHETIC EXAMPLE 71
2- [4, 5-Dichloro-6-oxopyridazin-l (6H) -yl] -N- [ (1R) -1 (pyridin-4-yl)ethyl]acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 67 by using (1R) -1- (pyridin-4-yl)ethanamine. Yield: 67%
(Formula Removed)
2-[(5-Methylpyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-
Morphology: colorless amorphous LC/MS: Condition 7, retention time 0.64 min LC/MS(ESI+) m/z; 32 7, 32 9, 331 [M+l]+ LC/MS(ESI") m/z; 32 5, 32 7, 32 9 [M-l]" REFERENCE SYNTHETIC EXAMPLE 72 (5-Methylpyridazin-4-yl)methanamine
dione
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 3,6-dichloro-4-methylpyridazine and 2-(1,3-dioxoisoindolin-2-yl)acetic acid. The obtained crude product was used for the next reaction.
Morphology: colorless solid
LC/MS: Condition 7, retention time 2.81 min LC/MS (ESI + ) m/z; 254 [M+l] + 1H-NMR (CDCl3)
δ: 2.52 (s, 3H), 4.88 (s, 2H), 7.76-7.80 (m, 2H), 7.87-7.91 (m, 2H), 8.98 (s, 1H), 9.05 (s, 1H) (5-Methylpyridazin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-[(5-methylpyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (6% yield, three steps). Morphology: colorless oil 1H-NMR (CDCl3)
δ: 2.34 (s, 3H), 3.95 (s, 2H), 8.93 (s, 1H), 9.17 (s, 1H) REFERENCE SYNTHETIC EXAMPLE 73 (3 -Chloropyridazin-4-yl)methanamine
(Formula Removed)
2-[(3-Chloropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione
(Formula Removed)
2-[(3-Oxo-2,3-dihydropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (1.1 g, 4.27 mmol) was mixed with phosphoryl chloride (10 mL) and heated to reflux for 1 hour. After completion of the reaction, phosphoryl chloride was removed under reduced pressure. The resulting residue was diluted with chloroform and water. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 9/1) to give the desired product (89% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 3.33 min LC/MS(ESI + ) m/z; 2 74, 2 76 [M+l] + 1H-NMR(CDCl3)
δ: 4.97 (s, 2H), 7.26 (d, J = 4.2 Hz, 1H), 7.82 (m, 2H), 7.93 (m, 2H), 9.05 (d, J = 4.2 Hz, 1H)
(3 -Chloropyridazin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-[(3-chloropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione
(136.9 mg, 0.5 mmol) (90% yield). Morphology: colorless solid 1H-NMR(CDCl3)
δ: 4.00 (s, 2H), 7.86 (d, J = 4.2 Hz, 1H), 9.04 (d, J = 4.2 Hz, 1H) REFERENCE SYNTHETIC EXAMPLE 74
(3-Methylpyridazin-4-yl)methanamine
(Formula Removed)
2-[(3-Methylpyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 49 by using 2-[(3-chloropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (136.5mg, 0.5mmol) (94.6mg, 75% yield). Morphology: colorless solid LC/MS: Condition 7, retention time 2.55 min
LC/MS (ESI + ) m/z; 254 [M+l] +
1H-NMR(CDCl3)
δ: 2.88 (s, 3H), 4.87 (s, 2H), 7.26 (d, J = 4.8 Hz, 1H), 7.79 (m, 2H), 7.92 (m, 2H), 9.00 (d, J = 4.8 Hz, 1H) (3-Methylpyridazin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-[(3-methylpyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione(108.8mg, 0.43 mmol). The obtained crude product was used for the next reaction (100% yield). REFERENCE SYNTHETIC EXAMPLE 75 4-(Aminomethyl)-N,N-dimethylpyridazin-3-amine
(Formula Removed)
2-{[3-(Dimethylamino)pyridazin-4-yl]methyl}-IH-isoindole-1,3(2H)-dione
(Formula Removed)
2-[(3-Chloropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (13 6 .8 mg, 0 .5 mmol) and 5 0% aqueous methylamine (1 mL) were sealed in a reaction tube and heated at 15 0°C for 2 0 minutes with stirring and
microwave irradiation. After completion of the reaction, the reaction mixture was cooled to room temperature, and the solvent was removed by vacuum distillation. The resulting residue was mixed with 4 M hydrogen chloride/1,4-dioxane (5 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under vacuum, treated with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (79.6 mg, 56% yield). Morphology: yellow solid
LC/MS: Condition 7, retention time 3.53 min LC/MS (ESI + ) m/z; 283 [M+l] + 1H-NMR(CDCl3)
δ: 3.07 (s, 6H), 4.87 (s, 2H), 6.95 (d, J = 4.8 Hz, 1H), 7.77-7.81 (m, 2H), 7.90-7.94 (m, 2H), 8.69 (d, J = 4.8 Hz, 1H) 4-(Aminomethyl)-N,N-dimethylpyridazin-3-amine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-{[3-(dimethylamino)pyridazin-4-yl]methyl}-1H-isoindole-1,3(2H)-dione (79.6mg, 0.28 mmol). The obtained crude product was used for the next reaction (100% yield). REFERENCE SYNTHETIC EXAMPLE 76
1-(6 -Chloro-3-methoxypyridazin-4-yl)ethanamine CI
(Formula Removed)
2-[1-(6-Chloro-3-methoxypyridazin-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione CI
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 3-chloro-6-methoxypyridazine, 2-(1,3-dioxoisoindolin-2-yl)propanoic acid (91% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 4.01 min LC/MS(ESI + ) m/z; 318, 32 0 [M+l] + 1H-NMR (CDCl3)
δ: 3.22 (d, J = 7.2 Hz, 3H), 4.06 (s, 3H), 5.62 (q, J = 7.2 Hz, 1H), 7.56 (s, lh), 7.72-7.77 (m, 2H), 7.81-7.85 (m, 2H) 1-(6 -Chloro-3-methoxypyridazin-4-yl)ethanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-[1-(6-chloro-3
methoxypyridazin-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione (92% yield).
Morphology: colorless solid 1H-NMR(CDCl3)
δ: 1.37 (d, J = 7.2 Hz, 3H), 4.15 (s, 3H), 4.35 (q, J = 7.2 Hz, 1H), 7.50 (s, lh) REFERENCE SYNTHETIC EXAMPLE 77 1-(3-Chloropyridazin-4-yl)ethanamine
(Formula Removed)
2-[1-(6-Chloro-3-oxo-2,3-dihydropyridazin-4-yl)ethyl]isoindoline-1,3-dione
(Formula Removed)
Synthesis was carried out in the same manner as in Reference Synthetic Example 56 by using 2-[1-(6-chloro-3-methoxypyridazin-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione. Morphology: colorless solid 1H-NMR (CDCl3)
δ: 1.78 (d, J = 6.9 Hz, 3H), 5.62 (q, J = 6.9 Hz, 1H), 7.3 8 (s, lh), 7.72-7.77 (m, 2H), 7.81-7.85 (m, 2H), 11.02 (brs, 1H)
2-[1-(3-Chloropyridazin-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione
(Formula Removed)
2-[1-(6-Chloro-3-oxo-2,3-dihydropyridazin-4-yl)ethyl]isoindoline-1,3-dione (93 3 mg, 3.07 mmol), triethylamine (0.43 mL, 3.07 mmol), 10% palladium-carbon (50 wt%, 100 mg) were stirred in tetrahydrofuran (10 mL) under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After filtering through celite, the filtrate was concentrated under vacuum. The residue was mixed with phosphoryl chloride (10 mL) and heated to reflux for 1 hour. After the reaction, phosphoryl chloride was removed by vacuum distillation. The resulting solid was dissolved with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, dried over anhydrous magnesium sulfate, and the solvent wad removed by vacuum distillation. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1:1) to give the desired product (543 mg, 62% yield, two steps).
Morphology: pale yellow solid 1H-NMR (CDCl3)
δ: 1.87 (d, J = 7.2 Hz, 3H), 5.73 (q, J = 7.2 Hz, 1H), 7.72-7.77 (m, 2H), 7.81-7.85 (m, 2H), 7.83 (d, J = 4.8 Hz, 1H), 9.16 (d, J = 4.8 Hz, 1H) 1-(3-Chloropyridazin-4-yl)ethanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2- [1- (3-chloropyridazin-4-yl)ethyl]-1H-isoindole-1,3(2H)-dione
(50.3 mg, 0.175 mmol). The obtained crude product was used for the next reaction (100% yield). REFERENCE SYNTHETIC EXAMPLE 78
(3 -1sopropylpyridazin-4-yl)methanamine
(Formula Removed)
2-{[3-(Propan-2-yl)pyridazin-4-yl]methyl}-1H-isoindole-1,3(2H)-dione
(Formula Removed)
2-[(3-Chloropyridazin-4-yl)methyl]-1H-isoindole-1,3(2H)-dione (137 mg, 0.5 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (252 mg, 0.28 mL, 1.5 mmol), tetrakis(triphenylphosphine)palladium (57.8 mg, 0.05 mmol) and sodium carbonate (106 mg, 2.00 mmol) were
mixed with water (0.2 mL) and 1,4-dioxane (0.9 mL) and
stirred at 110°C for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The resulting residue was mixed with 4 M hydrogen chloride/1,4-dioxane (5 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/2). The obtained colorless solid (76 mg) and 10% palladium-carbon (50 wt%, 100 mg) were stirred in methanol (5 mL) under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After filtering through celite, the filtrate was evaporated under reduce pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/2) to give the desired product (76.3 mg, 54% yield). Morphology: colorless solid 1H-NMR(CDCl3)
δ: 1.49 (d, J = 6.6 Hz, 6H), 3.555 (sept, J = 6.6 Hz, 1H), 4.94 (s, 2H), 7.23 (d, J = 4.8 Hz, 1H), 7.79 (m, 2H), 7.92 (m, 2H), 8.98 (d, J = 4.8 Hz, 1H)
(3 -1sopropylpyridazin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-{[3-(propan-2 yl)pyridazin-4-yl]methyl}-1H-isoindole-1,3(2H)-dione (50.3 mg, 0.175 mmol). The obtained crude product was used for the next reaction (100% yield).
REFERENCE SYNTHETIC EXAMPLE 7 9
1-(3-Methoxypyridazin-4-yl)ethanamine hydrochloride

(Formula Removed)
1-(6-Chloro-3-methoxypyridazin-4-yl)ethanamine (67.3 mg, 0.36 mmol) and 10% palladium-carbon (50 wt%, 20 mg) were stirred in methanol (5 mL) under hydrogen atmosphere (1 atm) at room temperature for 16 hours. After filtering through celite, the filtrate was evaporated under reduced pressure. The resulting crude reaction product was used for the next step.
REFERENCE SYNTHETIC EXAMPLE 8 0
1-[3-(Methylsulfonyl)pyridin-4-yl]methanamine
hydrochloride
(Formula Removed)
3-Chloro-5-(methylthio)isonicotinonitrile
(Formula Removed)
To a solution of 3,5-dichloroisonicotinonitrile (346 mg, 2 mmol) in N,N-dimethylformamide (2 mL) was added
sodium thiomethoxide (141 mg, 2 mmol) at 0°C. The mixture was stirred at room temperature for 4 hours. After completion of the reaction, the solution was concentrated under reduced pressure. To the resulting residue was added saturated aqueous sodium hydrogen carbonate and the mixture was extracted with ethyl acetate. The combined organic layer was separated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/1) to give the desired product (92 mg, 25% yield). Morphology: colorless solid 1H-NMR(CDCl3)
δ: 2.67 (s, 3H), 8.47 (s, 1H), 8.50 (s, 1H) 3-Chloro-5-(methylsulfonyl)pyridine-4-carbonitrile
(Formula Removed)
3-Chloro-5-(methylthio)isonicotinonitrile (92 mg, 0.5 mmol) was stirred with m-chloroperbenzoic acid (65
wt%, 265 mg, 1 mmol) in chloroform (5 mL) at 6 0°C for 3
hours. After completion of the reaction, the reaction
mixture was allowed to cool to room temperature and
purified by silica gel column chromatography (ethyl
acetate) to give the desired product (97 mg, 90%).
Morphology: colorless solid
1H-NMR (CDCl3)
δ: 3.35 (s, 3H), 9.09 (s, 1H), 9.26 (s, 1H)
1-[3-(Methylsulfonyl)pyridin-4-yl]methanamine
hydrochloride
1-[5-(Methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-
yl]methanamine hydrochloride
(Formula Removed)
3-Chloro-5-(methylsulfonyl)pyridine-4-carbonitrile(97.2mg, 0.44 9mmol) and 10% palladium-carbon (50 wt%, 2 0 mg) were stirred in methanol (5 mL) under hydrogen (1 atm) at room temperature for 16 hours. After filtering through celite, the mixture was concentrated under vacuum to give a mixture of 1-[3-(methylsulfonyl)pyridin-4-yl]methanamine hydrochloride and 1-[5-(methylsulfonyl)-1,2,3,4-tetrahydropyridin-4-
yl]methanamine hydrochloride. The mixture was used for the next reaction. REFERENCE SYNTHETIC EXAMPLE 81 (3 -Chloro-6-methylpyridazin-4-yl)methanamine
(Formula Removed)
2-[1-(3,6-Dichloropyridazin-4-yl)ethyl]isoindoline-1,3 dione

Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2- (1,3-dioxoisoindolin-2-yl)propanoic acid (16% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 4.08 min LC/MS(ESI+) m/z; 322, 324, 32 6 [M+l]+ 1H-NMR (CDCl3)
δ: 1.86 (d, J = 6.9 Hz, 3H), 5.68 (q, J = 6.9 Hz, 1H), 7.72-7.77 (m, 2H), 7.81-7.85 (m, 2H)
2-[1-(3-Chloro-6-methylpyridazin-4-yl)ethyl]isoindoline-1,3-dione
(Formula Removed)
2-[1-(3,6-Dichloropyridazin-4-yl)ethyl]isoindoline-1,3-dione (161 mg, 0.5 mmol), trimethylboroxine (0.209 mL, 1.5 mmol), [1,1'-
bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (35.1 mg, 0.05 mmol) and potassium carbonate (82.9 mg, 0.6 mmol) were mixed with water (0.2 mL) and 1,4-dioxane (0.9 mL) and stirred at
110°C for 8 hours. After completion of the reaction, the reaction solution was cooled to room temperature, and the solvent was removed by vacuum distillation. The resulting residue was mixed with 4 M hydrogen chloride/1,4-dioxane (10 mL) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (hexane/ethyl acetate = 1/1) to give the desired product (29 mg, 19% yield).
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.08 min LC/MS(ESI + ) m/z; 3 02, 3 04 [M+l] +
1H-NMR(CDCl3)
δ: 1.86 (d, J = 7.2 Hz, 3H), 2.75 (s, 1H), 5.69 (q, J = 7.2 Hz, 1H), 7.64 (s, 1H), 7.72-7.77 (m, 2H), 7.81-7.85
(m, 2H)
(3 -Chloro-6-methylpyridazin-4-yl)methanamine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-[1-(3-chloro-6-methylpyridazin-4-yl)ethyl]isoindoline-1,3-dione (91% yield).
Morphology: colorless oil 1H-NMR (CDCl3)
δ: 1.40 (d, J = 6.6 Hz, 3H), 2.70 (s, 1H), 4.42 (q, J = 6.6 Hz, 1H), 7.60 (s, 1H) REFERENCE SYNTHETIC EXAMPLE 82 1-(Pyridazin-4-yl)butan-l-amine
(Formula Removed)
Synthesis was carried out in the same manner as in
2-[1-(Pyridazin-4-yl)butyl]isoindoline-1,3-dione
(Formula Removed)
Reference Synthetic Example 54 by using 2- (1,3-dioxoisoindolin-2-yl)pentanoic acid (12% yield, two steps).
Morphology: colorless oil 1H-NMR(CDCl3)
δ: 0.99 (t, J = 7.2 Hz, 3H), 1.36 (m, 2H), 2.10-2.25 (m, 1H), 2.50-2.70 (m, 1H), 5.36 (dd, J = 6.0 Hz, J = 7.2 Hz, 1H), 7.62 (m, 1H), 7.71-7.78 (m, 2H), 7.84-7.89 (m, 2H), 9.16 (d, J = 5.1 Hz, 1H), 9.29 (s, 1H) 1-(Pyridazin-4-yl)butan-1-amine
Synthesis was carried out in the same manner as in Reference Synthetic Example 54 by using 2-[1-(pyridazin-4-yl)butyl]isoindoline-1,3-dione. The obtained crude product was used for the next reaction (100% yield). REFERENCE SYNTHETIC EXAMPLE 83 to 85
Amines were synthesized in the same manner as in Reference Synthetic Example 2, and the yields and morphology of the resulting amines, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 8. "crude" in the remarks column means that the crude reaction product was used for the next step without purification.
TABLE 8
(Table Removed)
The structures of the compounds obtained are shown below
REFERENCE SYNTHETIC EXAMPLES 83 to 85
(Formula Removed)
REFERENCE SYNTHETIC EXAMPLE 86 1-(3-Methylpyridin-4-yl)ethanol
(Formula Removed)
3-Methylpyridine-4-carbaldehyde
(Formula Removed)
3-Chloropyridine-4-carbaldehyde(141.6 mg, 1.00 mmol),trimethylboroxine (278.4 ul 2.00 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) dichloromethane complex (81.6 mg, 0.10 mmol) and potassium carbonate (414.6 mg, 3.00 mmol) were mixed with water (0.2 mL) and 1,4-dioxane (1.8 mL) and stirred at 100°C for 3 hours. After completion of the reaction, the reaction solution was allowed to cool, and the solvent was removed by vacuum distillation. The resulting crude reaction product containing the desired product was used
for the next step (594.7 mg).
(Formula Removed)
1-(3-Methylpyridin-4-yl)ethanol
(Formula Removed)
3-Methylpyridine-4-carbaldehyde (310 . 6 mg, 1.OOmmol) in tetrahydrofuran (6 mL) was mixed with methylmagnesium bromide (0.98 M in tetrahydrofuran, 4.74 mL, 4.65 mmol) under -78°C, and the mixture was warmed slowly to room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (310.6 mg).
REFERENCE SYNTHETIC EXAMPLE 87 1-(3-Chloro-2-fluoropyridin-4-yl)ethanol
(Formula Removed)
4-({[tert-Butyl(dimethyl)silyl]oxyjmethyl)-2-fluoropyridine
(Formula Removed)
2-Fluoro-4-pyridinemethanol (508 . 5 mg, 4.00 mmol) , t-butyldimethylsilylchloride (1.21 g, 8.00 mmol) and imidazole (1.09 g, 16.00 mmol) were stirred in dichloromethane (10 mL) at room temperature for an hour. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the resulting organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 10/1) to give the desired product (785.2 mg, 81% yield). Morphology: colorless oil 1H-NMR(CDCl3)
δ: 0.01 (s, 6H), 0.83 (s, 9H), 4.60 (s, 2H), 6.80 (s, 1H), 6.97 (d, J = 5.3 Hz, 1H), 8.02 (d, J = 5.3 Hz, 1H). 4-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-chloro-2-fluoropyridine
(Formula Removed)
A tetrahydrofuran solution (10 mL) of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluoropyridine(469.1 mg, 1.94 mmol) was mixed with lithium diisopropylamide
(1.08 M in tetrahydrofuran, 2.16 mL, 2.33 mmol) under
cooling with ice. The reaction mixture was stirred at
0°C for an hour, then added to hexachloroethane (840.0 mg, 3.50 mmol) and warmed slowly to room temperature for 12 hours with stirring. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 9/1 to 5/1) to give the desired product (157.7 mg, 30% yield). Morphology: pale yellow oil 1H-NMR(CDCl3)
δ: 0.01 (s, 6H) , 0.83 (s, 9H), 4.65 (s, 2H), 7.29 (d, J = 5.1 Hz, 1H), 7.95 (d, J = 5.1 Hz, 1H). 3-(Chloro-2-fluoropyridin-4-yl)methanol
(Formula Removed)
A tetrahydrofuran solution (10 mL) of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-chloro-2-fluoropyridine (194 .1 mg,0.71 mmol) was mixed with tetra-n-butylammonium fluoride (1.0 M in tetrahydrofuran, 0.85 mL, 0.85 mmol) under cooling with ice, and the mixture was stirred at room temperature for 3 days. After
completion of the reaction, the reaction solution was
mixed with ethyl acetate, and the organic layer was
washed with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate and evaporated under reduced
pressure. The resulting residue was purified by silica
gel column chromatography (hexane/ethyl acetate = δ:1 to
2:1, ethyl acetate/methanol = 20/1 to 4/1) to give the
desired product (99.1 mg, 86% yield).
Morphology: pale yellow oil
1H-NMR(CDCl3)
δ: 4.86 (s, 2H), 7.46 (d, J = 4.6 Hz, 1H), 8.12 (d, J =
4.6 Hz, 1H).
3-Chloro-2-fluoropyridine-4-carbaldehyde
(Formula Removed)
A chloroform solution (4 mL) of (3-chloro-2-fluoropyridin-4-yl)methanol (99.1 mg, 0.61 mmol) was mixed with manganese dioxide (308.6 mg, 3.55 mmol) and stirred at 80°C for 1 day. After completion of the reaction, the reaction solution was allowed to cool and filtered through celite, and the filtrate was evaporated under reduced pressure. The resulting containing the desired product was used for the next step (56.1 mg) . Morphology: pale yellow oil 1H-NMR(CDCl3)
δ: 7.64 (d, J = 5.0 Hz, 1H), 8.28 (d, J = 5.0 Hz, 1H), 10.5 (s, 1H). 1-(3-Chloro-2-fluoropyridin-4-yl)ethanol
(Formula Removed)
3-Chloro-2-fluoropyridine-4-carbaldehyde (56.1 mg, 0.35 mmol) in tetrahydrofuran (2mL) was mixed with methylmagnesium bromide (0.98 M in tetrahydrofuran, 1.13
mL, 1.05 mmol) under -78°C, and the reaction mixture was warmed slowly to room temperature for 16 hours with stirring. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (64.7 mg) . Morphology: pale yellow oil 1H-NMR (CDCl3)
δ: 1.49 (d, J = 6.3 Hz, 1H), 5.27 (q, J = 6.3 Hz, 1H), 7.49 (d, J = 5.1 Hz, 1H), 8.08 (d, J = 5.1 Hz, 1H), 10.5 (s, 1H).
REFERENCE SYNTHETIC EXAMPLE 88 Bicyclo[3.3.1]nonan-3-amine
(Formula Removed)
To bicyclo[3.3.1]non-6-en-3-amine (100 mg, 0.729 mmol) in ethanol (3 mL), 10% palladium-carbon (10 mg) was added in a nitrogen stream, and the reaction solution was stirred in a hydrogen stream at room temperature for 1 day. After completion of the reaction, the reaction solution was filtered through celite and the filtrate was evaporated under reduced pressure. The resulting crude reaction product was used for the next step without further purification (98.5mg). Morphology: colorless solid REFERENCE SYNTHETIC EXAMPLE 8 9
1- (1-{ [2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanamine

(Formula Removed)
N-Methoxy-N-methyl-1H-pyrazole-4-carboxamide
(Formula Removed)
A N,N-dimethylformamide solution (3 mL) of 4-
pyrazolecarboxylic acid (15 0 mg, 1.34 mmol), N,0-
dimethylhydroxylamine hydrochloride (261.4 mg, 2.68 mmol),
1-ethyl- 3 -(3 -dimethylaminopropyl)carbodiimide,
hydrochloride (513.8 mg, 2 . 68 mmol) , 1-
hydroxybenzotriazoleimidazole anhydride (54.2 mg, 0.40
mmol), and triethylamine (0.38 mL, 2.68 mmol) was stirred
for 1 day. After completion of the reaction, the
reaction solution was mixed with ethyl acetate and washed
with saturated aqueous sodium chloride. The organic
layer was dried over anhydrous sodium sulfate and
evaporated under reduced pressure. The resulting crude
reaction product containing the desired product was used
for the next step (142.7 mg) .
Morphology: colorless oil
1H-NMR(CDCl3)
δ: 2.89 (s, 3H), 2.96 (s, 3H), 8.03 (s, 1H), 8.13 (s, IH).
N-Methoxy-N-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole-4-carboxamide
(Formula Removed)
A dichloromethane solution (3 mL) of N-methoxy-N-
methyl-IH-pyrazole-4-carboxamide (142 .7 mg,2.68 mmol) was
mixed with 2-(trimethysilyl)ethoxymethyl chloride (0.47
mL, 2.68 mmol) and N, N-diisopropylethylamine (0.94 mL,
5.36 mmol) and stirred at room temperature for 16 hours.
After completion of the reaction, the reaction solution
was mixed with ethyl acetate washed with saturated
aqueous sodium chloride and the organic layer was dried
over anhydrous sodium sulfate and evaporated under
reduced pressure. The resulting residue was purified by
silica gel column chromatography (hexane/ethyl acetate =
10/1) to give the desired product (325.8 mg, 85% yield).
Morphology: colorless oil
1H-NMR (CDCl3)
δ: 0.01 (s, 9H), 0.89-0.97 (m, 2H), 3.32 (s, 3H), 3.54-
3.68 (m, 2H), 3.70 (s, 3H), 5.42 (s, 2H), 7.99 (s, 1H),
8.09 (s, 1H).
1- (1-{ [2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanone
(Formula Removed)
N-Methoxy-N-methyl-1-{[2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carboxamide
(325.8 mg,1.14 mmol) in tetrahydrofuran(2 mL) was mixed
with methylmagnesium bromide (0.98 M in tetrahydrofuran,
4.32 mL, 4.23 mmol) under cooling with ice and the
reaction mixture was warmed slowly to room temperature
for 16 hours with stirring. After completion of the
reaction, the reaction solution was mixed with saturated
aqueous ammonium chloride, and extracted with ethyl
acetate. The organic layer was dried over anhydrous
sodium sulfate and evaporated under reduced pressure.
The resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 2/1, to ethyl
acetate/MeOH = 20/1) to give the desired product (89.9 mg,
33% yield).
Morphology: colorless oil
1H-NMR (CDCl3)
δ: 0.01 (s, 9H), 0.94 (t, J = 5.1 Hz, 2H), 2.46 (s, 3H),
3.61 (t, J = 5.1 Hz, 2H), 5.46 (s, 2H), 7.95 (s, 1H),
8.09 (s, 1H).
1- (1-{ [2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanol
(Formula Removed)
1- (1-{ [2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanone (39.7 mg, 0.17 mmol) in methanol(2 mL) was mixed with sodium borohydride (12.5 mg, 0.34 mmol) and stirred at room temperature for 90 minutes. After completion of the reaction, the reaction solution was mixed with ethyl acetate and washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude reaction product containing the desired product was used for the next step (43.7 mg).
Morphology: colorless oil
1H-NMR(CDCl3)
δ: 0.01 (s, 9H), 0.92 (t, J = 5.1 Hz, 2H), 1.54 (d, J =
6.6 Hz 3H), 3.58 (t, J = 5.1 Hz, 2H), 4.87-4.97 (m, 1H),
5.41 (s, 2H), 7.54-7.56 (m, 2H).
1- (1-{ [2-(Trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanamine
Synthesis was carried out in the same manner as in
Reference Synthetic Example 2 by using 1- (l-{ [2-
(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanol.
The obtained crude product was used for the next reaction
Morphology: colorless oil
SYNTHETIC EXAMPLE 1
4-Bromo-2-(2-morpholino-2-oxoethyl)-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3 (2H)one
(Formula Removed)
4-Bromo-5-[{1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)one
(Formula Removed)
4,5-Dibromopyridazin-3(2H)-one (3.00 g, 11.8 mmol, prepared in accordance with Journal of Heterocyclic Chemistry, 33(6), 1579-1582; 1996) in dioxane-water (1:1, 30 mL) was stirred with triethylamine (4 .94 mL, 35.5
mmol) and (li?,2i?,3i?,5,S) -isopinocampheylamine (2.41 mL,
14.2 mmol) at 120°C for 17 hours. After cooling, the reaction solution was mixed with 1 M aqueous hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate = 5/1) to give the desired product (1.26 g, 33% yield).
Morphology: yellow amorphous
LC/MS: Condition 3, retention time 4.07 min LC/MS(ESI+) m/z; 32 6, 32 8 [M+l]+ 1H-NMR(CDCl3)
δ : 0.95 (d, J = 9.9 Hz, 1H), 1.18 (s, 3H), 1.19 (d, J = 7.0 Hz, 3H), 1.28 (s, 3H), 1.70-1.75 (m, 1H), 1.90-2.10 (m, 2H), 2.40-2.50 (m, 1H), 2.60-2.70 (m, 1H), 3.80-3.90 (m, 1H), 4.82 (d, J = 8.3 Hz, 1H), 7.56 (s, 1H), 11.21 (s, 1H) .
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-
Ethyl 2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
(Formula Removed)
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(6 00 mg, 1.84 mmol) in N, N-dimethylformamide (6 mL) was mixed with ethyl bromoacetate (306 uL, 2.76 mmol) and potassium carbonate (381 mg, 2.76 mmol) at room temperature and stirred at 80°C for 1.5 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography
(chloroform/ethyl acetate = 8/1) to give the desired product (670 mg, 88% yield). Morphology: light brown oil
LC/MS: Condition 2, retention time 3.63 min LC/MS(ESI+) m/z; 412, 414 [M+l]+ LC/MS(ESI") m/z; 410, 412 [M-l]" 1H-NMR(CDCl3)
δ : 0.97 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.21 (d, J = 7.4 Hz, 3H), 1.27 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H), 1.70-1.80 (m, 1H), 1.90-2.00 (m, 1H), 2.00-2.10 (m, 1H), 2.40-2.55 (m, 1H), 2.57-2.70 (m, 1H), 3.80-3.90 (m, 1H), 4.24 (q, J = 7.0 Hz, 2H), 4.74 (d, J = 8.2 Hz, 1H), 4.87
(s, 2H), 7.54 (s, 1H).
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
yl}acetic acid
(Formula Removed)
Ethyl 2-{5-bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (64 6 mg, 1.57 mmol) in 1,4-dioxane (6.5 mL) was mixed with 1 M aqueous sodium hydroxide (4.71 mL, 4.71 mmol) and stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (567 mg, 94% yield). Morphology: pale yellow solid LC/MS: Condition 3, retention time 4.12 min LC/MS(ESI+) m/z; 3 84, 3 86 [M+l]+ LC/MS(ESI") m/z; 3 82, 3 84 [M-l]" 1H-NMR(CDCl3)
δ : 0.97 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.18 (d, J = 7.4 Hz, 3H), 1.27 (s, 3H), 1.70-1.80 (m,1 H), 1.90-2.00 (m, 1H), 2.00-2.10 (m, 1H), 2.40-2.50 (m, 1H), 2.60-2.70 (m, 1H), 3.80-3.90 (m, 1H), 4.82 (d, J = 8.2 Hz, 1H), 4.92 (s, 2H), 6.23 (br s, 1H), 7.58 (s, 1H).
4-Bromo-2-(2-morpholino-2-oxoethyl)-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (30 mg, 0.078 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(22 mg, 0.117 mmol), 1-hydroxybenzotriazole anhydride (16 mg, 0.117 mmol) and triethylamine (16 µL, 0.117 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with morpholine (10 µL, 0.117 mmol) at room temperature for 5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium sulfate and saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography
(chloroform/ethyl acetate = 1/1) to give the desired product (20 mg, 57% yield). Morphology: colorless amorphous LC/MS: Condition 3, retention time 4.18 min LC/MS(ESI+) m/z; 4 53, 4 55 [M+l]+ LC/MS(ESI") m/z; 4 51, 4 53 [M-l]" SYNTHETIC EXAMPLES 2 to 4 0
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the
resulting compounds, the LC/MS conditions used for their
analysis and the observed peaks and retention times are
shown in Table 9.
TABLE 9
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
Synthetic Examples 2 to 40
(Formula Removed)
SYNTHETIC EXAMPLE 41
3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (l-phenylethyl)propanamide
(Formula Removed)
Ethyl 3-{5-bromo-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate
(Formula Removed)
4-Bromo-5-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (32 0 mg, 0.637 mmol) in N,N-dimethylformamide (3.2 mL) was mixed with ethyl 3-bromopropionate (0.187 mL, 1.47 mmol) and potassium carbonate (244 mg, 1.76 mmol) at room temperature and stirred at 80°C for 4 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired
product (4 53 mg, quant.). Morphology: light brown oil
LC/MS: Condition 1, retention time 4.75 min LC/MS(ESI + ) m/z: 426, 428 [M+l] + LC/MS(ESI") m/z: 424, 426 [M-l]~ 1H-NMR(CDCl3)
δ:0.97 (d, J = 12.0 Hz, 1H), 1.05 (s, 3H), 1.18 (d, J = 6.0 Hz, 3H),1.25 (t, J = 9.0 Hz, 3H), 1.27(s, 3H),1.68-1.75 (m, 1H), 1.90-2.00 (m, 1H), 2.00-2.10 (m, 1H), 2.40-2.55 (m, 1H), 2.55-2.70 (m, 1H), 2.81 (t, J = 7.5 Hz, 2H), 3.81-3.90 (m, 1H), 4.15 (q, J = 9.0 Hz, 2H), 4.44 (t, J = 7.5 Hz, 2H), 4.68 (d, J = 9.0 Hz, 1H), 7.50 (s, 1H). 3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid
(Formula Removed)
Ethyl 3-{5-bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate (4 53 mg, 1.06 mmol) in 1,4-dioxane (4 mL) was stirred with 1 M aqueous sodium hydroxide (2.93 mL, 2.93 mmol) at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (314 mg, 80% yield). Morphology: yellow solid
LC/MS: Condition 2, retention time 3.20 min LC/MS(ESI + ) m/z: 398, 400 [M+l] + LC/MS(ESI") m/z: 396, 398 [M-l]~ 1H-NMR(CDCl3)
δ:0.97 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 6.9 Hz, 3H), 1.27 (s, 3H),1.68-1.76 (m, 1H), 1.90-2.00 (m, 1H), 2.00-2.10 (m, 1H), 2.43-2.52 (m, 1H), 2.59-2.68 (m, 1H), 2.88 (t, J = 6.9 Hz, 2H), 3.81-3.90 (m, 1H), 4.46 (t, J = 6.9 Hz, 2H), 4.73 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H). 3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (l-phenylethyl)propanamide
(Formula Removed)
3-{5-Bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid (32 mg, 0.080 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31 mg, 0.160 mmol), 1-hydroxybenzotriazole anhydride (11 mg, 0.080 mmol) and triethylamine (22 µL, 0.160 mmol) in N,N-dimethylformamide (1 mL) were stirred with 1-phenylethylamine (20 uL, 0.160 mmol) at room temperature
for 24 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography
(chloroform/methanol = 15/1) to give the desired product
(38 mg, 95% yield). Morphology: yellow oil
LC/MS: Condition 3, retention time 4.67 min LC/MS(ESI + ) m/z: 501, 503 [M+l] + LC/MS(ESI") m/z: 499, 501 [M-l]~ SYNTHETIC EXAMPLES 42 to 44
Compounds were synthesized in the same manner as in Synthetic Example 41, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 10.
Table 10
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
SYNTHETIC EXAMPLE 42 to 44
(Formula Removed)
SYNTHETIC EXAMPLE 45
4-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)butanamide

(Formula Removed)
Ethyl 4-{5-bromo-6-oxo-4- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
Yl}butanoate
(Formula Removed)
4-Bromo-5- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (224 mg, 0.688 mmol) in N, N- dimethylformamide (2.2 mL) was mixed with ethyl 4-bromobutyrate (0.148 mL, 1.03 mmol) and potassium carbonate (142 mg, 1.03 mmol) at room
temperature and stirred at 80°C for 2 hours. After cooling, the reaction solution was mixed with saturated
aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (4 54 mg, quant.). Morphology: yellow amorphous
LC/MS: Condition 2, retention time 3.74 min LC/MS(ESI + ) m/z: 440, 442 [M+l] + LC/MS(ESI") m/z: 438, 440 [M-l]~ 1H-NMR(CDCl3)
δ:0.98 (d, J = 10.2 Hz, 1H), 1.06 (s, 3H), 1.19 (d, J = 6.6 Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H), 1.27 (s, 3H),1.67-1.77 (m, 1H), 1.90-1.98 (m, 1H), 2.00-2.08 (m, 1H), 2.18
(dd, J = 6.9, 6.9 Hz, 2H), 2.37 (t, J = 6.9 Hz, 2H),2.45-2.55 (m, 1H), 2.58-2.70 (m, 1H), 3.80-3.90 (m, 1H), 4.14
(q, J = 7.2 Hz, 2H), 4.36 (t, J = 6.9 Hz, 2H), 4.68 (d, J =6.8 Hz, 1H), 7.52 (s, 1H). 4-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}butanoic acid
(Formula Removed)
Ethyl 4-{5-bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}butanoate (4 54 mg, 0.981 mmol) in 1,4-dioxane (4.5 mL)
was stirred with 1 M aqueous sodium hydroxide (2.06 mL, 2.06 mmol) at room temperature for 6.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (182 mg, 64% yield). Morphology: yellow amorphous
LC/MS: Condition 3, retention time 4.35 min LC/MS(ESI + ) m/z: 412, 414 [M+l] + LC/MS(ESI") m/z: 410, 412 [M-l]~ 1H-NMR(CDCl3)
δ:0.98 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.67-1.76 (m, 1H), 1.90-2.00
4-{5-Bromo-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
(m, 1H), 2.00-2.09 (m, 1H), 2.15 (dd, J = 7.2, 6.6 Hz, 2H) , 2.41 (t, J = 7.2 Hz, 2H) ,2 .45-2 .55 (m, 1H) , 2.59-2.70 (m, 1H), 3.80-3.90 (m, 1H), 4.25 (t, J = 6.6 Hz, 2H), 4.72 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H). 4- {5-Bromo-6-oxo-4- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)butanamide
(Formula Removed)
yl}butanoic acid (38 mg, 0.091 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(35 mg, 0.182 mmol), 1-hydroxybenzotriazole anhydride (12 mg, 0.091 mmol) and triethylamine (25 uL, 0.182 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (25 uL, 0.182 mmol) at room temperature for 24 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography
(chloroform/methanol = 15/1) to give the desired product
(30 mg, 58% yield). Morphology: pale yellow solid LC/MS: Condition 3, retention time 3.67 min LC/MS(ESI+) m/z: 502, 504 [M+l]+ LC/MS(ESI") m/z: 500, 502 [M-l]~ SYNTHETIC EXAMPLE 46
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)propanamide
(Formula Removed)
Ethyl 2-{5-bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate
(Formula Removed)
4-Bromo-5- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (2 08 mg, 0.637 mmol) in N, N-dimethylformamide (2 mL) was mixed with ethyl 2-bromopropionate (124 δL, 0.955 mmol) and potassium carbonate (132 mg, 0.955 mmol) at room
temperature and stirred at 80°C for 2 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (149 mg, 55% yield). Morphology: pale yellow oil
LC/MS: Condition 2, retention time 3.82 min LC/MS(ESI + ) m/z: 426, 428 [M+l] + LC/MS(ESI") m/z: 424, 426 [M-l]~ 1H-NMR(CDCl3)
δ:0.98 (d, J = 9.9 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 7.2 Hz, 3HX1/2), 1.20 (d, J = 7.2 Hz, 3HX1/2), 1.25 (t, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.65 (d, J =7.2 Hz, 3H),
1.69-1.80 (m, 1H), 1.90-1.99 (m, 1H), 2.00-2.08 (m, 1H), 2.43-2.53 (m, 1H), 2.58-2.70 (m, 1H), 3.82-3.92 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 4.74 (d, J = 8.1 Hz, 1H), 5.60 (q, J = 7.2 Hz, 1HX1/2), 5.61 (q, J = 7.2 Hz, lHXl/2), 7.59 (s, 1H).
2- {5-Bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid
(Formula Removed)
Ethyl 2-{5-bromo-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate (14 9 mg, 0.349 mmol) in 1,4-dioxane (1 mL) was stirred with 1 M aqueous sodium hydroxide (0-698 mL, 0.698 mmol) at room temperature for 5.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (220 mg, quant.). Morphology: yellow solid
LC/MS: Condition 2, retention time 3.35 min LC/MS(ESI + ) m/z: 398, 400 [M+l] + LC/MS(ESI") m/z: 396, 398 [M-l]~ 1H-NMR(CDCl3)
δ:0.97 (d, J = 9.9 Hz, 1H), 1.05 (s, 3H), 1.18 (d, J = 6.9 Hz, 3H), 1.27 (s, 3H), 1.66 (d, J =7.2 Hz, 3H), 1.70-1.78 (m, 1H), 1.90-1.98 (m, 1H), 2.00-2.08 (m, 1H), 2.42-2.51 (m, 1H), 2.60-2.70 (m, 1H), 3.80-3. 92 (m, 1H), 4.79
(d, J = 7.5 Hz, 2H), 5.41-5.58 (m, 1H), 7.54 (s, 1H). 2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)propanamide
(Formula Removed)
2-{5-Bromo-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoic acid (4 0 mg, 0.099 mmol), 1-(3-dimethylaminopropyl)- 3 -ethylcarbodiimide hydrochloride
(38 mg, 0.199 mmol), 1-hydroxybenzotriazole anhydride (4 mg, 0.03 mmol) and triethylamine (28 µL, 0.199 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (20 µL, 0.199 mmol) at room temperature for 17.5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography
(chloroform/methanol = 20/1) to give the desired product
(25 mg, 52% yield). Morphology: yellow amorphous
LC/MS: Condition 2, retention time 2.25 min LC/MS(ESI + ) m/z: 488, 490 [M+l] + LC/MS(ESI") m/z: 486, 488 [M-l]~ SYNTHETIC EXAMPLE 47 4-Bromo-2-[2-(pyridin-4-ylmethylamino)ethyl]-5-
[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
2-{5-Bromo-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (35 mg, 0.073 mmol) in N,N-dimethylformamide (1 mL) was mixed with a borane-tetrahydrofuran complex (1.13 M in tetrahydrofuran, 78 µL, 0.088 mmol) under cooling with ice and stirred at room temperature for 5.5 hours. After completion of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (32 mg, 92% yield). Morphology: colorless solid
LC/MS: Condition 2, retention time 3.34 min
LC/MS(ESI") m/z: 458, 460 [M-l]~ 1H-NMR(CDCl3)
δ:0.98 (d, J = 9.9 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 6.9 Hz, 3H), 1.19(d, J = 6.9 Hz, 3H), 1.28 (s, 3H), 1.70-1.78 (m, 1H), 1.92-1.97 (m, 1H), 1.99-2.05 (m, 1H), 2.46-2.52 (m, 2H), 2.60-2.69 (m, 2H), 3.83-3.93 (m, 1H), 4.51
(d, J = 6.3 Hz, 1H), 4.84 (d, J = 8.1 Hz, 1H), 4.89 (s, 2H), 7.38 (d, J = 6.6 Hz, 2H), 7.60 (s, 1H), 8.46 (d, J = 6.6 Hz, 2H). SYNTHETIC EXAMPLE 48
2-[5-Bromo-4-(1,1,3,3-tetramethylbutylamino)-6-oxopyridazin-1(6H)-yl]-N- (pyridin-4-ylmethyl)acetamide
(Formula Removed)
Ethyl 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetate
(Formula Removed)
4,5-Dibromopyridazin-3(2H)-one (5.0 g, 19.7 mmol) in N,N-dimethylformamide (50 mL) was stirred with ethyl bromoacetate (3.28 g, 29.5 mmol) and potassium carbonate
(4.08 g, 29.5 mmol) at 80°C for 1 hour and 40 minutes. After completion of the reaction, ethyl acetate was
added, and the organic layer was washed with saturated aqueous ammonium chloride three times and with saturated aqueous sodium chloride once, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (7.42 g, 100% yield). Morphology: brown solid
LC/MS: Condition 3, retention time 1.67 min LC/MS(ESI+) m/z; 341, 34 3 [M+l]+ 1H-NMR(CDCl3)
δ : 1.30 (t, J = 7.0 Hz, 3H), 4.27 (q, J = 7.0 Hz, 2H), 4.88 (s, 2H), 7.83 (s, 1H). 2-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)acetic acid
(Formula Removed)
Ethyl 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetate (6.01 g, 17.7 mmol) in 1,4-dioxane (60 mL) was stirred with 1 M aqueous sodium hydroxide (53.1 mL, 53.1 mmol) at room temperature for 1 hour. After completion of the reaction, the reaction solution was mixed with ethyl acetate and extracted with 1 M aqueous sodium hydroxide twice. The resulting aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate twice. The resulting organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced
pressure to give the desired product (5.30 g, 88% yield). Morphology: brown solid 1H-NMR(DMSO-d6)
δ : 4.82 (s, 2H), 8.21 (s, 1H).
2-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)-N- (pyridin-4-ylmethyl)acetamide
(Formula Removed)
2-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)acetic acid (1.48 g, 4.38 mmol) in tetrahydrofuran (30 mL) was mixed with N,N-dimethylformamide (1 drop) and oxalyl chloride (570 uL, 6.53 mmol) at room temperature and stirred at room temperature for 3 0 minutes. The solvent was removed by distillation, and the residue was dissolved in tetrahydrofuran (10 mL) and added dropwise to 4-picolylamine (53 8 uL, 5.22 mmol) and triethylamine (1.22 mL, 8.70 mmol) in tetrahydrofuran (20 mL) and stirred at room temperature for 3 0 minutes. After completion of the reaction, the reaction solution was mixed with water and extracted with chloroform three times, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting solid was washed with 2-propanol-hexane to give the desired product (572 mg, 33% yield). Morphology: pale gray solid
1H-NMR(DMSO-d6)
δ : 4.31 (d, J = 6.2 Hz, 2H), 4.82 (s, 2H), 7.26 (d, J = 6.2 Hz, 2H), 8.21 (s, 1), 8.50 (d, J = 6.2 Hz, 2H), 8.80
(t, J = 6.2 Hz, 1H).
LC/MS: Condition 3, retention time 0.45 min
LC/MS(ESI+) m/z; 4 01, 4 03, 4 05 [M+l]+
LC/MS(ESI") m/z; 3 99, 4 01, 4 03 [M-l] "
2-[5-Bromo-4-(1,1,3,3-tetramethylbutylamino)-6-
oxopyridazin-1(6H)-yl]-N- (pyridin-4-ylmethyl)acetamide
2-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)-N- (pyridin-4-ylmethyl) acetamide (50 mg, 124 µmol) in dioxane-water
(1:1, 2 mL) was stirred with triethylamine (52 µL, 3 72 µmol) and 2,5,5-trimethylhexan-2-amine (16 mg, 112 µmol)
at 90°C for 26 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the residue was mixed with saturated aqueous sodium chloride and extracted with chloroform three times. The combined organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation. The resulting residue was purified by silica gel chromatography (chloroform/methanol = 10/1) to give the desired product (13 mg, 25% yield). Morphology: colorless solid
LC/MS: Condition 4, retention time 1.85 min LC/MS(ESI+ ) m/z; 450, 4 52 [M+l] + LC/MS(ESI") m/z; 44 8, 450 [M-l] " SYNTHETIC EXAMPLES 4 9 to 75
Compounds were synthesized in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 11.
TABLE 11
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below. Synthetic Examples 49 to 7 5
(Formula Removed)
Isopropylamine (0.262 mL, 3.07 mmol), chloromethylsulfonyl chloride (0.274 mL, 3.07 mmol) and
triethylamine (0.856 mL, 6 .14 mmol) were added to dichloromethane (2 mL) under cooling with ice, and the resulting mixture was stirred for 2 hours under cooling with ice. After completion of the reaction, the reaction mixture was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting reaction product was dissolved in N,N-dimethylformamide (3.2 mL) and mixed with potassium carbonate (267 mg, 1.93 mmol) and 4-bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one (276 mg, 0 .844 mmol) at room
temperature and stirred at 80°C for 4 hours. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol = 80/1) to give the desired product (22 mg, 4% yield). Morphology: colorless solid
LC/MS: Condition 2, retention time 3.50 min LC/MS(ESI+) m/z: 461, 463 [M+l]+ LC/MS(ESI") m/z: 459, 461 [M-l]"
1H-NMR(CDCl3)
δ:0.97 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 7.2 Hz, 3H), 1.27(d, J = 6.6 Hz, 3HX2), 1.28 (s, 3H), 1.61-1.78 (m, 1H), 1.92-1.98 (m, 1H), 2.02-2.08 (m, 1H), 2.46-2.52 (m, 1H), 2.59-2.68 (m, 1H), 3.70 (q, J = 6.6 Hz, 1H), 3.81-3.92 (m, 1H), 4.49-4.52 (m, 1H), 4.85 (d, J = 8.4 Hz, 1H), 5.42 (d, J = 2.4 Hz, 2H), 7.63 (s, 1H). SYNTHETIC EXAMPLE 77
4-Bromo-2-cyclopentyl-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (30 mg, 0.092 mmol) in N, N- dimethylformamide (0.9 mL) was mixed with bromocyclopentane (20 mg, 0.138 mmol) and potassium carbonate (19 mg, 0.138 mmol) at room
temperature and stirred at 80°C overnight. After cooling, the reaction solution was concentrated, mixed with water and extracted with ethyl acetate three times. The resulting organic layer was filtered through silica gel and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate = 1/1) to give the desired product (25 mg, 67% yield).
Morphology: colorless amorphous LC/MS: Condition 3, retention time 5.22 min LC/MS(ESI + ) m/z: 394, 396 [M+l] + LC/MS(ESI") m/z: 392, 394 [M-l]~ SYNTHETIC EXAMPLES 78 to 94
Compounds were synthesized in the same manner as in Synthetic Example 77, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 12.
TABLE 12
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
Synthetic Examples 78 to 94

(Formula Removed)
SYNTHETIC EXAMPLES 95 to 127
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 13.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below. Synthetic Examples 9 5 to 127
(Formula Removed)
SYNTHETIC EXAMPLES 128 to 131
Compounds were synthesized in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 14.
TABLE 14
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
SYNTHETIC EXAMPLES 128 to 131
(Formula Removed)
SYNTHETIC EXAMPLE 132
2-(2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetamido)acetic acid
(Formula Removed)
tert-Butyl 2-(2-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetamido)acetate (18 mg, 0.036 mmol) prepared in Synthetic Example 10 in dichloromethane (1 mL) was stirred with trifluoroacetic acid (0.1 mL) at room temperature. After completion of the reaction, the reaction solution was concentrated to give the desired product (15 mg, 94% yield). Morphology: pale green solid
LC/MS: Condition 3, retention time 3.97 min LC/MS(ESI + ) m/z: 441, 443 [M+l] + LC/MS(ESI") m/z: 439, 441 [M-l]~ SYNTHETIC EXAMPLE 133
Ethyl 2-{5-chloro-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
(Formula Removed)
trimethylbicyclo[3.1.1]hept-3-ylamino}pyridazin-3(2H)-one
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4,5-dichloropyridazin-3(2H)-one (prepared in accordance with Journal of Heterocyclic Chemistry, 33 (6), 1579-1582; 1996) (100% yield) . Morphology: pale yellow solid LC/MS: Condition 3, retention time 4.09 min LC/MS(ESI + ) m/z: 282, 284 [M+l] + LC/MS(ESI") m/z: 280, 282 [M-l]~ Ethyl {5-chloro-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4-chloro-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (33% yield). Morphology: colorless solid
SYNTHETIC EXAMPLES 134 to 135
Synthesis of 2- { 5-chloro-6-oxo-4- [ (1R, 2R, 3R, SS) -2 , 6 , 6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl 2-{5-chloro-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (100% yield). Morphology: colorless solid
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 15.
TABLE 15
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
Synthetic Examples 134 to 13 5
SYNTHETIC EXAMPLE 13 6
4-Chloro-2-{2-[4-(dimethylamino)phenyl]-2-oxoethyl}-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 77 by using 4-chloro-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (88% yield). Morphology: orange solid
LC/MS: Condition 3, retention time 4.09 min LC/MS(ESI + ) :471, 473 [M+l] + LC/MS (ESI") :469, 471 [M-l] " SYNTHETIC EXAMPLE 13 7
2-{2-[4-(Dimethylamino)phenyl]-2-oxoethyl}-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
5- [ (1R,2R,3R,5S) -2,6,6-Trimethylbicyclo[3 .l.l]hept-3-ylamino] pyridazin-3 (2H) –one
(Formula Removed)
4-Bromo-5-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(300 mg, 0.92 mmol) and 10% palladium-carbon (50 wt%, 30 mg) in methanol were stirred in a hydrogen stream at room temperature for 1 day. The reaction solution was filtered through celite, and the filtrate was concentrated to give the desired product (100% yield). Morphology: pale yellow solid 2-{2-[4-(Dimethylamino)phenyl]-2-oxoethyl}-5-
[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one
Synthesis was carried out in the same manner as in Synthetic Example 77 by using 5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one.
Morphology: orange solid SYNTHETIC EXAMPLES 138 to 139 Ethyl 2-{6-oxo-4-[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 5- [ (1R, 2R, 3R, SS) -2 , 6 , 6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (42% yield).
Morphology: pale yellow oil
LC/MS: Condition 3, retention time 4.17 min LC/MS(ESI + ) :3 34 [M+l] + 2-{6-Oxo-4- [ (1R,2R,3R,5S) -2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl 2-{6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetate. Morphology: pale yellow solid LC/MS: Condition 3, retention time 3.70 min
LC/MS (ESI + ) :3 06 [M+l] +
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the
resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 16.
Table 16
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
SYNTHETIC EXAMPLE 14 0
4-Chloro-6-ethoxy-2-{2-[4-(dimethylamino)phenyl]-2-oxoethyl}-5- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
4-Chloro-6-ethoxy-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4,5-dichloro-6-ethoxypyridazin-3(2H)-one (prepared in accordance with WO9501343) (77% yield). Morphology: colorless solid
LC/MS: Condition 3, retention time 4.60 min LC/MS(ESI + ) :326, 328 [M+l] + LC/MS (ESI") :324, 32 6 [M-l] "
4-Chloro-6-ethoxy-2-{2-[4-(dimethylamino)phenyl]-2-oxoethyl}-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
Synthesis was carried out in the same manner as in Synthetic Example 77 by using 4-chloro-6-ethoxy-5-
[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3. l.l]hept-3-ylamino]pyridazin-3(2H)-one (100% yield). Morphology: pale yellow solid LC/MS: Condition 3, retention time 5.52 min LC/MS(ESI + ) :515, 517 [M+l] + LC/MS(ESI"):513, 515 [M-l]" SYNTHETIC EXAMPLES 141 to 142
Synthesis of 2-{5-chloro-3-ethoxy-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
(Formula Removed)
Ethyl 2-{5-chloro-3-ethoxy-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4-chloro-6-ethoxy-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one (96% yield). Morphology: colorless solid
LC/MS: Condition 3, retention time 5.05 min LC/MS (ESI + ) :412, 414 [M+l] +
2-{5-Chloro-3-ethoxy-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
Synthesis was carried out in the same manner as in Synthetic Example 1 by using Ethyl 2-{5-chloro-3-ethoxy-6-OXO-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (8 9% yield). Morphology: colorless solid
LC/MS: Condition 3, retention time 4.59 min LC/MS (ESI + ) :384, 386 [M+l] + LC/MS (ESI") :382, 384 [M-l] "
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 17.
TABLE 17
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
SYNTHETIC EXAMPLE 143
6-Ethoxy-5-[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
2-{3-Ethoxy-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-W-isopropylacetamide
(Formula Removed)
4-Chloro-6-ethoxy-5- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (200 mg, 0.614 mmol) and 10% palladium-carbon (50 wt%, 40 mg) were stirred in methanol in a hydrogen stream at room temperature for 8 days. The reaction solution was filtered through celite and concentrated under reduced pressure to give the desired product (94% yield). Morphology: pale yellow solid LC/MS: Condition 2, retention time 3.15 min LC/MS(ESI + ) :2 92 [M+l] + LC/MS (ESI") :2 90 [M-l] "
Ethyl 2-{3-ethoxy-6-oxo-4- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
yl}acetate
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 6-ethoxy-5- [ [IR, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (80% yield). Morphology: colorless oil
LC/MS: Condition 3, retention time 4.72 min LC/MS(ESI + ) :3 78 [M+l] + LC/MS (ESI") :3 76 [M-l] "
2-{3-Ethoxy-6-oxo-4-[(IR,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl 2-{3-ethoxy-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (86% yield). Morphology: colorless solid 2-{3-Ethoxy-6-oxo-4-[(IR,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-isopropylacetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 2-{3-ethoxy-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (54% yield). Morphology: colorless solid
LC/MS: Condition 3, retention time 4.43 min LC/MS(ESI + ) :3 91 [M+l] +
SYNTHETIC EXAMPLE 144
(Formula Removed)
2-{3-Ethoxy-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 2-{3-ethoxy-6-oxo-4-[ (1R,2R, 3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (90% yield). Morphology: colorless solid
LC/MS: Condition 3, retention time 3.70 min LC/MS (ESI + ) :44 0 [M+l] + LC/MS (ESI") :438 [M-l] " SYNTHETIC EXAMPLE 145 Ethyl 2-{5-methylthio-6-oxo-4- [ (1R, 2R, 3R, 5S) -2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
(Formula Removed)
2-{5-Methylthio-6-oxo-4- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
(Formula Removed)
Ethyl 2-{5-bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (220 mg, 0.533 mmol) and sodium thiomethoxide (112 mg, 1.60 mmol) in toluene (22 mL) were stirred at
80°C for 3 hours. After cooling, the reaction solution was stirred with 1,4-dioxane (6 mL) and 1 M aqueous sodium hydroxide (1.59 mL) at room temperature for 4 hours. After completion of the reaction, the reaction solution was mixed with toluene and extracted with 1 M aqueous sodium hydroxide twice. The resulting aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate twice, and the extract was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (16 9
mg, 90% yield). Morphology: yellow amorphous
LC/MS: Condition 3, retention time 4.20 min LC/MS(ESI + ) :3 52 [M+l] + LC/MS (ESI") :350 [M-l] " 1H-NMR(CDCl3)
δ :0.97 (d, J = 9.9 Hz, 1H), 1.06 (s, 3H), 1.17 (d, J = 7.5 Hz, 3H), 1.27 (s, 3H), 1.68-1.75 (m, 1H), 1.90-2.10
(m, 1H), 2.30 (s, 3H), 2.40-2.70 (m, 2H), 3.80-3.90 (m, 1H), 4.89 (s, 2H), 5.62 (d, J = 8.3 Hz, 1H), 7.64 (s, 1H). Ethyl 2-{5-methylthio-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
2-{5-Methylthio-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (105 mg, 0.299 mmol) in tetrahydrofuran (1 mL) was stirred with 1,1-carbonyldiimidazole (14 5 mg, 0.897 mmol) at room temperature for 1 hour and then with ethanol (0.2 mL) at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the resulting organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel chromatography
(hexane/ethyl acetate = 1/1) to give the desired product
(93 mg, 82% yield). Morphology: yellow oil
LC/MS: Condition 3, retention time 4.65 min
LC/MS(ESI + ) :380 [M+l] +
LC/MS (ESI") :3 78 [M-l] "
SYNTHETIC EXAMPLE 146
2-{5-Methylthio-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
yl}-N-pyridin-4-ylmethyl)acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 2-{5-methylthio-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (85% yield). Morphology: yellow amorphous
LC/MS: Condition 3, retention time 3.50 min LC/MS (ESI + ) :442 [M+l] + LC/MS (ESI") :44 0 [M-l] " SYNTHETIC EXAMPLE 147
Ethyl 2-{5-methylsulfonyl-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate
(Formula Removed)
Ethyl 2-{5-metylthio-6-oxo-4- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (77 mg, 0.203 mmol) and m-chloroperbenzoic acid (60% purity, 150 mg, 0.609 mmol) in dichloromethane were stirred at 0°C for 1 hour and 20 minutes. After completion of the reaction, the reaction solution was washed with saturated aqueous sodium thiosulfate, 1 M aqueous sodium hydroxide and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate = 4/1) to give the desired product (70 mg, 84% yield). Morphology: colorless amorphous LC/MS: Condition 3, retention time 4.49 min LC/MS(ESI + ) :412 [M+l] + LC/MS (ESI") :410 [M-l] " 1H-NMR(CDCl3)
δ :0.97 (d, J = 10.5 Hz, 1H), 1.03 (s, 3H), 1.17 (d, J = 6.9 Hz, 3H), 1.27 (s, 3H), 1.75-1.85 (m, 1H), 1.90-2.05
(m, 2H), 2.40-2.50 (m, 1H), 2.55-2.65 (m, 1H), 3.38 (s, 3H), 3.85-3.95 (m, 1H), 4.78 (s, 2H), 7.67 (s, 1H), 8.36
(d, J = 7.8 Hz, 1H). SYNTHETIC EXAMPLE 148
2-{5-Methylsulfonyl-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
2-{5-Methylsulfonyl-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl 2-{5-Methylsulfonyl-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetate (92% yield). Morphology: colorless solid
LC/MS: Condition 3, retention time 4.02 min LC/MS(ESI + ) :3 84 [M+l] + LC/MS (ESI") :3 82 [M-l] "
2-{5-Methylsulfonyl-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)acetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 2-{5-methylsulfonyl-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (52% yield). Morphology: colorless solid
LC/MS: Condition 3, retention time 3.80 min
LC/MS(ESI + ) :4 74 [M+l] +
LC/MS (ESI") :4 72 [M-l] ~
SYNTHETIC EXAMPLE 14 9
N-{5-Bromo-6-oxo-1-[2-oxo-2-(pyridin-4-
ylmethylamino)ethyl]-1,6-dihydropyridazin-4-
yl}adamantanecarboxamide
(Formula Removed)
Ethyl 2-[5-bromo-4-(4-ethoxy-3-methoxybenzylamino)-6-oxopyridazin-1(6H)-yl]acetate
(Formula Removed)
Ethyl 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)acetate (500 mg, 1.47 mmol) and 3 -ethoxy-4-methoxybenzylamine (96 0 mg, 4.41 mmol) in 1,4-dioxane-water (1:1, 5 mL) were stirred with triethylamine (0.615 mL) at 100°C for 2.5 hours. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was removed by distillation. The resulting residue was purified by silica gel chromatography (chloroform/2-
propanol = 20/1) to give the desired product (640 mg, 98% yield).
Morphology: pale yellow solid LC/MS: Condition 3, retention time 3.70 min LC/MS(ESI + ) :440, 442 [M+l] + LC/MS (ESI") :438, 44 0 [M-l] " Ethyl 2-(5-bromo-4-amino-6-oxopyridazin-1(6H)-yl)acetate
(Formula Removed)
Ethyl 2-[5-bromo—4-(4-ethoxy-3-methoxybenzylamino)-6-oxopyridazin-1(6H)-yl]acetate (57 0 mg, 1.29 mmol) in ethanol (11 mL) was stirred with concentrated
hydrochloric acid (3.4 mL) at 90°C for 4 hours. After cooling, the solvent was removed by distillation, and the residue was stirred with ethanol (10 mL) and 4 M hydrogen
chloride-l,4-dioxiane (1 mL) at 90°C for 1 hour. After
cooling, the solvent was removed by distillation.
Toluene was added, and the resulting crystals were
collected by filtration as the desired product (184 mg,
52% yield).
Morphology: light brown solid
LC/MS: Condition 3, retention time 3.70 min
LC/MS (ESI + ) :276, 278 [M+l] +
LC/MS (ESI") :274, 276 [M-l] "
2-(5-Bromo-4-adamantanecarboxamido-6-oxopyridazin-1(6H)-
yl)acetic acid
(Formula Removed)
Ethyl 2-(5-bromo-4-amino-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.362 mmol) in tetrahydrofuran (2 mL) was mixed with sodium hydride (58 mg, 1.46 mmol) and adamantanecarbonyl chloride (144 mg, 0.724 mmol) at room temperature and stirred at room temperature for 3 0 minutes. After completion of the reaction, the reaction solution was mixed with water and ethyl acetate and extracted with 1 M aqueous sodium hydroxide. The aqueous layer was acidified to pH 1 with 1 M hydrochloric acid
and extracted with ethyl acetate. The extract was washed
with saturated aqueous sodium chloride, dried over
anhydrous sodium sulfate, and the solvent was removed by
distillation to give the desired product.
Morphology: colorless solid
LC/MS: Condition 2 , retention time 3.13 min
LC/MS(ESI + ) :410, 412 [M+l] +
LC/MS (ESI") :408, 410 [M-l] "
N-{5-Bromo-6-oxo-1-[2-oxo-2-(pyridin-4-
ylmethylamino)ethyl]-1,6-dihydropyridazin-4-
yl}adamantanecarboxamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 2-(5-bromo-4-adamantanecarboxamido-6-oxopyridazin-1(6H)-yl)acetic
acid.
Morphology: colorless amorphous LC/MS: Condition 2, retention time 2.20 min LC/MS(ESI + ) :500, 5 02 [M+l] + LC/MS (ESI") :498, 500 [M-l] "
1H-NMR(CDCl3)
δ :1.50-2.00 (m, 10H), 2.00-2.20(m, 5H), 4.47 (d, J = Hz, 2H), 4.93 (s, 2H), 6.69 (br t, J = 6.2 Hz, 2H), 7
(d, J = 4.5 Hz, 2H), 8.00 (s, 1H), 8.55 (d, J = 4.5 H 2H), 9.13 (s, 1H). SYNTHETIC EXAMPLE 15 0
2-[5-Bromo-6-oxo-4-({[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-
yl]carbamoyl}amino)pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
[5-Bromo-6-oxo-4-({[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-
yl]carbamoyl}amino)pyridazin-1(6H)-yl]acetic acid O
(Formula Removed)
1,1-Carbonyldiimidazole (176 mg, 1.09 mmol
suspended in tetrahydrofuran (1 mL) was stirred with
(1R,2R,3R,5S) -isopinocampheylamine (0.19 mL, 1.09 mmol)
at room temperature for 1 hour. The reaction solution
was added dropwise to ethyl 2 -(5-bromo-4 -amino-6 -
oxopyridazin-1(6H)-yl)acetate (100 mg, 0 . 362 mmol) and
sodium hydride (58 mg, 1.45 mmol) in tetrahydrofuran, and
the resulting reaction solution was stirred at room
temperature for 2 hours. The reaction solution was mixed
with 1 M aqueous sodium hydroxide and stirred at room
temperature for 1 hour. The reaction solution was washed
with diethyl ether, and the aqueous layer was acidified
to pH 1 with 1 M hydrochloric acid and extracted with
ethyl acetate. The extract was washed with saturated
aqueous sodium chloride and dried over anhydrous
magnesium sulfate, and the solvent was removed by
distillation to give the desired product.
Morphology: colorless solid
LC/MS: Condition 2, retention time 3.13 min
LC/MS(ESI + ) :427, 429 [M+l] +
LC/MS (ESI") :425, 427 [M-l] "
2-[5-bromo-6-oxo-4-({[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-
yl]carbamoyl}amino)pyridazin-1(6H)-yl]-N-(pyridin-4-
ylmethyl)acetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using [5-bromo-6-oxo-4-
({ [ (1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-
yl]carbamoyl}amino)pyridazin-1(6H)-yl]acetic acid. Morphology: colorless amorphous LC/MS: Condition 2, retention time 2.38 min LC/MS(ESI + ) :517, 519 [M+l] + LC/MS(ESI"):515, 517 [M-l]" 1H-NMR(CDCl3)
δ :0.84 (d, J = 9.9 Hz, 1H), 1.06 (s, 3H), 1.18 (d, J = 4.8 Hz, 3H), 1.25 (s, 3H), 1.80-1.90 (m, 2H), 2.0 (br s, 1H), 2.40-2.50 (m, 1H), 2.70-2.80 (m, 1H), 4.10-4.20 (m, 1H) , 4.45 (s, 2H) , 4.95 (d, J = 5.7 Hz, 2H) , 6.80-6.90
(m, 1H), 7.26 (d, J = 6.0 Hz, 2H), 8.36 (d, J = 6.0 Hz, 2H), 9.00 (s, 1H). SYNTHETIC EXAMPLE 151
2-{5-Ethylthio-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)acetamide
(Formula Removed)
2-{5-Ethylthio-6-oxo-4- [ (1R, 2R, 3R, SS) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 14 5 by using sodium thioethoxide (85% yield).
Morphology: brown amorphous
LC/MS: Condition 2, retention time 3.31 min LC/MS(ESI + ) :366 [M+l] + LC/MS (ESI") :3 64 [M-l] "
2-{5-Ethylthio-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 2-{5-ethylthio-6-oxo-4-[ (1R,2R, 3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid.(78% yield) Morphology: pale yellow amorphous LC/MS: Condition 2, retention time 2.32 min LC/MS (ESI + ) :4 56 [M+l] + LC/MS (ESI") :4 54 [M-l] " SYNTHETIC EXAMPLE 152
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
2-{5-Phenyl-6-oxo-4- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)acetamide
(Formula Removed)
yl}-N- (pyridin-4-ylmethyl)acetamide (50 mg, 0.105 mmol),
phenylboronic acid (26 mg, 0.21 mmol) and
tetrakistriphenylphosphinepalladium (13 mg, 0. 011 mmol)
in 2 M aqueous sodium carbonate-1-propanol (1:5, 2.4 mL)
were stirred in a nitrogen stream at 100°C overnight.
After cooling, the reaction solution was concentrated,
and the resulting residue was purified by silica gel
chromatography (chloroform/methanol = 2 0/1) to give the
desired product (60 mg, 100% yield).
Morphology: pale yellow solid
LC/MS: Condition 2, retention time 2.37 min
LC/MS(ESI + ) :4 72 [M+l] +
LC/MS (ESI") :470 [M-l] "
1H-NMR(CDCl3) δ :0.74 (d, J = 9.9 Hz, 1H), 1.02 (s, 3H), 1.13 (d, J =
7.5 Hz, 3H), 1.21 (s, 3H), 1.60-1.70 (m, 1H), 1.80-1.85 (m, lH),1.95-2.05 (m, 1H), 2.30-2.40 (m, 1H), 2.50-2.60 (m, 1H), 3.75-3.90 (m, 1H), 4.34 (d, J = 8.4 Hz, 1H),
4.44 (d, J = 6.3 Hz, 2H), 4.87 (s, 2H), 7.13 (d, J = 6.3
Hz, 2H), 7.30-7.60 (m, 5H), 7.77 (s, 1H), 8.51 (d, J =
6.3 Hz, 2H).
SYNTHETIC EXAMPLE 153
2-{5-Cyclopropyl-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
yl}-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (62 mg, 0.131mmol), cyclopropylboronic acid (45 mg, 0.524 mmol) , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (13 mg, 0.013 mmol) and potassium carbonate (72 mg, 0.524 mmol) in 1,4-dioxane-water (9/1, 0.7 mL) were stirred in
a nitrogen stream at 100°C for 6 hours. After cooling the reaction solution was concentrated, and the resulting residue was purified by silica gel chromatography
(chloroform/methanol = 8/1) to give the desired product
(42 mg, 74% yield). Morphology: light brown solid LC/MS: Condition 2, retention time 2.20 min LC/MS(ESI + ) :436 [M+l] + LC/MS (ESI") :4 34 [M-l] " SYNTHETIC EXAMPLE 154
2-{5-Methyl-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 153 by using trimethylboroxine (95% yield).
Morphology: pale gray amorphous LC/MS: Condition 2, retention time 2.10 min LC/MS(ESI + ) :410 [M+l] + LC/MS (ESI") :4 08 [M-l] " SYNTHETIC EXAMPLE 155
4-Bromo-2- [4- (pyridin-4-yl) butyl] -5- [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
4-Bromo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one (221 mg, 0.677 mmol) in N, N-dimethylformamide (4 mL) was mixed with 4-(4-chlorobutyl)pyridine hydrochloride (278 mg, 1.35 mmol) and potassium carbonate (375 mg, 2.71
mmol) at room temperature and stirred at 80°C for 6.5 hours. After cooling, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol = 50/1) to give the desired product (38 mg, 12% yield).
Morphology: pale yellow oil
LC/MS: Condition 2, retention time 2.37 min LC/MS(ESI + ) :459, 461 [M+l] + LC/MS (ESI") :457, 459 [M-l] " 1H-NMR(CDCl3)
δ:0.98 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J = 6.9 Hz, 3H), 1.26 (s, 3H), 1.66-1.76 (m, 3H), 1.79-1.88
(m, 2H), 1.90-1.97 (m, 2H), 2.46-2.50 (m, 1H), 2.58-2.68
(m, 1H), 2.66 (t, J = 7.2 Hz, 2H), 3.80-3.89 (m, 1H), 4.11 (t, J = 6.9 Hz, 2H), 4.67 (d, J = 8.4 Hz, 1H) , 7.11
(d, J = 6.0 Hz, 2H), 7.50 (s, 1H), 8.47 (d, J = 6.0 Hz, 2H) .
SYNTHETIC EXAMPLE 156
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)ethanethioamide
(Formula Removed)
2-{5-Bromo-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (99 mg, 0.208 mmol) in toluene (1 mL) was mixed with Lawesson's reagent (168
mg, 0.416 mmol) and refluxed at 120°C for 1 hour. After cooling, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by
silica gel chromatography (chloroform/methanol = 5 0/1) to give the desired product (28 mg, 27% yield). Morphology: orange solid
LC/MS: Condition 2, retention time 2.40 min LC/MS(ESI + ) :490, 492 [M+l] + LC/MS (ESI") :488, 490 [M-l] " 1H-NMR(CDCl3)
δ:0.97 (d, J = 10.2 Hz, 1H), 1.05 (s, 3H), 1.19 (d, J =
6.9 Hz, 3H), 1.29 (s, 3H), 1.69-1.77 (m, 1H), 1.92-1.98 (m, 1H), 2.00-2.07 (m, 1H), 2.47-2.53 (m, 1H), 2.60-2.69 (m, 1H), 3.82-3.95 (m, 1H), 4.85 (d, J = 5.7 Hz, 1H+2H),
5.29 (s, 2H), 7.17 (d, J = 6.0 Hz, 2H), 7.64 (s, 1H),
8.53 (d, J = 6.0 Hz, 2H), 9.87 (s, 1H).
SYNTHETIC EXAMPLE 157
4-Bromo-2-{[1-(pyridin-4-ylmethyl)-1H-tetrazol-5-
yl]methyl}-5-[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
2-{5-Bromo-6-oxo-4-[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)ethanethioamide (38 mg, 0.077 mmol) in dichloromethane (1 mL) was mixed with azidotrimethylsilane (41 µL, 0.308 mmol) and iron
trichloride (30 mg, 0.185 mmol) at room temperature and stirred at room temperature for 17 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/methanol = 5 0/1) to give the desired product (9 mg, 24% yield). Morphology: orange solid
LC/MS: Condition 3, retention time 4.02 min LC/MS(ESI + ) :499, 501 [M+l] + LC/MS (ESI") :497, 499 [M-l] " 1H-NMR(CDCl3)
δ:0.95 (d, J = 10.2 Hz, 1H), 1.03 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.64-1.71 (m, 1H), 1.86-1.94 (m, 1H), 2.00-2.07 (m, 1H), 2.45-2.53 (m, 1H), 2.53-2.62 (m, 1H), 3.74-3.80 (m, 1H), 4.73 (d, J = 7.5 Hz, 1H), 5.55 (s, 2H), 5.88 (s, 2H), 6.99 (d, J = 6.0 Hz, 2H), 7.45 (s, 1H), 8.53 (d, J = 6.0 Hz, 2H). SYNTHETIC EXAMPLE 158
4-[(2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetamido)methyl]pyridine 1-oxide
(Formula Removed)
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.105 mmol) and m-chloroperbenzoic acid (35 mg, 0.112 mmol) suspended in tetrahydrofuran (1.5 mL) were stirred at room
temperature for 5 minutes and at 80°C for 30 minutes.
After cooling, the reaction solution was concentrated,
and the resulting residue was purified by silica gel
chromatography (chloroform/methanol = 5/1) to give the
desired product (49 mg, 95% yield).
Morphology: pale yellow solid
LC/MS: Condition 2, retention time 2.70 min
LC/MS(ESI + ) :490, 492 [M+l] +
LC/MS (ESI") :488, 490 [M-l] "
SYNTHETIC EXAMPLE 15 9
4-Bromo-2-{2-[4-(diethylamino)phenyl]-2-
(methoxyimino)ethyl}-5-[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
4-Bromo-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one (50 mg, 0 . 097 mmol) and methoxamine hydrochloride (41 mg, 0.485 mmol) in ethanol (0.5 mL) were stirred at 80°C for 1 hour. After cooling,
ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate = 3/1) to give the desired product (56 mg, 100% yield). Morphology: pale yellow amorphous LC/MS: Condition 2, retention time 3.99 min LC/MS(ESI + ) :544, 54 6 [M+l] + LC/MS(ESI") :542, 544 [M-l]" SYNTHETIC EXAMPLE 16
4-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)benzoic acid
4-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)benzamide
(Formula Removed)
4-Hydrazinobenzoic acid (2 .00 g, 13.1 mmol) in ethanol-water (1:1, 20 mL) was stirred with mucobromic

acid (2.26 g, 8.76 mmol) and concentrated hydrochloric
acid (10 mL) at 70°C for 2 days. After cooling, the
resulting crystals were collected by filtration, washed
with ethanol and water and dried under reduced pressure
to give the desired product (3.05 g, 62% yield).
Morphology: pale yellow solid
LC/MS: Condition 2, retention time 2.60 min
LC/MS(ESI + ) :373, 375, 377 [M+l] +
LC/MS(ESI") :371, 373, 375 [M-l] ~
4-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
yl}benzoic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)benzoic acid (35% yield). Morphology: pale yellow amorphous LC/MS: Condition 2, retention time 3.55 min LC/MS (ESI + ) :446, 448 [M+l] + LC/MS (ESI") :444, 44 6 [M-l] ~
4-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)benzamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-1(6H)-yl}benzoic acid (54% yield). Morphology: colorless solid
LC/MS: Condition 2, retention time 2.42 min LC/MS(ESI + ) :536, 538 [M+l] + LC/MS(ESI"):534, 53 6 [M-l]" 1H-NMR(CDCl3)
δ :1.00 (d, J = 10.0 Hz, 1H), 1.08 (s, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.29 (s, 3H), 1.75-1.82 (m, 1H), 1.90-2.02
(m, 2H), 2.03-2.10 (m, 1H), 2.45-2.55 (m, 1H), 2.60-2.75
(m, 1H), 3.85-4.00 (m, 1H), 4.67 (d, J = 6.0 Hz, 2H),
4.85 (d, J = 9.0 Hz, 1H), 6.74-6.84 (br d, J = 4.0 Hz,
1H), 7.24 (s, 1H), 7.70 (s, 1H), 7.73 (d, J = 8.0 Hz, 2H),
7.90 (d, J = 8.0 Hz, 2H), 8.56 (d, J = 6.0 Hz, 2H).
SYNTHETIC EXAMPLE 161
4-Bromo-2-[4-(pyrrolidine-1-carbonyl)phenyl]-5-
4-{5-Bromo-6-oxo-4- [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-
[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
yl}benzoic acid (30 mg, 0.067 mmol), pyrrolidine (8.3 µL, 0.10 mmol), 1-hydroxybenzotriazole anhydride (0.9 mg, 0.007 mmol) in dichloromethane (0.6 mL) was stirred with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16 mg, 0.080 mmol) at room temperature for 22 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel chromatography (ethyl acetate) to give the desired product (35 mg, quant.). Morphology: colorless solid
LC/MS: Condition 2, retention time 3.57 min LC/MS(ESI + ) :499, 501 [M+l] + LC/MS (ESI") :497, 499 [M-l] " 1H-NMR(CDCl3)
δ :1.00 (d, J = 11.0 Hz, 1H), 1.08 (s, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.29 (s, 3H), 1.75-1.82 (m, 1H), 1.85-2. 02 (m, 6H), 2.03-2.09 (m, 1H), 2.45-2.55 (m, 1H), 2.63-2.73 (m, 1H), 3.47 (t, J = 7.0 Hz, 2H), 3.66 (t, J = 7.0 Hz, 2H), 3.87-3.98 (m, 1H), 4.83 (d, J = 8.0 Hz, 1H), 7.57-7.78 (m, 5H). SYNTHETIC EXAMPLE 162
3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)benzamide
(Formula Removed)
3-(4,5-Dibromo-6-oxopyridazin-1(6H)-yl)benzoic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 16 0 by using 3-hydrazinobenzoic acid. Morphology: pale yellow amorphous LC/MS: Condition 2, retention time 2.59 min LC/MS(ESI + ) :373, 375, 377 [M+l] + LC/MS(ESI") :371, 373, 375 [M-l] ~ 3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}benzoic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 160 by using 3-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)benzoic acid (35% yield). Morphology: colorless amorphous LC/MS: Condition 2, retention time 3.54 min LC/MS (ESI + ) :446, 448 [M+l] + LC/MS (ESI") :444, 44 6 [M-l]
3-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}-N- (pyridin-4-ylmethyl)benzamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 3-{5-Bromo-6-oxo-4-[ (1R,2R, 3R,5S) -2, 6, 6-trimethylbicyclo [3 .1.1] hept-3-ylamino]pyridazin-1(6H)-yl}benzoic acid (84% yield). Morphology: colorless amorphous LC/MS: Condition 2, retention time 2.43 min LC/MS(ESI + ) :536, 538 [M+l] + LC/MS(ESI"):534, 53 6 [M-l]" 1H-NMR(CDCl3)
δ :1.00 (d, J = 10.5 Hz, 1H), 1.08 (s, 3H), 1.22 (d, J = 7.0 Hz, 3H) , 1.2 9 (s, 3H) , 1.73-1.82 (m, 1H) , 1.89-2 .02
(m, 2H) , 2 .04-2 .08 (m, 1H) , 2 .47-2 .55 (m, 1H) , 2 .63-2 .72
(m, 1H), 3.89-3.99 (m, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.86 (d, J = 8.0 Hz, 1H), 7.19-7.25 (m, 2H), 7.48-7.55 (m, 1H), 7.68-7.74 (m, 2H), 7.84-7.88 (m, 1H), 8.06 (d, J = 1.0 Hz, 1H), 8.51-8.55 (m, 2H). SYNTHETIC EXAMPLE 16 3 4-Bromo-2-[3-(pyrrolidine-1-carbonyl)phenyl]-5-
[ (1R,2R, 3R,5S) -2, 6, 6-trimethylbicyclo [3 .1.1] hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 161 by using 3-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}benzoic acid (87% yield). Morphology: colorless solid
LC/MS: Condition 2, retention time 3.59 min LC/MS(ESI + ) :499, 501 [M+l] + LC/MS (ESI") :497, 499 [M-l] " 1H-NMR(CDCl3)
δ :1.00 (d, J = 10.5 Hz, 1H), 1.07 (s, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.29 (s, 3H), 1.75-1.82 (m, 1H), 1.86-2.01
(m, 6H), 2. 02-2.10 (m, 1H), 2.47-2.55 (m, 1H), 2.63-2.73
(m, 1H), 3.52 (t, J = 6.0 Hz, 2H), 3.64 (t, J = 6.0 Hz, 2H) 3.88-3.94 (m, 1H), 4.83 (d, J = 8.0 Hz, 1H), 7.46-7.55 (m, 2H), 7.62-7.67 (m, 1H) 7.69 (s, 1H), 7.84 (s, 1H) .
SYNTHETIC EXAMPLE 164 4-Bromo-2-[2-oxo-2-(piperazin-1-yl)ethyl]-5-
[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-3(2H)-one 2,2,2-trifluoroacetate
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 132 by using t-butyl 4-(2-{5-bromo-6-oxo-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-
ylamino]pyridazin-1(6H)-yl}acetyl)piperazine-1-carboxylate (83% yield). Morphology: pale yellow solid LC/MS: Condition 3, retention time 3.70 min LC/MS(ESI + ) :452, 454 [M+l] + SYNTHETIC EXAMPLE 16 5
4-Chloro-2-(2-{[1-(pyridin-4-yl)propyl]amino}ethyl)-5-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-3(2H)-one
(Formula Removed)
2-(5-Chloro-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)acetamide (4 0 mg, 0.0873 mmol) was added to lithium aluminum hydride (4.3 mg, 0.104
mmol) in tetrahydrofuran (1 mL) at 0°C, and the resulting reaction solution was stirred at room temperature for 1.5 hours. After completion of the reaction, the reaction solution was mixed with water, ethyl acetate and anhydrous magnesium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The resulting residue was purified by preparative thin layer chromatography (chloroform/methanol = 13/1) to give the desired product (9.5 mg, 25% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 1.89 min
LC/MS(ESI+) :m/z;444, 446 [M+l] + LC/MS(ESI~) :m/z;442, 444 [M-l] ~ 1H-NMR (CDCl3)
δ:0.79(t, J = 7.4 Hz, 3H), 0.97(d, J = 9.9 Hz, 1H), 1.06(s, 3H), 1.16-1.22(m, 3H), 1.27 (s, 3H), 1.55-1.76(m, 3H), 1.83-1.94(m, 2H), 1.96-2.07(m, 1H), 2.43-2.54(m, 1H), 2.56-2.68(m, 1H), 2.77-2.90(m, 2H), 3.54(t, J = 6.6 Hz, 1H), 3.77-3.89(m, 1H), 4.10-4.34(m, 2H), 4.58(d, J = 8.1 Hz, 1H), 7.18(d, J = 5.7 Hz, 2H), 7.56(s, 1H), 8.50(d, J =5.7 Hz, 2H). SYNTHETIC EXAMPLES 166 to 222
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 18.
TABLE 18
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
Synthetic Examples 166 to 192

(Formula Removed)
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their
analysis and the observed peaks and retention times are shown in Table 19.
TABLE 19
(Table Removed)
The structures of the compounds obtained in these
Synthetic Examples are shown below.
(Formula Removed)
Compounds were synthesized from 2-{6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.l.l]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 20.
TABLE 2 0
(Table Removed)
The structures of the compounds obtained in these
Synthetic Examples are shown below.
Synthetic Examples 295 to 296
(Formula Removed)
Compounds were synthesized in the same manner as in Synthetic Example 77, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 21.
TABLE 21
(Table Removed)
The structures of the compounds obtained in these
Synthetic Examples are shown below. Synthetic Examples 297 to 311
(Formula Removed)
Compounds were synthesized in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 22.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below. Synthetic Examples 312 to 334
(Formula Removed)
Compounds were synthesized from from 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4-
yl)propyl]acetamide, 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-[1-(3-methylpyridin-4-yl)methyl]acetamide, 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)acetamide, 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4-yl)propyl]acetamide or 2-(4,5-
dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(3-methylpyridin-4-yl)methyl]acetamide in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 23.
(Table Removed)
The structures of the compounds obtained in these
Synthetic Examples are shown below. Synthetic Examples 335 to 339
(Formula Removed)
Compounds were synthesized from [5-chloro-4-(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)-6-oxopyridazin-1(6H)-yl]acetic acid or [5-bromo-4-(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)-6-oxopyridazin-1(6H)-yl]acetic acid in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 24.
TABLE 24
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
Synthetic Examples 340 to 354
(Formula Removed)
Compounds were synthesized from 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4-
yl)propyl]acetamide, 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-[1-(3-methylpyridin-4-yl)methyl]acetamide or 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(3-methylpyridin-4-yl)methyl]acetamide in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 25.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below. Synthetic Examples 355 to 357
(Formula Removed)
Compounds were synthesized from 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4-
yl)propyl]acetamide, 2-(4,5-dibromo-6-oxopyridazin-1(6H) -yl)-N-[1-(3-methylpyridin-4-yl)methyl]acetamide, 2- (4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4-yl)propyl]acetamide or 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(3-methylpyridin-4-yl)methyl]acetamide (1S,2S,3R,5S)-3-amino-2,6,6-
trimethylbicyclo[3.1.1]heptan-2-ol in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 26.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
Compounds were synthesized from (5-chloro-4-{[(1S,2S,3R,5S)-2-hydroxy-2,6,6-
trimethylbicyclo[3.1.1]hept-2-yl]amino}-6-oxopyridazin-1(6H)-yl)acetic acid in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 27.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
Compounds were synthesized from [5-chloro-4-(2-adamantanamino)-6-oxopyridazin-1(6H)-yl]acetic acid in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 28.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
Compounds were synthesized from 2-[4,5-dichloro-6-oxopyridazin-1 (6H) -yl] -N- [ (1R) -1- (pyridin-4-yl)ethyl]acetamide2-adamantamine or bicyclo[3.3.1]nonan-9-amine in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 29.
(Table Removed)
the structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
Compounds were synthesized from [5-chloro-4-(2-adamantanamino)-6-oxopyridazin-1(6H)-yl]acetic acid in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 30.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
Compounds were synthesized from [4-(bicyclo[3.1.1]non-9-ylamino)-5-bromo-6-oxopyridazin-1(6H)-yl]acetic acid or [4-(bicyclo[3.1.1]non-9-ylamino)-5-chloro-6-oxopyridazin-1(6H)-yl]acetic acid in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 31.
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
2- [6-OXO-5-(pyridin-4-yl)-4-{ [(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N- (pyridin-4-ylmethyl)acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 152 by using 4-pyridylboronic acid. Yield: 91%
Morphology: colorless solid
LC/MS: Condition 2, retention time 1.70 min LC/MS(ESI+)m/z;473 [M+l]+ LC/MS(ESI")m/z;471 [M-l]" SYNTHETIC EXAMPLE 380 2-[6-OXO-5-(pyrimidin-5-yl)-4-{[(1R,2R, 3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N- (pyridin-4-ylmethyl)acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 152 by using 4-pyrimidinylboronic acid. Yield: 100%
Morphology: colorless solid
LC/MS: Condition 2, retention time 2.00 min LC/MS(ESI+)m/z;474 [M+l]+ LC/MS(ESI")m/z;472 [M-l]" SYNTHETIC EXAMPLES 381 to 383
4-Bromo-2- (tetrahydro-2H-pyran-2-yl) -5- { [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]aminojpyridazin-3(2H)-one
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4,5-dibromo-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one. Yield: 74%
Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 4.62 min
LC/MS(ESI")m/z;408, 410 [M-l] "
4-Hydroxy-2- (tetrahydro-2H-pyran-2-yl) -5-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one
(Formula Removed)
4-Bromo-2-(tetrahydro-2H-pyran-2-yl)-5-{[(lR,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one (2 00 mg, 0.49 mmol), tris(dibenzylideneacetone)dipalladium (9 mg, 0.01 mmol), potassium hydroxide (82 mg, 1.46 mmol) and 2-di-t-butylphosphino-2',4',6'-triisopropylbiphenyl (17 mg, 0.04 mmol) in 1,4-dioxane-water (1/1) were stirred in an argon stream at 100°C for 1 hour. After completion of the reaction, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with chloroform three times, and the organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1 to 1/1) to give the desired product (170 mg, 100% yield). Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 4.39 min LC/MS(ESI+)m/z;348 [M+l]+ LC/MS(ESI")m/z;346 [M-l]"
4-Difluoromethoxy-2-(tetrahydro-2H-pyran-2-yl)-5-{ [ (1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one
(Formula Removed)
-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)-5-{ [ (lR,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-2-yl]amino}pyridazin-3(2H)-one (170 mg, 0.49 mmol) in N,N-dimethylformamide (1.7 mL) was mixed with ethyl bromodifluoroacetate (94 µL, 0.73 mmol) and potassium carbonate (101 mg, 0.73 mmol) at room temperature and
stirred at 65°C for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 8/1 to 1/1) to give the desired product (104 mg, 54% yield). Morphology: pale yellow oil
LC/MS: Condition 7, retention time 4.74 min LC/MS(ESI")m/z;396 [M-l] "
4-Difluoromethoxy-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one

(Formula Removed)
4-Difluoromethoxy—2-(tetrahydro-2H-pyran-2-yl)-5-{ [ (1R,2R,3R,5,S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one (80 mg, 0.20 mmol) in acetic
acid-tetrahydrofuran-water (5/1/1) was stirred at 9 0°C for 3 hours and then stirred with two drops of concentrated hydrochloric acid for another 3 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography
(hexane/ethyl acetate = 4/1 to 1/1) to give the desired product (48 mg, 79% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.15 min LC/MS(ESI+)m/z;314 [M+l]+ LC/MS(ESI")m/z;312 [M-l]"
[5-Difluoromethoxy-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in

Synthetic Example 1 by using 4-difluoromethoxy-5-{ [ (lR,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one. Yield: 79% (two steps) Morphology: light brown amorphous LC/MS: Condition 7, retention time 4.4 9 min LC/MS(ESI+)m/z;372 [M+l]+ LC/MS(ESI")m/z;370 [M-l]"
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 32.
TABLE 32
(Table & Formula Removed)
4-Methoxy-2- (tetrahydro-2H-pyran-2-yl) -5-{ [ (1R, 2R, 3R, 5S] 2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one O
4-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)-5-{ [ (lR,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one (250 mg, 0.72 mmol) in N,N-dimethylformamide (2.5 mL) was mixed with methyl iodide (70 µL, 0.76 mmol) and potassium carbonate (104 mg, 0.76
mmol) at room temperature and stirred at 6 5°C for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1 to 1/1) to give the desired product (154 mg, 59% yield). Morphology: light brown oil 4-Methoxy-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-

(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 381 by using 4-methoxy-2-(tetrahydro-2H-pyran-2-yl)-5-{[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one.
Yield: 44%
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.11 min LC/MS(ESI+)m/z;278 [M+l]+
[5-Methoxy-6-oxo-4-{[(1R,2R, 3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4-methoxy-5- { [ (1R, 2R, 3R, SS) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one.
Yield: 55% (two steps) Morphology: light brown amorphous LC/MS: Condition 7, retention time 4.2 0 min LC/MS(ESI+)m/z;336 [M+l]+ LC/MS(ESI")m/z;334 [M-l]"
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 33.
TABLE 3 3

(Table Removed)
2-[5-Cyano-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
2-[5-Bromo-6-oxo-4{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (100 mg, 0.21 mmol) in N-methylpyrrolidone (2.5 mL) was mixed with copper cyanide (100 mg, 1.05 mmol) at room temperature and stirred at 110°C for 24 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate and chloroform. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was
purified by silica gel column chromatography
(chloroform/methanol = 10/1) to give the desired product
(4.3 mg, 5% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 2.95 min LC/MS (ESI + ) m/z; 421 [M+l] + LC/MS (ESI") m/z; 419 [M-l] " 1H-NMR (CDCl3)
δ:0.92-0.99 (m, 1H), 1.05 (s, 3H), 1.17 (d, J = 7.2 Hz, 3H) , 1.2 7 (s, 3H) , 1.83-2 .11 (m, 3H) , 2 .46-2 .52 (m, 1H) , 2.58-2.72 (m, 1H) , 2 .92-3 .02 (m, 1H) , 3 .92-4 .05 (m, 1H) , 4.54 (d, J = 6.0 Hz, 2H), 4.80 (s, 2H), 7.19 (d J = 5.7 Hz, 2H), 6.68-6.78 (m, 1H), 8.51 (d, J = 5.1 Hz, 2H) SYNTHETIC EXAMPLE 3 88
4-[({[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl] acetyl}amino)methyl]pyridine-2-carboxamide
(Formula Removed)
2- [5-Bromo-6-oxo-4-{ [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(2-cyanopyridin-4-yl)methyl]acetamide (34.0 mg, 0.07 mmol) was dissolved in ethanol/3 0% aqueous potassium hydroxide (4 mL, 1:1) and stirred at 80°C for 2 hours.
After cooling, ethyl acetate was added, and the organic
layer was washed with saturated aqueous ammonium
chloride, dried over anhydrous sodium sulfate and
evaporated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (ethyl
acetate/methanol = 8/1) to give the desired product.
Yield: 6%
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.13 min
LC/MS(ESI+)m/z;517, 519 [M+l]+
LC/MS(ESI")m/z;515, 517 [M-l]-
SYNTHETIC EXAMPLE 389
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,55)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}-3-{[2-
(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]-N-
(pyridin-4-ylmethyl)acetamide
(Formula Removed)
4-Chloro-5-{ [ (1R, 2R, 3R, 55) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-6-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-3(2H)-one

(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4,5-dichloro-6-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-3(2H)-one, and the resulting crude reaction product was used for the next step.
Ethyl [5-chloro-6-oxo-4- { [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-3-{[2-
(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]acetate
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4-Chloro-5-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-6-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-3(2H)-one (27% yield, two steps).

Morphology: colorless amorphous LC/MS: Condition 7, retention time 5.77 min LC/MS(ESI+)m/z;514, 516 [M+l]+ LC/MS(ESI")m/z;512, 514 [M-l]"
[5-Chloro-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-3-{[2-
(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl [5-chloro-6-oxo-4-{ [ (lR,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]acetate (99% yield). Morphology: colorless oil
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using [5-chloro-6-oxo-4-
{ [ (lR,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 . l.l]hept-3-yl]amino}-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]acetic acid (29% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.44 min LC/MS(ESI+)m/z;576, 578 [M+l] + LC/MS(ESI")m/z;574, 576 [M-l]" 1H-NMR (CDCl3)
δ :0.01 (s, 9H), 0.85-0.98(m, 3H), 0.99 (s, 3H), 1.12(dd, J= 6.9, 0.9 Hz, 3H), 1.24(s, 3H), 1.67(dd, J = 13.9, 6,1 Hz, 1H), 1.78-1.91(m, 2H), 1.93-2.02(m, 1H), 2.42-2.48(m, 1H), 2.56(t, J = 11.6 Hz, 1H), 3.66-3.77(m, 2H), 4.54(m, 2H) , 4.66-4.73(m, 1H) , 4.80-4.92(m, 3H) , 5.27 (s, 2H) , 7.18-7.22(m, 2H), 7.98 (s, 1H), 8.50-8.54(m, 2H) SYNTHETIC EXAMPLE 3 90
2-[5-Chloro-3-hydroxy-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide hydrochloride
(Formula Removed)
2- [5-Chloro-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}-3-{[2-(trimethylsilyl)ethoxy]methoxy}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (12 mg, 0.02 08 mmol) in
methanol (1 mL) was stirred with 10 mass% hydrogen
chloride-methanol (5 mL) at 60°C for 5 hours. After
completion of the reaction, the reaction solution was
concentrated under reduced pressure and purified by
preparative HPLC to give the desired product.
Morphology: colorless amorphous
LC/MS: Condition 7, retention time 4.18/4.32 min
LC/MS(ESI+)m/z;44 6, 44 8 [M+l]+
LC/MS(ESI")m/z;444, 44 6 [M-l]"
SYNTHETIC EXAMPLE 3 91
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-
4,5-Dibromo-6-nitropyridazin-3(2H)-one
yl]-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
To 4,5-dibromopyridazin-3(2H)-one (2 g, 7.87 mmol) in concentrated sulfuric acid (12 mL), fuming nitric acid
(978 µL, 23.8 mmol) was gradually added at 100°C with
stirring, and the resulting reaction solution was stirred
at 100°C for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and poured onto ice-cold water. The precipitated crystals were collected by filtration and dried under reduced pressure to give the desired product (2.2 g, 93%). Morphology: colorless solid
LC/MS: Condition 7, retention time 3.23 min LC/MS(ESI+)m/z;298, 300, 302 [M+l] + LC/MS(ESI")m/z;2 96, 298, 300 [M-l] ~ 4-Bromo-6-nitro-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4,5-dibromo-6-nitropyridazin-3(2H)-one (48% yield). Morphology: yellow solid
LC/MS: Condition 7, retention time 4.73 min LC/MS(ESI+)m/z;371, 373 [M+l]+ LC/MS(ESI")m/z;369, 371 [M-l]"
Ethyl [5-bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetate
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using 4-bromo-6-nitro-5-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one (90% yield). Morphology: yellow oil
LC/MS: Condition 7, retention time 5.18 min LC/MS(ESI+)m/z;457, 459 [M+l] + LC/MS(ESI")m/z;455, 457 [M-l] "
[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl [5-bromo-3-nitro-6-oxo-4-{ [ (lR,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 . l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]acetate (83% yield). Morphology: yellow oil
LC/MS: Condition 7, retention time 4.88 min LC/MS(ESI+)m/z;429, 431 [M+l] +
LC/MS(ESI")m/z;427, 429 [M-l] "
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using [5-bromo-3-nitro-6-oxo-4-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid (56% yield). Morphology: yellow oil
LC/MS: Condition 7, retention time 3.80 min LC/MS(ESI+)m/z;519, 521 [M+l]+ LC/MS(ESI")m/z;517, 519 [M-l]" 1H-NMR (CDCl3)
δ:0.90(d, J = 10.2 Hz, 1H), 1.00(s, 3H), 1.13(d, J = 7.2 Hz, 3H), 1.25 (s, 3H), 1.67-1.73(m, 1H), 1.86-1.95(m, 2H), 1.96-2.04(m, 1H), 2.43-2.64(m, 2H), 4.48(d, J = 6.3 Hz, 2H), 4.49-4.61(m, 1H), 4.88(s, 2H), 6.45(d, J = 9.3 Hz, 1H), 6.86-6.94(m, 1H), 7.19(d, J = 6.3 Hz, 2H), 8.54(d, J = 6.3 Hz, 2H) SYNTHETIC EXAMPLE 3 92
2-[3-Amino-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (11 mg, 0 . 0211 mmol) in methanol (1 mL) was stirred with 10mass% palladium-carbon (about 5 mg) in a hydrogen atmosphere at room temperature for 2.5 hours. The reaction solution was filtered through celite and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol = 10/1) to give the desired product (1.5 mg, 17% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 3.03 min LC/MS(ESI+)m/z;411 [M+l]+ LC/MS(ESI")m/z;409 [M-l]" SYNTHETIC EXAMPLE 3 93
2-[3-Amino-5-bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
2-[5-Bromo-3-nitro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (32 mg, 0.0616 mmol in ethyl acetate (3 mL) was stirred with tin (II)
chloride dihydrate (72 mg, 0.319 mmol) at room temperature for 2 hours. After completion of the reaction, the reaction solution was basified to pH 9-10 with aqueous sodium hydroxide and filtered through celite. The filtrate was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol = 6/1) to give the desired product (13 mg, 43% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 3.43 min LC/MS(ESI+)m/z;489, 491 [M+l] + LC/MS(ESI")m/z;487, 489 [M-l] " 1H-NMR (DMSO-d6)
δ :0.97-1.03(m, 6H), 1.14(d, J = 9.6 Hz, 1H), 1.21(s, 3H), 1.67 (dd, J = 12.9, 6.7 Hz, 1H), 1.79(t, J = 6.1 Hz, 1H), 1.90-1.97(m, 1H), 2.07-2.14(m, 1H), 2.26-2.44(m, 2H), 4.30(d, J = 6.3 Hz, 2H), 4.51(s, 2H), 4.73-4.79(m, 1H), 5.30(d, J = 9.9 Hz, 1H), 5.70(s, 2H), 7.25(d, J = 6.0 Hz, 2H), 8.45-8.55(m, 3H) SYNTHETIC EXAMPLE 3 94
4-Bromo-2-(pyridin-4-ylmethyl)-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one

(Formula Removed)
4 , 5-Dibromo-2-(pyridin-4-ylmethyl)pyridazin-3(2H)-one o
(Formula Removed)
4-Picolylhydrazine hydrochloride (500 mg, 3.13 mmol), mucobromic acid (807 mg, 3.13 mmol) and concentrated hydrochloric acid (500 uL) in ethanol (5 mL)
were stirred at 90°C for 1 day. After completion of the reaction, the resulting crystals were collected by filtration, washed with methanol and dried to give the desired product (59% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 3.70 min LC/MS(ESI+)m/z;344, 346, 348 [M+l] + 1H-NMR (CDCl3)
δ:2.50 (m, 2H), 5.57 (s, 1H), 7.83 (d, J = 6.6 Hz, 2H), 8.82 (d, J = 6.6 Hz, 2H).
4-Bromo-2-(pyridin-4-ylmethyl)-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one Synthesis was carried out in the same manner as in
Synthetic Example 48 by using 4,5-dibromo-2-(pyridin-4 ylmethyl)pyridazin-3(2H)-one. Yield: 86%
Morphology: pale pink oil SYNTHETIC EXAMPLE 3 95
2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H) yl]-N-[(3S)-pyrrolidin-3-ylmethyl]acetamide
(Formula Removed)
t-Butyl (3S) -3- [ ({ [5-bromo-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]aminojpyridazin-1(6H)-yl]acetyl}amino)methyl]pyrrolidine-1-carboxylate (72.5 mg, 0.13 mmol) in dichloromethane (2 mL) was mixed with trifluoroacetic acid (19.7 µL, 0.26 mmol) at room temperature and stirred at room temperature for 12 hours After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 2 0/1) to give the desired product. Yield: 29.6 mg (49%)
Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 3.50 min LC/MS (ESI+)m/z; 466, 468 [M+l]+ LC/MS (ESI") m/ z;464, 466 [M-1 ] ~ SYNTHETIC EXAMPLE 3 96
2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl] -N- [ (2R) -pyrrolidin-2-ylmethyl] acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 395 by using tert-butyl (2R)-2- [ ({ [5-bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H) -yl]acetyl}amino)methyl]pyrrolidine-1-carboxylate. Yield: 38.5 mg (52%) Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 3.51 min LC/MS(ESI+)m/z;466, 468 [M+l] + LC/MS (ESI-) m/ z;464, 466 [M-l]" SYNTHETIC EXAMPLE 3 97
2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H) -yl]-N-(piperidin-4-ylmethyl)acetamide
(Formula Removed)
t-Butyl 4-[({[5-bromo-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]piperidine-1-carboxylate (34.4 mg, 0.06 mmol) was dissolved in 4 M hydrogen chloride/1,4-dioxane (1 mL) and stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol = 50/1) to give the desired product. Yield: 19.1 mg (67%) Morphology: yellow amorphous
LC/MS: Condition 7, retention time 3.10 min LC/MS(ESI+)m/z;480, 482 [M+l] + LC/MS(ESI")m/z;478, 480 [M-l] " SYNTHETIC EXAMPLE 3 98
2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-3-(pyridin-4-yl)propanoic acid
(Formula Removed)
Ethyl 2-[5-bromo-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-3-(pyridin-4-yl)propanoate (16 5 mg, 0.294 mmol) in 1,4-dioxane (4 mL) was stirred with 1 M aqueous sodium hydroxide (1 mL) at room temperature for 4 hours. After completion of the reaction, the reaction solution was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (156 mg, quant). Morphology: colorless solid
LC/MS: Condition 7, retention time 3.68 min LC/MS(ESI+)m/z;532, 534 [M+l] + LC/MS(ESI")m/z;530, 532 [M-l]" SYNTHETIC EXAMPLE 3 99
N-{2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]ethyl}pyridine-4-carboxamide
(Formula Removed)
2-{2- [5-Bromo-6-oxo-4-{ [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione
(Formula Removed)
4-Bromo-5-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (100 mg, 0.306 mmol) and potassium carbonate (51 mg, 0.0369 mmol) in N,N-dimethylformamide (3 mL) were stirred with 2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione (93 mg, 0.366 mmol) at 80°C for 7 hours. After completion of the reaction, the reaction solution was mixed with aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was used for the next reaction without purification. LC/MS: Condition 7, retention time 4.14 min LC/MS(ESI+)m/z;499, 501 [M+l]+
2- (2-Aminoethyl) -4-bromo-5- { [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-
one
(Formula Removed)
2-{2- [5-Bromo-6-oxo-4-{ [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione prepared above in methanol (6 mL) was stirred with hydrazine monohydrate
(50 uL, 1.6 mmol) at 80°C for 6 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 4/1) to give the desired product (32 mg, 28% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 3.38 min LC/MS(ESI+)m/z;369, 371 [M+l]+ LC/MS(ESI")m/z;367, 369 [M-l]" 1H-NMR (CDCl3)
δ:0.97(d, J = 9.9 Hz, 1H), 1.05(s, 3H), 1.19(d, J = 6.9 Hz, 3H), 1.27 (s, 3H), 1.69-1.77(m, 1H), 1.88-2.08(m, 3H), 2.43-2.51(m, 1H), 2.56-2.69(m, 1H), 3.11(t, J = 6.0 Hz, 2H), 3.78-3.91(m, 1H), 4.22(t, J = 6.0 Hz, 2H), 4.67(d, J =8.4 Hz, 1H), 7.52(s, 1H)
N-{2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]ethyl}pyridine-4-carboxamide
2-(2-Aminoethyl)-4-bromo-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (28 mg, 0.0758 mmol) and triethylamine (21 uL, 0.152 mmol) in dichloromethane (1 mL) were stirred with
pyridine-4-carbonyl chloride (20 mg, 0.112 mmol) at room temperature for 5 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 9/1) to give the desired product (19 mg, 52% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.35 min LC/MS (ESI+)m/z; 474, 4 76 [M+l] + LC/MS (ESI")m/z; 472, 4 74 [M-l] " 1H-NMR (CDCl3)
δ:0.96(d, J = 10.5 Hz, 1H), 1.06(s, 3H), 1.19(d, J = 6.9 Hz, 3H), 1.27(s, 3H), 1.72(ddd, J = 14.1, 5.7, 2.4 Hz, 1H), 1.89-2.05(m, 3H), 2.43-2.51(m, 1H), 2.58-2.70(m, 1H), 3.79-3.91(m, 3H), 4.48-4.54(m, 2H), 4.80(d, J = 8.7 Hz, 1H), 7.57(s, 1H), 7.68-7.78(m, 2H), 8.17(m, 1H), 8.72-8.75(m, 2H) SYNTHETIC EXAMPLE 4 00
N-{2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]ethyl}pyridine-3-carboxamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 399 by using pyridine-3-carbonyl chloride (20% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.4 0 min LC/MS (ESI+)m/z; 474, 4 76 [M+l] + LC/MS (ESI")m/z; 472, 4 74 [M-l] " SYNTHETIC EXAMPLE 4 01
2-({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butyric acid
(Formula Removed)
Ethyl 2-({[5-chloro-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butyrate (64 mg, 0 .14 5 mmol) in 1,4-dioxane (2 mL) was stirred with 1 M aqueous sodium hydroxi de (435 uL, 0.435 mmol) at room temperature for 2 hours. After completion of the reaction, the reaction solution was neutralized with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product. Morphology: colorless solid LC/MS: Condition 7, retention time 4.24 min
LC/MS(ESI+)m/z;425, 427 [M+l] + LC/MS(ESI")m/z;42 3, 42 5 [M-l] ~ SYNTHETIC EXAMPLE 4 02
2-({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butanamide
(Formula Removed)
2- ({ [5-Chloro-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)butyric acid (48 mg, 0.113 mmol) in N,N-dimethylformamide (2 mL) was stirred with di-1H-imidazolylmethanone (55 mg, 0.340 mmol) at room temperature for 2 days and then with 3 0% aqueous ammonia (0.2 mL) at room temperature for 5 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product (14 mg, 29% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.08 min LC/MS (ESI+)m/z; 424, 42 6 [M+l] + LC/MS(ESI")m/z;422, 424 [M-l]"
SYNTHETIC EXAMPLE 4 03
({ [5-Bromo-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)(phenyl)acetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 401 by using methyl ({[5-bromo-6-oxo-4-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)(phenyl)acetate (99% yield).
Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.91 min
LC/MS(ESI")m/z;515, 517 [M-l]"
SYNTHETIC EXAMPLE 4 04
N-(2-Amino-2-oxo-1-phenylethyl)-2-[5-bromo-6-oxo-4-
{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .1.1]hept-3-
Synthesis was carried out in the same manner as in
yl]amino}pyridazin-1(6H)-yl]acetamide
(Formula Removed)
Synthetic Example 402 by using ({[5-bromo-6-oxo-4-
{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-
yl]amino}pyridazin-1(6H)-yl]acetyl}amino)(phenyl)acetic
acid (21% yield).
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.60 min
LC/MS(ESI+)m/z;516, 518 [M+l] +
LC/MS(ESI")m/z;514, 516 [M-l]"
SYNTHETIC EXAMPLE 4 05
[5-Bromo-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-2-fluoro-N-(pyridin-4-ylmethyl)acetamide

(Formula Removed)
Ethyl [5-bromo-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]fluoroacetate
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl bromofluoroacetate (49% yield).
Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 5.01 min LC/MS(ESI+)m/z;430, 432 [M+l] + LC/MS(ESI")m/z;428, 430 [M-l] " [5-Bromo-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]fluoroacetic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using ethyl [5-bromo-6-oxo-4-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]fluoroacetate, and the crude product was used for the next reaction. LC/MS: Condition 7, retention time 5.15, 5.43 min LC/MS(ESI+)m/z;4 02, 4 04 [M+l] + [5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl] -2-fluoro-N-(pyridin-4-ylmethyl)acetamide
Synthesis was carried out in the same manner as in Synthetic Example 1 by using [5-bromo-6-oxo-4-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]fluoroacetic acid (5% yield, two steps). Morphology: colorless oil
LC/MS: Condition 7, retention time 3.75 min LC/MS(ESI + ) m/z; 4 92, 4 94 [M+l] + LC/MS (ESI") m/z; 4 90, 4 92 [M-l] ~ SYNTHETIC EXAMPLE 4 06
3-Oxo-2-{2-OXO-2-[(pyridin-4-ylmethyl)amino]ethyl}-5-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}-2,3-dihydropyridazine-4-carboxylic acid
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 388 by using 2-[5-cyano-6-oxo-4-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (3% yield). Morphology: colorless oil
LC/MS: Condition 7, retention time 3.49 min LC/MS(ESI+)m/z;440 [M+l]+ LC/MS(ESI")m/z;438 [M-l]" SYNTHETIC EXAMPLE 4 07
4-[({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]pyridine-2-carboxamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 388 by using 2-[5-chloro-6-oxo-4-{ [ (1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(2-cyanopyridin-4-yl)methyl]acetamide. Yield: 79%
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.06 min LC/MS(ESI+)m/z;473, 4 75 [M+l] + LC/MS(ESI")m/z;471, 473 [M-l] " SYNTHETIC EXAMPLE 4 08
4-Chloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}-5-(hexahydro-2,5-methanopentalen-3a(1H)-ylamino)pyridazin-3(2H)-one
(Formula Removed)
4,5-Dichloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}pyridazin-3(2H)-one
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 48 by using 2-bromo-1-[4-(diethylamino)phenyl]ethanone (yield 61%). Morphology: yellow solid 1H-NMR (CDCl3)
δ:1.22(t, J = 7.1 Hz, 6H) , 3.19(q, J = 7.9 Hz, 4H) , 5.53(s, 2H), 6.65(d, J = 9.0 Hz, 2H), 7.83(s, 1H), 7.85(d, J = 9.0 Hz, 2H)
4-Chloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}-5-(hexahydro-2,5-methanopentalen-3a(IH)-ylamino)pyridazin-3(2H)-one
4,5-Dichloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl}pyridazin-3(2H)-one (30 mg, 0 . 084 6 mmol) , hexahydro-2,5-methanopentalen-3a(1H)-amine (22 mg, 0.126 mmol) and triethylamine (59 µL, 0.423 mmol) were stirred in N,N-dimethylacetamide (1 mL) at 90°C for 3 days. After completion of the reaction, the reaction solution was mixed with aqueous ammonium chloride and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane = 1/1) to give the
desired product (7 mg, 17% yield). Morphology: colorless oil
LC/MS: Condition 7, retention time 4.93 min LC/MS(ESI+)m/z;455, 457 [M+l] + SYNTHETIC EXAMPLE 4 09
3-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(l-hydroxycycloheptyl)methyl]benzamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 162 by using 1-(aminomethyl)cycloheptanol (47% yield). Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 4.88 min LC/MS(ESI+) m/z; 571, 573 [M+l]+ LC/MS(ESI") m/z; 56 9, 571 [M-l]" 1H-NMR (CDCl3)
δ:1.00 (d, J = 10.2 Hz, 1H), 1.08 (s, 3H), 1.23 (d, J = 6.9 Hz, 3H), 1.29 (s, 3H), 1.39-1.85 (m, 12H) , 1.92-2 .13 (m, 3H), 2.48-2.78 (m, 3H), 3.45 (d, J = 5.7 Hz, 2H), 3.89-4.00 (m, 2H), 4.85 (d, J = 7.8 Hz, 1H), 6.84-6.91(m, 1H), 7.50(t, J = 7.8 Hz, 1H), 7.69-7.75(m, 2H), 7.82(d, J = 7.8 Hz, 1H) , 8.00 (s, 1H) SYNTHETIC EXAMPLE 410
4-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl] -N-[(1-hydroxycyloheptyl)methyl]benzamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 160 by using 1-(aminomethyl)cycloheptanol (43% yield). Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 4.83 min LC/MS(ESI + ) m/z; 571, 573 [M+l] + LC/MS(ESI") m/z; 56 9, 571 [M-l]" 1H-NMR (CDCl3)
δ:1.00 (d, J = 9.9 Hz, 1H), 1.08 (s, 3H), 1.22 (d, J = 7.2 Hz, 3H), 1.29 (s, 3H), 1.39-1.83(m, 13H), 1.93-2.11(m, 3H), 2.45-2.56(m, 1H), 2.62-2.74(m, 1H), 3.46(d, J = 5.7 Hz, 2H), 3.88-3.99(m, 1H), 4.84(d, J = 8.1 Hz, 1H), 6.67(br.s, 1H), 7.70(s, 1H), 7.72(d, J = 8.7 Hz, 2H), 7.85(d, J = 8.7 Hz, 2H) SYNTHETIC EXAMPLE 411
4-Chloro-2-{2-[4-(diethylamino)phenyl]-2-hydroxyethyl}-5-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl] amino}pyridazin-3 (2H) -one
(Formula Removed)
4-Chloro-2-{2-[4-(diethylamino)phenyl]-2-oxoethyl-}-5-{ [ (1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one (42 mg, 0.0891 mmol) in tetrahydrofuran (2 mL) was added dropwise to lithium aluminum hydride (11 mg, 0.315 mmol) in tetrahydrofuran
(2 mL) at 0°C and stirred at room temperature for 10 minutes. After completion of the reaction, the reaction solution was mixed with aqueous sodium hydroxide, anhydrous sodium sulfate, then filtered and evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (hexane/ethyl acetate = 1/1) to give the desired product (14 mg, 33% yield).
Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 3.68 min LC/MS(ESI+)m/z;455, 457 [M-18] + LC/MS(ESI")m/z;471, 473 [M-l] " 1H-NMR (CDCl3)
δ:0.97(d, J = 10.2 Hz, 1H), 1.06(s, 3H), 1.13-1.23(m, 9H), 1.27(s, 3H), 1.65-1.77(m, 1H), 1.81-2.08(m, 3H), 2.44-2.53(m, 1H), 2.58-2.67(m, 1H), 3.35(q, J = 7.0 Hz, 4H), 3.73-3.92(m, 2H), 4.26-4.53(m, 2H), 4.65(d, J = 9.3
Hz, 1H), 6.67(d, J = 8.4 Hz, 2H), 7.29(d, J = 8.4 Hz, 2H), 7.62(s, 1H) SYNTHETIC EXAMPLE 412
3-[5-Chloro-6-oxo-4-{[(1R,2R,3R,55)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(25)-2-hydroxy-3-methoxypropyl]propanamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 41 by using (5)-1-amino-3-methoxypropan-2-ol. Yield: 67%
Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.03 min LC/MS(ESI + )m/z;441, 443 [M+l] + LC/MS(ESI")m/z;439, 441 [M-l] " SYNTHETIC EXAMPLE 413
3-[5-Chloro-6-oxo-4-{[(1R,2R,3R,55)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(25)-2-hydroxy-3-methoxypropyl]-N-methylpropanamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 41 by using (S)-1-methoxy-3-(methylamino)propan-2-ol. Yield: 60%
Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.16 min LC/MS(ESI+)m/z;455, 457 [M+l] + LC/MS (ESI")m/z; 453, 4 55 [M-l] " SYNTHETIC EXAMPLE 414
Ethyl ({4- [ ({ [5-chloro-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H) -yl]acetyl}amino)methyl]pyridin-3-yl}oxy)acetate
(Formula Removed)
2-[5-Chloro-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(3-hydroxypyridin-4-yl)methyl]acetamide (12 . 7 mg, 0.03 mmol) in acetone (2 mL) was mixed with ethyl
bromoacetate (4.4 uL, 0.04 mmol) and potassium carbonate (5.9 mg, 0.04 mmol) at room temperature and stirred at
5 0°C for 1 hour. After cooling, the reaction solution
was mixed with saturated aqueous ammonium chloride and
extracted with ethyl acetate. The resulting organic
layer was dried over anhydrous sodium sulfate and
evaporated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (ethyl
acetate/methanol = 20/1) to give the desired product (4.8
mg, 3 0%).
Morphology: pale yellow oil
LC/MS: Condition 7, retention time 3.89 min
LC/MS(ESI+)m/z;532, 534[M+l]+
LC/MS(ESI")m/z;530, 532 [M-l]"
SYNTHETIC EXAMPLES 415 to 416
Compounds were synthesized in the same manner as in Synthetic Example 414, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 34.
(Table Removed)
SYNTHETIC EXAMPLE 417
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-{[3-(2-hydroxyethoxy)pyridin-4-yl]methyl}acetamide
(Formula Removed)
2- ({4- [ ({ [5-Chloro-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]pyridin-3-yl}oxy)ethyl benzoate (23.8 mg, 0.04 mmol) in methanol (2 mL) was mixed with 1 M aqueous sodium hydroxide (0.12 mL, 0.12 mmol) at room temperature and stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was evaporated azeotropically with ethanol, and the resulting residue was purified by silica gel chromatography (ethyl acetate/methanol = 10/1 to 8/1) to give the desired product (19.7 mg, 100% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 3.45 min LC/MS(ESI+)m/z;490, 492 [M+l] + LC/MS(ESI")m/z;488, 490 [M-l]" SYNTHETIC EXAMPLE 418 2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(3-isopropyloxypyridin-4-yl)methyl]acetamide
(Formula Removed)
2-[5-Chloro-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(3-hydroxypyridin-4-yl)methyl]acetamide (26.6 mg, 0.06 mmol) in tetrahydrofuran (1 mL) was mixed with 2-propanol (10.9 mg, 0.18 mmol), triphenylphosphine (23.6 mg, 0.09 mmol) and diethyl azodicarboxylate in toluene
(2.2 M, 0.04 mL, 0.09 mmol) at 0°C and stirred at room
temperature for 4 hours. After completion of the
reaction, the reaction solution was evaporated under
reduced pressure, and the resulting residue was purified
by silica gel chromatography (ethyl acetate/methanol =
20/1) to give the desired product (4.48 mg, 15%) .
Morphology: colorless amorphous
LC/MS: Condition 7, retention time 3.71 min
LC/MS(ESI+)m/z;488, 490 [M+l] +
LC/MS(ESI")m/z;486, 488 [M-l]"
SYNTHETIC EXAMPLE 419
4-Chloro-2-{(2S)-2-hydroxy-3-[(pyridin-4-
ylmethyl)amino]propyl}-5-{[(1R,2R,3R,5S)-2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-

one
(Formula Removed)
4-Chloro-2- [ (2R) -oxiran-2-ylmethyl] -5-{ [ {1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one
(Formula Removed)
4-Chloro-5-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (120 mg, 0.425 mmol) in N,N-dimethylformamide (2 mL) was mixed with (2S)-oxiran-2-ylmethyl 4-
methylbenzenesulfonate (117 mg, 0.513 mmol) and potassium carbonate (71 mg, 0.0514 mmol) at room temperature and
stirred at 80°C for 3 hours. After cooling, the reaction
solution was mixed with water and extracted with ethyl
acetate, and the extract was evaporated under reduced
pressure. The resulting crude product was used for the
next reaction without purification.
LC/MS: Condition 7, retention time 4.44 min
LC/MS(ESI + )m/z;338, 34 0 [M+1] +
LC/MS(ESI")m/z;336, 338 [M-1]"
4-Chloro-2-{(2S)-2-hydroxy-3-[(pyridin-4-
ylmethyl)amino]propyl}-5-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one
4-Chloro-2-[(2R)-oxiran-2-ylmethyl]-5-{ [ (1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}pyridazin-3(2H)-one (0 .141 mmol) in ethanol (2 mL) was stirred with 1- (pyridin-4-yl)methanamine (17 µL,
0.17 mmol) at 80°C for 8 hours. After cooling, the reaction solution was concentrated, mixed with water and extracted with ethyl acetate, and the extract was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography
(chloroform/methanol = 9/1) to give the desired product
(19 mg, 29% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 3.13 min LC/MS(ESI+)m/z;44 6, 44 8 [M+l] + LC/MS(ESI")m/z;444, 44 6 [M-l]" 1H-NMR (CDCl3)
δ:0.97(d, J = 10.2 Hz, 1H), 1.06(s, 3H), 1.19(d, J = 6.9 Hz, 3H) , 1.28 (s, 3H) , 1.65-1.77(m, 1H) , 1.92-2.08(m, 3H) , 2.45-2.54(m, 1H), 2.57-2.76(m, 3H), 3.82-3.93(m, 3H), 4.08-4.13(m, 1H), 4.24-4.39(m, 2H), 4.67(d, J = 8.4 Hz, 1H) , 7.25-7.2 9(m, 2H) , 7.62 (s, 1H) , 8.52-8.55(m, 2H) SYNTHETIC EXAMPLE 42 0
1-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-
yl]-N-(pyridin-4-ylmethyl)cyclobutanecarboxamide

(Formula Removed)
Ethyl 1- [5-bromo-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]cyclobutanecarboxylate
(Formula Removed)
4-Bromo-5-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one (112.8 mg, 0.35 mmol) in N,N-dimethylformamide (2 mL) was mixed with ethyl 1-bromocyclobutanecarboxylate (85.8 µL, 0.53 mmol) and potassium carbonate (73.0 mg, 0.53
mmol) at room temperature and stirred at 15 0°C for 2 hours in a microwave reactor. After cooling, the reaction solution was mixed with saturated aqueous ammonium chloride and extracted with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude product containing the desired product was used for the next reaction (222.1 mg) .
Morphology: orange oil
LC/MS: Condition 7, retention time 5.11 min LC/MS(ESI + ) m/z; 4 52, 4 54 [M+l] + LC/MS (ESI") m/z; 450, 4 52 [M-l] " 2-(5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)cyclobutaneacetic acid
(Formula Removed)
Ethyl 1-(5-bromo-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)cyclobutanecarboxylate (222 .1 mg, 0.35 mmol) in 1,4-dioxane (2 mL) was stirred with 1 M aqueous sodium hydroxide (1.06 mL, 1.06 mmol) at room temperature for 4.5 hours. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude product containing the desired product was used for the next step (120.3 mg, 81% yield).
Morphology: orange oil LC/MS: Condition 7, retention time 4.60 min
LC/MS(ESI + ) m/z; 424, 42 6 [M+l] + LC/MS(ESI") m/z; 422, 424 [M-l]~ 1-(5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)cyclobutanecarboxamide
2- (5-Bromo-6-oxo-4-{ [ {1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)cyclobutaneacetic acid (108.7 mg, 0.256 mmol), 1-(3-dimethylaminopropyl)- 3 -ethylcarbodiimide hydrochloride (98.2 mg, 0.512 mmol), 1-hydroxybenzotriazole anhydride (10.8 mg, 0.08 mmol) and triethylamine (71.4 uL, 0.512 mmol) in N,N-dimethylformamide (1 mL) were stirred with 4-picolylamine (51.3 uL, 0.512 mmol) at room temperature for 22 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 20/1) to give the desired product (53.8 mg, 41% yield). Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 3.68 min LC/MS(ESI + ) m/z; 514, 516 [M+l] + LC/MS(ESI") m/z; 512, 514 [M-l]" 1H-NMR (CDCl3) δ:0.98(d, J = 10.5 Hz, 1H), 1.06(s, 3H), 1.18-1.21(m.
2H), 1.27(d, J = 7.5 Hz, 3H), 1.28(s, 3H), 1 . 65-1.75(m, 1H), 1.90-2.00(m, 2H), 2.04-2.17(m, 2H), 2.28-2.37(m, 1H), 2.45-2.55(m, 1H), 2.62-2.70(m, 1H), 2.84-2.96(m, 1H), 3.16-3.25(m, 1H), 3.80-4.00(m, 1H), 4.47(d, J = 6.0 Hz, 2H), 4.82(d, J = 8.4 Hz, 1H), 7.25-7.27(m, 2H), 7.67(s, 1H), 8.52(d, J = 6.3 Hz, 2H) SYNTHETIC EXAMPLE 421
2-(5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 4 02 by using [5-chloro-6-oxo-4-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid. Morphology: colorless solid
LC/MS: Condition 7, retention time 4.01 min LC/MS(ESI+)m/z;339, 341 [M+l] + LC/MS(ESI")m/z;337, 339 [M-l] " SYNTHETIC EXAMPLE 422
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(Z)-(methoxyimino)methyl]acetamide
(Formula Removed)
2-[5-Chloro-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetamide (32 mg, 0.0944 mmol) in tetrahydrofuran/N,N-dimethylformamide (1/0.1 mL) was stirred with 1,1-dimethoxy-N,N-dimethylmethanamine (25 µL, 0.188 mmol) at room temperature for 3 hours. The reaction solution was concentrated and stirred with tetrahydrofuran/water (1/2 mL) and methoxyamine hydrochloride (12 mg, 0.143 mmol) at room temperature for 2 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (29 mg, 78% yield).
Morphology: colorless solid
LC/MS: Condition 7, retention time 4.43 min LC/MS(ESI")m/z;3 94, 3 96 [M-l] ~ SYNTHETIC EXAMPLE 42 3
3-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(Z)-(methoxyimino)methyl]propanamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 422 by using 3-[5-chloro-6-oxo-4-{ [ (1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]propanamide. Morphology: colorless amorphous LC/MS: Condition 7, retention time 4.38 min LC/MS(ESI+)m/z;410, 412 [M+l] + LC/MS(ESI")m/z;408, 410 [M-l] " SYNTHETIC EXAMPLE 424
rac-2-[5-Bromo-4-{[2-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]amino}-6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
rac-2-[5-Bromo-4-({2-[(methoxymethoxy)methyl]-6,6-dimethylbicyclo[3.1.1]hept-3-yl}amino)-6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (35 mg, 0 . 0655 mmol) in 10 mass% hydrogen chloride-methanol (3 mL) was
stirred at 6 0°C for 1 hour. After completion of the reaction, the reaction solution was evaporated under
reduced pressure, and the resulting solid was collected by filtration, then mixed with saturated aqueous sodium hydrogen sulfate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired product (37% yield). Morphology: colorless oil
LC/MS: Condition 7, retention time 2.88 min LC/MS(ESI+)m/z;490, 492 [M+l] + LC/MS(ESI")m/z;488, 490 [M-l] " SYNTHETIC EXAMPLE 42 5
rac-2-[5-Bromo-4-({2-[(dimethylamino)methyl]-6,6-dimethylbicyclo[3.1.1]hept-3-yl}amino)-6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
rac-2-[5-Bromo-4-{[2-(hydroxymethyl)-6,6-dimethylbicyclo[3.1.1]hept-3-yl]amino}-6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide (43 mg, 0.0877 mmol) in dichloromethane (3 mL) was mixed with (diethylamino)sulfur trifluoride (17 uL, 0,12 8 mmol) at -
78°C and stirred at -78°C for 10 minutes and then stirred at room temperature for 1 hour. After completion of the
reaction, the reaction solution was mixed with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (chloroform/methanol = 10/1) to give the desired product (16% yield). Morphology: colorless oil 1H-NMR (CDCl3)
δ:1.00-1.10 (m, 9H), 1.27 (s, 3H), 1.77-1.86 (m, 1H), 2.05-2.10 (m, 2H), 2.16-2.32 (m, 1H), 2.50-2.60 (m, 1H), 2.60-2.75 (m, 1H), 2.95-3.20 (m, 4H), 3.65-4.10 (m, 3H), 4.44 (d, J = 6.0 Hz, 2H), 4.80-5.05 (m, 3H), 7.17 (d, J = 5.7 Hz, 2H), 7.61 (s, 1H), 8.52 (d, J = 6.0 Hz, 2H) SYNTHETIC EXAMPLE 42 6
2- {5-Bromo-4- [ (5-hydroxytricyclo [3 .3 .1 .l3,7] dec-2-yl)amino]-6-oxopyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide hydrochloride
(Formula Removed)
2- [5-Bromo-4-{ [5-
(methoxymethoxy) tricyclo [3.3.1.13'7] dec-2-yl] amino} -6-oxopyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
(30 mg, 0.056 3 mmol)in 10 mass% hydrogen chloride-methanol (3 mL) was stirred at room temperature for 1
hour. After completion of the reaction, the reaction solution was evaporated under reduced pressure, and the resulting solid was collected by filtration and dried to give the desired product (51% yield). Morphology: colorless solid
LC/MS: Condition 7, retention time 0.93 min LC/MS(ESI+)m/z;488, 490 [M+l] + LC/MS (ESI")m/z; 486, 4 88 [M-l] " SYNTHETIC EXAMPLE 42 7
3-[({[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]benzamide
(Formula Removed)
3-[({[5-Chloro-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)methyl]benzoic acid (23 mg, 0 . 04 72 mmol)in 1,4-dioxane (1 mL) was stirred with 1 M aqueous sodium hydroxide (100 uL, 0.100 mmol) at room temperature for 24 hours. The reaction solution was diluted with ethyl acetate and neutralized with water and 1 M hydrochloric acid, and the organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure.
The residue was dissolved in N,N-dimethylformamide (2 mL) and stirred with di-1H-imidazolylmethanone (38 mg, 0.234 mmol) at room temperature for 6 hours and then with 3 0% aqueous ammonia (0.15 mL) at room temperature for 15 hours. After completion of the reaction, the reaction solution was mixed with water and extracted with ethyl acetate. The extract was washed with 1 M aqueous sodium hydroxide, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (16 mg, 71% yield). Morphology: caramel amorphous
LC/MS: Condition 7, retention time 4.16 min LC/MS(ESI+)m/z;472, 4 74 [M+l] + LC/MS(ESI")m/z;470, 472 [M-l] " SYNTHETIC EXAMPLE 42 8
3-({[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetyl}amino)-3-(pyridin-4-yl)propanamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 402 by using 3-({[5-bromo-6-oxo-4-{ [ (1R,2R,3R,5S) -2,6,6-trimethylbicyclo[3 .l.l]hept-3-yl] amino}pyridazin-1(6H)-yl]acetyl}amino)-3-(pyridin-4-
yl)propanoic acid (50% yield). Morphology: colorless amorphous LC/MS: Condition 7, retention time 3.6 0 min LC/MS(ESI+)m/z;531, 533 [M+l]+ LC/MS(ESI")m/z;529, 531 [M-l]" SYNTHETIC EXAMPLE 42 9
2- [5-Hydroxy-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 381 by using 2-[5-bromo-6-oxo-4-{ [ (1R,2R,3R,5S) -2, 6, 6-trimethylbicyclo [3 .l.l]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide. Morphology: colorless solid 1H-NMR (CDCl3)
δ:0.94 (d, J = 10.3 Hz, 1H), 1.04 (s, 3H), 1.16 (d, J = 7.0 Hz, 3H), 1.25 (s, 3H), 1.6-1.7 (m, 1H), 1.8-1.9 (m, 2H), 2.0 (s, 1H), 2.4-2.5 (m, 1H), 2.5-2.7 (m, 1H), 3.77 (m, 1H), 4.45 (s, 2H), 4.90 (s, 2H), 7.24 (s, 2H), 7.37 (s, 1H), 7.72 (s, 1H), 8.4 8 (s, 2H). SYNTHETIC EXAMPLE 43 0
2- [5-Bromo-6-oxo-4- (tricyclo [3 .3 .1 .l3'7] dec-1-ylsulfanyl)pyridazin-1-(6H)-yl]-N-(pyridin-4-ylmethyl)acetamide

Synthesis was carried out in the same manner as in Synthetic Example 4 8 by using 1-adamantanethiol (15% yield).
Morphology: colorless oil
LC/MS: Condition 7, retention time 3.51 min LC/MS(ESI+)m/z;489, 491 [M+l] + LC/MS(ESI")m/z;487, 489 [M-l] " SYNTHETIC EXAMPLE 431
2- {5-Bromo-6-oxo-4- [2- (tricyclo [3 .3 .1 .l3'7] dec-1-yl)ethoxy]pyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide
(Formula Removed)
2-{4,5-Dibromo-6-oxopyridazin-1(6H)-yl}-N-(pyridin-4-ylmethyl)acetamide (48 mg, 0.119 mmol) and 1-adamantanethanol (92 mg, 0.510 mmol) in 1,4-dioxane (2 mL) were stirred with 6 M aqueous sodium hydroxide (50 uL, 0.300 mmol) at 100°C for 6 hours. After completion
of the reaction, the reaction solution was mixed with saturated aqueous sodium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 3/1 to 0/1) to give the desired product (9% yield). Morphology: colorless oil
LC/MS: Condition 7, retention time 3.86 min LC/MS(ESI+)m/z;501, 503 [M+l]+ LC/MS(ESI")m/z;499, 501 [M-l]" Pharmacological Analysis SYNTHETIC EXAMPLES 4 32 to 44 9
Compounds were synthesized in the same manner as in Synthetic Example 1, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 35.
TABLE 3 5
(Table Removed)
The structures of the compounds obtained i Synthetic Examples are shown below.
(Formula Removed)
2-[5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(2-hydroxypyridin-4-yl)methyl]acetamide OH
(Formula Removed)
2- [5-Bromo-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]-N-[(2-methoxypyridin-4-yl)methyl]acetamide (55.3 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was mixed with 12 M
hydrochloric acid (1 drop) at 100°C for 11 hours. After completion of the reaction, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol = 50/1) to give the desired product. (2.8 mg, 6% yield) Morphology: pale yellow oil
LC/MS: Condition 7, retention time 4.00 min LC/MS(ESI + ) m/z; 44 6, 44 8 [M+l] + LC/MS(ESI") m/z; 444, 44 6 [M-l]+ SYNTHETIC EXAMPLE 4 51
4-Chloro-2-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl] methyl}-5-{ [ (1R, 2R, 3R, 5S) -2,6,6-
trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-3(2H)-one
(Formula Removed)
To [5-chloro-6-oxo-4-{ [ (1R, 2R, 3R, 5S) -2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]acetic acid (80 mg, 0.235 mmol) in dichloromethane (3 mL), N'-hydroxypyridine-4-carboximidamide (38.6 mg, 0.281 mmol) and N,N'-dicyclohexylcarbodiimide (58.2 mg, 0.282 mmol) were added and stirred at room temperature for 18 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure. The resulting oil in toluene (2 mL) was stirred at 110°C for 5 hours and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate = 1/4) to give the desired product (78 mg, 75% yield). Morphology: pale yellow amorphous LC/MS: Condition 7, retention time 4.55 min LC/MS(ESI + ) m/z; 441, 44 3 [M+l] + LC/MS (ESI") m/z; 43 9, 441 [M-l] + 1H-NMR(CDCl3)
δ:0.98 (d, J = 10.2 Hz, 1H), 1.06 (s, 3H), 1.21 (d, J = 7.2 Hz, 3H), 1.28 (s, 3H), 1.76 (ddd, J = 13.8, 5.7, 2.1
Hz, 1H), 1.91-2.09(m, 3H), 2.44-2.72(m, 2H), 3.83-3.95(m, 1H), 4.74(d, J = 7.5 Hz, 1H), 5.62 (s, 2H), 7.68 (s, 1H), 7.92 (d, 6.3 Hz, 2H), 8.75 (d, J = 6.3 Hz, 2H). SYNTHETIC EXAMPLES 452 to 456
Compounds were synthesized from 2-(4,5-dichloro-6-oxopyridazin-1(6H)-yl)-N-[1-(pyridin-4-yl)ethyl]acetamide in the same manner as in Synthetic Example 48, and the yields and morphology of the resulting compounds, the LC/MS conditions used for their analysis and the observed peaks and retention times are shown in Table 36.
TABLE 3 6
(Table Removed)
The structures of the compounds obtained in these Synthetic Examples are shown below.
(Formula Removed)
2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]oxy}pyridazin-1(6H)-yl] N-(pyridin-4-ylmethyl)acetamide O
To 2-(4,5-dibromo-6-oxopyridazin-1(6H)-yl)-N-(pyridin-4-ylmethyl)acetamide (50 mg, 0.124 mmol) and (1R,2R, 3R, 5S) - (-) -isopinocampheol (50 mg, 0.324 mmol) in 1,4-dioxane (2 mL), sodium hydride (15 mg, 0.313 mmol)
was added at 0°C, and stirred at 100°C for 5 days. After
completion of the reaction, the reaction mixture was
mixed with water and extracted with chloroform and ethyl
acetate. The combined organic layer was evaporated under
reduced pressure. The resulting residue was purified by
silica gel column chromatography (ethyl acetate) to give
the desired product (1.7 mg, 3% yield).
Morphology: colorless amorphous
LC/MS: Condition 7, retention time 3.68 min
LC/MS(ESI + ) m/z; 4 75, 4 77 [M+l] +
LC/MS(ESI") m/z; 473, 475 [M-1]-
SYNTHETIC EXAMPLE 4 57
2-(5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-[1-(lH-pyrazol-4-yl)ethyl]acetamide
(Formula Removed)
2-(5-Chloro-6-oxo-4-{[{1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-[1-(l-{ [2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethyl]acetamide
(Formula Removed)
Synthesis was carried out in the same manner as in Synthetic Example 1 by using l-(l-{[2-
(trimethyls ilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethanamine The obtained crude product was used for the next reaction LC/MS: Condition 7, retention time 4.94 min LC/MS(ESI + ) m/z; 563, 565 [M+l] + LC/MS(ESI") m/z; 561, 563 [M-1]-
2-(5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-[1-(lH-pyrazol-4-yl)ethyl]acetamide
2-(5-Chloro-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl)-N-[1-(l-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)ethyl]acetamide (56.2 mg,0.10 mmol) was mixed with 4 M hydrogen chloride/1,4-dioxane (2 mL) and
stirred at 100°C for 5 hours. After completion of the reaction, the reaction solution was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/MeOH = 20/1 ) to give the desired product (5.2 mg, 12% yield).
Morphology: pale yellow solid LC/MS: Condition 7, retention time 4.13 min LC/MS(ESI + ) m/z; 433, 435 [M+l] + LC/MS(ESI") m/z; 431, 433 [M-1]-
TEST EXAMPLE 1: Dye Assay
Human P2X7 (hP2X7) was cloned from a normal human brain total RNA library by reverse transcription (using Superscript II (Invitrogen)) and PCR (using KOD -plus-
(TOYOBO)). PCR primers were designed according to hP2X7 sequence registered in GENBANK with a putative amino acid sequence consisting of 5 95 amino acid residues. The PCR fragments were inserted into pcDNA3.1/myc-HisA vector
(Invitrogen) and sequenced for confirmation.
HEK293 cells were transfected with hP2X7/pcDNA3.1/myc-HisA by lipofection, and 1 day later, the cells were treated with 1 mg/mL G418, and resistant cells were selected by appropriately dilution. The resistant cells were cloned by reseeding at a low density. Each clone was analyzed by a die assay
(described in the next paragraph) to select one clone
highly responsive to 2'(3')-O-(4-benzoylbenzoyl)adenosine 5'-triphosphate (BzATP), a highly selective ligand for the P2X7 receptor, which was used for screening of P2X7 receptor antagonists.
P2X7 receptor antagonists were screened by a dye uptake assay using HEK293 cells stably expressing hP2X7. Cells were plated on a type I collagen-coated black/clear bottom 96-well plate at 2 0000 cells/well and a day later, treated with varying concentrations of various test compounds for 3 0 minutes, then treated with a dye (Yo-Pro-1) (final concentration 2 µM) and BzATP (final concentration 0.1 mM) and incubated for 90 minutes. Then, the fluorescence (indicating the BzATP-induced Yo-Pro-1 uptake mediated by the P2X7 receptor) was measured with a microplate reader (excitation wavelength: 485 nm, emission wavelength: 535 nm). The % inhibition rates were calculated and plotted against the logarithms of the concentrations to determine IC50. The results are shown in Tables 37 to 39.
TABLE 3 7
(Table Removed)
Human whole blood from healthy volunteers was diluted with equal volume of saline and peripheral blood mononuclear cells were collected by using a Limphoprep tube (Daiichi Pure Chemicals), washed with physiological saline and seeded onto a 96-well plate with a medium containing 1-10 ng/mL LPS (SIGMA). 30 minutes later, the cells were treated with varying concentrations of various compounds and incubated for 3 0 minutes. Then, the cells were treated with BzATP (final concentration 1 mM) or ATP (final concentration 5 mM) and incubated for 12 0 minutes. The cells were centrifugated to collect supernatents, and the concentration of IL-1|3 in supernatants were determined by IL-1|3 HTRF kit (CIS biointernational) . The % inhibition rates were calculated and plotted
against the logarithms of the concentrations to determine IC50. The results are shown in Tables 40 to 42.
TABLE 40
(Table Removed)
FORMULATION EXAMPLE 1
A granule preparation containing the following
ingredients is prepared.
Ingredients
Compound represented by the formula (I) 10 mg
Lactose 700 mg
Corn Starch 274 mg
HPC-L 16 mg
1000 mg
A compound represented by the formula (I) and lactose are sifted through a 60-mesh sieve. Corn starch is sifted though a 120-mesh sieve. They are mixed in a V-type blender. The powder mixture is kneaded with a low-viscosity hydroxypropylcellulose (HPC-L) aqueous solution, granulated (extrusion granulation, die size 0.5-1 mm) and dried. The resulting dry granules are sifted through a shaking sieve (12/60 mesh) to obtain a granule preparation. FORMULATION EXAMPLE 2
A powder preparation for capsulation containing the
following ingredients is prepared.
Ingredients
Compound represented by the formula (I) 10 mg
Lactose 79 mg
Corn Starch 10 mg
Magnesium Stearate 1 mg
100 mg A compound represented by the formula (I) and
lactose are sifted through a 60-mesh sieve. Corn starch
is sifted though a 120-mesh sieve. They are mixed with
magnesium stearate in a V-type blender. The 10% powder
is put in hard gelatin capsules No. 5, 100 mg each.
FORMULATION EXAMPLE 3
A granule preparation for capsulation containing the
following ingredients is prepared.
Ingredients
Compound represented by the formula (I) 15 mg
Lactose 90 mg
Corn Starch 42 mg
HPC-L 3 mg
15 0 mg A compound represented by the formula (I) and
lactose are sifted through a 60-mesh sieve. Corn starch
is sifted though a 120-mesh sieve. They are mixed in a
V-type blender. The powder mixture is kneaded with a
low-viscosity hydroxypropylcellulose (HPC-L) aqueous
solution, granulated and dried. The resulting dry
granules are sifted through a shaking sieve (12/60 mesh).
The granules are put in hard capsules No. 4, 150 mg each.
FORMULATION EXAMPLE 4
A tablet preparation containing the following
ingredients is prepared.
Ingredients
(Table Removed)
compound represented by the formula (I), lactose,
microcrystalline cellulose and CMC-Na
(carboxymethylcellulose sodium salt) are sifted through a
60-mesh sieve and mixed. The powder mixture is mixed
with magnesium stearate to give a bulk powder mixture.
The powder mixture is compressed directly into 150 mg
tablets.
FORMULATION EXAMPLE 5
An intravenous preparation is prepared as follows.
Compound represented by the formula (I) 100 mg
Saturated Fatty Acid Glyceride 1000 mL
Solutions having the above-mentioned composition are
usually administered to a patient intravenously at a rate
of 1 ml per 1 minute.
INDUSTRIAL APPLICABILITY
The compounds of the present invention which inhibit activation of the P2X7 receptor are useful as preventive, therapeutic and improving agents for diseases against which activation of the P2X7 receptor is effective, especially as anti-rheumatoid arthritis agents with antiinflammatory action, anti-pain action and bone metabolism improving action, drugs for inflammatory bowel diseases or anti-pain agents for inflammatory pain or cancer pain, and are useful as medicines.
The entire disclosures of Japanese Patent Application No. 2007-284189 filed on October 31, 2007 and Japanese Patent Application No. 2008-229921 filed on September 8, 2 0 08 including specifications, claims and summaries are incorporated herein by reference in their entireties.

CLAIMS
1. A compound represented by the formula (I):
(Formula Removed)
wherein R means a hydrogen atom, a hydroxy group, a nitro group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C1-6 alkoxy group (the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or more halogen atoms),
R2 means a hydrogen atom, a hydroxy group, a nitro group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a mono-C1-6 alkylamino group, a di-C1-6 alkylamino group, a C1-6 alkylthio group or a C1-6 alkylsulfonyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the mono-C1-6 alkylamino group, the di-C1-6 alkylamino group, the C1-6 alkylthio group and the C1-6 alkyl sulfonyl group are unsubstituted or substituted with one or more halogen atoms), Q means any of the structures represented by the formula
(Formula Removed)
(wherein each of R3 and R5 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group (the C1-6 alkyl group, the C2-6 alkenyl group and the C2-6 alkynyl group are unsubstituted or substituted with one or more halogen atoms), R4 means a C1-20 alkyl group, a C2-20 alkenyl group or a C2-19 heterocyclyl group (the C1-20 alkyl group, the C2-20 alkenyl group and the C2-19 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from a substituent set V1) , or
R3 and R4 mean, together with each other, a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1 or one or more C1-20 alkyl groups),
m means 0, 1 or 2, and
T means an oxygen atom or a sulfur atom), X means a single bond or a C1-6 alkylene group (the C1-6 alkylene group is unsubstituted or substituted with one or more identical or different substituents selected from
the substituent set V1) ,
Y means a single bond, a C2-14 arylene group, a C2-9 heterocyclylene group (the C2-14 arylene group and the C2-9 heterocyclylene group are unsubstituted or substituted with one or more identical or different substituents selected from a substituent set V2) or any of the structures represented by the formula (III) :

(Formula Removed)
(wherein each of R6 and R7 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group (the C1-6 alkyl group and the C2-6 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) or a C1-3 haloalkyl group, each of U and W independently means an oxygen atom, a sulfur atom or NOR10 (wherein R10 means a hydrogen atom, a C1-3 alkyl group or a C1-3 haloalkyl group), and n means 0, 1 or 2) , Z means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl
group, a C1-6 alkoxy group, a C3-12 cycloalkyl group, a C3-
12 cycloalkenyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C3-12 cycloalkyl group and the C3-12 cycloalkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a fused C2-14 aryl group, a C2-14 aryloxy group or a C2-9 heterocyclyl group (the C2-14 aryl group, the fused C2-14 aryl group, the C2-14 aryloxy group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , the substituent set V1 consists of carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, sulfo groups, tetrazolyl groups, formyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C2-6 alkenyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups and C1-6 alkylsulfonyl groups (the mono-C1-6 alkylamino groups, the di-C1-6 alkylamino groups, the C1-6 alkyl groups, the C2-6 alkenyl groups, the C1-6 alkoxy groups, the C2-9 heterocyclyl groups, the C1-6 alkyl thio groups and the C1-6 alkylsulfonyl groups are unsubstituted or substituted with one or more carboxy groups, one or more carbamoyl groups, one or more sulfamoyl groups, one or more phosphono groups, one or more sulfo groups, one
or more tetrazolyl groups, one or more formyl groups, one
or more nitro groups, one or more cyano groups, one or more halogen atoms, one or more C1-6 alkyl groups, one or more C1-3 haloalkyl groups, one or more C1-6 alkoxy groups, one or more C1-3 haloalkoxy groups, one or more hydroxy groups, one or more amino groups, one or more mono-C1-6 alkylamino groups, one or more di-C1-6 alkylamino groups, one or more C1-6 alkylthio groups or one or more C1-6 alkylsulfonyl groups), and
the substituent set V2 consists of the substituent set V1, C2-14 aryl groups and fused C2-14 aryl groups (the C2-14 aryl groups and the fused C2-14 aryl groups are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof. 2. A compound represented by the formula (I):
(Formula Removed)
wherein R means a hydrogen atom, a hydroxy group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C1-6 alkoxy group (the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group
and the C1-6 alkoxy group are unsubstituted or substituted
with one or more halogen atoms),
R2 means a hydrogen atom, a hydroxy group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C1-6 alkylthio group or a C1-6 alkylsulfonyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C1-6 alkyl thio group and the C1-6 alkylsulfonyl group are unsubstituted or substituted with one or more halogen atoms), Q means any of the structures represented by the formula (IV) :
(Formula Removed)
(wherein each of R3 and R5 independently means a hydrogen
atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6
alkynyl group (the C1-6 alkyl group, the C2-6 alkenyl group
and the C2-6 alkynyl group are unsubstituted or
substituted with one or more halogen atoms),
R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the
C1-20 alkyl group and the C2-20 alkenyl group are
unsubstituted or substituted with one or more identical
or different substituents selected from a substituent set
V1) , or
R3 and R4 mean, together with each other, a nitrogen-
containing heterocyclyl group (the nitrogen-containing
heterocyclyl group is unsubstituted or substituted with
one or more identical or different substituents selected
from the substituent set V1 or one or more C1-20 alkyl
groups), and
T means an oxygen atom or a sulfur atom),
X means a single bond or a C1-6 alkylene group (the C1-6
alkylene group is unsubstituted or substituted with one
or more identical or different substituents selected from
the substituent set V1) ,
Y means a single bond, a C2-14 arylene group, a C2-9
heterocyclylene group (the C2-14 arylene group and the C2-9
heterocyclylene group are unsubstituted or substituted
with one or more identical or different substituents
selected from a substituent set V2) or any of the
structures represented by the formula (V):
(Formula Removed)
(wherein each of R6 and R7 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C1-3 haloalkyl group, U means an oxygen atom, a sulfur atom or NOR10 (wherein R10 means a hydrogen atom, a C1-3 alkyl
group or a C1-3 haloalkyl group), and n means 0, 1 or 2),
Z means a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C3-12 cycloalkyl group and the C3-12 cycloalkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a fused C2-14 aryl group, a C2-14 aryloxy group or a C2-9 heterocyclyl group (the C2-14 aryl group, the fused C2-14 aryl group, the C2-14 aryloxy group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , the substituent set V1 consists of carboxy groups, carbamoyl groups, sulfamoyl groups, phosphono groups, sulfo groups, tetrazolyl groups, formyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C2-6 alkenyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups and C1-6 alkylsulfonyl groups (the mono-C1-6 alkylamino groups, the di-C1-6 alkylamino groups, the C1-6 alkyl groups, the C2-6 alkenyl groups, the C1-6 alkoxy groups, the C2-9 heterocyclyl groups, the C1-6 alkyl thio groups and the C1-6 alkylsulfonyl groups are unsubstituted or substituted with one or more carboxy groups, one or
more carbamoyl groups, one or more sulfamoyl groups, one
or more phosphono groups, one or more sulfo groups, one
or more tetrazolyl groups, one or more formyl groups, one
or more nitro groups, one or more cyano groups, one or
more halogen atoms, one or more C1-6 alkyl groups, one or
more C1-3 haloalkyl groups, one or more C1-6 alkoxy groups,
one or more C1-3 haloalkoxy groups, one or more hydroxy
groups, one or more amino groups, one or more mono-C1-6
alkylamino groups, one or more di-C1-6 alkylamino groups,
one or more C1-6 alkylthio groups or one or more C1-6
alkylsulfonyl groups), and
the substituent set V2 consists of the substituent set
V1, C2-14 aryl groups and fused C2-14 aryl groups (the C2-14
aryl groups and the fused C2-14 aryl groups are
unsubstituted or substituted with one or more identical
or different substituents selected from the substituent
set V1), a tautomer, prodrug or pharmaceutically
acceptable salt of the compound or a solvate thereof.
3. The compound according to Claim 1 or 2, wherein R1 is a hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
4. The compound according to Claim 1 or 2, wherein R1 is a hydrogen atom or an ethoxy group, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
5. The compound according to any one of Claims 1 to 4,
wherein R2 is a hydrogen atom, a halogen atom, a C1-3
alkoxy group, a C1-3 alkyl group, a C1-3 alkylthio group or
a C1-3 alkylsulfonyl group (the C1-3 alkoxy group, the C1-3
alkyl group, the C1-3 alkylthio group and the C1-3
alkylsulfonyl group are unsubstituted or substituted with
one or more halogen atoms), a tautomer, prodrug or
pharmaceutically acceptable salt of the compound or a
solvate thereof.
6. The compound according to Claim 5, wherein R2 is a halogen atom, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
7. The compound according to any one of Claims 1 to 6, wherein Q is represented by the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms) , and R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the C1-20 alkyl group and the C2-20 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) , a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
8. The compound according to any one of Claims 1 and 3
to 6, wherein Q is represented by the formula (VII):
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the C1-20 alkyl group and the C2-20 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) , a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
9. The compound according to Claim 7 or 8, wherein R3 means a hydrogen atom, and R4 means a C3-12 cycloalkyl group or a C3-12 cycloalkenyl group (the C3-12 cycloalkyl group and the C3-12 cycloalkenyl group are unsubstituted or substituted with one to three identical or different substituents selected from the substituent set V1) , a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
10. The compound according to any one of Claims 1 and 3 to 6, wherein R3 means a hydrogen atom, and R4 means a C2 19 heterocyclyl group (the C2-19 heterocyclyl group is unsubstituted or substituted with one to three identical or different substituents selected from the substituent set V1), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
11. The compound according to Claim 10, wherein R3 means a hydrogen atom, and R4 means a C2-11 heterocyclyl group
(the C2-n heterocyclyl group is unsubstituted or
substituted with one to three identical or different
substituents selected from the substituent set V1) , a
tautomer, prodrug or pharmaceutically acceptable salt of
the compound or a solvate thereof.
12. The compound according to any one of Claims 1 to 11,
wherein X means a C1-6 alkylene group (the C1-6 alkylene
group is unsubstituted or substituted with one or two
identical or different substituents selected from the
substituent set V1) ,
Y means a single bond or any of the structures
represented by the formula (VIII):
(Formula Removed)
(wherein R6 means a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms), and U means an oxygen atom or a sulfur atom), and
Z means a C1-6 alkyl group, a C1-6 alkoxy group (the C1-6 alkyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a C2-14 aryloxy group or a C2-9 heterocyclyl group (the C2-14 aryl group, the C2-14 aryloxy group and the C2-9 heterocyclyl group are unsubstituted or
substituted with one substituent selected from the
substituent set V2) , a tautomer, prodrug or
pharmaceutically acceptable salt of the compound or a
solvate thereof.
13. The compound according to any one of Claims 1 to 12, wherein Z means a C1-6 alkyl group (the C1-6 alkyl group is substituted with a C2-9 heteroaryl group (the C2-9 heteroaryl group is unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V1)), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
14. A compound represented by the formula (I):
(Formula Removed)
wherein R means a hydrogen atom, a hydroxy group, a cyano group, a carboxy group, a carbamoyl group, an amino group, a halogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a C1-6 alkoxy group (the C1-6 alkyl group, the C2-6 alkenyl group, the C2-6 alkynyl group and the C1-6 alkoxy group are unsubstituted or substituted with one or more halogen atoms),
R2 means a C2-14 aryl group (the C2-14 aryl group is unsubstituted or substituted with one or more identical
or different substituents selected from a substituent set
V2),
Q means any of the structures represented by the formula
(Formula Removed)
(wherein each of R3 and R5 independently means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group (the C1-6 alkyl group, the C2-6 alkenyl group and the C2-6 alkynyl group are unsubstituted or substituted with one or more halogen atoms), R4 means a C1-20 alkyl group or a C2-20 alkenyl group (the C1-20 alkyl group and the C2-20 alkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from a substituent set V1) , or
R3 and R4 mean, together with each other, a nitrogen-containing heterocyclyl group (the nitrogen-containing heterocyclyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1 or one or more C1-20 alkyl groups),
m means 0, 1 or 2, and
T means an oxygen atom or a sulfur atom), X means a C1-6 alkylene group (the C1-6 alkylene group is
unsubstituted or substituted with one or more identical
or different substituents selected from the substituent
set V1) ,
Y means a structure represented by the formula (IX):
(Formula Removed)
(wherein R6 means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group or a C1-3 haloalkyl group, and U means an oxygen atom, a sulfur atom or NOR10 (wherein R10 means a hydrogen atom, a C1-3 alkyl group or a C1-3 haloalkyl group)),
Z means a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 alkoxy group, a C3-12 cycloalkyl group, a C3-12 cycloalkenyl group (the C1-6 alkyl group, the C2-6 alkenyl group, the C1-6 alkoxy group, the C3-12 cycloalkyl group and the C3-12 cycloalkenyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , a C2-14 aryl group, a fused C2-14 aryl group or a C2-9 heterocyclyl group (the C2-14 aryl group, the fused C2-14 aryl group and the C2-9 heterocyclyl group are unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V2) , the substituent set V1 consists of carboxy groups,
carbamoyl groups, sulfamoyl groups, phosphono groups,
sulfo groups, tetrazolyl groups, formyl groups, nitro groups, cyano groups, halogen atoms, hydroxy groups, amino groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C1-6 alkyl groups, C2-6 alkenyl groups, C1-6 alkoxy groups, C2-9 heterocyclyl groups, C1-6 alkylthio groups and C1-6 alkylsulfonyl groups (the mono-C1-6 alkylamino groups, the di-C1-6 alkylamino groups, the C1-6 alkyl groups, the C2-6 alkenyl groups, the C1-6 alkoxy groups, the C2-9 heterocyclyl groups, the C1-6 alkyl thio groups and the C1-6 alkylsulfonyl groups are unsubstituted or substituted with one or more carboxy groups, one or more carbamoyl groups, one or more sulfamoyl groups, one or more phosphono groups, one or more sulfo groups, one or more tetrazolyl groups, one or more formyl groups, one or more nitro groups, one or more cyano groups, one or more halogen atoms, one or more C1-6 alkyl groups, one or more C1-3 haloalkyl groups, one or more C1-6 alkoxy groups, one or more C1-3 haloalkoxy groups, one or more hydroxy groups, one or more amino groups, one or more mono-C1-6 alkylamino groups, one or more di-C1-6 alkylamino groups, one or more C1-6 alkylthio groups or one or more C1-6 alkylsulfonyl groups), and
the substituent set V2 consists of the substituent set V1, C2-144 aryl groups and fused C2-14 aryl groups (the C2-14 aryl groups and the fused C2-14 aryl groups are unsubstituted or substituted with one or more identical
or different substituents selected from the substituent
set V1), a tautomer, prodrug or pharmaceutically
acceptable salt of the compound or a solvate thereof.
15. The compound according to Claim 14, wherein R1 is a
hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy
group,
R2 is a C2-14 aryl group,
Q is represented by the formula (VI):
(Formula Removed)
(wherein R3 means a hydrogen atom or a C1-6 alkyl group (the C1-6 alkyl group is unsubstituted or substituted with one or more halogen atoms),
R4 means a C1-20 alkyl group (the C1-20 alkyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1) ) , and
Z means a C1-6 alkyl group (the C1-6 alkyl group is substituted with a C2-9 heteroaryl group (the C2-9 heteroaryl group is unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V1)), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
16. The compound according to Claim 14, wherein R1 is a hydrogen atom, a C1-3 alkoxy group or a C1-3 haloalkoxy
group,
R2 is a C2-14 aryl group,
Q means any of the structures represented by the formula
(VII):
(Formula Removed)
(wherein m means 0, 1 or 2, and R4 means a C1-20 alkyl group (the C1-20 alkyl group is unsubstituted or substituted with one or more identical or different substituents selected from the substituent set V1)), and Z means a C1-6 alkyl group (the C1-6 alkyl group is substituted with a C2-9 heteroaryl group (the C2-9 heteroaryl group is unsubstituted or substituted with one or two identical or different substituents selected from the substituent set V1)), a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof.
17. A P2X7 receptor inhibitor containing the compound according to any one of Claims 1 to 16, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient.
18. A preventive, therapeutic or improving agent for diseases against which inhibition of the P2X7 receptor is effective, which contains the P2X7 receptor inhibitor according to Claim 17, as an active ingredient.
19. A therapeutic agent for rheumatoid arthritis, which
contains the P2X7 receptor inhibitor according to Claim
17, as an active ingredient.
20. Medicament containing the compound according to any
one of Claims 1 to 16, a tautomer, prodrug or pharmaceutically acceptable salt of the compound or a solvate thereof, as an active ingredient.
20. A compound represented by the formula (I)
substantially as herein described with reference to the
foregoing description, tables and the accompanying
examples.