HK1101880A

HK1101880A - Diaryl-substituted five-membered heterocycle derivative

Info

Publication number: HK1101880A
Application number: HK07109545.4A
Authority: HK
Inventors: 川元博; 伊藤智; 佐藤淳志; 永富康司; Y．平田; 木村敏史; 铃木元太郎; 佐藤启生; 太田尚
Original assignee: 万有制药株式会社
Priority date: 2004-03-05
Filing date: 2005-03-07
Publication date: 2007-10-26

Description

Diaryl substituted heterocyclic 5-membered ring derivatives

Technical Field

The invention relates to diaryl substituted heterocyclic 5-membered ring derivatives.

Technical Field

Glutamate is a neurotransmitter in the central nervous system that mediates excitatory conduction. In addition to various neurotransmission actions, glutamate is involved in many important brain functions such as survival and death, differentiation and proliferation of nerve cells, development of nerves and glial cells, and plasticity change of nerve transmission efficiency of mature or developed brain. (see, for example, Annual Review of Biophysics and Biomolecular Structure, Vol. 23, p. 319 (1994), etc.).

Through studies of pharmacology and molecular biology, glutamate receptors in the central nervous system of mammals are classified into 2 types, i.e., ion channel type glutamate receptors and metabotropic type glutamate receptors (hereinafter referred to as "mGluR"). An ion channel type glutamate receptor is composed of a complex of different subunit proteins, and is an ion channel that is opened and closed by binding of a ligand. On the other hand, mglurs are conjugated to GTP-binding proteins and exhibit effects via the modulation of intracellular second messenger production or ion channel activity by GTP-binding proteins (see, for example, Brain research reviews, volume 26, page 230 (1998)).

Through continuing research, it has been reported that mGluRs exist as distinct 8 subtypes of mGluR 1-8. They are divided into 3 subgroups by homology, signaling, pharmacological properties of the amino acid sequence. For intracellular signaling, group I (mGluR1 and 5) activates phospholipase C, and group II (mGluR2 and 3) and group III (mGluR4, 6, 7, 8) modulate adenylate cyclase activation, thereby inhibiting the accumulation of cyclic adenosine monophosphate (cAMP) by forskolin stimulation. Group II is selectively activated by LY354740, as described, for example, in Journal of Medicinal Chemistry, volume 42, page 1027 (1999), etc., and group III is selectively activated by L-AP 4. It is believed that in addition to mGluR6, which is specifically present in the retina, various receptors are expressed in a wide range of brain and nervous systems, and each exhibit a characteristic intracerebral distribution, with each receptor playing a different physiological role. (see, for example, neurochemistry International, Vol.24, p.439 (1994) and European Journal of Pharmacology, Vol.375, p.277 (1999), etc.).

As the compound having a structure similar to the above formula (I), for example, the formula (A)

The compounds shown (see, for example, WO 03/051315).

The group bonded to the 1-position of the triazolyl group is a phenyl group substituted with fluorine, and in this regard, the compounds having a structure similar to that of the above formula (I) have a common point with the compounds to which the present invention relates, but the group bonded to the 4-position having the triazolyl group of the formula (a) is a pyridyl group, and the group bonded to the 4-position having the triazolyl ring of the compound (I) to which the present invention relates is a bicyclic group, which is different. (A) The compounds represented are modulators of mGluR5, whereas the compounds (I) to which the present invention relates are compounds which exhibit mGluR1 inhibitory effect, and differ in this regard.

Disclosure of Invention

The object of the present invention is to provide novel substances having an inhibitory effect on mGluR 1.

The present inventors have found that a specific oxadiazole-substituted 5-membered heterocyclic derivative has an mGluR1 inhibitory effect, and have completed the present invention.

That is, the present invention provides the compounds described in the following (1) to (20) or pharmaceutically acceptable salts thereof for achieving the above object.

(1) A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

[ in the formula, X₁Represents an oxygen atom, a nitrogen atom or CR²，

X₂Represents a nitrogen atom or a carbon atom,

X₃represents a nitrogen atom or a carbon atom,

X₄represents a nitrogen atom or a carbon atom,

R¹represents the following formula (II-1):

(in the formula, -X₅-represents-S-or-A ₄＝A₃-，A₁Represents a carbon atom or a nitrogen atom, A₂～A₄Is CR in its entirety⁴Or A is₂～A₄Any 1 or 2 of (A) represents a nitrogen atom, A₂～A₄The remaining 2 or 1 of (a) represent CR⁴，

In A₁When it is a carbon atom, it represents a double bond, A₁When it is a nitrogen atom, it represents a single bond)

R⁴Represents a hydrogen atom, a lower alkyl groupLower alkoxy, halogen atom, mono-or di-lower alkylamino, hydroxy, lower alkoxycarbonyl, carbamoyl or mono-or di-lower alkylcarbamoylamino,

ring A represents the following (1) or (2) which may have 1 to 3 substituents selected from substituent group alpha,

(1) the constituent atoms of the A ring are all carbon atoms, a saturated, partially saturated or unsaturated 5-or 6-membered ring which may be substituted by 1 or 2 oxo groups, or

(2) As the constituent atoms of the A ring, a saturated, partially saturated or unsaturated 5-or 6-membered ring which may have 1 to 3 hetero atoms selected from N, S and O in the ring, in addition to carbon atoms (the ring may be substituted with 1 or 2 oxo groups),

R²represents a group selected from a hydrogen atom, a lower alkyl group, a cyano group, a lower alkoxy group, a lower alkoxycarbonyl group and a trialkylsilyl group,

R³represents a group (A) or (B) which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group which may be substituted with a halogen atom, a cyano group, a nitro group, a lower alkoxy group, a hydroxyl group and an amino group,

(A) Phenyl radical

(B) A 5-or 6-membered unsaturated or partially saturated heterocyclic group having 1 to 3 heteroatoms selected from N, S and O in the ring. ]

Wherein the compound represented by the formula (1) does not include 4- [5- (2-naphthyl) -1H- [1, 2, 4] triazol-3-yl ] -pyridine, 3- (1, 3-benzodioxol-5-yl) -5- (2-ethylphenyl) -1H-1, 2, 4-triazole, 6- [5- (4-pyridyl) -1H-1, 2, 4 triazol-4-yl ] -quinoline, 3- [ 5-phenyl-4H- [1, 2, 4] triazol-3-yl ] naphthalen-2-ol, 3- [ 5-pyridin-4-yl-1H- [1, 2, 4] triazol-3-yl ] -naphthalen-2-ol, and a pharmaceutically acceptable salt thereof, 5- (quinolin-2-yl) -2- (3-cyano-phenyl) -tetrazole, 3- [5- (3, 5-dichloropyridin-4-yl) -2-methyl-2H- [1, 2, 4] triazol-3-yl ] -quinoline, 3-naphthalen-2-yl-5-phenyl-4H- [1, 2, 4] triazole, 3-benzo [1, 3] dioxan-5-yl-1-methyl-5-o-tolyl-1H- [1, 2, 4] triazole, 5- (5-phenyl-4H- [1, 2, 4] triazol-3-yl) isobenzofuran-1, 3-diketones.

Substituent group α: lower alkyl (the lower alkyl may be substituted with hydroxy, halogen, aryl, di-lower alkylamino (the di-lower alkyl may be bonded to each other and may form an aliphatic heterocyclic ring of 5 to 7 members together with a nitrogen atom, or 1 carbon atom constituting the aliphatic heterocyclic ring may be substituted with an oxygen atom), lower alkoxy, oxo, lower alkoxycarbonyl, alkanoyloxy or lower alkylsulfonylamino, when the lower alkyl is branched lower alkyl, the branched alkyl may be bonded to each other to form cycloalkyl or cycloalkylene having 3 to 6 carbon atoms, when the lower alkyl is branched lower alkyl, the branched alkyl may be bonded to each other to form cycloalkyl having 3 to 6 carbon atoms (the cycloalkyl may be substituted with lower alkyl, hydroxy, aralkyl or lower alkoxy), when the same carbon atom constituting the A ring has 2 lower alkyl groups, the lower alkyl groups may together form a cycloalkyl group. ) Cycloalkyl (any 1 carbon atom constituting the cycloalkyl group may be substituted by an oxygen atom), lower alkoxy, a halogen atom, mono-or di-lower alkylamino, alkanoyl, alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, mono-or di-lower alkylcarbamoyl, amino and hydroxy.

(2) The compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the formula (I) is represented by the formula (I-1),

Formula (I-2),

Formula (I-3),

Formula (I-4),

[ in the formula, the symbols are as defined above ].

(3) The compound according to the above (1) or (2) or a pharmaceutically acceptable salt thereof, wherein R¹Is of the formula (II-A)

[ in the formula, the symbols are as defined above ].

(4) The compound according to the above (3) wherein the formula (II-B) in the formula (II-A) is a phenyl group, or a pharmaceutically acceptable salt thereof.

(5) The compound according to the above (3) or (4), wherein the A ring has at least 1 nitrogen atom as a constituent atom of the A ring, or a pharmaceutically acceptable salt thereof.

(6) The compound according to the above (3) or a pharmaceutically acceptable salt thereof, wherein the formula (II-A) is a formula (II-C)

Or formula (II-D)

[ in the formula, X₆Represents CH₂Or CH ═ CH, X₇～X₁₀One of them is a nitrogen atom and the others represent carbon atoms]A group represented by (the group may have 1 to 3 substituents selected from the above substituent group α which may have a ring a).

(7) The compound according to the above (6) or a pharmaceutically acceptable salt thereof, wherein the formula (II-A) is the formula (II-C).

(8) The compound according to the above (6) or a pharmaceutically acceptable salt thereof, wherein the formula (II-A) is the formula (II-D).

(9) The compound according to the above (1), (2), (3) or (4) wherein the formula (I) is the formula (I-1) or the formula (I-4) (wherein R is not included), or a pharmaceutically acceptable salt thereof ¹In the case of a substituted or unsubstituted naphthyl group).

(10) The compound according to the above (1) or a pharmaceutically acceptable salt thereof, wherein the compound represented by the formula (I) is

5-methyl-1-phenyl-4- (quinolin-6-yl) -1H- [1, 2, 3] triazole,

5-methyl-4- (1-oxo-indan-5-yl) -1-phenyl-1H- [1, 2, 3] triazole,

5-methyl-4- (2-methylbenzothiazol-5-yl) -1-phenyl-1H- [1, 2, 3] triazole,

4- (1H-indol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (quinolin-6-yl) -1-phenyl-1H- [1, 2, 3] triazole,

5-methyl-4- (naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (3-cyclohexyl-5-fluoro-6-methyl-4-oxo-4H-chromen-7-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-quinolin-6-yl) -1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4-quinazolin-6-yl) -1H- [1, 2, 3] triazole,

4- (1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

4- (1, 3-dioxo-2, 3-dihydro-2-methyl-1H-isoindol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-imidazo [1, 2-a ] pyridin-6-yl) -1H- [1, 2, 3] triazole,

5-methyl-4- (4-oxo-4H-chromen-6-yl) -1-phenyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- ([1, 2, 4] triazolo [4, 3-a ] pyridin-7-yl) -1H- [1, 2, 3] triazole,

4- (3, 4-dihydro-2H-1-oxa-9-aza-anthracen-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- ([1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -1H- [1, 2, 3] triazole,

1- (2-fluoropyridin 3-yl) -4-isoquinolin-7-yl-5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4-isoquinolin-3-yl-5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-5-yl) -5-methyl-4- (2-methyl-quinolin-6-yl) -1H- [1, 2, 3] triazole,

1- (6-chloro- [1, 5] naphthyridin-2-yl) -4- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (5, 6, 7, 8-tetrahydro- [1, 5] naphthyridin-2-yl) -1H- [1, 2, 3] triazole,

4- (5-acetyl-5, 6, 7, 8-tetrahydro- [1, 5] naphthyridin-2-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-chloroquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -1-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-1-oxoindan-5-yl) -1H- [1, 2, 3] triazole,

1- (2-Fluoropyridin-3-yl) -5-methyl-4- ((2R)^*) -methyl-1-oxoindan-5-yl) -1H- [1, 2, 3]Triazole, triazole,

1- (2-Fluoropyridin-3-yl) -5-methyl-4- ((2S)^*) -methyl-1-oxoindan-5-yl) -1H- [1, 2, 3]Triazole, triazole,

1- (2-fluoropyridin-5-yl) 4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-methoxyquinolin-6-yl) -5-methyl- [1, 2, 3] triazole,

4- (2-tert-butyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxo-indan-2-spiro-1' -cyclobutane-5-yl) -1H- [1, 2, 3] triazole,

4- (2-dimethylamino-quinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxo-indan-2-spiro-1' -cyclopropyl-5-yl) -1H- [1, 2, 3] triazole,

4- (2-chloro-3-ethyl-quinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-methoxy-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-morpholino-4-yl-quinolin-6-yl) -1H- [1, 2, 3] triazole,

4- (3-methyl-4-oxo-4H-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2- (4-methylpiperazin-1-yl) -quinolin-6-yl) -5-methyl- [1, 2, 3] triazole,

4- (2-isopropyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (5-oxo-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole,

4- (2-ethyl-3-methyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (1-oxo-2-methylcarbonyloxy-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-5-yl) -4- (2-isopropyl-imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (1-oxo-4-hydroxy-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-cyclopropyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-isopropyl-1-oxo-indan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-methyl-2-methylcarbonyloxy-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-hydroxy-2-methyl-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-methoxy-2-methyl-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

4-((2S^*) -methoxy- (2R)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole, triazole,

4-((2R^*) -methoxy- (2S)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole, triazole,

1- (2-fluoropyridin-3-yl) -4- (2-pyrrolidin-1-yl-quinolin-6-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-4-oxo-4-methyl-chromen-7-yl) -1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-5-yl) -4- (1-oxo-2-methyl-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxo-1H-inden-5-yl) -1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-methyl-1-oxo-1H-inden-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-5-yl) -4- (3-methyl-4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (benzothiazol-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (5-fluoro-3-methyl-4-oxo-4H-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

5-methyl-4- (3-methyl-4-oxo-4H-chromen-7-yl) -1- (pyridin-3-yl) -1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-methanesulfonyl-quinolin-6-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- [ (2-isopropyl-methyl-amino) -quinolin-6-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (5-oxo-6-methyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1-phenyl-1H- [1, 2, 3] triazole,

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-4-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-tert-butyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-ethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (2-methoxy-4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (3-methyl-4-oxo-3, 4-dihydro-quinazolin-7-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (3-methyl-4-oxo-3, 4-dihydro-quinazolin-6-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- [2- (2-hydroxy-1-methyl-ethyl) -1-oxo-isoindolin-5-yl ] -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl- (2, 3-dimethyl-4-oxo-3, 4-dihydro-quinazolin-7-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4- (3-methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-Fluoropyridin-3-yl) -4- ((3R)^*) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3]Triazole, triazole,

1- (2-Fluoropyridin-3-yl) -4- ((3S)^*) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3]Triazole, triazole,

1- (2-fluoropyridin-3-yl) -4- (1-oxo-isoindolin-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (3-benzyl-2-ethyl-4-oxo-3, 4-dihydroquinazolin-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-propyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole,

4- (2-benzyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-cyclopropylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-isobutyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (3-methyl-4-oxo-4H-pyrano [2, 3-b ] pyridin-7-yl) -1H- [1, 2, 3] triazole,

4- (3, 3-dimethyl-4-oxo-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1-phenyl-5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1 a-methyl-2-oxo-1, 1a, 2, 7 a-tetrahydro-7-oxo-6-cycloprop [ b ] naphthalen-5-yl) -1H- [1, 2, 3] triazole,

4- (2-methyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-ethyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2-methyl-1-oxo-3, 4-dihydroisoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

([1, 8] naphthyridin-3-yl) -4-phenyl-5-methyl-1H- [1, 2, 3] triazole,

5- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -4-carbonitrile-1H- [1, 2, 3] triazole,

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole or

1- (4-fluorophenyl) -5-methyl-4- (2- (2-hydroxy-2-methyl-propyl) -quinolin-6-yl) -1H- [1, 2, 3] triazole.

(11) The compound according to the above (1) wherein the compound represented by the formula (I) is 1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxoindan-2-spiro-1' -cyclopropyl-5-yl) -1H- [1, 2, 3] triazole or a pharmaceutically acceptable salt thereof.

(12) The compound according to the above (1) wherein the compound represented by the formula (I) is 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(13) The compound according to the above (1) wherein the compound represented by the formula (I) is 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(14) The compound according to the above (1) wherein the compound represented by the formula (I) is 1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-propyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(15) The compound according to the above (1) wherein the compound represented by the formula (I) is 4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(16) The compound according to the above (1) wherein the compound represented by the formula (I) is 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(17) The compound according to the above (1) wherein the compound represented by the formula (I) is 4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(18) The compound according to the above (1) wherein the compound represented by the formula (I) is 4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(19) The compound according to the above (1) wherein the compound represented by the formula (I) is 4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

(20) The compound according to the above (1) wherein the compound represented by the formula (I) is 1- (4-fluorophenyl) -5-methyl-4- (2- (2-hydroxy-2-methyl-propyl) -quinolin-6-yl) -1H- [1, 2, 3] triazole or a pharmaceutically acceptable salt thereof.

The compounds of the above (1) to (20) or pharmaceutically acceptable salts thereof, having an mGluR1 inhibitory activity. Namely, the present invention provides an mGluR1 inhibitor comprising the compound according to any one of (1) to (20) or a pharmaceutically acceptable salt thereof.

When 3, 5-dihydroxyphenylglycine (hereinafter referred to as DHPG), which is a selective agonist for group I, is administered intracerebroventricularly, it has been reported that spasm occurs (see, for example, Journal of neuroscience Research, vol. 51, p. 339 (1998)).

On the other hand, it has been reported that in a pentylenetetrazol-induced spasm model commonly used for evaluating the action of anticonvulsants in an experiment using an mGluR1 selective antagonist, RS-1-aminoindan-1, 5-dicarboxylic acid (hereinafter referred to as "aid a") shows a dose-dependent anticonvulsant action (see, for example, Neuropharmacology, volume 37, page 1465 (1998), etc.), and in addition, shows an inhibitory action on voice-stimulated spasm-induced spasm in mice and rats that exhibit hereditary spasticity (see, for example, European Journal of Pharmacology, volume 368, page 17 (1999), etc.). It has also been reported that LY456236, an alternative selective antagonist, reduces the duration and extent of spasticity in tonsillar epileptic rats known as a model of human spasticity (see, e.g., Neuropharmacology, volume 43, page 308 (2002), etc.).

These recognitions reveal that mGluR1 inhibitors are useful for the prevention or treatment of spasticity.

Accordingly, the compounds described in (1) to (20) above or pharmaceutically acceptable salts thereof having an mGluR1 inhibitory activity are considered to be effective for the prevention or treatment of spasticity.

Following intraluminal administration of DHPG, rats developed allodynia and hyperalgesia to mechanical stimuli or hyperalgesia to thermal stimuli (see, e.g., Neuroreport, volume 9, page 1169 (1998), etc.).

On The other hand, in The research using antagonists, when The threshold of pain rises after The administration of AIDA in The brain (see, for example, The Journal of Pharmacology & Experimental Therapeutics, volume 281, page 721 (1997)), and when ADIA is administered in The spinal cord cavity, analgesic effects are shown in The persistent pain model of The spinal cord injury hyperalgesia model (see, for example, Journal of neurosuma, volume 19, page 23 (2002)), and The arthritis model (see, for example, The Journal of Pharmacology & Experimental Therapeutics, volume 300, page 149 (2002)).

These recognitions suggest that mGluR1 inhibitors may have analgesic effects not only on acute pain, but also on inflammatory and chronic pain.

Therefore, the compounds of the above (1) to (20) or pharmaceutically acceptable salts thereof having an mGluR1 inhibitory activity are considered to be useful for the prevention or treatment of acute pain, inflammatory pain, or chronic pain.

In addition, AIDA was observed to inhibit the delayed neuronal death in hippocampus in a transient whole-brain ischemia-reperfusion model (see, for example, Neuropharmacology, Vol. 38, p. 1607 (1999) and Neuroscience Letters, Vol. 293, p. 1 (2000)), mGluR1 selective antagonists (3aS, 6aS) -6 a-naphthalen-2-ylmethyl-5-methano-hexahydro-cyclopenta [ c ] furan-1-one (hereinafter referred to aS "BAY 36-7620") cause a reduction in cerebral cortical infarct volume in a rat subdural hemorrhage model (see, e.g., European Journal of Parmacology, Vol.428, p.203 (2001), etc.) and other selective antagonists R128494 cause a reduction in total infarct volume in a rat cerebral artery ligation model (see, e.g., Neuropharmacogology, Vol.43, p.295 (2002), etc.).

These findings suggest that mGluR1 inhibitors may have a protective effect on brain damage such as cerebral infarction or transient ischemic attack.

Therefore, the compounds described in (1) to (20) above or pharmaceutically acceptable salts thereof having an mGluR1 inhibitory activity are considered to be useful for the prevention or treatment of brain injury such as cerebral infarction or transient ischemic attack.

In addition, an increase in spontaneous motility can be seen by administering DHPG to the nucleus accumbens of the brain, which is similar to the response after administration of dopamine receptor agonists (see, for example, European journal of Neuroscience, Vol. 13, p. 2157 (2001), etc.), and the occurrence of prepulse inhibition disorders in experimental animal models and schizophrenic patients after administration of DHPG to the nucleus accumbens of the brain is reported, for example, in Psychopharmacology, Vol. 141, p. 405 (1999), etc. These responses by DHPG are similar to those seen in dopamine-releasing drugs such as apomorphine-based dopamine receptor agonists or amphetamines, methamphetamines, and the like. On the other hand, existing antipsychotics are believed to express effects by inhibiting hyperactivated dopamine nerves.

DHPG elicits responses similar to dopamine stimulation, suggesting that mGluR1 and mGluR5 are involved in mental dysfunction in the nucleus accumbens, and mGluR1 inhibitors may ameliorate these symptoms.

Therefore, the compounds of the above (1) to (20) or pharmaceutically acceptable salts thereof having an mGluR1 inhibitory activity are considered to be useful for the prevention or treatment of mental disorders such as schizophrenia.

It has been reported that selective agonist R128494 increases drinking water accompanied by punishment in Vogel type kudzu test using rats commonly used as an evaluation system for anxiolytic effect of a detectable agent (refer to, for example, Neuropharmacology, volume 43, page 295 (2002), etc.).

Therefore, the compounds (1) to (20) or pharmaceutically acceptable salts thereof are considered to be useful for the prevention or treatment of anxiety.

In the above-described non-patent document 16, it is described that mGluR 1-selective antagonist BAY36-7620 can inhibit self-stimulation in brain promoted by NMDA receptor antagonist MK-801. Since it is clinically known that most NMDA receptor antagonists develop dependence, the test system is considered to be a model reflecting a part of the dependence caused by MK-801.

These recognitions suggest that selective antagonists of the mGluR1 receptor may be drug-dependent prophylactic or therapeutic agents.

Therefore, the compounds (1) to (20) or pharmaceutically acceptable salts thereof are considered to be useful for the prophylaxis or treatment of drug dependence.

In experiments using Brain sections containing rat hypothalamic nuclei and recording extracellular potentials, it was observed that topical application of DHPG could cause an increase in the frequency of activation potential generation (see, e.g., Brain Research, volume 766, page 162 (1997)), thus revealing that mGluR1 or mGluR5 caused activation of the hypothalamic nuclei. It is well known that the excitation of the subthalamic nucleus is characteristic of parkinson's disease.

These findings suggest that mGluR1 inhibitors may be useful as prophylactic or therapeutic agents for parkinson's disease.

Therefore, the compounds (1) to (20) or pharmaceutically acceptable salts thereof are considered to be useful for the prevention or treatment of parkinson's disease.

Reflux esophagitis (GERD) is the most common upper digestive tract injury. Current pharmacotherapy aims to inhibit gastric acid secretion or the neutralization of gastric acid in the esophagus. It is currently believed that the primary mechanism of reflux is caused by chronic hypotony of the lower esophageal sphincter. However, reports on Gastroentenol Clin. North Am., Vol.19, p.517-535 (1990) indicate that transient relaxations of The Lower Esophageal Sphincter (TLESRs), i.e., relaxations occurring beyond swallowing, cause almost all reflux episodes. It has also been increasingly found that gastric acid secretion is generally normal in patients with GERD.

The Lower Esophageal Sphincter (LES) is prone to intermittent relaxation. As a result, when the sphincter relaxes, the mechanical barrier is temporarily lost and consequently gastric juice can flow into the esophagus, a phenomenon defined as "reflux".

The word "TLESR" indicating transient relaxation of the lower esophageal sphincter is defined according to Gastroenterology, volume 109 (2), page 601-610 (1995).

The term "reflux" can be defined as the gastric fluid that flows from the stomach into the esophagus. This is because the mechanical barrier is temporarily lost in this state. The word "GERD" indicating reflux esophagitis is defined in terms of Baillire's Clinical gastroenterology, volume 14, pages 759-774 (2000).

Based on the above physiological and pathophysiological meanings, the compounds of the above (1) to (20) or pharmaceutically acceptable salts thereof are considered to be useful for the prevention or treatment of gastrointestinal disorders.

Detailed Description

The meaning of the terms used in the present specification will be described first, and then the compounds of the present invention will be described.

Examples of the "aryl group" include a hydrocarbon ring aryl group having 6 to 14 carbon atoms.

The "lower alkyl group" refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, isopentyl, 1-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 1, 2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-dimethylbutyl, 3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1, 2, 2-trimethylpropyl, 1-ethyl, 2-ethylbutyl, 1-isopropyl, 2-dimethylpropyl, 1, 2-dimethylpropyl, 1, 1-ethyl-2-methylpropyl, and the like.

The "cycloalkyl group" refers to a cycloalkyl group having 3 to 9 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.

The "lower alkoxy group" refers to a group in which a hydrogen atom of a hydroxyl group is substituted with the above-mentioned lower alkyl group, and examples thereof include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, isohexyloxy group and the like.

The "halogen atom" means, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.

"Mono-lower alkylamino" refers to an amino group mono-substituted with the above-mentioned lower alkyl, and examples thereof include methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, and the like.

"Dilower alkylamino" refers to an amino group which is disubstituted with the same or different lower alkyl groups, and examples thereof include dimethylamino, diethylamino, dipropylamino, methylpropylamino and diisopropylamino.

"alkanoyl" refers to a group in which the lower alkyl group is bonded to a carbonyl group, and examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl and isopropylcarbonyl.

The "lower alkoxycarbonyl group" refers to a group in which a hydrogen atom in a hydroxyl group is substituted with the aforementioned alkanoyl group, and examples thereof include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl.

"Mono-lower alkylcarbamoyl" refers to a carbamoyl group mono-substituted with the above-mentioned lower alkyl, and examples thereof include methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, sec-butylcarbamoyl and tert-butylcarbamoyl.

"Dilower alkylcarbamoyl" refers to a carbamoyl group which is disubstituted by the same or different lower alkyl groups as described above, and examples thereof include dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, dipropylcarbamoyl, methylpropylcarbamoyl and diisopropylcarbamoyl.

"Mono-lower alkylcarbamoylamino" refers to a carbamoylamino group mono-substituted with the above-mentioned lower alkyl group, and examples thereof include methylcarbamoylamino, ethylcarbamoylamino, isopropylcarbamoylamino and the like.

"Dilower alkylcarbamoylamino" refers to a carbamoylamino group which is di-substituted by the same or different lower alkyl groups as described above, and examples thereof include dimethylcarbamoylamino, diethylcarbamoylamino, ethylmethylcarbamoylamino, and ethylisopropylcarbamoylamino.

The "alkylsulfonyl group" refers to a group in which the above-mentioned alkyl group is bonded to a sulfonyl group, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, an isopropylsulfonyl group, and a butylsulfonyl group.

The "trialkylsilyl group" refers to a silyl group substituted with the same or different lower alkyl group, and examples thereof include a trimethylsilyl group and a triethylsilyl group.

In order to further specifically disclose the above formula (I) related to the present invention, various symbols used in the formula (I) are described with reference to specific examples.

X₁Represents an oxygen atom, a nitrogen atom or CR²Among them, nitrogen atom or CR is preferred²More preferably CR²。

R²Represents a hydrogen atom, a lower alkyl group, a cyano group, a lower alkoxy group, a lower alkoxycarbonyl group or a trialkylsilyl group, among which a hydrogen atom, a cyano group or a lower alkyl group is preferred, and a cyano group or a lower alkyl group is more preferred.

X₂Represents a nitrogen atom or a carbon atom, and among them, a nitrogen atom is preferable.

X₃Represents a nitrogen atom or a carbon atom, and among them, a nitrogen atom is preferable.

X₄Represents a nitrogen atom or a carbon atom, and among them, a nitrogen atom is preferable.

R¹Represents a group of the formula (II-1).

Next, the group represented by (II-10) in the above formula (II-1) will be described.

A₁Represents a carbon atom or a nitrogen atom.

-X₅-represents-S-or-A₄＝A₃-。

A₂～A₄Is CR in its entirety⁴Or A is₂～A₄Any 1 or 2 of (A) represents a nitrogen atom, A₂～A₄The remaining 1 or 2 of (a) represent CR⁴。

R⁴Represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a mono-or di-lower alkylamino group, a hydroxyl group, a lower alkoxycarbonyl group, a carbamoyl group or a mono-or di-lower alkylcarbamoylamino group.

In the above formula (II-1) or (II-10)

In A₁When it is a carbon atom, it represents a double bond, A₁In the case of a nitrogen atom, it represents a single bond, preferably a double bond.

As can be seen from the above, the compound represented by the formula (II-10) is preferably a compound represented by the formula (II-A),

[ wherein the symbols are as defined above ]

Specific examples thereof include a group represented by the following formula (II-11),

among them, the group represented by the formula (II-12) is preferable,

more preferred is a group represented by the following formula (II-13).

Ring A represents the following (1) or (2),

(1) the constituent atoms of the A ring being all carbon atoms, a saturated, partially saturated or unsaturated 5-or 6-membered ring, or

(2) The constituent atoms of the A ring may be a saturated, partially saturated or unsaturated 5-or 6-membered ring having 1 to 3 heteroatoms selected from N, S and O in the ring, in addition to carbon atoms.

The a ring preferably has at least one nitrogen atom as a constituent atom of the a ring.

The ring A may have 1 to 3 substituents selected from the group consisting of lower alkyl (which may be further substituted by hydroxy, halogen or aryl, and when the same carbon atom constituting the ring A has 2 lower alkyl groups, the lower alkyl groups may together form cycloalkyl), cycloalkyl, lower alkoxy, halogen, mono-or di-lower alkylamino, alkanoyl, alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, mono-or di-lower alkylcarbamoyl and hydroxy, and further, the ring A may be substituted by 1 or 2 oxo groups.

The "lower alkyl" of the substituent is preferably, for example, methyl, ethyl, isopropyl, etc.

When the same carbon atom constituting the a ring has 2 lower alkyl groups, the lower alkyl groups may together form a cycloalkyl group.

The cycloalkyl group is preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like.

The "lower alkyl group substituted with hydroxy" of the substituent is preferably hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 2-hydroxy-1-methylethyl, etc.

The "lower alkyl group substituted with a halogen atom" of the substituent is preferably, for example, chloromethyl, bromomethyl, fluoromethyl, etc.

The "lower alkyl group substituted with aryl" of the substituent is preferably, for example, benzyl, phenethyl and the like.

The "cycloalkyl group" of the substituent is preferably, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The "lower alkoxy" of the substituent is preferably, for example, methoxy, ethoxy, isopropoxy, etc.

The "halogen atom" of the substituent is preferably, for example, a fluorine atom, a chlorine atom, a bromine atom or the like.

The "mono-lower alkylamino" group as the substituent is preferably, for example, methylamino, ethylamino, isopropylamino.

The "di-lower alkylamino" group as the substituent is preferably, for example, dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, etc.

The di-lower alkylamino group also includes the case where the same or different lower alkyl groups together form a 5-6 membered ring, and any 1 methylene group constituting the 5-6 membered heterocyclic ring may be substituted with O, N or S.

When the methylene group is substituted with N, N may be further substituted with a lower alkyl group.

The 5-to 6-membered heterocyclic ring is preferably, for example, pyrrolidin-1-yl, piperidin-1-yl, 4-methyl-piperidin-1-yl, 4-ethyl-piperidin-1-yl, morpholin-4-yl or the like.

The "alkanoyl" group as the substituent is preferably, for example, acetyl, propionyl or the like.

The "alkylsulfonyl" of such substituents is preferably, for example, methylsulfonyl, ethylsulfonyl, isopropylsulfonyl and the like.

The "mono-lower alkylcarbamoyl" of the substituent is preferably, for example, methylcarbamoyl, ethylcarbamoyl, isopropylcarbamoyl and the like.

The "di-lower alkylcarbamoyl" of the substituent is preferably, for example, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl or the like.

The "mono-lower alkylcarbamoylamino" of the substituent is preferably, for example, methylcarbamoylamino, ethylcarbamoylamino, isopropylcarbamoylamino and the like.

The "di-lower alkylcarbamoylamino" of the substituent is preferably, for example, dimethylcarbamoylamino, diethylcarbamoylamino, ethylmethylcarbamoylamino, diisopropylcarbamoylamino and the like.

When ring a has an alkyl group and a lower alkoxy group as substituents, the lower alkyl group and the lower alkoxy group may together form a 5-or 6-membered heterocyclic ring.

R¹Preference is given to formula (II-C)

Or formula (II-D)

[ in the formula, X₆Represents CH₂CH or CH₂-CH₂，X₇～X₁₀One of them is a nitrogen atom and the others represent carbon atoms]Specific examples of the group represented by (a) (the group may have 1 to 3 substituents selected from the above substituent group α which may have an A ring) include quinolin-6-yl, quinolin-7-yl, isoquinolin-6-yl, 2-methylquinolin-6-yl, isoquinolin-3-yl, 2-methoxyquinolin-6-yl, 3-methoxyquinolin-6-yl, 2-dimethylaminolin-6-yl, 2-chloro-3-ethyl-quinolin-6-yl, 2-morpholin-4-yl-quinolin-6-yl, 2- (4-methylpiperazin-1-yl) -quinolin-6-yl, and the like, 2-pyrrolidin-1-yl-quinolin-6-yl, 2-methanesulfonyl-quinolin-6-yl, 2-isopropyl-methylamino-quinolin-6-yl, 2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl, quinoxalin-6-yl, 1-oxo-isoindolin-5-yl, 2-isopropyl-1-oxo-isoindolin-5-yl, 2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl, 2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl A group, 2-methyl-1-oxo-isoindolin-5-yl, 2-cyclopropyl-1-oxo-isoindolin-5-yl, 2-ethyl-1-oxo-isoindolin-5-yl, 2- (2-hydroxy-1-methylethyl) -1-oxo-isoindolin-5-yl, and the like.

R³To represent

(A) Phenyl, or

(B) 5-6 membered unsaturated or partially saturated heterocyclic group having 1-3 hetero atoms selected from N, S and O in the ring.

The R is³May have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group and a hydroxyl group. R³When 2 or 3 of the substituents are present, these substituents may be the same or different.

As can be seen from the above, R may have such a substituent³For example, the compound represented by the above formula (I) is preferably a compound represented by the following formula (I-A),

[ wherein the symbols are as defined above ]

More preferred is a group represented by the following formula (I-B).

[ wherein the symbols are as defined above ]

Further preferred is a group represented by the following formula (I-1).

[ in the formula, the symbols are as defined above ].

However, the compounds represented by the above formula (1) do not include 4- [5- (2-naphthyl) -1H- [1, 2, 4] triazol-3-yl ] -pyridine, 3- (1, 3-benzodioxol-5-yl) -5- (2-ethylphenyl) -1H-1, 2, 4-triazole, 6- [5- (4-pyridyl) -1H-1, 2, 4 triazol-4-yl ] -quinoline, 3- (5-phenyl-4H- [1, 2, 4] triazol-3-yl) naphthalen-2-ol, 3- [ 5-pyridin-4-yl-1H- [1, 2, 4] triazol-3-yl ] -naphthalen-2-ol, and, 5- (quinolin-2-yl) -2- (3-cyano-phenyl) -tetrazole, 3- [5- (3, 5-dichloropyridin-4-yl) -2-methyl-2H- [1, 2, 4] triazol-3-yl ] -quinoline, 3-naphthalen-2-yl-5-phenyl-4H- [1, 2, 4] triazole, 3-benzo [1, 3] dioxan-5-yl-1-methyl-5-o-tolyl-1H- [1, 2, 4] triazole, 5- (5-phenyl-4H- [1, 2, 4] triazol-3-yl) isobenzofuran-1, 3-diketones, further excluding the case where R1 in (I-B) and (I-1) is a substituted or unsubstituted naphthyl group.

It is to be noted that X₁、X₂、X₃、X₄、X₅、X₆、X₇、X₈、X₉、X₁₀、R¹、R²、R³、A₁、A₂、A₃、A₄、A₅Ring A andcan be made into any group

5-methyl-4- (2-methylbenzothiazol-5-yl) -1-phenyl-1H- [1, 2, 3] triazole,

4- (1H-indol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

5-methyl-4- (naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4-quinazolin-6-yl) -1H- [1, 2, 3] triazole,

4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

5-methyl-4- (4-oxo-4H-chromen-6-yl) -1-phenyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin 3-yl) -4-isoquinolin-7-yl-5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4-isoquinolin-3-yl-5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-5-yl) -4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole,

([1, 8] naphthyridin-3-yl) -4-phenyl-5-methyl-1H- [1, 2, 3] triazole,

1- (4-fluorophenyl) -5-methyl-4- (2- (2-hydroxy-2-methyl-propyl) -quinolin-6-yl) -1H- [1, 2, 3] triazole. Among these, 1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxoindan-2-spiro-1' -cyclopropyl-5-yl) -1H- [1, 2, 3] triazole,

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3] triazole,

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole,

The compound (I) according to the present invention can be produced by a known reaction method or a method known per se. The compound (I) of the present invention can be produced not only by a usual liquid-phase synthesis method but also by a method using a solid phase, which has been developed rapidly in recent years, such as a combinatorial synthesis method or a parallel synthesis method.

The present invention relates to a compound (I)

[ in the formula, the same symbols as above ] can be produced, for example, by the following method.

[ in the formula, R⁵Represents a lower alkyl group, X represents a leaving group, and the other symbols are the same as those described above]

(step 1)

This step is a method for producing the compound (I) according to the present invention by reacting the compound (1a) with the compound (2a) in the presence of a catalyst.

R in Compound (1a)⁵Represents a lower alkyl group, preferably, for example, methyl, ethyl, propyl, butyl, etc.

X in the compound (2a) is not particularly limited as long as it is capable of leaving in the reaction of the compounds (1a) and (2a) to produce the compound (I), and among them, a halogen atom or OSO is preferable₃CF₃。

The reaction in this step is a so-called Stille coupling reaction.

The amount of the compound (2a) to be used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, based on 1 equivalent of the compound (1 a).

The catalyst used in this step may be, for example, Pd (PPh)₃)₄、Pd₂(dba)₃And the like.

The amount of the catalyst to be used is usually 1 to 200 mol%, preferably 5 to 20 mol%, based on 1 equivalent of the compound (1).

The ligand used in this step is exemplified by PPh₃、P(o-tolyl)₃、dppp、BINAP、AsPh₃And the like.

The amount of the ligand to be used is usually 1 to 200 mol%, preferably 5 to 20 mol%, based on 1 equivalent of the compound (1).

The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, DMF, NMP, THF, DMSO, and the like, and among them, toluene, DMF, NMP, and the like are preferable.

The reaction temperature is usually 0 to 150 degrees, preferably 50 to 120 degrees.

The reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours.

The compound (I) of the present invention thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, and the like.

The compound (I) according to the present invention can be produced by the following method.

[ wherein the symbols are as defined above ]

(step 2)

This step is a method for producing the compound (I) according to the present invention by reacting the compound (1b) with the compound (2b) in the presence of a catalyst.

The reaction in this step is a so-called Stille coupling reaction, as in step 1.

This step will be specifically described below.

The amount of the compound (2b) to be used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, based on 1 equivalent of the compound (1 b).

The kind of catalyst and the amount of catalyst used in this step are the same as in step 1.

The kind of the ligand and the amount of the ligand used in the present step are also the same as in the above step 1.

The reaction solvent, reaction temperature and reaction time used in this step are also the same as in step 1.

The compound (I) according to the present invention can also be produced by the following method.

[ wherein the symbols are as defined above ]

(step 3)

This step is a method for producing the compound (I) according to the present invention by reacting the compound (1c) with the compound (2a) in the presence of a catalyst and a base.

The reaction in this step is a so-called suzuki coupling reaction.

The amount of the compound (2a) to be used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, based on 1 equivalent of the compound (1 c).

The catalyst used in this step may be, for example, Pd (PPh)₃)₄、Pd₂(dba)₃、PdCl₂(dppf)₂And the like.

The amount of the catalyst to be used is usually 1 to 200 mol%, preferably 5 to 20 mol%, based on 1 equivalent of the compound (1 c).

Examples of the base used include sodium carbonate and potassium carbonate.

The amount of the base used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, based on 1 equivalent of the compound (1 c).

The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, DMF, NMP, dioxane, THF, DMSO, water, etc., and among them, toluene, DMF, and NMP are preferable.

The reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours.

The compound (I) according to the present invention can be produced, for example, by the following method.

[ wherein the symbols are as defined above ]

(step 3-1)

This step is a method for producing the compound (I) according to the present invention by reacting the compound (1d) with the compound (2 c).

The reaction in this step is a so-called suzuki coupling reaction, and the reaction conditions may be as in the above step 3.

Of the compounds (1a) used in the above step 1, the compounds represented by the formula (1a-1)

[ wherein the symbols are as defined above ]

The compound represented by (a) can be produced, for example, by the following method.

[ wherein the symbols are as defined above ]

(step 4)

The step of reacting the compound (3) with NaNO in the presence of water and hydrogen chloride₂And NaN₃A process for producing the compound (4) by the reaction.

NaNO in the invention₂The amount of (3) is usually 1 to 50 equivalents, preferably 1 to 5 equivalents, based on 1 equivalent of the compound (3)

NaN in the invention₃The amount of (3) is usually 1 to 50 equivalents, preferably 1 to 5 equivalents, based on 1 equivalent of the compound (3).

The amount of water and hydrogen chloride to be used is usually 1 to 1000 equivalents, preferably 1 to 100 equivalents, based on 1 equivalent of the compound (3).

The reaction solvent is not particularly limited as long as it does not affect the reaction, and examples thereof include a water-ether mixed solvent, THF, ethyl acetate, chloroform and the like, and among them, a water-ether mixed solvent is preferable.

The reaction temperature is usually 0 to 100 degrees, preferably 0 to room temperature.

The reaction time is usually 30 minutes to 24 hours, preferably 1 to 12 hours.

The compound (I) of the present invention thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, and the like.

(step 5)

This step is a method for producing the compound (1a-1) by reacting the compound (4) produced in the above step 4 with the compound (5).

Examples of the compound (5) used in the present step include tributyl (1-propynyl) tin and ethynyl tri-N-butyltin.

As the compound (5) used in the present step, a commercially available compound can be used, or the compound represented by the formula (5A) can be used in the presence of butyllithium

[ wherein the symbols are as defined above ]

The compound represented by (1) and the compound (4A) or (4B)

R³SnCl or (R)³Sn)₂O

(4A) (4B)

[ wherein the symbols are as defined above ]

The compounds shown are reacted to prepare. This reaction can be carried out by a method described in the literature (e.g., J.org.chem.1987, 52(19), 4296, Tetrahedron Lett.1984, 25(28), 3019, etc.), a method based thereon, or a combination thereof with a conventional method.

The amount of the compound (4) to be used is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, based on 1 equivalent of the compound (3).

The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include toluene, benzene, xylene, DMF, NMP, dioxane, THF, DMSO, and the like, and among them, toluene, benzene, and xylene are preferable.

The reaction time is usually 30 minutes to 7 days, preferably 2 to 12 hours.

The compound (1a-1) according to the present invention thus obtained can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography and the like.

The compound (I-1) according to the present invention can be produced, for example, by the following method using the above-mentioned compound (4).

(step 6)

This step is a method for producing the compound (I-1) according to the present invention by reacting the compound (4) with the compound (6) in the presence of a copper salt.

The amount of the compound (6) to be used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, based on 1 equivalent of the compound (4).

Examples of the copper salt used in the step include copper sulfate 5 hydrate/sodium ascorbate, copper iodide, copper bromide, and CuOTf-C₆H₆And (3) a complex.

The amount of the copper salt to be used is usually 0.1 to 20 mol%, preferably 1 to 10 mol%, based on 1 equivalent of the compound (4).

The solvent to be used is not particularly limited as long as it does not affect the reaction, and examples thereof include a mixed solvent of water and t-butanol, a mixed solvent of water and ethanol, and the like.

The reaction temperature is usually 0 to 60 degrees, preferably 20 to 30 degrees.

The reaction time is usually 1 to 36 hours, preferably 3 to 24 hours.

The compound (I-1) thus obtained according to the present invention can be isolated and purified by a known isolation and purification method such as concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography and the like.

In the presence of copper salts such as copper iodide and bases such as triethylamine, PdCl can be used₂(PPd₃)₂The compound (6) used in the present step is prepared by reacting the compound (2a) with trimethylsilylacetylene in the presence of a Pd catalyst or a solvent such as DMF. The reaction can be carried out by a method described in the literature (e.g., J.chem.Soc., Perkin Tran.1, 2000, 4339-S4346, Angew.chem.Int.Ed.2002, 41, No.14, 2596-S2599, etc.), a method based thereon, or a combination thereof with a conventional method.

The present invention relates to a compound (I-1)

[ wherein the symbols are as defined above ]

(step 7)

This step is a method for producing the compound (I-1) according to the present invention by reacting the compound (1e) with the compound (2a) in the presence of a base and a catalyst.

The reaction in this step is a so-called Heck reaction.

In the compound (2a) used in the present step, X represents a leaving group, and examples thereof include a chlorine atom, a bromine atom, an iodine atom, and a trifluoromethanesulfonyloxy group.

The amount of the compound (2a) to be used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, based on 1 equivalent of the compound (1 e).

The catalyst used in the present step is preferably a palladium catalyst, and specific examples thereof include Pd (OAc)₂、Pd(PPh₃)₄、Pd₂(dba)₃、PdCl₂(dppf)₂And the like.

The amount of the catalyst to be used is usually 0.01 to 1 equivalent, preferably 0.1 to 0.2 equivalent, based on 1 equivalent of the compound (1 e).

In this step, a ligand is used, and examples of the ligand include PPh₃、P(o-tolyl)₃Dppp, BINAP, etc.

The amount of the ligand to be used is usually 1 to 200 mol%, preferably 5 to 20 mol%, based on 1 equivalent of the compound (1 e).

Examples of the base used in this step include triethylamine, sodium acetate, sodium hydrogen carbonate, and potassium carbonate.

The amount of the base to be used is usually 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents, based on 1 equivalent of the compound (1 e).

The reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours.

The compounds of the present invention can be prepared into pharmaceutically acceptable salts or esters by conventional methods, and conversely, the compounds can be converted into free compounds by conventional methods from bases or esters.

Specifically, the compounds of the above-mentioned (I), (I-A), (I-B), (I-1) and (Ia-1), when having a basic group derived from, for example, an amino group, a pyridyl group or the like in the molecule, can be converted into the corresponding pharmaceutically acceptable salts by treating the compounds with an acid.

Examples of the acid addition salts include hydrohalic acid salts such as hydrochloride, hydrofluoride, hydrobromide and hydroiodic acid; inorganic acid salts such as nitrate, perchlorate, sulfate, phosphate, and carbonate; lower alkylsulfonic acid salts such as methanesulfonic acid salt, trifluoromethanesulfonic acid salt, ethanesulfonic acid salt and the like; arylsulfonates such as benzenesulfonate and p-toluenesulfonate; organic acid salts such as fumaric acid, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, and maleic acid salts; and acid addition salts of organic acids such as amino acids including glutamate and aspartate.

When the compound of the present invention has a hydroxyl group in the group, for example, a carboxyl group, the compound can be converted into a corresponding pharmaceutically acceptable salt by treating the compound with a base. Examples of the base addition salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, and organic bases such as ammonium salts, guanidine, triethylamine and dicyclohexylamine.

The compounds of the invention may also be present as any hydrate or solvate of the free compound or salt thereof.

Conversely, the base or ester can be converted into the free compound by a conventional method.

The compounds according to the present invention may have stereoisomers or tautomers such as optical isomers, diastereoisomers, geometric isomers and the like depending on the forms of the substituents. All of these isomers are naturally included in the compounds to which the invention relates. Any mixtures of these isomers are naturally also included in the compounds to which the invention relates.

When the compound of the present invention is used clinically, it may be formulated by adding a pharmaceutically acceptable additive depending on the administration form. In this case, various additives generally used in the field of pharmaceutical preparations can be used, and examples thereof include gelatin, lactose, white sugar, titanium oxide, starch, crystalline cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, corn starch, microcrystalline wax, white petrolatum, magnesium aluminum silicate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropyl cellulose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polyvinylpyrrolidone, magnesium stearate, light anhydrous silicic acid, talc, vegetable oil, benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin, hydroxypropyl cyclodextrin, and the like.

The mixture of the compound of the present invention and the above additives can be used as solid preparations (tablets, capsules, granules, powders, suppositories, etc.) or liquid preparations (syrups, elixirs, injections, etc.). These formulations can be formulated according to methods commonly used in the formulation art. It should be noted that the liquid preparation may be a preparation dissolved or suspended in water or other suitable medium at the time of use. In particular, in the case of an injection, the injection may be dissolved or suspended in physiological saline or a glucose solution, and a buffer or a preservative may be added as required. These preparations may contain the compound of the present invention in an amount of 1.0 to 100% by weight, preferably 1.0 to 60% by weight.

The compound of the present invention can be formulated, for example, by the following formulation examples.

(preparation example 1)

10 parts of the compound of example 1, 15 parts of heavy magnesium oxide and 75 parts of lactose were uniformly mixed to prepare a powder having a particle size of 350 μm or less. The powders are filled into capsules to prepare capsules.

(preparation example 2)

After uniformly mixing 45 parts of the compound of example 1, 15 parts of starch, 16 parts of lactose, 21 parts of crystalline cellulose, 3 parts of polyvinyl alcohol and 30 parts of distilled water, the mixture was pulverized, granulated, dried and sieved, thereby obtaining granules having a diameter of 1410 to 177 μm.

(preparation example 3)

After preparing granules in the same manner as in preparation example 2, 96 parts of the granules were added with 3 parts of calcium stearate, and compression-molded to prepare tablets having a diameter of 10 mm.

(preparation example 4)

90 parts of the granules prepared by the method of preparation example 2 were added with 10 parts of crystalline cellulose and 3 parts of calcium stearate, compression-molded to prepare tablets having a diameter of 8mm, and then a mixed suspension of syrup gelatin and precipitated calcium carbonate was added thereto to prepare sugar-coated tablets.

When the compound of the present invention is clinically used, the dose and the frequency of administration vary depending on the sex, age, body weight, degree of symptoms, type and range of the intended therapeutic effect of the patient, and the like. Generally, when the administration is oral, the administration is usually 0.01 to 100mg/kg, preferably 0.03 to 1mg/kg, per day for 1 to several times per adult. In the case of parenteral administration, the dose is 0.001 to 10mg/kg, preferably 0.001 to 0.1mg/kg, for 1 to several times.

The effective amount of drug required to prevent, inhibit or terminate the progression of the condition can be readily determined by the ordinarily skilled physician, veterinarian or clinician.

(examples)

The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to these examples.

The silica gel column chromatography used in the examples was a silica gel pre-packed column prepared from Wakogel (registered trademark) C-300 manufactured by Wakogaku corporation or KP-Sil (registered trademark) silica gel manufactured by Biotage corporation. For the preparation, Kieselgel manufactured by Merck was used^TM 60F₂₅₄Art.5744. The basic silica gel column chromatography used was chromatex (registered trademark) NH (100-250 mesh or 200-350 mesh) manufactured by Fuji Silysia chemical company.

The mass spectrum was measured by electrospray ionization (ESI) or Atmospheric Pressure Chemical Ionization (APCI) using mircomass ZQ manufactured by Waters corporation.

NMR spectra were measured using dimethylsulfoxide as an internal standard when measured as a deuterated dimethylsulfoxide solution, using a Gemini-200(200 MHz; Varian), Gemini-300(300 MHz; Varian), Mercury400(400 MHz; Varian) or Inova400(400 MHz; Varian) type chromatograph, and all delta values were expressed in ppm.

The meanings of the abbreviations in the following embodiments are explained below.

i-Bu: isobutyl radical

n-Bu: n-butyl

t-Bu: tert-butyl radical

Me: methyl radical

Et: ethyl radical

Ph: phenyl radical

i-Pr: isopropyl group

n-Pr: n-propyl radical

CDCl₃: deuterated chloroform

CD₃OD: deuterated methanol

DMSO-d 6: deuterated dimethyl sulfoxide

The meaning of the abbreviations in the NMR spectra is explained below.

s: single peak

d: double peak

dd: double doublet

t: triplet peak

m: multiple peaks

br: broad peak

q: quartet peak

J: constant of coupling

Hz: hertz's scale

(example 1)

5-methyl-1-phenyl-4- (quinolin-6-yl) -1H- [1, 2, 3] triazole

A solution of 20mg of 6-bromo-quinoline, 30mg of the tin preparation 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 5, and 11mg of tetrakis (triphenylphosphine) palladium in 2.0ml of dimethylformamide was stirred overnight at 115 ℃ under a nitrogen atmosphere. After water was added, the product was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate 1: 1) to give the title compound as a white solid (8.5 mg).

¹H NMR(300MHz、CDCl₃)δ：2.60(3H，s)，7.40-7.50(1H，m)，7.51-7.66(5H，m)，8.08-8.28(4H，m)，8.90-8.98(1H，m)

ESI-MS found: m/z 287.2[ M + H ] +

(example 2)

5-methyl-4- (1-oxo-indan-5-yl) -1-phenyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 21mg of 5-bromo-1-oxoindane and 30mg of 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which is a compound of reference example 5 were dissolved in 3ml of dimethylformamide, and 11mg of tetrakis (triphenylphosphine) palladium was added thereto, and the mixture was stirred overnight at 115 ℃. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer silica gel chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (2.8 mg).

¹H NMR(400MHz、CDCl₃)δ：2.53(3H，s)，2.74-2.77(2H，m)，3.21-3.24(2H，m)，7.49-4.56(5H，m)，7.76(21，d，J＝8.0Hz)，7.85(1H，J＝8.0Hz)，7.96(1H，s)

ESI-MS found: m/z 290.2[ M + H ] +

(example 3)

5-methyl-4- (2-methylbenzothiazol-5-yl) -1-phenyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 21mg of 5-bromo-2-methylbenzothiazole and 30mg of 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole, which is a compound of reference example 5, were dissolved in 3ml of toluene, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was stirred overnight at 98 ℃. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (2.8 mg).

¹H NMR(400MHz、CDCl₃)δ：2.54(3H，s)，2.87(3H，s)，7.51-4.57(5H，m)，7.92-7.93(2H，m)，8.21(1H，s)

ESI-MS found: m/z 307.2[ M + H ] +

(example 4)

4- (1H-indol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 5-bromo-1H-indole and 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as the tin reagent obtained in reference example 5.

¹H NMR(300MHz、CDCl₃)δ：1.56(3H，s)，6.60-6.68(1H，m)，7.48-7.62(7H，m)，7.62-7.71(1H，m)，7.99(1H，s)，8.20-8.30(1H，brs)

ESI-MS found: m/z 275.1[ M + H ] +

(example 5)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (quinolin-6-yl) -1-phenyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 42mg of 6-bromoquinoline and 30mg of the compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole of reference example 1 were dissolved in 3ml of dimethylformamide, 11mg of tetrakis (triphenylphosphine) palladium was added, and stirring was carried out overnight at 115 ℃ under reflux. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol: 50: 1) to give the title compound as a white solid (2.4 mg).

¹H NMR(400MHz、CDCl₃)δ：2.56(3H，d，J＝2.4Hz)，7.24-7.50(2H，m)，8.06-8.11(1H，m)，8.15-8.16(1H，m)，8.18-8.23(3H，m)，8.44-8.4.5(1H，m)，8.93-8.94(1H，m)

ESI-MS found: m/z 306.2[ M + H ] +

(example 6)

5-methyl-4- (naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 2-bromo-naphthalene and 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as the tin reagent obtained in reference example 5.

¹H NMR(300MHz、CDCl₃)δ：2.59(3H，s)，7.48-7.65(7H，m)，7.82-8.02(4H，m)，8.21(1H，s)

ESI-MS found: m/z 286.2[ M + H ] +

(example 7)

4- (3-cyclohexyl-5-fluoro-6-methyl-4-oxo-4H-chromen-7-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole

1) Preparation of 1- (3-bromo-2-fluoro-4, 6-dimethoxyphenyl) -2-cyclohexylethane-1-one

In a nitrogen atmosphere, a solution of 2-bromo-3, 5-dimethoxy-1-fluorobenzene in 6ml of 2.3g of dichloroethane and a solution of cyclohexylacetyl chloride in 6ml of 2.3g of dichloroethane were added dropwise in this order at-10 ℃ to 15ml of dichloroethane containing 1.8g of aluminum trichloride and 180mg of zinc dichloride, and then the mixture was stirred at room temperature for 2 hours. After a 20% aqueous hydrochloric acid solution was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 5: 1) to give the title compound (780 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.90-1.78(10H，m)，1.85-1.97(1H，m)，2.66(2H，dd，J＝1.0，2.6Hz)，3.85(3H，s)，3.93(3H，s)，6.27(1H，d，J＝2.0Hz)

ESI-MS found: m/z 359.2[ M + H ] +

2) Preparation of 2-cyclohexyl-1- (2-fluoro-3-methyl) -4, 6-dimethoxyphenyl) ethan-1-one

To a solution of 600mg of the compound obtained in the above 1) in 15ml of dioxane was added 400mg of methyl borate, 770mg of tetrakis (triphenylphosphine) palladium and 2.3g of potassium carbonate in this order at room temperature under a nitrogen atmosphere, followed by stirring at 95 ℃ for 26 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 20: 1) to give the title compound (370 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.90-1.78(10H，m)，1.83-1.97(1H，m)，2.03(3H，d，J＝2.4Hz)，2.67(2H，d，J＝7.2Hz)，3.81(3H，s)，3.85(3H，s)，6.20(1H，d，J＝2.0Hz)

ESI-MS found: m/z 295.3[ M + H ] +

3) Preparation of 2-cyclohexyl-1- (6-fluoro-2, 4-dihydroxy-5-methylphenyl) ethan-1-one

500mg of aluminum trichloride was added to 10ml of a toluene solution of 370mg of the compound obtained in the above 2) under a nitrogen atmosphere, and then stirred at 95 ℃ for 2 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 30: 1) to give the title compound (230 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.98-1.90(10H，m)，1.93-1.98(1H，m)，2.08(3H，d，J＝2.4Hz)，2.82(1H，dd，J＝4.4，6.8Hz)，5.80(1H，brs)，6.17(1H，d，J＝2.0Hz)

ESI-MS found: m/z 267.3[ M + H ] +

4) Preparation of 3-cyclohexyl-5-fluoro-7-hydroxy-6-methyl-4H-chromen-4-one

1.4ml of dimethylformamide was added dropwise to 0.37ml of a boron trifluoride etherate solution (230 mg) of the compound obtained in the above 3) at 0 ℃ under a nitrogen atmosphere, and then stirred at 0 ℃ for 15 minutes. A mixed solution of 283mg of phosphorus pentachloride and 7ml of dimethylformamide was added dropwise to the reaction mixture, followed by stirring at room temperature for 12 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to give the title compound (110 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.15-1.95(10H，m)，2.19(3H，d，J＝2.4Hz)，2.73-2.83(1H，m)，5.70(1H，s)，6.59(1H，d，J＝2.0Hz)，7.47(1H，s)

ESI-MS found: m/z 277.3[ M + H ] +

5) Preparation of 3-cyclohexyl-5-fluoro-7- (trifluoromethyl) sulfonyloxy-6-methyl-4H-chromen-4-one

0.1ml of trifluoromethanesulfonic anhydride was added dropwise to 1ml of a pyridine solution containing 20mg of the compound obtained in the above item 4) at room temperature under a nitrogen atmosphere, and then the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (7 mg).

ESI-MS found: m/z 409.1[ M + H ] +

6) Preparation of 4- (3-cyclohexyl-5-fluoro-6-methyl-4-oxo-4H-chromen-7-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 5) and the alkyltin compound 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole similar to referential example 5, a coupling reaction was carried out in the same manner as in example 1 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.18-1.32(3H，m)，1.39-1.53(2H，m)，1.70-1.98(5H，m)，2.32(3H，d，J＝3.2Hz)，2.34(3H，J＝3.2Hz)，2.79-2.89(1H，m)，7.50-7.61(6H，m)

ESI-MS found: m/z 418.2[ M + H ] +

(example 8)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-quinolin-6-yl) -1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 6-fluoro-2-methyl-quinoline and the tin preparation 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1.

¹H NMR(300MHz、CDCl₃)δ：2.55(3H，d，J＝2.0Hz)，2.79(3H，s)，7.34(1h，d，J＝7.6Hz)，7.48-7.52(1H，m)，8.05-8.22(5H，m)，8.41-8.50(1H，m)

ESI-MS found: m/z 320.2[ M + H ] +

(example 9)

1- (2-fluoropyridin-3-yl) -5-methyl-4-quinoxalin-6-yl) -1H- [1, 2, 3] triazole

A reaction was carried out in the same manner as in example 5 except for using 6-bromoquinoline instead of 6-bromoquinoline used in example 5 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.60(3H，d，J＝2.0Hz)，7.48-7.51(1H，m)，8.07-8.11(1H，m)，8.21-8.24(1H，m)，8.37-8.46(3H，m)，8.85-8.88(2H，m)

ESI-MS found: m/z 307.2[ M + H ] +

(example 10)

4- (1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 2 except for using 4-bromophthalic acid amide instead of 5-bromo-1-oxoindane used in example 2, thereby obtaining the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.56(3H，s)，7.49-7.51(2H，m)，7.57-7.59(3H，m)，7.95-7.97(1H，m)，8.20-8.21(1H，m)，8.28-8.30(1H，m)

ESI-MS found: m/z 305.1[ M + H ] +

(example 11)

4- (1, 3-dioxo-2, 3-dihydro-2-methyl-1H-isoindol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 10mg of 4- (1, 3-dioxo-2, 3-dihydro-1H-isoindol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole obtained in the above example 10 was dissolved in 2ml of dimethylformamide, and sodium hydride and methyl iodide were added thereto and stirred at room temperature for 30 minutes. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer silica gel chromatography (ethyl acetate: hexane: 1: 2) to give the title compound (10 mg).

¹H NMR(400MHz、CDCl₃)δ：2.56(3H，s)，3.21(3H，s)，7.48-7.51(2H，m)，7.55-7.59(3H，m)，7.94(1H，d，J＝8.0Hz)，8.19(1H，m)，8.22-8.24(1H，m)

ESI-MS found: m/z 319.2[ M + H ] +

(example 12)

4- (2, 2-dimethyl-1-oxoindan-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 35mg of 5-bromo-2, 2-dimethyl-1-oxoindane and 30mg of 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole, which is the compound of reference example 5, were dissolved in 3ml of toluene, and 11mg of tetrakis (triphenylphosphine) palladium was added thereto, and the mixture was stirred overnight at 95 ℃. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate: hexane: 1: 2) to give the title compound (5.87 mg).

¹H NMR(400MHz、CDCl₃)δ：1.27(6H，s)，2.53(3H，s)，3.07(2H，s)，7.49-7.60(5H，m)，7.74-7.76(1H，m)，7.83-7.85(1H，m)，7.91(1H，s)

ESI-MS found: m/z 318.2[ M + H ] +

(example 13)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-imidazo [1, 2-a ] pyridin-6-yl) -1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 6-fluoro-2-methyl-imidazo [1, 2-a ] pyridine and tin preparation 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1.

¹H NMR(300MHz、CDCl₃)δ：2.48(3H，d，J＝2.0Hz)，2.50(3H，s)，7.44(1H，s)，7.47-7.53(2H，m)，7.63(1H，d，＝7.0Hz)，8.02-8.12(1H，m)，8.43-8.50(1H，m)，8.54(1H，s)

ESI-MS found: m/z 309.2[ M + H ] +

(example 14)

5-methyl-4- (4-oxo-4H-chromen-6-yl) -1-phenyl-1H- [1, 2, 3] triazole

The coupling reaction was carried out in the same manner as in example 1 using 6-bromochromone and the same alkyltin compound 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 5 to give the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.57(3H，s)，6.37(1H，d，J＝6.4Hz)，7.47-7.59(6H，m)，7.88(1H，d，J＝6.0Hz)，8.32-8.42(2H，m)

ESI-MS found: m/z 304.2[ M + H ] +

(example 15)

1- (2-Fluoropyridin-3-yl) -5-methyl-4- ([1, 2, 4] triazolo [4, 3-a ] pyridin-7-yl) -1H- [1, 2, 3] triazole

1) Preparation of 7-iodo- [1, 2, 4] triazolo [4, 3-a ] pyridines

1g of 2-fluoro-4-iodo-pyridine and 5mL of hydrazine 1 hydrate were dissolved in 6mL of acetonitrile, and the mixture was stirred at 80 ℃ for 2 hours, followed by evaporation of the solvent under reduced pressure. To the residue were added 5mL of dimethylformamide and 3mL of ethyl orthoformate, and the mixture was stirred at 150 ℃ for 2 hours, cooled to room temperature, and then added water to terminate the reaction. The product was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound as a white solid (680 mg).

¹H NMR(400MHz，DMSO)δ：7.18-7.22(1H，m)，8.29-8.38(2H，m)，9.21(1H，s)

ESI-MS found: m/z 245.9[ M + H ] +

2)1- (2-Fluoropyridin-3-yl) -5-methyl-4- ([1, 2, 4] triazolo [4, 3-a ] pyridin-7-yl) -1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using the halide obtained above and the tin reagent 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 5.

¹H NMR(300MHz、CDCl₃)δ：2.58(3H，s)，7.48-7.55(1H，m)，7.70(1H，d，J＝7.4Hz)，8.00(1H，s)，8.02-8.12(1H，m)，8.24(1H，d，J＝7.4Hz)，8.42-8.51(1H，m)，8.87(1H，s)

ESI-MS found: m/z 296.1[ M + H ] +

(example 16)

4- (3, 4-dihydro-2H-1-oxa-9-aza-anthracen-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 6-bromo-3, 4-dihydro-2H-1-oxo-9-aza-anthracene and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1.

¹H NMR(300MHz、CDCl₃)δ：2.05-2.18(2H，m)，2.52(3H，d，J＝2.0Hz)，3.06(2H，t，J＝6.4Hz)，4.50(2H，t，J＝5.3Hz)，7.45-7.52(1H，m)，7.89-8.15(5H，m)，8.41-8.50(1H，m)

ESI-MS found: m/z 362.1[ M + H ] +

(example 17)

1, (2-fluoropyridin-3-yl) -5-methyl-4- ([1, 2, 4] triazolo [4, 3-a ] pyridin-6-yl) -1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 6-bromo- [1, 2, 4] triazolo [4, 3-a ] pyridine and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1.

¹H NMR(300MHz、CDCl₃)δ：2.52(3H，d，J＝1.6Hz)，7.49-7.58(1H，m)，7.74(1H，d，J＝9.6Hz)，7.93(1H，d，J＝9.6Hz)，8.02-8.12(1H，m)，8.43-9.51(1H，m)，8.43-9.51(1H，m)，8.60(1H，s)，8.92(1H，s)

ESI-MS found: m/z 296.1[ M + H ] +

(example 18)

1- (2-fluoropyridin-3-yl) -4-isoquinolin-7-yl-5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 5 except for using isoquinolin-7-yl trifluorosulfonate instead of 6-bromoquinoline used in example 5 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.57(3H，d，J＝2.0Hz)，7.47-7.51(1H，m)，7.69(1H，d，J＝6.0Hz)，7.95(1H，d，J＝8.4Hz)，8.06-8.11(1H，m)，8.20-8.23(1H，m)，8.30(1H，s)，8.44-8.46(1H，m)，8.55(1H，d，J＝6.0Hz)，9.32(1H，s)

ESI-MS found: m/z 306.2[ M + H ] +

(example 19)

1- (2-fluoropyridin-3-yl) -4-isoquinolin-3-yl-5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 5 except for using isoquinolin-3-yl trifluorosulfonate instead of 6-bromoquinoline used in example 5 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.76-2.77(3H，m)，7.45-7.48(1H，m)，7.57-7.61(1H，m)，7.68-7.72(1H，m)，7.92(1H，d，J＝8.0Hz)，7.97(1H，d，J＝8.0Hz)，8.02-8.06(1H，m)，8.42-8.44(1H，m)，8.58(1H，s)，8.27(1H，m)

ESI-MS found: m/z 306.2[ M + H ] +

(example 20)

1- (2-fluoropyridin-3-yl) -4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 35mg of 5-bromo-2, 2-dimethyl-1-oxoindane and 30mg of the compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole of reference example 1 were dissolved in 3ml of toluene, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was stirred overnight at 115 ℃ under reflux. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate: hexane: 1: 2) to give the title compound 21.8mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.28(6H，s)，2.51(3H，m)，3.08(2H，s)，7.47-7.50(1H，m)，7.77(1H，d，J＝7.6Hz)，7.85(1H，d，J＝8.0Hz)，7.89(1H，s)，8.04-8.09(1H，m)，8.43-8.45(1H，m)

ESI-MS found: m/z 337.2[ M + H ] +

(example 21)

1- (2-fluoropyridin-5-yl) -5-methyl-4- (2-methyl-quinolin-6-yl) -1H- [1, 2, 3] triazole

The coupling reaction was carried out in the same manner as in example 1 using 2-methyl-6-bromoquinoline and the same alkyltin compound 1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 3 to give the title compound as a white solid.

¹H NMR(300MHz、CDCl₃)δ：2.60(3H，s)，2.78(4H，s)，7.20(1H，dd，J＝3.6，8.8Hz)，7.33(1H，d，J＝8.4Hz)，8.01-8.09(1H，m)，8.09-8.14(3H，m)，8.17(1H，d，J＝1.6Hz)，8.45(1H，dd，J＝0.8，2.0Hz)

ESI-MS found: m/z 320.2[ M + H ] +

(example 22)

1- (6-chloro- [1, 5] naphthyridin-2-yl) -4- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 2-chloro-6-chloro- [1, 5] naphthyridine and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1.

¹H NMR(300MHz、CDCl₃)δ：2.80-2.89(3H，m)，7.47-7.57(1H，m)，7.68-7.77(1H，m)，8.02-8.13(1H，m)，8.41(1H，td，J＝1.7，8.5Hz)，8.47-8.51(1H，m)，8.80-8.87(1H，m)，9.02-9.11(1H，m)

ESI-MS found: m/z 341.0[ M + H ] +

(example 23)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (5, 6, 7, 8-tetrahydro- [1, 5] naphthyridin-2-yl) -1H- [1, 2, 3] triazole

7.0mg of the compound obtained in example 22 was dissolved in 1.5mL of ethanol and 1.5mL of ethyl acetate, and then 3.0mg of palladium hydroxide was added thereto, followed by stirring under a hydrogen atmosphere at room temperature for 30 minutes. After the catalyst was filtered off, the solvent was distilled off, and the residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate 50: 50) to give the title compound (2.6 mg).

¹H NMR(300MHz、CDCl₃)δ：2.00-2.12(2H，m)，2.60-2.67(3H，m)，2.97(2H，t，J＝6.6H z)，3.36(2H，t，J＝5.5Hz)，3.92(1H，brs)，6.8106.88(1H，m)，7.40-7.49(1H，m)，7.78(1H，d，J＝8.2Hz)，7.83-8.03(1H，m)，8.42(1H，d，J＝4.9Hz)

ESI-MS found: m/z 311.1[ M + H ] +

(example 24)

4- (5-acetyl-5, 6, 7, 8-tetrahydro- [1, 5] naphthyridin-2-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

After 2.0mg of the compound of example 23 was dissolved in 400. mu.l of pyridine, 40. mu.l of acetic anhydride was added and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate 50: 50, 3 drops of aqueous ammonia) to give the title compound (2.0 mg).

¹H NMR(300MHz、CDCl₃)δ：2.02-2.17(2H，m)，2.31(3H，s)，2.65-2.70(3H，m)，3.01(2H，t，J＝6.6Hz)，3.84(2H，t，J＝6.3Hz)，7.22-7.38(1H，m)，7.43-7.50(1H，m)，7.99-8.09(2H，m)，8.40-8.48(1H，m)

ESI-MS found: m/z 353.1[ M + H ] +

(example 25)

4- (2-chloroquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -1-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 6-bromo-2-chloroquinoline and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1.

¹H NMR(300MHz、CDCl₃)δ：2.56(3H，d，J＝1.1Hz)，7.45(1H，d，J＝8.6Hz)，7.47-7.54(1H，m)，8.03-8.44(4H，m)，8.26(1H，d，J＝0.3Hz)，8.42-8.50(1H，m)

ESI-MS found value M/z 340.0[ M + H ] +

(example 26)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-1-oxoindan-5-yl) -1H- [1, 2, 3] triazole

A reaction was carried out in the same manner as in example 20 except for using 5-bromo-2-methyl-1-oxoindane instead of 5-bromo-2, 2-dimethyl-1-oxoindane used in example 20 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.36(3H，d，J＝7.2Hz)，2.51(3H，d，J＝2.4Hz)，2.76-2.84(2H，m)，3.45-3.52(1H，m)，7.49-7.52(1H，m)，7.77-7.80(1H，m)，7.87(1H，d，J＝8.4Hz)，7.94(1H，s)，8.07-8.11(1H，m)，8.46-8.48(1H，m)

ESI-MS found: m/z 323.2[ M + H ] +

(example 27)

1- (2-Fluoropyridin-3-yl) -5-methyl-4- ((2R)^*) -methyl-1-oxoindan-5-yl) -1H- [1, 2, 3]Triazole and 1- (2-fluoropyridin-3-yl) -5-methyl-4- ((2S)^*) -methyl-1-oxoindan-5-yl) -1H- [1, 2, 3]Triazole compounds

1- (2-Fluoropyridin-3-yl) -5-methyl-4- (2-methyl-1-oxoindan-5-yl) -1H- [1, 2, 3 obtained in example 26 above was optically resolved using an optically active column (CHIRALPAK AD-H column manufactured by ダイセル, Hexane: EtOH 2: 3)]Triazole 10mg, and for convenience, 4.35mg of the obtained precut compound was referred to as (2R of the title compound)^*) As a result, 4.59mg of the obtained compound as a post-fraction was referred to as (2S) of the title compound^*) Body, both white solids.

1- (2-Fluoropyridin-3-yl) -5-methyl-4- ((2R)^*) -methyl-1-oxoindan-5-yl) -1H- [1, 2, 3]Triazole compounds

ESI-MS found: m/z 323.2[ M + H ] +

1- (2-Fluoropyridin-3-yl) -5-methyl-4- ((2S)^*) -methyl-1-oxoindan-5-yl) -1H- [1, 2, 3]Triazole compounds

ESI-MS found: m/z 323.2[ M + H ] +

(example 28)

1- (2-fluoropyridin-5-yl) -4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

The coupling reaction was carried out in the same manner as in example 1 using 5-bromo-2, 2-dimethylindan-1-one and the same alkyltin compound 1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 3 to give the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.28(6H，s)，2.58(3H，s)，3.09(2H，s)，7.22(1H，dd，J＝3.6，8.4Hz)，7.76(1H，d，J＝8.0Hz)，7.88(1H，d，J＝8.0Hz)，7.91(1H，s)，8.01-8.07(1H，m)，8.45(1H，d，J＝2.0Hz)

ESI-MS found: m/z 337.2[ M + H ] +

(example 29)

1- (2-fluoropyridin-3-yl) -4- (4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 7- ((2-trifluoromethyl) sulfonyloxy) -4H-chromen-4-one

0.24ml of trifluoromethanesulfonic anhydride was added dropwise to a solution of 180mg of 7-hydroxy-4H-chromen-4-one in 4ml of pyridine at 0 ℃ under a nitrogen atmosphere, and then the mixture was stirred at room temperature for 5 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol: 10: 1) to give the title compound (83 mg) as a white solid.

ESI-MS found: m/z 295.0[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 1 and the alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which was the same as in reference example 1, a coupling reaction was carried out in the same manner as in example 1 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.55(3H，d，J＝2.0Hz)，6.39(1H，d，J＝6.4Hz)，7.47-7.57(1H，m)，7.86(1H，dd，J＝1.4，8.0Hz)，7.90(1H，d，J＝5.6Hz)，7.96(1H，d，J＝1.6Hz)，8.05-8.15(1H，m)，8.32(1H，d，J＝8.4Hz)，8.44-8.52(1H，m)

ESI-MS found: m/z 323.1[ M + H ] +

(example 30)

1- (2-fluoropyridin-3-yl) -4- (2-methoxyquinolin-6-yl) -5-methyl- [1, 2, 3] triazole

A coupling reaction was carried out in the same manner as in example 20 using 2-methoxy-6-bromoquinoline and the same alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 1 to give the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.53(3H，s)，4.11(3H，d，J＝1.2Hz)，6.96(1H，dd，J＝0.8，8.8Hz)，7.45-7.55(1H，m)，8.05(1H，d，J＝4.4Hz)，8.05-8.13(3H，m)，8.14(1H，s)，8.46(1H，dd，J＝0.8，3.6Hz)

ESI-MS found: m/z 336.2[ M + H ] +

(example 31)

4- (2-tert-butyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-tert-butyl-imidazo [1, 2-a ] pyridine

178ml of 1-bromopinacolone was dissolved in 2.0ml of ethanol, and 156mg of 2-amino-5-bromopyridine was added thereto, followed by stirring under reflux with heating overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were successively added. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate 75: 25) to give the title compound as a white solid (186 mg).

1H NMR(300MHz，CDCl3)δ：1.39(9H，s)，7.16(1H，dd，J＝1.8，9.5Hz)，7.31(1H，s)，7.47(1H，d，J＝9.5Hz)，8.19(1H，d，J＝1.8Hz)

ESI-MS found: m/z 253.2[ M + H ] +

2) Preparation of 4- (2-tert-butyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using the halide obtained above and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in the reference example.

¹H NMR(300MHz、CDCl₃)δ：1.43(9H，s)，2.47(3H，d，J＝1.7Hz)，7.44(1H，s)，7.45-7.53(2H，m)，7.68(1H，d，J＝9.6Hz)，8.02-8.13(1H，m)，8.42-8.49(1H，m)，8.54(1H，s)

ESI-MS found: m/z 351.2[ M + H ] +

(example 32)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxo-indan-2-spiro-1' -cyclobutane-5-yl) -1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-1-oxoindane-2-spiro-1' -cyclobutane

100ml of 5-bromo-1-oxoindane was dissolved in 10ml of toluene, 0.3mg of 1, 4-dibromobutane and 132mg of potassium tert-butoxide were added, and the mixture was stirred at 130 ℃ under reflux overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 2) to give the title compound 71mg as a yellow oil.

2) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxoindan-2-spiro-1' -cyclobutane-5-yl) -1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 20 except for using 5-bromo-1-oxoindan-2-spiro-1' -cyclobutane obtained in the above-mentioned 1) instead of using 5-bromo-2, 2-dimethyl-1-oxoindan used in example 20, to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.63-1.68(2H，m)，1.80-1.83(2H，m)，1.94-1.97(2H，m)，2.02-2.07(2H，m)，2.51(3H，d，J＝1.6Hz)，3.12(2H，s)，7.49-7.52(1H，m)，7.78(1H，d，J＝8.4Hz)，7.87(1H，d，J＝8.4Hz)，7.91(1H，m)，8.08-8.11(1H，m)，8.46-8.47(1H，m)

ESI-MS found: m/z 363.2[ M + H ] +

(example 33)

4- (2-dimethylamino-quinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl- [1, 2, 3] triazole

Using 2-dimethylamino-6-bromoquinoline and the same alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 1, a coupling reaction was carried out in the same manner as in example 20 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.51(3H，d，J＝2.0Hz)，3.27(6H，s)，6.95(1H，d，9.2Hz)，7.45-7.55(1H，m)，7.81(1H，d，J＝8.4Hz)，7.95(2H，t，J＝9.0Hz)，8.01(1H，brs)，8.09(1H，t，J＝7.4Hz)，8.44(1H，d，5.2Hz)

ESI-MS found: m/z 349.2[ M + H ] +

(example 34)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxoindan-2-spiro-1' -cyclopropyl-5-yl) -1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-1-oxo-2-spiro-1' -cyclopropylindane

To 15ml of a dimethylformamide solution (1.0 g) of 5-bromo-1-indanone was added 500mg of 60% sodium hydride under ice cooling. After the reaction mixture was stirred for 10 minutes, 1.2ml of dibromoethane was added thereto, and the mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 95: 5) to give the title compound as a white solid (700 mg).

¹H NMR(300MHz、CDCl₃)δ：1.14-1.22(2H，m)，1.42-1.50(2H，m)，3.20(2H，s)，7.51-7.56(1H，m)，7.63-7.70(2H，m)

2) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxoindan-2-spiro-1' -cyclopropyl-5-yl) -1H- [1, 2, 3] triazole

Using the compound obtained in the above 1) and the compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole of reference example 1, the title compound was obtained according to the method of example 1.

¹H NMR(300MHz、CDCl₃)δ：1.19-1.22(2H，m)，1.48-1.52(2H，m)，2.53(3H，s)，3.31(2H，s)，7.498-7.53(1H，m)，7.81(1H，d，J＝8.1Hz)，7.90(1H，d，J＝8.1Hz)，8.00(1H，s)，8.06-8.12(1H，m)，8.40-8.50(1H，m)

ESI-MS found: m/z 335.2[ M + H ] +

(example 35)

4- (2-chloro-3-ethyl-quinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

A coupling reaction was carried out in the same manner as in example 20 using 2-chloro-3-ethyl-6-bromoquinoline and the same alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 1 to give the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.40(3H，t，J＝7.4Hz)，2.56(3H，d，J＝1.6Hz)，2.95(2H，q，J＝7.6，14.8Hz)，7.48-7.54(1H，m)，8.05(1H，s)，8.09-8.16(3H，m)，8.21(1H，s)，8.47(1H，dd，J＝1.2，4.8Hz)

ESI-MS found: m/z 368.1[ M + H ] +

(example 36)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-isopropyl-1-oxo-isoindoline

In a nitrogen atmosphere, 500mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in 10ml of methanol, 0.42ml of isopropylamine and 0.67ml of triethylamine were added, and the mixture was stirred overnight under reflux with heating at 100 ℃. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound 222mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.39(6H，d，J＝6.8Hz)，4.31(2H，s)，4.62-4.69(1H，m)，7.59(1H，d，J＝8.0Hz)，7.61(1H，s)，7.70(1H，d，J＝8.0Hz)

ESI-MS found: m/z 254.1[ M + H ] +

2) Preparation of 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

280mg of 5-bromo-2-isopropyl-1-oxo-isoindoline obtained in 1) above and 171mg of 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole, a compound of reference example 1, were dissolved in 10ml of toluene in a nitrogen atmosphere, 42mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was stirred at 115 ℃ under reflux for 12 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 3: 1) to give the title compound (179 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝7.2Hz)，2.50(3H，d，J＝2.0Hz)，4.43(2H，s)，4.68-4.75(1H，m)，7.49-7.52(1H，m)，7.81(1H，d，J＝8.0Hz)，7.96(1H，d，J＝8.0Hz)，7.99(1H，s)，8.06-8.11(1H，m)，8.46-8.47(1H，m)

ESI-MS found: m/z 352.2[ M + H ] +

(example 37)

1- (2-fluoropyridin-3-yl) -4- (2-methoxy-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-methoxy-1-indanone

To a solution of 100mg of 5-bromo-1-indanone in 15ml of acetonitrile was added 232mg of [ hydroxy (p-nitrobenzenesulfonyloxy) iodo ] benzene at room temperature, and the mixture was refluxed for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved in 20ml of methanol and refluxed overnight. The reaction mixture was returned to room temperature, the solvent was removed by evaporation under reduced pressure, and the obtained residue was dissolved in chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 95: 5) to give the title compound (59 mg) as a white solid.

¹H NMR(300MHz、CDCl₃)δ：3.00(1H，dd，J＝4.8，17.1Hz)，3.44(1H，dd，J＝7.5Hz)，4.16(1H，dd，J＝4.8，7.5Hz)，7.52-7.66(3H，m)

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-methoxy-1-oxo-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(300MHz、CDCl₃)δ：2.52(3H，d，J＝2.1Hz)，3.10(1H，dd，J＝3.9，16.8Hz)，3.60(1H，dd，J＝7.8，16.8Hz)，3.68(3H，s)，4.26(1H，dd，J＝3.9，7.8Hz)，7.48-7.59(1H，m)，7.82(1H，d，J＝8.1Hz)，7.89(1H，d，J＝8.1Hz)，7.94(1H，s)，8.06-8.12(1H，m)，8.45-8.50(1H，m)

ESI-MS found: m/z 339.1[ M + H ] +

(example 38)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-morpholin-4-yl-quinolin-6-yl) -1H- [1, 2, 3] triazole

1) Preparation of 2-morpholine-6-bromoquinoline

0.28ml of morpholine and 490mg of potassium carbonate were sequentially added to a solution of 78mg of 2-chloro-6-bromoquinoline in 2ml of dimethylformamide at room temperature, followed by stirring at 115 ℃ for 7 hours. After water was added to the reaction mixture, the mixture was extracted with diethyl ether, and the diethyl ether layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to give the title compound (63 mg) as a white solid.

ESI-MS found: m/z 293.1[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-morpholin-4-yl-quinolin-6-yl) -1H- [1, 2, 3] triazole

Using the compound obtained in the above 1) and the same alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 1, a coupling reaction was carried out in the same manner as in example 20 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.52(3H，d，J＝2.0Hz)，3.76(4H，t，J＝4.8Hz)，3.88(4H，t，J＝4.8，9.6Hz)，7.02(1H，d，J＝9.6Hz)，7.49(1H，t，J＝4.8Hz)，7.82(1H，d，J＝9.2Hz)，8.00(2H，dd，J＝2.2，9.0Hz)，8.04(1H，d，J＝2.0Hz)，8.10(1H，t)，8.44(1H，d，J＝4.4Hz)

ESI-MS found: m/z 391.2[ M + H ] +

(example 39)

4- (3-methyl-4-oxo-4H-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 7- ((trifluoromethyl) sulfonyloxy) -3-methyl-4H-chromen-4-one

After 0.23ml of trifluoromethanesulfonic anhydride was added to 3ml of a solution of 120mg of 7-hydroxy-3-methyl-4H-chromen-4-one in pyridine at 0 ℃, the mixture was stirred at room temperature for 2 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 10: 1) to give the title compound (183 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)5：2.05(3H，d，J＝0.8Hz)，7.30(1H，dd，J＝2.0，8.4Hz)，7.40(1H，d，J＝2.0Hz)，7.83(1H，d，J＝1.2Hz)，8.83(1H，d，J＝9.2Hz)

ESI-MS found: m/z 309.1[ M + H ] +

2) Preparation of 4- (3-methyl-4-oxo-4H-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：2.08(3H，d，J＝1.2Hz)，2.54(3H，d，J＝2.0Hz)，7.51(1H，t，J＝4.8Hz)，7.84(2H，dd，J＝1.2，8.4Hz)，7.92(1H，s)，8.09(1H，t，J＝8.2Hz)，8.35(1H，d，J＝8.4Hz)，8.48(1H，d，J＝4.8Hz)

ESI-MS found: m/z 359.1[ M + H ] +

(example 40)

1- (2-fluoropyridin-3-yl) -4- (2- (4-methylpiperazin-1-yl) -quinolin-6-yl) -5-methyl- [1, 2, 3] triazole

1) Preparation of 2- (4-methylpiperazine) -6-bromoquinoline

After adding 130mg of 1-methylpiperazine to 3ml of a dioxane solution of 63mg of 2-chloro-6-bromoquinoline at room temperature, the mixture was stirred at 115 ℃ for 11 hours. After water was added to the reaction mixture, the mixture was extracted with diethyl ether, and the diethyl ether layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to give the title compound (45 mg) as a white solid.

ESI-MS found: m/z 306.1[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2- (4-methylpiperazin-1-yl) -quinolin-6-yl) -5-methyl- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：2.38(3H，s)，2.52(3H，d，J＝1.6Hz)，2.58(4H，t，J＝5.2Hz)，3.82(4H，t，J＝4.8Hz)，7.04(1H，d，J＝8.8Hz)，7.49(1H，dd，J＝4.8，7.6Hz)，7.81(1H，d，J＝8.4Hz)，7.94-8.00(2H，m)，8.02(1H，d，J＝1.6Hz)，8.09(1H，t，J＝8.2，Hz)，8.45(1H，d，J＝4.8Hz)

ESI-MS found: m/z 404.2[ M + H ] +

(example 41)

4- (2-isopropyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-isopropyl-imidazo [1, 2-a ] pyridine

20ml of a solution of 2.24g of 3-methyl-2-butanone in anhydrous methanol was cooled to-15 ℃ and 866. mu.l of bromine was added dropwise. After stirring at-15 ℃ for 5 minutes and at room temperature for 1 hour, 20ml of water was added and further stirring was carried out for 2 hours. After addition of 2.6g of potassium carbonate, the product was extracted with diethyl ether, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 80ml of ethanol, and 2.94g of 2-amino-5-bromopyridine was added thereto, followed by stirring under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and aqueous sodium hydrogencarbonate solution were added successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain 1.46g of the title compound as a white solid.

1H NMR(300MHz，CDCl3)δ：1.35(6H，d，J＝6.9Hz)，3.09(1H，sept，J＝6.9Hz)，7.16(1H，dd，J＝1.9，9.6Hz)，7.30(1H，s)，7.44(1H，d，J＝9.6Hz)，8.19(1H，d，J＝1.9Hz)

ESI-MS found: m/z 239.1[ M + H ] +

2) Preparation of 4- (2-isopropyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The procedure of example 1 was repeated using the halide obtained in the above-mentioned 1) and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in the reference example to obtain the title compound as a white solid.

¹H NMR(300MHz、CDCl₃)δ：1.40(6H，d，J＝6.8Hz)，2.47(3H，d，J＝2.2Hz)，3.15(1H，sept，J＝6.8Hz)，7.43(1H，t，＝0.7Hz)，7.48-7.52(2H，m)，7.66(1H，dt，J＝9.3，0.7Hz)，8.06-8.11(1H，m)，8.45-8.47(1H，m)，8.54(1H，dd，J＝1.0，1.7Hz)

ESI-MS found: m/z 337.1[ M + H ] +

(example 42)

1- (2-fluoropyridin-3-yl) -4- (5-oxo-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 5 except for using trifluoromethanesulfonic acid 5-oxo-5, 6, 7, 8-tetrahydro-naphthalen-2-yl ester instead of 6-bromoquinoline used in example 5 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.16-2.23(2H，m)，2.50(3H，d，J＝2.0Hz)，2.69-2.72(2H，m)，3.05-3.08(2H，m)，7.48-7.51(1H，m)，7.69(1H，d，J＝8.4Hz)，7.80(1H，m)，8.06-8.14(1H，m)，8.15(1H，d，J＝8.0Hz)，8.45-8.47(1H，m)

ESI-MS found: m/z 323.2[ M + H ] +

(example 43)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-methyl-1-oxo-isoindoline

A reaction was carried out in the same manner as in example 36-1 except for using methylamine instead of isopropylamine used in example 36-1 to obtain the title compound.

2) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 36-2 except for using 5-bromo-2-methyl-1-oxo-isoindoline obtained in the above-mentioned 1) instead of using 5-bromo-2-isopropyl-1-oxo-isoindoline used in example 36-2, to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.51(3H，d，J＝2.0Hz)，3.24(3H，s)，4.47(2H，s)，7.49-7.52(1H，m)，7.81(1H，d，J＝8.0Hz)，7.95(1H，d，J＝8.4Hz)，7.97(1H，s)，8.07-8.11(1H，m)，8.46-8.47(1H，m)

ESI-MS found: m/z 324.2[ M + H ] +

(example 44)

4- (2-ethyl-3-methyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of N- (5-iodo-1H-pyridin-1-ylidene) -toluene-4-sulfonamide

A solution of 25g of 5-iodo-2-aminopyridine and 23.9g of p-toluenesulfonyl chloride in 125ml of pyridine was stirred at 100 ℃. After cooling to room temperature, 250ml of water was added thereto, and the mixture was stirred at room temperature for 3 hours. The precipitate was collected by filtration and dried under reduced pressure to obtain 44.1g of the title compound.

2) Preparation of 2- [2- (toluene-4-sulfonylimino) -2H-pyridin-1-yl ] -pentan-3-one

25.6g of the compound obtained in the above 1) and 13.56g of 2-bromo-pentan-3-one were dissolved in 260ml of tetrahydrofuran, and after cooling to 0 ℃, 35.8ml of diisopropylamine was added dropwise. After stirring overnight at room temperature, the reaction was quenched by addition of saturated aqueous sodium bicarbonate and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to obtain 22.4g of the objective compound in the form of yellow amorphous.

3) Preparation of 6-iodo-2-ethyl-3-methyl-imidazo [1, 2-a ] pyridine

22.4g of the compound obtained in 2) above was dissolved in 220ml of chloroform, and after cooling to 0 degrees, 17.3ml of trifluoroacetic anhydride was added dropwise. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure. After a saturated aqueous sodium hydrogencarbonate solution was added to the obtained residue, extraction was performed with chloroform, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with diisopropyl ether to give 11.4g of the title compound as a pale yellow solid.

¹H NMR(400MHz、CDCl₃)δ：1.32(3H，t，J＝7.6Hz)，2.39(3H，s)，2.76(2H，q，J＝7.6Hz)，7.26(1H，dd，J＝1.6，9.4Hz)，7.34(1H，dd，J＝0.8，9.4Hz)，8.04(1H，dd，J＝0.8，1.6Hz)

4)4- (2-ethyl-3-methyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using the halide obtained in the above-mentioned 3) and 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in the reference example.

¹H NMR(300MHz、CDC1₃)δ：1.37(3H，t，J＝7.6Hz)，1.59(3H，s)，2.49(3H，s)，2.82(2H，q，J＝7.6Hz)，7.40-7.52(2H，m)，7.66(1H，d，J＝9.2Hz)，8.02-8.11(1H，m)，8.34(1H，s)，8.42-8.50(1H，m)

ESI-MS found: m/z 337.2[ M + H ] +

(example 45)

1- (2-fluoropyridin-3-yl) -4- (1-oxo-2-methylcarbonyloxy-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-methylcarbonyloxy-1-indanone

[ hydroxy (p-nitrobenzenesulfonyloxy) iodo ] benzene 465mg was added to an acetonitrile 30ml solution of 5-bromo-1-indanone 200mg at room temperature, followed by heating and refluxing for 4 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved in 40ml of acetic acid, 340mg of silver carbonate was added thereto at room temperature, and the mixture was refluxed for 12 hours. After the reaction mixture was returned to room temperature, the solvent was distilled off under reduced pressure, and then the reaction mixture was dissolved in chloroform. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound as a white solid (200 mg).

¹H NMR(300MHz、CDCl₃)δ：2.18(3H，s)，3.03(1H，dd，J＝4.5，17.1Hz)，3.64(1H，dd，J＝7.5，17.1Hz)，5.39(1H，dd，J＝4.5Hz)，7.5Hz)，7.55-7.69(3H，m)

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (1-oxo-2-methylcarbonyloxy-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(300MHz、CDCl₃)δ：2.21(3H，s)，2.52(3H，d，J＝2.1Hz)，3.13(1H，dd，J＝5.1，17.1Hz)，3.75(1H，dd，J＝7.8，17.1Hz)，5.49(1H，dd，J＝.5.1，7.8Hz)，7.48-7.54(1H，m)，7.85(1H，d，J＝8.1Hz)，7.92(1H，d，J＝8.1Hz)，7.96(1H，s)，8.05-8.12(1H，m)，8.45-8.49(1H，m)

ESI-MS found: m/z 367.1[ M + H ] +

(example 46)

1- (2-fluoropyridin-5-yl) -4- (2-isopropyl-imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using the halide obtained in example 41 and the tin reagent 1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 3.

¹H NMR(300MHz、CDCl₃)δ：1.40(6H，d，J＝6.9Hz)，2.53(3H，s)，3.15(1H，sept，J＝6.9Hz)，7.19-7.29(1H，m)，7.40-7.50(2H，m)，7.67(1H，d，J＝9.6Hz)，7.99-8.09(1H，m)，8.45(1H，s)，8.53(1H，s)

ESI-MS found: m/z 337.0[ M + H ] +

(example 47)

1- (2-fluoropyridin-3-yl) -4- (1-oxo-4-hydroxy-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

To 1ml of a tetrahydrofuran solution containing 6mg of 1- (2-fluoropyridin-3-yl) -4- (1-oxo-2-methylcarbonyloxy-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 45 was added 3 drops of a 2M aqueous solution of sodium hydroxide dropwise at room temperature. After stirring at room temperature for 1 hour, the mixture was diluted with chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 80: 20) to obtain 1.3g of the title compound as a white solid.

¹H NMR(300MHz、CDCl₃)δ：2.52(3H，d，J＝2.1Hz)，2.89(1H，brs)，3.10(1H，dd，J＝5.1，16.5Hz)，3.66(1H，dd，J＝7.5，16.5Hz)，4.61(1H，dd，J＝5.1，7.5Hz)，7.49-7.53(1H，m)，7.86(1H，d，J＝7.8Hz)，7.90(1H，d，J＝7.8Hz)，7.96(1H，s)，8.06-8.13(1H，m)，8.47-8.50(1H，m)

ESI-MS found: m/z 325.2[ M + H ] +

(example 48)

4- (2-cyclopropyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-chloropropyl-imidazo [1, 2-a ] pyridine

A solution of 2.24g of cyclopropylmethyl ketone in 20ml of anhydrous methanol was cooled to-15 ℃ and 866. mu.l of bromine was added dropwise. After stirring at 0 ℃ for 5 minutes and at room temperature for 1 hour, 20ml of water was added and further stirred for 2 hours. After addition of 2.6g of potassium carbonate, the product was extracted with diethyl ether, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 80ml of ethanol, and 2.94g of 2-amino-5-bromopyridine was added thereto, followed by stirring under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and aqueous sodium hydrogencarbonate solution were added successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 80: 20) to obtain 1.77g of the title compound as a white solid.

¹H NMR(300MHz，CDCl3)δ：0.82-1.08(4H，m)，1.93-2.08(1H，m)，7.16(1H，d，J＝9.6Hz)，7.33(1H，s)，7.38(1H，d，J＝9.6Hz)，8.16(1H，s)

ESI-MS found: m/z 237.1[ M + H ] +

2) Preparation of 4- (2-cyclopropyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using the halide obtained in 1) above and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example.

¹H NMR(400MHz、CDCl₃)δ：0.98-1.03(4H，m)，2.00-2.18(1H，m)，2.47(3H，d，J＝1.2Hz)，7.45-7.52(3H，m)，7.60(1H，d，J＝9.3Hz)，8.06-8.10(1H，m)，8.46(1H，td，J＝1.7，4.8Hz)，8.51(1H，dd，J＝1.0，1.7Hz)

ESI-MS found: m/z 335.2[ M + H ] +

(example 49)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-cyclopropyl-1-oxo-isoindoline

In a nitrogen atmosphere, 700mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in 20ml of toluene, 0.40ml of cyclopropylamine and 1.0ml of triethylamine were added, and the mixture was stirred overnight under reflux. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (336 mg).

¹H NMR(400MHz、CDCl₃)δ：0.68-0.93(4H，m)，2.88-2.93(1H，m)，4.29(2H，s)，7.56-7.59(2H，m)，7.68(1H，d，J＝8.0Hz)

ESI-MS found: m/z 252.1[ M + H ] +

2) Preparation of 4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 300mg of 5-bromo-2-cyclopropyl-1-oxo-isoindoline and 185mg of 1- (2-fluoropyridin-3-yl) -4-tri-n-butyltin-5-methyl-1H- [1, 2, 3] triazole were dissolved in 10ml of toluene, 45mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was stirred overnight under reflux. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 3: 1, 5: 1) to give the title compound (87.7 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.88-0.98(4H，m)，2.50(3H，d，J＝2.4Hz)，2.95-3.00(1H，m)，4.41(2H，s)，7.48-7.52(1H，m)，7.93(1H，m)，7.94-7.95(2H，m)，8.06-8.10(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 350.2[ M + H ] +

(example 50)

4- (2-isopropyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-isopropyl-1-oxoindane

In a nitrogen atmosphere, 100mg of 5-bromo-1-oxoindane was dissolved in 2ml of tetrahydrofuran, and after cooling to-78 degrees, 0.4ml of hexamethylphosphoramide, 0.3ml of a 1.57M hexane solution of n-butyllithium, and 1.0ml of isopropyl iodide were added thereto, and the mixture was stirred at-78 degrees for 2 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate: hexane: 1: 2) to give the title compound (26 mg) as a white solid.

2) Preparation of 4- (2-isopropyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 20 except for using 5-bromo-2-isopropyl-1-oxoindane instead of 5-bromo-2, 2-dimethyl-1-oxoindane used in example 20 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：0.83(3H，d，J＝6.8Hz)，1.08(3H，d，J＝7.2Hz)，2.43-2.47(1H，m)，2.51(3H，d，J＝2.0Hz)，2.70-2.76(1H，m)，2.99-3.04(1H，m)，3.20-3.26(1H，m)，7.49-7.52(1H，m)，7.77(1H，d，J＝8.0Hz)，7.86(1H，d，J＝8.0Hz)，7.97(1H，s)，8.07-8.11(1H，m)，8.46-8.47(1H，m)

ESI-MS found: m/z 351.2[ M + H ] +

(example 51)

1- (2-fluoropyridin-3-yl) -4- (2-methyl-2-methylcarbonyloxy-1-oxoindan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

To 1ml of a dimethylformamide solution of 10mg of 1- (2-fluoropyridin-3-yl) -4- (1-oxo-2-methylcarbonyloxy-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole prepared in example 45 was added dropwise 3mg of 60% sodium hydride at room temperature. After stirring at room temperature for 30 minutes, 5 drops of methyl iodide were added and stirred at room temperature for 1 hour.

The extract was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 80: 20) to obtain 3.5g of the title compound as a white solid.

¹H NMR(300MHz、CDCl₃)δ：1.52(3H，s)，2.12(3H，s)，2.51(3H，d，J＝2.1Hz)，3.24(1H，d，J＝16.8Hz)，3.59(1H，d，J＝16.8Hz)，7.47-7.55(1H，m)，7.81(1H，d，J＝8.1Hz)，7.91(1H，s)，7.93(1H，d，J＝8.1Hz)，8.06-8.12(1H，m)，8.45-8.49(1H，m)

ESI-MS found: m/z 381.1[ M + H ] +

(example 52)

1- (2-fluoropyridin-3-yl) -4- (2-hydroxy-2-methyl-1-oxoindan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

To 1ml of a 30mg solution of 1- (2-fluoropyridin-3-yl) -4- (2-methyl-2-methylcarbonyloxy-1-oxoindan-5-yl) -5-methyl-1H- [1, 2, 3] triazole in tetrahydrofuran was added dropwise 100. mu.l of a 2M aqueous solution of sodium hydroxide at room temperature. After stirring at room temperature for 1 hour, the mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 80: 20) to give the title compound as a white solid (10 mg).

¹H NMR(300MHz、CDCl₃)δ：1.49(3H，s)，2.52(3H，d，J＝1.8Hz)，2.70(1H，brs)，3.32(3H，s)，7.47-7.59(1H，m)，7.83(1H，d，J＝8.1Hz)，7.90(1H，d，J＝8.1Hz)，7.93(1H，s)，8.05-8.12(1H，s)，8.42-8.49(1H，m)

ESI-MS found: m/z 351.2[ M + H ] +

(example 53)

1- (2-fluoropyridin-3-yl) -4- (2-methoxy-2-methyl-1-oxoindan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-methylcarbonyloxy-1-indanone

To a 150ml acetonitrile solution of 1.0g of 5-bromo-1-indanone was added 2.1g of [ hydroxy (p-nitrobenzenesulfonyloxy) iodo ] benzene at room temperature, and the mixture was refluxed for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was removed by evaporation under reduced pressure. The resulting residue was dissolved in 200ml of acetic acid, and 1.7g of silver carbonate was added thereto at room temperature, followed by refluxing with heating for 12 hours. After the reaction mixture was returned to room temperature, the solvent was distilled off under reduced pressure, and then the reaction mixture was dissolved in chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate: 90: 10) to give the title compound as a white solid (910 mg).

¹H NMR(300MHz、CDC1₃)δ：2.18(3H，s)，3.03(1H，dd，J＝4.5，17.1Hz)，3.64(1H，dd，J＝7.5，17.1Hz)，5.39(1H，dd，J＝4.5Hz)，7.5Hz)，7.55-7.69(3H，m)

2) Preparation of 5-bromo-2-methyl-2-methoxy-1-indanone

640mg of 60% sodium hydride was added to 20ml of a dimethylformamide solution containing 850mg of 5-bromo-2-methylcarbonyloxy-1-indanone obtained in the above step 1) at room temperature. After stirring at room temperature for 10 minutes, 3.5ml of methyl iodide was added, and the mixture was stirred at room temperature for 1 hour. 2ml of 5% aqueous dimethylformamide was added thereto, and the mixture was stirred at room temperature for 1 hour.

The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound as a white solid (400 mg).

¹H NMR(300MHz、CDCl₃)δ：1.44(3H，s)，3.05(1H，d，J＝17.5Hz)，3.28(3H，s)，3.33(1H，d，J＝17.5Hz)，7.52-7.66(3H，m)

3) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-methoxy-2-methyl-1-oxoindan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained according to the procedure of example 1 using the compound obtained in the above 2) and the compound of reference example 1, 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole.

¹H NMR(300MHz、CDCl₃)δ：1.48(3H，s)，2.51(3H，d，J＝2.1Hz)，3.15(1H，d，J＝17.4Hz)，3.33(3H，s)，3.44(1H，d，J＝17.4Hz)，7.45-7.53(1H，m)，7.81(1H，d，J＝8.1Hz)，7.79(1H，d，J＝8.1Hz)，8.05-8.12(1H，m)，8.44-8.50(1H，m)

ESI-MS found: m/z 381.1[ M + H ] +

(example 54)

4-((2S^*) -methoxy- (2R)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole and 4- ((2R)^*) -methoxy- (2S)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

The racemate 1- (2-fluoropyridin-3-yl) -4- (2-methoxy-2-methyl-1-oxo-racemate obtained in example 53 was optically resolved using an optically active column (CHIRALPAK AD-H column manufactured by ダイセル, Hexane: EtOH 400: 600)Indan-5-yl) -5-methyl-1H- [1, 2, 3 ]7.0mg of triazole, and for the sake of convenience, 2.5mg of the obtained precut compound was referred to as (2S) of the title compound^*，2R^*) As a result, 2.5mg of the obtained compound of the latter fraction was referred to as (2R) of the title compound^*，2S^*) Body, both white solids.

4-((2S^*) -methoxy- (2R)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

¹H NMR(300MHz、CDCl₃)1.48(3H，s)，2.51(3H，d，J＝2.1Hz)，3.15(1H，d，J＝17.4Hz)，3.33(3H，s)，3.44(1H，d，J＝17.4Hz)，7.45-7.53(1H，m)，7.81(1H，d，J＝8.1Hz)，7.79(1H，d，J＝8.1Hz)，8.05-8.12(1H，m)，8.44-8.50(1H，m)

ESI-MS found: m/z 381.1[ M + H ] +

4-((2R^*) -methoxy- (2S)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

1.48(3H，s)，2.51(3H，d，J＝2.1Hz)，3.15(1H，d，J＝17.4Hz)，3.33(3H，s)，3.44(1H，d，J＝17.4Hz)，7.45-7.53(1H，m)，7.81(1H，d，J＝8.1Hz)，7.79(1H，d，J＝8.1Hz)，8.05-8.12(1H，m)，8.44-8.50(1H，m)

ESI-MS found: m/z 381.1[ M + H ] +

(example 55)

1- (2-Fluoropyridin-3-yl) -4- (2-pyrrolidin-1-yl-quinolin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 2-pyrrolidine-6-bromoquinoline

Pyrrolidine was added to a solution of 40mg of 2-chloro-6-bromoquinoline in 2ml of dioxane at room temperature under a nitrogen atmosphere at 100m and stirred at 115 ℃ for 6 hours. After water was added to the reaction mixture, the mixture was extracted with diethyl ether, and the diethyl ether layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (35 mg).

ESI-MS found: m/z 277.0[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-pyrrolidin-1-yl-quinolin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：2.07(3H，t，J＝6.8Hz)，2.52(3H，d，J＝2.0Hz)，3.66(4H，brs)，6.78(1H，d，J＝8.8Hz)，7.49(1H，t，J＝6.2Hz)，7.80(1H，d，J＝8.4Hz)，7.93(2H，t，J＝10.6Hz)，8.01(1H，d，J＝2.0Hz)，8.01(1H，t，J＝8.4，16.8Hz)，8.45(1H，d，J＝4.4Hz)

ESI-MS found: m/z 375.2[ M + H ] +

(example 56)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-4-oxo-4-methyl-chromen-7-yl) -1H- [1, 2, 3] triazole

1) Preparation of 7- ((trifluoromethyl) sulfonyloxy) -2-methyl-4H-chromen-4-one

After 0.2ml of trifluoromethanesulfonic anhydride was added dropwise to 3ml of a pyridine solution containing 110mg of 7-hydroxy-2-methyl-4H-chromen-4-one at 0 ℃ under a nitrogen atmosphere, the mixture was stirred at room temperature for 2 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate: 10: 1) to give the title compound (112 mg) as a white solid.

ESI-MS found: m/z 309.1[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-methyl-4-oxo-4-methyl-chromen-7-yl) -1H- [1, 2, 3] triazole

Using the compound obtained in the above 1 and the alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which was the same as in reference example 1, a coupling reaction was carried out in the same manner as in example 20 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.43(3H，s)，2.55(3H，s)，6.21(1H，s)，7.48-7.56(1H，m)，7.83(1H，dd，J＝1.2，8.4Hz)7.91(1H，d，J＝1.2Hz)，8.05-8.15(1H，m)，8.29(1H，J＝8.0Hz)，8.48(1H，J＝4.8Hz)

ESI-MS found: m/z 337.1[ M + H ] +

Example 57

1- (2-fluoropyridin-5-yl) -4- (1-oxo-2-methyl-indan-5-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 20 except for using 5-bromo-2-methyl-1-oxoindane instead of 5-bromo-2, 2-dimethyl-1-oxoindane used in example 20 and using 1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as the compound in reference example 3 instead of 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as the compound in reference example 1, to obtain the titled compound.

¹H NMR(400MHz、CDCl₃)δ：1.36(3H，d，J＝6.8Hz)，2.57(3H，s)，2.79-2.83(1H，br)，3.46-3.52(1H，m)，7.21-7.23(1H，m)，7.75(1H，d，J＝8.0Hz)，7.87(1H，d，J＝8.0Hz)，7.93(1H，s)，8.02-8.05(1H，m)，8.45(1H，s)

ESI-MS found: m/z 323.2[ M + H ] +

(example 58)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxo-1H-inden-5-yl) -1H- [1, 2, 3] triazole

A reaction was carried out in the same manner as in example 20 except for using 5-bromo-1-oxo-1H-indene instead of 5-bromo-2, 2-dimethyl-1-oxoindan used in example 20 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.37(3H，d，J＝1.2Hz)，3.87(1H，m)，4.55(1H，m)，7.44-7.47(1H，m)，7.58-7.66(2H，m)，7.81(1H，s)，7.99-8.03(1H，m)，8.43-8.44(1H，m)

ESI-MS found: m/z 613.3[2M + H ] +

(example 59)

1- (2-fluoropyridin-3-yl) -4- (2-methyl-1-oxo-1H-inden-5-yl) -5-methyl-1H- [1, 2, 3] triazole

A reaction was carried out in the same manner as in example 20 except for using 5-bromo-2-methyl-1-oxo-1H-indene instead of 5-bromo-2, 2-dimethyl-1-oxoindan used in example 20 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.92(3H，d，J＝2.0Hz)，2.48(3H，d，J＝2.4Hz)，7.21-7.22(1H，m)，7.48-7.51(4H，m)，8.05-8.09(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 321.1[ M + H ] +

(example 60)

1- (2-fluoropyridin-5-yl) -4- (3-methyl-4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole

The coupling reaction was carried out in the same manner as in example 20 using 7- ((trifluoromethyl) sulfonyloxy) -3-methyl-4H-chromen-4-one and the same alkyltin compound 1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 3 to give the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.07(3H，d，J＝1.2Hz)，2.60(3H，s)，7.22(1H，dd，J＝3.6，8.8)，7.80(1H，dd，J＝1.6，8.4Hz)，7.84(1H，s)，7.90(1H，s)，8.00-8.07(1H，m)，8.35(1H，d，J＝8.4Hz)，8.44-8.47(1H，d，m)

ESI-MS found: m/z 337.1[ M + H ] +

(example 61)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-5-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-cyclopropyl-1-oxo-isoindoline

A reaction was carried out in the same manner as in example 49-1 to obtain the title compound.

2) Preparation of 4- (2-cyclopropyl-butyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained by carrying out the reaction in the same manner as in example 49-2 except for using 1- (2-fluoropyridin-5-yl) -4-tributyltin-5-methyl-1H- [1, 2, 3] triazole which is the compound of reference example 3 in place of 1- (2-fluoropyridin-3-yl) -4-tributyltin-5-methyl-1H- [1, 2, 3] triazole which is the compound of reference example 1 used in example 49-2.

¹H NMR(400MHz、CDCl₃)5：0.88-0.98(4H，m)，2.55(3H，s)，2.96-3.00(1H，m)，4.41(2H，s)，7.20-7.23(1H，m)，7.77(1H，d，J＝8.4Hz)，7.93-7.95(2H，m)，8.01-8.05(1H，m)，8.45(1H，m)

ESI-MS found: m/z 350.0[ M + H ] +

(example 62)

4- (benzothiazol-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 1 using 6-bromobenzothiazole and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole of reference example 1 to give the title compound as a colorless solid.

¹H NMR(300MHz、CDCl₃)δ：2.53(3H，d，J＝2.0Hz)，7.48-8.48(6H，m)，9.06(1H，s)

ESI-MS found: m/z 312.0[ M + H ] +

(example 63)

4- (5-fluoro-3-methyl-4-oxo-4H-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 1- (2-fluoro-4, 6-dimethoxyphenyl) propan-1-one

In a nitrogen atmosphere, a solution of 2.4g of aluminum trichloride and 240mg of zinc dichloride in 40ml of dichloroethane were added dropwise in this order at-10 ℃ to a solution of 2g of 3, 5-dimethoxy-1-fluorobenzene in 5ml of dichloroethane and a solution of 1.3mg of propionyl chloride in 5ml of dichloroethane, followed by stirring at room temperature for 2 hours. After a 20% aqueous hydrochloric acid solution was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 5: 1) to give the title compound (1.5 g) as a white solid.

2) Preparation of 1- (6-fluoro-2, 4-dihydroxyphenyl) propan-1-one

2.4g of aluminum trichloride was added to a solution of 1.5g of the compound obtained in the above 1) in 20ml of toluene under a nitrogen atmosphere, and then stirred at 95 ℃ for 8 hours. After water was added to the reaction mixture, the precipitated white solid was collected by filtration to obtain 930mg of the title compound as a white solid.

ESI-MS found: m/z 185.0[ M + H ] +

3) Preparation of 5-fluoro-7-hydroxy-3-methyl-4H-chromen-4-one

8.4ml of dimethylformamide was added dropwise to 2.2ml of a boron trifluoride etherate solution of 930mg of the compound obtained in the above 2) at 0 ℃ under a nitrogen atmosphere, and then stirred at 0 ℃ for 15 minutes. A mixed solution of 1.74g of phosphorus pentachloride and 45ml of dimethylformamide was added dropwise to the reaction solution, followed by stirring at room temperature for 2 hours. After adding the methanol solution to the reaction mixture, the mixture was stirred at 70 ℃ for 20 minutes. After methanol was distilled off under reduced pressure, water was added thereto, and the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform: methanol 10: 1) to give the title compound (980 mg) as a white solid.

ESI-MS found: m/z 195.0[ M + H ] +

4) Preparation of 5-fluoro-7- ((trifluoromethyl) sulfonyloxy) -3-methyl-4H-chromen-4-one

1.7ml of trifluoromethanesulfonic anhydride was added dropwise to a solution of 980mg of the compound obtained in 3) above in 10ml of pyridine under a nitrogen atmosphere at room temperature, and then stirred at room temperature for 2 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (760 mg).

ESI-MS found: m/z 327.0[ M + H ] +

5) Preparation of 4- (5-fluoro-3-methyl-4-oxo-4H-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above-mentioned 4) and the alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which was the same as in reference example 1, a coupling reaction was carried out in the same manner as in example 20 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.03(3H，d，J＝0.8Hz)，2.54(3H，d，J＝2.0Hz)，7.49-7.54(2H，m)，7.72(1H，s)，7.76(1H，d，J＝1.2Hz)，8.09(1H，t，J＝8.2Hz)，8.49(1H，d，J＝4.8Hz)

ESI-MS found: m/z 355.0[ M + H ] +

(example 64)

5-methyl-4- (3-methyl-4-oxo-4H-chromen-7-yl) -1- (pyridin-3-yl) -1H- [1, 2, 3] triazole

A coupling reaction was carried out in the same manner as in example 20 using 7- ((trifluoromethyl) sulfonyloxy) -3-methyl-4H-chromen-4-one and the alkyltin compound 1- (3-pyridine) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 6 to give the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.08(3H，d，J＝1.2Hz)，2.61(3H，s)，5.59(1H，dd，J＝5.0，8.2Hz)，7.82(1H，dd，J＝1.6，8.4Hz)，7.85(1H，d，J＝1.2Hz)，7.90-7.96(2H，m)，8.35(1H，d，J＝8.4Hz)，8.81-8.86(2H，m)

ESI-MS found: m/z 319.1[ M + H ] +

(example 65)

1- (2-fluoropyridin-3-yl) -4- (2-methanesulfonyl-quinolin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using 6-bromo-2-methanesulfonyl-quinoline and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1.

¹H NMR(300MHz、CDCl₃)δ：2.60(3H，d，J＝2.0Hz)，3.40-3.55(3H，m)，7.49-7.57(1H，m)，8.05-8.56(7H，m)

ESI-MS found: m/z 384.0[ M + H ] +

(example 66)

4- [ (2-isopropyl-methyl-amino) -quinolin-6-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of (6-bromo-2-quinolyl) methyl (methylethyl) amine

To a solution of 63mg of 2-chloro-6-bromoquinoline in 5ml of dimethylformamide was added 180mg of N-methylisopropylamine and 200mg of potassium carbonate in this order at room temperature, and the mixture was stirred at 110 ℃ for 4 hours. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 3: 1) to give the title compound (18 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.23(6H，d，J＝6.8Hz)，2.99(3H，s)，4.94-5.03(1H，m)，6.88(1H，d，J＝9.2Hz)，7.49-7.58(2H，m)，7.69(1H，dd，J＝0.8，2.0Hz)，7.74(1H，d，J＝9.2Hz)

ESI-MS found: m/z 279.1[ M + H ] +

2) Preparation of 4- [ (2-isopropyl-methyl-amino) -quinolin-6-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.22-1.30(6H，m)，2.51(3H，d，J＝2.4Hz)，3.04(3H，s)，5.00-5.10(1H，m)，6.94(1H，d，J＝9.2Hz)，7.45-7.52(1H，m)，7.77(1H，d，J＝8.8Hz)，7.94(2H，t，J＝6.6Hz)，7.99(1H，brs)，8.05-8.15(1H，m)，8.45(1H，dt，J＝1.6，3.2，4.8Hz)

ESI-MS found: m/z 377.2[ M + H ] +

Example 67

4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

To a solution of 102mg of 6-bromo-3-benzyl-4-oxo-3, 4-dihydroquinazoline in 3ml of dimethylformamide under a nitrogen atmosphere were added 78.4mg of 1- (2-fluoropyridin-3-yl) -4-tributylstannyl-1H- [1, 2, 3] triazole, 8.8mg of dipalladium tris (benzylideneacetone), and 18.7mg of triphenylarsine, and the mixture was stirred at 80 ℃ for 8 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol: 19: 1) to give the title compound 6.0mg as a colorless solid.

¹H NMR(300MHz、CDCl₃) δ: 2.55(3H, d, J ═ 1.9Hz), 5.24(2H, s), 7.33^7.39(5H, m), 7.50(1H, dd, J ═ 4.7 and 6.9Hz), 7.85(1H, d, J ═ 8.4Hz), 8.06-8.12(1H, m), 8.15(1H, s), 8.38-8.47(2H, m), 8.59(1H, d, J ═ 2.2Hz)

ESI-MS found: m/z 413.1[ M + H ] +

(example 68)

1- (2-fluoropyridin-3-yl) -4- (5-oxo-6-methyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-methyl-5-oxo-5, 6, 7, 8-tetrahydro-naphthalen-2-yl trifluoromethanesulfonate

Trifluoromethanesulfonic acid 5-oxo-5, 6, 7, 8-tetrahydro-naphthalen-2-yl ester (200 mg) was dissolved in dimethylformamide (3 ml) at room temperature, and 60% sodium hydride (54 mg) and methyl iodide (1.0 ml) were added thereto, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate: hexane: 1: 2) to give the title compound 42mg as a yellow oil.

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (5-oxo-6-methyl-5, 6, 7, 8-tetrahydro-naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 20 except for using 6-methyl-5-oxo-5, 6, 7, 8-tetrahydro-naphthalen-2-yl trifluoromethanesulfonate obtained in 1) above instead of 5-bromo-2, 2-dimethyl-1-oxoindane used in example 20 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.31(3H，d，J＝6.4Hz)，1.88-1.99(1H，m)，2.22-2.29(1H，m)，2.50(3H，d，J＝1.6Hz)，2.62-2.68(1H，m)，3.05-3.16(2H，m)，7.48-7.51(1H，m)，7.68(1H，d，J＝8.4Hz)，7.77(1H，s)，8.06-8.10(1H，m)，8.15(1H，d，J＝7.6Hz)，8.45-8.46(1H，m)

ESI-MS found: m/z 337.2[ M + H ] +

(example 69)

Preparation of 4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1-phenyl-1H- [1, 2, 3] triazole 1) 3-benzyl-4-oxo-6- (2-trimethylsilylethynyl)) -3, 4-dihydroquinazoline

To a solution of 501mg of 3-benzyl-6-bromo-4-oxo-3, 4-dihydroquinazoline in 1.5mL of dimethylformamide was added 947mg of trimethylsilylacetylene, 54.7mg of copper (I) iodide, 54.2mg of tin (triphenylphosphine) palladium (II) dichloride and 3mL of triethylamine in this order under a nitrogen atmosphere, and the mixture was stirred at 100 ℃ for 14 hours. After the solvent was distilled off under reduced pressure, water was added thereto, and the mixture was extracted with diethyl ether, and the diethyl ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 3: 7) to give the title compound 570mg as a colorless oil.

2) Preparation of 3-benzyl-6-ethynyl-4-oxo-3, 4-dihydroquinazoline

To a 34mL solution of 570mg of the compound obtained in 1) above in methanol was added 1.16g of potassium carbonate under a nitrogen atmosphere, and the mixture was stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, water was added thereto, and the mixture was extracted with diethyl ether, and the diethyl ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1) to give the title compound 322mg as a colorless oil.

¹H NMR (300MHz, CDCl3) delta: 3.19(1H, s), 5.20(2H, s), 7.31-7.37(5H, m), 7.65(1H, d, J ═ 8.5Hz), 7.81(1H, dd, J ═ 1.9 and 8.5Hz), 8.10(1H, s), 8.45(1H, d, J ═ 1.9Hz)

3) Preparation of 4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-6-yl) -1-phenyl-1H- [1, 2, 3] triazole

Under a nitrogen atmosphere, 1M aqueous sodium ascorbate solution and copper sulfate (II)5 hydrate were added to 3mL of water-tert-butanol (1: 1) containing 114mg of the compound obtained in the above 2) and 52.4mg of azidobenzene in this order, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate: hexane: 1) to give the title compound 23.0mg as a colorless solid.

¹H NMR(300MHz、CDCl₃) δ: 5.24(2H, s), 7.31-7.39(5H, m), 7.46-7.61(3H, m), 7.80-7.84(3H, m), 8.13(1H, s), 8.36(1H, s), 8.52(1H, dd, J ═ 2.0 and 8.6Hz), 8.69(1H, d, J ═ 1.9Hz)

ESI-MS found: m/z 352.0[ M + H ] +

(example 70)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-4-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 4-azido-5-bromo-2-fluoro-pyridine

Under a nitrogen atmosphere, 20ml of a tetrahydrofuran solution containing 1.39ml of diisopropylamine was cooled to-78 ℃ and 3.8ml of a 2.66M n-butyllithium/hexane solution was added dropwise thereto. The reaction mixture was warmed to 0 ℃ and stirred for 5 minutes, then cooled again to-78 ℃ and 5.74 g of tetrahydrofuran 5.0mg of 5-bromo-2-fluoro-pyridine was added. Stirring at-78 deg.C for 10 min, adding 2.34g of tetrahydrofuran 5.0ml of n-dodecyl azido phenylsulfone, stirring, heating the reaction solution to-60 deg.C, and adding water to terminate the reaction. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate: 80: 20) to give the crude title compound as a dark brown oil (1.70 g).

2) Preparation of 1- (5-bromo-2-fluoro-pyridin-4-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a solution of 1.70g of the compound obtained in the above 1) in 3.0ml of toluene was added 2.20g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. The resulting solution was cooled to room temperature and purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give 670mg of a mixture of the title compound and 1- (5-bromo-2-fluoro-pyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole.

3) Preparation of 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (5-bromo-2-fluoropyridin-4-yl) -5-methyl-1H- [1, 2, 3] triazole

The same procedures used in example 67 were repeated except for using the mixture of tin reagents obtained in 2) above and the halide obtained in example 36 to give 6.0mg of a mixture of the title compound and 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (5-bromo-2-fluoro-pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole.

2.5mg of the compound mixture obtained above was dissolved in methanol, and 2.5mg of 10% palladium on charcoal was added thereto, followed by stirring at room temperature for 20 minutes. The catalyst was filtered off, the solvent was then distilled off, and the residue was purified by preparative thin layer silica gel chromatography (ethyl acetate) to give the title compound (0.68 mg).

¹H NMR(300MHz、CDCl₃)δ：1.32(6H，d，J＝6.8Hz)，2.67(3H，s)，4.47(2H，s)，4.72(1H，sept，J＝6.8Hz)，7.49-7.56(1H，m)，7.73-7.80(1H，m)，7.93-7.99(2H，m)，8.47-8.51(1H，m)

ESI-MS found: m/z 352.0[ M + H ] +

(example 71)

4- (2-tert-butyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-tert-butyl-1-oxoisoindoline

The reaction was carried out in the same manner as in example 49-1 except that tert-butylamine was used instead of cyclopropylamine used in example 49-1 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.56(9H，s)，4.43(2H，s)，7.55-7.63(3H，m)

ESI-MS found: m/z 268.1[ M + H ] +,

2) preparation of 4- (2-tert-butyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 49-2 except for using 5-bromo-2-tert-butyl-1-oxoisoindoline obtained in the above-mentioned 1) in place of 5-bromo-2-cyclopropyl-1-oxoisoindoline used in example 49-2 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.60(9H，s)，2.49(3H，d，J＝2.0Hz)，4.55(2H，s)，7.48-7.52(1H，m)，7.78-7.80(1H，m)，7.89-7.91(1H，m)，7.93(1H，s)，8.05-8.11(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 366.2[ M + H ] +

(example 72)

4- (2-Ethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-ethyl-1-oxoisoindoline

A reaction was carried out in the same manner as in example 50-1 except that ethylamine was used instead of cyclopropylamine used in example 49-1 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.27(3H，t，J＝7.2Hz)，3.66(2H，q，J＝7.2Hz)，4.36(2H，s)，7.58-7.61(2H，m)，7.69-7.71(1H，m)

ESI-MS found: m/z 240.1[ M + H ] +

2) Preparation of 4- (2-ethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 49-2 except for using 5-bromo-2-ethyl-1-oxoisoindoline obtained in the above-mentioned 1) in place of 5-bromo-2-cyclopropyl-1-oxoisoindoline used in example 49-2 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.31(3H，t，J＝7.2Hz)，2.51(3H，d，J＝2.0Hz)，3.72(2H，q，J＝7.2Hz)，4.48(2H，s)，7.49-7.52(1H，m)，7.80-7.83(1H，m)，7.84-7.96(1H，m)，7.98(1H，s)，8.06-8.11(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 338.2[ M + H ] +

(example 73)

1- (2-fluoropyridin-3-yl) -4- (2-methoxy-4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 7-hydroxy-2-methoxy-4H-chromen-4-one

170mg of aluminum trichloride was added to a solution of 103mg of 2, 7-dimethoxy-4H-chromen-4-one in 5ml of toluene under a nitrogen atmosphere, and the mixture was stirred at 90 ℃ for 4 hours. After water was added to the reaction mixture, the precipitated white solid was collected by filtration and separated and purified by preparative thin layer chromatography (chloroform: methanol 9: 1) to obtain 62mg of the title compound as a white solid.

¹H NMR(400MHz、CD₃OD)δ：4.02(3H，s)，5.58(1H，s)，6.81(1H，d，J＝2.0Hz)，6.90(1H，dd，J＝2.3，8.8Hz)，7.91(1H，d，J＝8.8Hz)

ESI-MS found: m/z 193.0[ M + H ] +

2) Preparation of 7- ((trifluoromethyl) sulfonyloxy) -2-methoxy-4H-chromen-4-one

0.11ml of trifluoromethanesulfonic anhydride was added to 2ml of a pyridine solution of 62mg of the compound obtained in the above 1) at 0 ℃ under a nitrogen atmosphere, and then stirred at room temperature for 20 minutes. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol 9: 1) to give the title compound as a white solid (18 mg).

ESI-MS found: m/z 325.0[ M + H ] +

3) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-methoxy-4-oxo-4H-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 2) and the same alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 1, a coupling reaction was carried out in the same manner as in example 67 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.54(3H，d，J＝2.0Hz)，4.02(3H，s)，5.66(1H，s)，7.49-7.54(1H，m)，7.84(1H，dd，J＝1.2，8.0Hz)，7.91(1H，d，J＝1.2Hz)，8.06-8.13(1H，m)，8.28(1H，d，J＝8.0Hz)，8.48(1H，d，J＝4.8Hz)

ESI-MS found: m/z 353.1[ M + H ] +

(example 74)

1- (2-fluoropyridin-3-yl) -4- (3-methyl-4-oxo-3, 4-dihydro-quinazolin-7-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 69 except for using 101mg of 7-bromo-3-methyl-4-oxo-3, 4-dihydroquinazoline in place of 6-bromo-3-benzyl-4-oxo-3, 4-dihydroquinazoline used in example 69 to obtain 16.7mg of the title compound as a colorless solid.

¹H NMR(300MHz、CDCl₃)δ：2.56(3H，d，J＝2.1Hz)，3.64(3H，s)，7.49-7.53(1H，m)，8.05-8.13(4H，m)，8.42-8.48(2H，m)

ESI-MS found: m/z 337.0[ M + H ] +

(example 75)

1- (2-fluoropyridin-3-yl) -4- (3-methyl-4-oxo-3, 4-dihydro-quinazolin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 69 except for using 109mg of 6-bromo-3-methyl-4-oxo-3, 4-dihydroquinazoline in place of the 6-bromo-3-benzyl-4-oxo-3, 4-dihydroquinazoline used in example 69 to obtain 21.0mg of the title compound as a colorless solid.

¹H NMR(300MHz、CDCl₃)δ：2.56(3H，d，J＝1.6Hz)，3.64(3H，s)，7.48-7.53(1H，m)，7.85(1H，d，J＝8.6Hz)，8.06-8.12(2H，m)，8.36-8.48(2H，m)，8.59(1H，d，J＝1.7Hz)

ESI-MS found: m/z 337.0[ M + H ] +

(example 76)

1- (2-fluoropyridin-3-yl) -4- [2- (2-hydroxy-1-methyl-ethyl) -1-oxo-isoindolin-5-yl ] -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-hydroxy-1-methyl-ethyl) -1-oxo-isoindoline

The reaction was carried out in the same manner as in example 49-1 except for using 2-hydroxy-1-methyl-ethylamine instead of cyclopropylamine used in example 49-1 to obtain 21.0mg of the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.33(3H，d，J＝7.2Hz)，3.72-3.76(1H，m)，3.85-3.89(1H，m)，4.35-4.50(3H，m)，7.58-7.61(2H，m)，7.66(1H，d，J＝8.0Hz)

ESI-MS found: m/z 270.0[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- [2- (2-hydroxy-1-methyl-ethyl) -1-oxo-isoindolin-5-yl ] -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 49-2 except for using 5-bromo-2- (2-hydroxy-1-methyl-ethyl) -1-oxo-isoindoline obtained in the above-mentioned 1) in place of 5-bromo-2-cyclopropyl-1-oxo-isoindoline used in example 49-2, to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.38(3H，d，J＝7.2Hz)，1.63(1H，br)2.50(3H，d，J＝2.0Hz)，3.77-3.82(1H，m)，3.90-3.93(1H，m)，4.42-4.48(1H，m)，4.47-4.61(2H，m)，7.49-7.52(1H，m)，7.80-7.82(1H，m)，7.94(1H，d，J＝8.0Hz)，7.97(1H，s)，8.07-8.11(1H，m)，8.45-8.47(1H，m)

APCI-MS found: m/z 368.0[ M + H ] +

Example 77

1- (2-fluoropyridin-3-yl) -5-methyl- (2, 3-dimethyl-4-oxo-3, 4-dihydro-quinazolin-7-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of N-methyl-2-amino-4-bromobenzamide

To 6.28g of 7-bromo-1H-benzo [1, 3] oxazine-2, 4-dione was added 30mL of a 2.0M methylamine-methanol solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure to give 6.57g of the title compound.

2) Preparation of 7-bromo-2, 3-dimethyl-4-oxo-3, 4-dihydroquinazoline

To 979mg of N-methyl-2-amino-4-bromobenzamide was added 5mL of acetic anhydride, and the mixture was refluxed for 7 hours. After the excess reagent was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound 618mg as a colorless solid.

1H NMR(300MHz，CDCl3)δ：2.61(3H，s)，3.61(3H，s)，7.51-8.11(3H，m)

ESI-MS found: m/z 254.9[ M + H ] +

3) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl- (2, 3-dimethyl-4-oxo-3, 4-dihydro-quinazolin-7-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in production method 69 except for using 41.7mg of the compound obtained in the above 2) in place of 6-bromo-3-benzyl-4-oxo-3, 4-dihydroquinazoline used in production method 69, to obtain 7.6mg of the title compound as a colorless solid.

¹H NMR(300MHz、CDCl₃)δ：2.55(3H，d，J＝2.1Hz)，2.66(3H，s)，3.66(3H，s)，7.48-7.53(1H，m)，7.93(1H，d，J＝1.4Hz)，8.03-8.12(2H，m)，8.38(1H，d，J＝8.2Hz)，8.45-8.47(1H，m)

ESI-MS found: m/z 351.0[ M + H ]

(example 78)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using the halide obtained in example 36 and the tin reagent 1- (2-fluoropyridin-3 yl) -4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 2.

¹H NMR(300MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，4.43(2H，s)，4.71(1H，sept，J＝6.8Hz)，7.47-7.51(1H，m)，7.94(2H，d，J＝1.0Hz)，8.13(1H，d，J＝1.0Hz)，8.33-8.36(1H，m)，8.49(1H，d，J＝2.7Hz)，8.57-8.62(1H，m)

ESI-MS found: m/z 338.1[ M + H ] +

(example 79)

1- (2-fluoropyridin-3-yl) -4- (3-methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 7- ((trifluoromethyl) sulfonyloxy) -3-methylchromen-4-one

0.13ml of trifluoromethanesulfonic anhydride was added dropwise to 1ml of a solution of 70mg of 7-hydroxy-3-methyl-chromen-4-one in pyridine at 0 ℃ under a nitrogen atmosphere, and then the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 10: 1) to give the title compound as a white solid (92 mg).

¹H NMR(400MHz、CDCl₃)δ：1.24(3H，d，J＝6.8Hz)，2.80-2.96(1H，m)，4.21(1H，t，J＝11.4Hz)，4.58(1H，dd，J＝5.4，11.4Hz)，6.90-6.96(2H，m)，7.99(1H，d，J＝9.2Hz)

ESI-MS found: m/z 311.0[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- ((3SR) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 1 and an alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which was the same as in reference example 1, a coupling reaction was carried out in the same manner as in example 67 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.26(3H，d，J＝7.2Hz)，2.50(3H，d，J＝2.0Hz)，2.87-2.97(1H，m)，4.22(1H，t，J＝11.2Hz)，4.57(1H，dd，J＝5.0，11.4Hz)，7.42(1H，s)，7.46-7.55(2H，m)，8.01(1H，d，J＝8.0Hz)，8.04-8.13(1H，m)，8.46(1H，dt，J＝1.6，4.4Hz)

ESI-MS found: m/z 339.1[ M + H ] +

(example 80)

1- (2-Fluoropyridin-3-yl) -4- ((3R)^*) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3]Triazole and 1- (2-fluoropyridin-3-yl) -4- ((3S)^*) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

With optically active columnsOptical resolution of 1- (2-fluoropyridin-3-yl) -4- ((3SR) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3, 5 obtained in example 79 (CHIRALPAK-AD column manufactured by ダイセル: 0.1% diethylamine, hexane: isopropanol 80: 200)]Triazole, the compound of the obtained front cut being referred to as (3R) of the title compound for the sake of convenience^*) The compound obtained as the latter fraction is referred to as (3S) of the title compound^*) Body, both white solids.

1- (2-Fluoropyridin-3-yl) -4- ((3R)^*) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

¹H NMR(400MHz、CDCl₃)δ：1.26(3H，d，J＝7.2Hz)，2.50(3H，d，J＝2.0Hz)，2.87-2.97(1H，m)，4.22(1H，t，J＝11.2，22.4Hz)，4.57(1H，dd，J＝5.0，11.4Hz)，7.42(1H，s)，7.46-7.55(2H，m)，8.01(1H，d，J＝8.0Hz)，8.04-8.13(1H，m)，8.46(1H，dt，J＝1.6，3.2，4.4Hz)

ESI-MS found: m/z 339.1[ M + H ] +

1- (2-Fluoropyridin-3-yl) -4- ((3S)^*) -methyl-4-oxo-chromen-7-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

ESI-MS found: m/z 339.1[ M + H ] +

(example 81)

1- (2-fluoropyridin-3-yl) -4- (1-oxo-isoindolin-5-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-tert-butoxycarbonyl-1-oxo-isoindoline

In a nitrogen atmosphere, 5-bromo-1-oxo-isoindoline (70 mg) was dissolved in tetrahydrofuran (2 ml), and after cooling to 0 ℃, N-dimethylaminopyridine (4 mg) and di-tert-butyl dicarbonate (144 mg) were added and the mixture was stirred at room temperature for 30 minutes. Methanol was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound (51.2 mg) as a white solid.

¹H NMR(400MHz，CDCl3)δ：1.60(9H，s)，4.74(2H，s)，7.62-7.65(2H，m)，7.76(1H，d，J＝8.0Hz)

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-tert-butoxycarbonyl-1-oxo-isoindolin-5-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 5 except for using 5-bromo-2-tert-butoxycarbonyl-1-oxo-isoindoline obtained in the above-mentioned 1) in place of 6-bromoquinoline used in example 5, to obtain the title compound.

3) Preparation of 1- (2-fluoropyridin-3-yl) -4- (1-oxo-isoindolin-5-yl) -5-methyl-1H- [1, 2, 3] triazole

25mg of 1- (2-fluoropyridin-3-yl) -4- (2-tert-butoxycarbonyl-1-oxo-isoindolin-5-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in the above 2) was dissolved in 1.0ml of a 5% trifluoroacetic acid chloroform solution under a nitrogen atmosphere, and the solution was stirred at room temperature for 10 minutes. Water was added to the reaction mixture, which was extracted with chloroform, and the chloroform layer was washed with a saturated aqueous sodium bicarbonate solution and a saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol: 50: 1) to give the title compound as a white solid (4.1 mg).

¹H NMR(400MHz、CD₃OD)δ：2.49(3H，d，J＝1.2Hz)，4.56(2H，s)，7.65-7.68(1H，m)，7.96-7.98(2H，m)，8.04(1H，br)，8.25-8.30(1H，m)，8.52-8.53(1H，m)

ESI-MS found: m/z 310.2[ M + H ] +

(example 82)

4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of N-benzyl-2-amino-4-bromobenzamide

The reaction was carried out in the same manner as in example 79-4 except that benzylamine was used instead of methylamine used in example 79-1 to obtain the title compound.

2) Preparation of 3-benzyl-7-bromo-4-oxo-3, 4-dihydroquinazoline

To 1.85g of N-benzyl-2-amino-4-bromobenzamide was added 10mL of formic acid, and the mixture was refluxed for 2 hours. After the excess reagent was distilled off under reduced pressure, a saturated aqueous sodium bicarbonate solution was added, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 7: 3) to give the title compound 821mg as a colorless solid.

¹H NMR(300MHz，CDCl3)δ：5.18(2H，s)，3.61(3H，s)，7.7.34(5H，s)，7.59-7.63(1H，m)，7.87(1H，s)，8.09(1H，s)，8.16(1H，d，J＝8.6Hz)

3) Preparation of 4- (3-benzyl-4-oxo-3, 4-dihydroquinazolin-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 69 except for using 3-benzyl-7-bromo-4-oxo-3, 4-dihydroquinazoline obtained in the above-mentioned 2) instead of 6-bromo-3-benzyl-4-oxo-3, 4-dihydroquinazoline used in preparation example 69 to obtain the title compound.

¹H NMR(300MHz、CDCl₃)δ：2.55(3H，d，J＝1.9Hz)，5.24(2H，s)，7.33-7.41(5H，m)，7.50(1H，dd，J＝5.0，7.6Hz)，8.05-8.12(3H，m)，8.15(1H，s)，8.44(1H，s)，8.45-8.48(1H，m)

ESI-MS found: m/z 337.2[ M + H ] +

(example 83)

1- (2-fluoropyridin-5-yl) -4- (2-cyclopropyl-imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 1 using the halide obtained in example 48 and the tin reagent 1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 3.

¹H NMR(300MHz、CDCl₃)δ：0.88-0.98(4H，m)，2.51(3H，s)，2.94-3.02(1H，m)，4.41(2H，s)，7.25-7.33(2H，m)，7.49-7.54(2H，m)，7.76-7.80(1H，m)，7.92-7.96(2H，m)

ESI-MS found: m/z 349.3[ M + H ] +

(example 84)

4- (3-benzyl-2-ethyl-4-oxo-3, 4-dihydroquinazolin-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 7-bromo-2-ethyl-3-methyl-4-oxo-3, 4-dihydroquinazoline

To 1mL of a solution of 796mg of N-methyl-2-amino-4-bromobenzamide in N-methyl-pyrrolidine was added 1.5mL of ethyl propionate and 30. mu.L of acetic acid, and the mixture was stirred at 100 ℃ for 1 hour. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture, followed by extraction with ether, washing of the ether layer with saturated brine and drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give the title compound (653 mg) as a colorless solid.

2) Preparation of 4- (3-benzyl-2-ethyl-4-oxo-3, 4-dihydroquinazolin-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 69 except for using the compound obtained in the above 1) in place of 6-bromo-3-benzyl-4-oxo-3, 4-dihydroquinazoline used in example 69 to obtain the title compound as a colorless solid.

¹H NMR(300MHz、CDCl₃)δ：1.43(3H，t，J＝7.4Hz)，2.56(3H，d，J＝2.2Hz)，2.90(2H.q.J＝7.4Hz)，3.66(3H，s)，7.248-7.52(1H，m)，7.98-8.13(3H，m)，8.37(1H，d，J＝8.3Hz)，8.45-8.47(1H，m)

ESI-MS found: m/z 365.0[ M + H ] +

(example 85)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-propyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-propyl-1-oxo-isoindoline

In a nitrogen atmosphere, 300mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in toluene, and 0.2ml of propylamine and 0.1ml of triethylamine were added to the solution, followed by heating and refluxing for 1 hour. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound 289mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.96(3H，t，J＝7.6Hz)，1，66-1.71(2H，m)，3.56(2H，t，J＝7.6Hz)，4.35(2H，s)，7.58-7.60(2H，m)，7.70(1H，d，J＝8.8Hz)

ESI-MS found: m/z 254.2[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-propyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole

480mg of 5-bromo-2-propyl-1-oxo-isoindoline obtained in 1) above and 300mg of 1- (2-chloropyridin-3-yl) -4-tri-N-butyltin-5-methyl-1H- [1, 2, 3] triazole prepared in reference example 1 were dissolved in N, N-dimethylformamide under a nitrogen atmosphere, 73mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was heated at 115 ℃ and stirred for 3 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound (128 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.99(3H，t，J＝7.4Hz)，1.71-1.78(2H，m)，2.51(3H，d，J＝2.1Hz)，3.62(2H，dd，J＝7.2，7.6Hz)，4.47(2H，s)，7.49-7.52(1H，m)，7.81-8.82(1H，m)，7.92-7.98(2H，m)，8.06-8.11(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 352.3[ M + H ] +

(example 86)

1) Preparation of 5-bromo-2-benzyl-1-oxo-isoindoline

The reaction was carried out in the same manner as in example 49-1 except that benzylamine was used instead of cyclopropylamine used in example 49-1 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：4.24(2H，s)，4.78(2H，s)，7.26-7.36(5H，m)，7.54(1H，s)，7.59-7.62(1H，m)，7.75(1H，d，J＝8.0Hz)

ESI-MS found: m/z 302.1[ M + H ] +

2) Preparation of 4- (2-benzyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 49-2 except for using 5-bromo-2-benzyl-1-oxo-isoindoline obtained in the above-mentioned 1) in place of 5-bromo-2-cyclopropyl-1-oxoisoindoline used in example 49-2, to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.49(3H，d，J＝1.2Hz)，4.36(2H，s)，4.84(2H，s)，7.28-7.38(5H，m)，7.48-7.51(1H，m)，7.84(1H，d，J＝8.0Hz)，7.90(1H，s)，8.01(1H，d，J＝8.0Hz)，8.06-8.10(1H，m)，8.45-8.46(1H，m)

ESI-MS found: m/z 400.2[ M + H ] +

Example 87

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained by carrying out the reaction in the same manner as in example 20 except for using 5-bromo-2-cyclopropyl-1-oxoisoindoline obtained in example 49-1 and 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which is the compound of reference example 4.

ESI-MS found: m/z 349.3[ M + H ] +

(example 88)

4- (2-cyclopropylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-cyclopropylmethyl-1-oxo-isoindoline

The reaction was carried out in the same manner as in example 49-1 except that 2-cyclopropylmethylamine was used instead of cyclopropylamine used in example 49-1, to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：0.31-0.56(2H，m)，0.56-0.60(2H，m)，0.99-1.08(1H，m)，3.47(2H，d，J＝7.2Hz)，4.47(2H，s)，7.58-7.62(2H，m)，7.71(1H，d，J＝8.0Hz)

ESI-MS found: m/z 266.1[ M + H ] +

2) Preparation of 4- (2-cyclopropylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The reaction was carried out in the same manner as in example 49-2 except for using 5-bromo-2-cyclopropylmethyl-1-oxoisoindoline obtained in the above-mentioned 1) in place of 5-bromo-2-cyclopropyl-1-oxoisoindoline used in example 49-2 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：0.35-0.38(2H，m)，0.59-0.63(2H，m)，1.04-1.14(1H，m)，2.51(3H，d，J＝2.1Hz)，3.53(2H，d，J＝7.2Hz)，4.59(2H，s)，7.49-7.52(1H，m)，7.81-7.83(1H，m)，7.95-7.99(2H，m)，8.07-8.11(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 364.3[ M + H ] +

(example 89)

4- (2-isobutyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-isobutyl-1-oxo-isoindoline

The reaction was carried out in the same manner as in example 49-1 except that 2-isobutylamine was used instead of cyclopropylamine used in example 49-1 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：0.95(6H，d，J＝6.4Hz)，2.01-2.08(1H，m)，3.41(2H，d，J＝7.6Hz)，4.36(2H，s)，7.58-7.60(2H，m)，7.70-7.72(1H，m)

ESI-MS found: m/z 268.2[ M + H ] +

2) Preparation of 4- (2-isobutyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H-H, 2, 3] triazole

The reaction was carried out in the same manner as in example 49-2 except for using 5-bromo-2-isobutyl-1-oxo-isoindoline obtained in 1) above in place of 5-bromo-2-cyclopropyl-1-oxoisoindoline used in example 49-2 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：0，99(6H，d，J＝6.6Hz)，2.04-2.13(1H，m)，2.51(3H，d，J＝2.1Hz)，3.46-3.48(2H，m)，4.47(2H，s)，7.48-7.52(1H，m)，7.80-7.82(1H，m)，7.95-7.98(2H，m)，8.06-8.11(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 366.3[ M + H ] +

(example 90)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (3-methyl-4-oxo-4H-pyrano [2, 3-b ] pyridin-7-yl) -1H- [1, 2, 3] triazole

1) Preparation of 1- (2, 6-dimethoxy-3-pyridyl) propan-1-one

In a nitrogen atmosphere, a triethylaluminum 15% hexane solution was added dropwise to a solution of 0.6ml of N, N' -dimethyl-ethane-1, 2-diamine in 26ml of toluene, followed by stirring at room temperature for 1 hour, and a solution of 1g of methyl 2, 6-dimethoxy-nicotinate in 5ml of toluene was added dropwise thereto at room temperature, followed by stirring at 130 ℃ for 1 hour. The reaction mixture was cooled with ice, 1M hydrochloric acid was added thereto, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 156mg of the title compound.

ESI-MS found: m/z 196.1[ M + H ] +

2) Preparation of 3-methyl-7-methoxy-8-aza-4H-chromen-4-one

261ml of aluminum trichloride was added dropwise to 5ml of a toluene solution of 150mg of the compound obtained in the above 1) under a nitrogen atmosphere, and then stirred at 90 ℃ for 3 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 0.3ml of dimethylformamide was added dropwise to a 0.1ml solution of 37mg of boron trifluoride etherate in the obtained residue at 0 ℃ under a nitrogen atmosphere, and then the mixture was stirred at 0 ℃ for 15 minutes. A mixed solution of 68mg of phosphorus pentachloride and 1.6ml of dimethylformamide was added dropwise to the reaction mixture, followed by stirring at room temperature for 3 hours. After adding a methanol hydrochloride solution to the reaction mixture, the mixture was stirred at 70 ℃ for 20 minutes. After methanol was distilled off under reduced pressure, water was added thereto, and the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound (26 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.03(3H，d，J＝1.2Hz)，4.05(3H，s)，6.83(1H，d，J＝8.4Hz)，7.78(1H，d，J＝1.2Hz)，8.44(1H，d，J＝8.4Hz)

ESI-MS found: m/z 192.1[ M + H ] +

3) Preparation of 7-hydroxy-3-methyl-8-aza 4H-chromen-4-one

75mg of aluminum trichloride was added to 2ml of a toluene solution of 26mg of the compound obtained in the above 2) under a nitrogen atmosphere, and then stirred at 90 ℃ for 8 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol 9: 1) to give the title compound as a white solid (11 mg).

ESI-MS found: m/z 378.0[ M + H ] +

4) Preparation of 7- ((trifluoromethyl) sulfonyloxy) -3-methyl-8-aza 4H-chromen-4-one

0.01ml of 4-methyl-2, 6-di-tert-butylpyridine and 0.015ml of trifluoromethanesulfonic anhydride were added dropwise to a solution of 7mg of the compound obtained in the above 3) in 1ml of dichloromethane in this order at 0 ℃ under a nitrogen atmosphere, and then the mixture was stirred at room temperature for 1 hour. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (10 mg).

¹H NMR(400MHz、CDCl₃)δ：2.07(3H，d，J＝1.2Hz)，7.26(1H，d，J＝8.4Hz)，7.90(1H，d，J＝1.2Hz)，8.79(1H，d，J＝8.4Hz)

ESI-MS found: m/z 310.0[ M + H ] +

5) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4- (3-methyl-4-oxo-4H-pyrano [2, 3-b ] pyridin-7-yl) -1H- [1, 2, 3] triazole

Using the compound obtained in the above-mentioned 4) and the alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which was the same as in reference example 1, a coupling reaction was carried out in the same manner as in example 67 to obtain the title compound as a white solid.

ESI-MS found: m/z 338.2[ M + H ] +

(example 91)

4- (3, 3-dimethyl-4-oxo-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 3, 3-dimethyl-7-methoxy chromen-4-one

0.4ml of methyl iodide was added to a solution of 240mg of 3-methyl-7-methoxychromen-4-one in 10ml of tetrahydrofuran under a nitrogen atmosphere, and 100mg of potassium hydride was added thereto and the mixture was stirred at room temperature for 3 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane: ethyl acetate 5: 1) to give the title compound (145 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.19(6H，d，J＝0.8Hz)，3.84(3H，d，J＝0.8Hz)，4.14(2H，s)，6.40(1H，d，J＝2.4Hz)，6.57-6.62(1H，m)，7.84(1H，d，J＝8.4Hz)

ESI-MS found: m/z 207.1[ M + H ] +

2) Preparation of 7-hydroxy-3, 3-dimethylchromen-4-one

110mg of aluminum trichloride was added to 3ml of a toluene solution of 67mg of the compound obtained in the above 1) under a nitrogen atmosphere, and then stirred at 90 ℃ for 2 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol 9: 1) to give the title compound as a white solid (50 mg).

¹H NMR(400MHz、CDCl₃)δ：1.20(6H，s)，4.13(2H，s)，6.43(1H，d，J＝2.0Hz)，6.57(1H，dd，J＝2.0，8.4Hz)，7.81(1H，d，J＝8.4Hz)

ESI-MS found: m/z 193.1[ M + H ] +

3) Preparation of 7- ((trifluoromethyl) sulfonyloxy) -3, 3-dimethylchromen-4-one

0.06ml of 4-methyl-2, 6-di-t-butylpyridine and 0.05ml of trifluoromethanesulfonic anhydride were sequentially added dropwise to a solution of 50mg of the compound obtained in the above 2) in 2ml of dichloromethane at 0 ℃ under a nitrogen atmosphere, and then the mixture was stirred at room temperature for 2 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (40 mg).

¹H NMR(400MHz、CDCl₃)δ：1.22(6H，s)，4.21(2H，s)，6.90-6.97(2H，m)，8.00(1H，dd，J＝0.4，8.4Hz)

ESI-MS found: m/z 325.0[ M + H ] +

4) Preparation of 4- (3, 3-dimethyl-4-oxo-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 3) and the alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which was the same as in reference example 1, a coupling reaction was carried out in the same manner as in example 67 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.25(6H，s)，2.50(3H，d，J＝2.0Hz)，4.21(2H，s)，7.42(1H，d，J＝1.6Hz)，7.47-7.54(2H，m)，8.03(1H，d，J＝8.0Hz)，8.05-8.11(1H，m)，8.43-8.49(1H，m)

ESI-MS found: m/z 353.1[ M + H ] +

(example 92)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1-phenyl-5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained by conducting the reaction in the same manner as in example 20 except for using 5-bromo-2-cyclopropyl-1-oxoisoindoline used in example 49-1 and 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which is the compound of reference example 5.

¹H NMR(300MHz、CDCl₃)δ：0.89-0.98(4H，m)，2.53(3H，s)，2.93-3.02(1H，m)，4.41(2H，s)，7.50-7.62(5H，m)，7.77-7.82(1H，m)，7.91-7.97(2H，m)

ESI-MS found: m/z 331.3[ M + H ] +

(example 93)

1- (2-fluoropyridin-3-yl) -5-methyl-4- (1 a-methyl-2-oxo-1, 1a, 2, 7 a-tetrahydro-7-oxo-6-cycloprop [ b ] naphthalen-5-yl) -1H- [1, 2, 3] triazole

Under a nitrogen atmosphere, 3ml of dimethyl sulfonamide was added to a mixture of 3mg of sodium hydride and 13mg of trimethyl sulfoxide iodide, and after stirring at room temperature for 20 minutes, 3ml of dimethylformamide containing 20mg of 4- (3-methyl-4-oxo-4H-chromen-7-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole was added, and after stirring at room temperature for 2 hours, the mixture was stirred at 50 ℃ for 1 hour. After cold water was added to the reaction mixture, the mixture was extracted with diethyl ether, and the diethyl ether layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (13 mg).

¹H NMR(400MHz、CDCl₃)1.34-1.54(2H，m)，1.40(3H，s)，2.48(3H，d，J＝2.4Hz)，4.44(1H，dd，J＝4.0，5.2Hz)，7.39(1H，d，J＝1.6Hz)，7.47-7.53(2H，m)，8.01(1H，d，J＝7.6Hz)，8.03-8.10(1H，m)，8.46(1H，dt，J＝1.0，4.4Hz)

ESI-MS found: m/z 351.0[ M + H ] +

Example 94

4- (2-methyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-methylisoquinolin-1-one

Under a nitrogen atmosphere, 18mg of 60% sodium hydride was added to a solution of 100mg of 6-bromo-2H-isoquinolin-1-one in 2ml of dimethylformamide at 0 ℃ and stirred for 30 minutes, then 0.03ml of methyl iodide was added at 0 ℃ and stirred at room temperature for 2 hours. After cold water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (24 mg).

¹H NMR(400MHz、CDCl₃)δ：3.59(3H，s)，6.39(1H，d，J＝7.2Hz)，7.09(1H，d，J＝7.2Hz)，7.56(1H，dd，J＝2.0，8.4Hz)，7.67(1H，d，J＝2.0Hz)，8.27(1H，d，J＝8.4Hz)

ESI-MS found: m/z 238.1[ M + H ] +

2) Preparation of 4- (2-methyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The coupling reaction of the compound obtained in the above 1) and the alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole similar to that in reference example 1 was carried out in the same manner as in example 67 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.54(3H，d，J＝2.0Hz)，3.64(3H，s)，6.58(1H，d，J＝7.6Hz)，7.13(1H，d，J＝7.6Hz)，7.48-7.54(1H，m)，7.89(1H，dd，J＝1.6，8.0Hz)，8.00(1H，d，J＝1.6Hz)，8.06-8.14(1H，m)，8.45-8.49(1H，m)，8.55(1H，d，J＝8.4Hz)

ESI-MS found: m/z 323.3[ M + H ] +

Example 95

4- (2-ethyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-ethyl-imidazo [1, 2-a ] pyridine

5.0g of 1-bromo-2-butanone was dissolved in 80ml of ethanol, 5.71g of 2-amino-5-bromopyridine was added thereto, and the mixture was stirred under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were successively added. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate 75: 25) to give 4.82g of the title compound as a white solid.

¹H NMR(300MHz，CDCl3)δ：1.34(3H，t，J＝7.6Hz)，2.82(2H，d，J＝7.6Hz)，7.17(1H，dd，J＝1.9，9.5Hz)，7.32(1H，s)，7.42(1H，d，J＝9.5Hz)，8.19(1H，d，J＝1.9Hz)

ESI-MS found: m/z 225.1[ M + H ] +

2) Preparation of 4- (2-ethyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The halide obtained in the above 1) and the tin reagent 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 1 were treated in the same manner as in example 1 to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.39(3H，t，J＝7.6Hz)，2.48(3H，d，J＝2.0Hz)，2.87(2H，dq，J＝0.76，7.6Hz)，7.44(1H，d，J＝0.73Hz)，7.48-7.54(2H，m)，7.64(1H，td，J＝0.7，9.3Hz)，8.05-8.11(1H，m)，8.45-8.48(1H，m)，8.54-8.55(1H，m)

ESI-MS found: m/z 323.3[ M + H ] +

Example 96

4- (2-methyl-1-oxo-3, 4-dihydroisoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

After 20mg of palladium on charcoal was added to 10ml of an ethanol solution containing 5mg of 4- (2-methyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole, hydrogen was added under pressure of 4 atm to carry out hydrogenation. After 8 hours, the reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (chloroform: methanol: 10: 1) to give the title compound as a white solid, 1 mg.

ESI-MS found: m/z 336.2[ M + H ] +

(example 97)

([1, 8] naphthyridin-3-yl) -4-phenyl-5-methyl-1H- [1, 2, 3] triazole

1) Preparation of (6-fluoro- [1, 8] naphthyridin-3-yl) -4-phenyl-5-methyl-1H- [1, 2, 3] triazole

To a solution of 149mg of 3, 6-dibromo- [1, 8] naphthyridine in 1mL of dimethylformamide under a nitrogen atmosphere were added 79mg of 5-methyl-1-phenyl-1H- [1, 2, 3] triazole, 46mg of sodium acetate, and 55mg of trans-di-. mu. -acetate bis [2- (di-o-tolylphosphino) benzyl ] dipalladium (II) at 140 ℃ and stirred for 23 hours. To the reaction mixture was added a saturated aqueous sodium bicarbonate solution, followed by extraction with chloroform, washing of the chloroform layer with a saturated brine, and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was separated and purified by preparative thin layer chromatography (chloroform: methanol ═ 19: 1) to give the title compound 8.6mg as a colorless solid.

2) Preparation of ([1, 8] naphthyridin-3-yl) -4-phenyl-5-methyl-1H- [1, 2, 3] triazole

1mL of an alcoholic potassium hydroxide solution and a catalytic amount of palladium hydroxide-charcoal were added to 8.6mg of the compound obtained in the above 1), and the mixture was stirred for 30 minutes under a hydrogen atmosphere. The reaction mixture was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (ethyl acetate) to give the title compound (0.52 mg) as a colorless solid.

¹H NMR(300MHz、CDCl₃)δ：2.63(3H，s)，7.50-7.60(5H，m)，8.20-8.33(2H，m)，8.68(1H，d，J＝2.7Hz)，9.15-9.19(1H，m)，9.57(1H，d，J＝2.5Hz)

ESI-MS found: m/z 288.1[ M + H ] +

(example 98)

5- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -4-carbonitrile-1H- [1, 2, 3] triazole

1) Preparation of 2-isopropyl-1-oxo-5- (4, 4, 5, 5-tetramethyl [1, 3, 2] -dioxoborane-2-yl) isoindoline

A solution of 1.01g of 5-bromo-2-cyclopropyl-1-oxo-isoindoline obtained in example 39, 1.02g of bis (pinamate) diborane, 1.18g of potassium acetate, 110mg of 1, 1-bis (diphenylphosphino) -ferrocene, [1, 1-bis (diphenylphosphino) ferrocene ] dichloropalladium (ll) chloride 163.2mg of 1, 4-dioxane in 15ml of nitrogen was stirred at 90 degrees for 8 hours. After cooling to room temperature, the insoluble matter was filtered through celite, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to obtain 1.70g of the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.85-0.94(4H，m)，1.24(6H，s)，1.27(6H，s)，2.90-3.00(1H，m)，4.30(2H，s)，7.81-7.95(3H，m)

2) Preparation of ethyl 3- (2-fluoropyridin-3-yl) -5-trimethylsilanyl-1H- [1, 2, 3] triazole-2-carboxylate

To a solution of 800mg of the compound 3-azido-2-fluoropyridine of reference example 1-1 in 5ml of toluene was added 1.3ml of ethyl 3- (trimethylsilyl) propionate, and the mixture was stirred at 120 ℃ for 1 hour. The resulting solution was cooled to room temperature, and then purified by silica gel column chromatography (hexane: ethyl acetate 5: 1) to obtain 512mg of the title compound as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：1.22-1.31(3H，m)，4.09-4.14(2H，m)，7.41-7.45(1H，m)，7.97-8.01(1H，m)，8.38-8.40(1H，m)

ESI-MS found: m/z 309.2[ M + H ] +

3) Preparation of 3- (2-fluoropyridin-3-yl) -5-trimethylsilanyl-1H- [1, 2, 3] triazole-2-carboxylic acid

512mg of ethyl 3- (2-fluoropyridin-3-yl) -5-trimethylsilanyl-1H- [1, 2, 3] triazole-2-carboxylate obtained in the above-mentioned preparation 2) was dissolved in 10ml of ethanol, and after cooling to 0 ℃, 1.66ml of a 1N aqueous potassium hydroxide solution was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 4 hours. The reaction was terminated with 1M hydrochloric acid, and the solvent was distilled off under reduced pressure. To the residue was added a saturated aqueous sodium hydrogencarbonate solution, followed by back extraction with ethyl acetate, neutralization of the aqueous layer with 1M hydrochloric acid, extraction with ethyl acetate, washing of the ethyl acetate layer with saturated brine, and drying over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.17g of the crude title compound as a white solid.

¹H NMR(400MHz、CD₃OD)δ：0.42(9H，s)，7.52-7.55(1H，m)，8.12-8.17(1H，m)，8.38-8.40(1H，m)

ESI-MS found: m/z 281.2[ M + H ] +

4) Preparation of 3- (2-fluoropyridin-3-yl) -5-trimethylsilanyl-1H- [1, 2, 3] triazole-2-carboxamide

634mg of 3- (2-fluoropyridin-3-yl) -5-trimethylsilanyl-1H- [1, 2, 3] triazole-2-carboxylic acid, which was the compound obtained in 3) above, was dissolved in 5ml of tetrahydrofuran, 1.0ml of triethylamine was added, the reaction mixture was cooled to 0 degrees, 5ml of a tetrahydrofuran solution containing 927mg of isobutyl chloroformate was added, and the mixture was stirred for 30 minutes. Further, 214mg of ammonium hydrogencarbonate was added thereto and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction mixture, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 2) to give 435mg of the crude title compound as a white solid.

5) Preparation of 3- (2-fluoropyridin-3-yl) -5-trimethylsilyl-4-carbonitrile-1H- [1, 2, 3] triazole

170mg of the compound 3- (2-fluoropyridin-3-yl) -5-trimethylsilanyl-1H- [1, 2, 3] triazole-2-carboxamide obtained in the above-mentioned 4) was dissolved in 10ml of dichloromethane, and 0.11ml of trifluoroacetic acid was added thereto and the mixture was stirred for 5 minutes. 796mg of 2-chloro-1, 3-dimethyl-2-imidazolium hexafluorophosphate and 0.8ml of triethylamine were further added thereto, and the mixture was stirred for 4 hours. Water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 1: 2) to give the title compound as a white solid (79.4 mg).

¹H NMR(400MHz、CDCl₃)δ：0.50(9H，s)，7.49-7.52(1H，m)，8.05-8.10(1H，m)，8.48-8.50(1H，m)

ESI-MS found: m/z 262.2[ M + H ] +

6) Preparation of 3- (2-fluoropyridin-3-yl) -5-iodo-4-carbonitrile-1H- [1, 2, 3] triazole

35mg of 3- (2-fluoropyridin-3-yl) -5-trimethylsilyl-4-carbonitrile-1H- [1, 2, 3] triazole, which was the compound obtained in the above 5), was dissolved in 1.0ml of tetrahydrofuran, and 52mg of silver tetrafluoroborate and 168mg of iodine were added to stir at room temperature for 10 hours. The reaction mixture was filtered through celite, a saturated aqueous sodium thiosulfate solution was added to the filtrate, and the solvent was distilled off under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 2: 1) to give the title compound 31mg as a white solid.

7) Preparation of 5- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -4-carbonitrile-1H- [1, 2, 3] triazole

Under nitrogen, 35mg of the compound 2-isopropyl-1-oxo-5- (4, 4, 5, 5-tetramethyl [1, 3, 2] -dioxoborane-2-yl) isoindoline obtained in the above 1) and 31ml of the compound 3- (2-fluoropyridin-3-yl) -5-iodo-4-carbonitrile-1H- [1, 2, 3] triazole obtained in the above 6) were dissolved in 3.0ml of dimethylformamide, 27mg of [1, 1-bis (diphenylphosphino) -ferrocene ] dichloropalladium was added, and the mixture was stirred at 80 ℃ for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by preparative thin layer chromatography (hexane: ethyl acetate 1: 2) to give the title compound as a white solid (0.74 mg).

¹H NMR(400MHz、CDCl₃)5：0.93-0.98(4H，m)，2.99-3.00(1H，m)，4.45(2H，s)，7.54-7.57(1H，m)，8.01(1H，d，J＝8.0Hz)，8.14-8.16(1H，m)，8.21(1H，s)，8.25(1H，d，J＝8.4Hz)，8.55(1H，m)

ESI-MS found: m/z 361.3[ M + H ] +

(example 99)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-chloropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 49 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 7, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(300MHz、CDCl₃)δ：0.88-0.99(4H，m)，2.46(3H，s)，2.95-3.01(1H，m)，4.41(2H，s)，7.55(1H，dd，J＝4.9，7.9Hz)，7.81(1H，dd，J＝1.3，7.9Hz)，7.88-7.95(2H，m)，7.99(1H，d，J＝0.7Hz)，8.67(1H，dd，J＝2.0，4.9Hz)

ESI-MS found: m/z 366.0[ M + H ] +

(example 100)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-methoxypyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-hydroxypyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

180mg of 4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 49 was dissolved in 10ml of formic acid and stirred for 5 hours. After cooling to room temperature, the residue obtained by removing the solvent through silica gel column chromatography (chloroform: methanol 90: 10) through evaporation under reduced pressure was purified to obtain 112mg of the title compound as a white solid.

2) Preparation of 4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-methoxypyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The compound obtained in 1) 70mg, potassium carbonate 83mg and methyl iodide 50. mu.l were suspended in dimethylformamide 2.0ml, and stirred at 60 ℃ for 5 hours. After water was added to the reaction mixture, the mixture was extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer basic silica gel chromatography (ethyl acetate) to give the title compound (3.38 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.83-1.00(4H，m)，2.40(3H，s)，2.91-3.01(1H，m)，4.01(3H，s)，4.40(2H，s)，7.097.17(1H，m)，7.75-7.83(2H，m)，7.92(1H，d，J＝7.9Hz)，7.98(1H，s)，8.39(1H，dd，J＝1.9，5.0Hz)

ESI-MS found: m/z 362.1[ M + H ] +

(example 101)

4- (2-isopropyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-isopropylisoquinolin-1-one

Under a nitrogen atmosphere, 18mg of 60% sodium hydride was added to a solution of 100mg of 6-bromo-2H-isoquinolin-1-one in 2ml of dimethylformamide at 0 ℃ and stirred for 30 minutes, then 0.05ml of isopropyl iodide was added thereto at 0 ℃ and stirred for 2 hours at room temperature. After cold water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (17 mg).

¹H NMR(400MHz、CDCl₃)δ：1.39(6H，d，J＝7.2Hz)，5.32-5.40(1H，m)，6.46(1H，d，J＝7.2Hz)，7.17(1H，d，J＝7.6Hz)，7.56(1H，dd，J＝1.8，8.6Hz)，7.66(1H，d，J＝2.0Hz)，8.28(1H，d，J＝8.4Hz)

ESI-MS found: m/z 267.9[ M + H ] +

2) Preparation of 4- (2-isopropyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The coupling reaction of the compound obtained in 1) above and an alkyltin compound 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole similar to that in reference example 1 was carried out in the same manner as in example 3 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.42(6H，d，J＝7.2Hz)，2.54(3H，d，J＝2.4Hz)，5.39-5.47(1H，m)，6.64(1H，d，J＝7.2Hz)，7.21(1H，d，J＝7.6Hz)，7.48-7.54(1H，m)，7.88(1H.dd.J＝1.6，8.4Hz)，7.99(1H，d，J＝1.6Hz)，8.09(1H，td，J＝1.6，7.4Hz)，8.47(1h，dt，J＝1.5，4.8Hz)，8.56(1H，d，J＝8.8Hz)

ESI-MS found: m/z 364.3[ M + H ] +

(example 102)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (6-fluoropyridin-2-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 49 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 8, the title compound was obtained as a white solid using the same method as example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.87-0.98(4H，m)，2.84(3H，s)，2.95-3.01(1H，m)，4.41(2H，s)，7.04-7.07(1H，m)，7.77(1H，dd，J＝1.5，8.1Hz)，7.85-7.86(1H，m)，7.94(1H，d，J＝8.1Hz)，7.99-8.10(2H，m)

ESI-MS found: m/z 350.3[ M + H ] +

(example 103)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H-pyrazole

1) Preparation of 2-cyclopropyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxoborane-2-yl) isoindolin-1-one

5-bromo-2-cyclopropyl-1-oxo-isoindoline obtained in example 49, 1.01g, bis (pinacolato) diborane, 1.02g, potassium acetate, 1.18g, 1-bis (diphenylphosphino) -ferrocene, 110mg, [1, 1-bis (diphenylphosphino) ferrocene ] dichloropalladium dichloromethane complex (163 mg) was suspended in 15ml of 1, 4-dioxane and stirred at 90 ℃ overnight. The resulting suspension was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to give the title compound 1.46g as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.85-0.94(4H，m)1.24(6H，s)，1.27(6H，s)，2.90-3.00(1H，m)4.30(2H，s)，7.81-7.90(3H，m)

2) Preparation of 4-bromo-1- (2-fluorophenyl) -3-methyl-1H-pyrazole

580mg of 4-bromo-3-methylpyrazole, 1.0g of 2-fluorophenylboronic acid, 3.33g of acetone, 1.0g of 4A molecular sieve and 1.6ml of pyridine were suspended in 8.0ml of dimethylformamide, and the mixture was stirred at room temperature for 3 days. The resulting suspension was filtered through celite, and the filtrate was diluted with ethyl acetate. The organic layer was washed with 0.5 equivalent of sodium hydroxide, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to give 78mg of the crude purified product of the title compound.

3) Preparation of 4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H-pyrazole

90mg of 2-cyclopropyl-5- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxoborane-2-yl) isoindolin-1-one obtained in the above-mentioned 1), 78mg of 4-bromo-1- (2-fluorophenyl) -3-methyl-1H-pyrazole obtained in the above-mentioned 2), 25mg of [1, 1' -bis- (diphenylphosphino) -ferrocene ] dichloropalladium dichloromethane complex, 83mg of potassium carbonate, and stirred at 80 ℃ overnight were suspended in 3.0ml of dimethylformamide. Water was added to the reaction solution, and the product was extracted with ethyl acetate, washed with saturated ammonium chloride and water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by thin layer chromatography (ethyl acetate) to obtain a crude purified product. The crude purified product was purified again by using an optically active column (CHIRALPAK AD-H column manufactured by ダイセル Co.; hexane: isopropanol: 1) to obtain 1.9mg of the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.86-0.98(4H，m)，2.50(3H，s)，2.95-2.98(1H，m)，4.37(2H，s)，7.13-7.18(2H，m)，7.48-7.54(2H，m)，7.64-7.68(2H，m)，7.87(1H，d，J＝7.8Hz)，7.96(1H，s)

APCI-MS found: m/z 348.1[ M + H ] +

(example 104)

4- (2-dimethylcarbamoyl-1-oxo-indan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-N, N-dimethylcarbamoyl-1-oxo-indane

To a solution of 100mg of 5-bromo-2-methoxycarbonyl-1-oxo-indan in 3ml of tetrahydrofuran was added 60mg of dimethylamine hydrochloride followed by 0.75ml of a 2M solution of isopropyl magnesium chloride in tetrahydrofuran at room temperature. After stirring at room temperature for 1.5 hours, the mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distillation of the solvent under reduced pressure was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to give the title compound (24 mg).

¹H NMR(300MHz、CDCl₃)δ：3.02(3H，s)，3.17-3.26(1H，m)，3.34(3H，s)，3.72-3.84(1H，m)，4.10-4.18(1H，m)，7.50-7.70(3H，m)

2) Preparation of 4- (2-dimethylcarbamoyl-1-oxo-indan-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained according to the procedure of example 5 using the compound obtained in the above 1) and the compound of reference example 1, 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole.

¹H NMR(400MHz、CDCl₃)δ：2.52(3H，d，J＝2.1Hz)，3.06(3H，s)，3.34(1H，dd，J＝7.8，17.1Hz)，3.36(3H，s)，3.87(1H，dd，J＝3.6，17.1Hz)，4.20(1H，dd，J＝3.6，7.8Hz)，7.51(1H，ddd，J＝1.2，5.1，7.8Hz)，7.82-7.84(2H，m)，7.97(1H，s)，8.10(1H，ddd，J＝2.1，7.8，9.0Hz)，8.47(1H，dt，J＝2.1，5.1Hz)

ESI-MS found: m/z 380.3[ M + H ] +

(example 105)

4- (2-Ethyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-ethylisoquinolin-1-one

Under a nitrogen atmosphere, 22mg of 60% sodium hydride was added to a solution of 100mg of 6-bromo-2H-isoquinolin-1-one in 3ml of dimethylformamide at 0 ℃ and stirred for 30 minutes, then 0.04ml of methyl iodide was added at 0 ℃ and stirred at room temperature for 3 hours. After cold water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (30 mg).

¹H NMR(400MHz、CDCl₃)δ：1.38(3H，t，J＝7.4Hz)，4.04(2H，q，J＝7.2Hz)，6.41(1H，d，J＝7.2Hz)，7.10(1H，d，J＝7.6Hz)，7.56(1H，dd，J＝1.8，8.6Hz)，7.67(1H，d，J＝2.0Hz)，8.28(1H，d，J＝8.4Hz)

ESI-MS found: m/z 253.9[ M + H ] +

2) Preparation of 4- (2-ethyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.42(3H，t，J＝7.4Hz)，2.54(3H，d，J＝2.0Hz)，4.09(2H，q，J＝7.2Hz)，6.60(1H，d，J＝7.2Hz)，7.14(1H，d，J＝7.2Hz)，7.48-7.54(1H，m)，7.88(1H，dd，J＝2.0，8.4Hz)，8.00(1H，d，J＝2.0Hz)，8.09(1H，td，J＝2.0，7.4Hz)，8.44-8.49(1H，m)，8.55(1H，d，J＝8.4Hz)

ESI-MS found: m/z 350.3[ M + H ] +

(example 106)

4- (2-Ethyl-1-oxo-3, 4-dihydroisoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

After 20mg of palladium on charcoal was added to 10ml of an ethanol solution containing 5mg of 4- (2-ethyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole, hydrogen was added under pressure of 4 atm to carry out hydrogenation. After 8 hours, the reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was separated and purified by thin layer chromatography (chloroform: methanol: 10: 1) to give the title compound 1mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.25(3H，t，J＝7.2Hz)，2.49(3H，d，J＝2.0Hz)，3.09(2H，t，J＝6.6Hz)，3.58-3.70(4H，m)，7.47-7.53(1H，m)，7.68(1H，d，J＝7.6Hz)，7.74(1H，s)，8.04-8.11(1H，m)，8.20(1H，d，J＝8.0Hz)，8.46(1H，d，J＝5.2Hz)

ESI-MS found: m/z 352.0[ M + H ] +

(example 107)

4- (Thiazolo [5, 4-b ] pyridin-2-yl) -1- (2-chlorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 1- (2-chlorophenyl) -5-methyl-4-trimethylsilyl-1H- [1, 2, 3] triazole

Under nitrogen, 50mg of 2-chloroazidobenzene and 0.49mL of 1- (trimethylsilyl) -1-propane were dissolved in 1mL of toluene, and the mixture was refluxed for 16 hours, and then the solvent was distilled off to obtain a residue, which was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 5: 1) to obtain 66mg of the title compound.

¹H NMR(300MHz、CDCl₃)δ：0.40(9H，s)，2.20(3H，s)，7.33-7.59(4H，m)

ESI-MS found: m/z 266.1[ M + H ] +

2) Preparation of 1- (2-chlorophenyl) -4-iodo-5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 65mg of 1- (2-chlorophenyl) -5-methyl-4-trimethylsilyl-1H- [1, 2, 3] triazole was dissolved in 2ml of methanol, 95mg of silver tetrafluoroborate and 126mg of iodine were added, and the mixture was stirred at room temperature for 4 hours, followed by filtration of the reaction solution with celite. The filtrate was diluted with chloroform, washed with saturated sodium sulfite and water, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 10: 1) to give the title compound (67 mg).

¹H NMR(300MHz、CDCl₃)δ：2.20(3H，s)，7.36-7.63(4H，m)

3) Preparation of 4- (thiazolo [5, 4-b ] pyridin-2-yl) -1- (2-chlorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Under nitrogen, 344mg of 1- (2-chlorophenyl) -4-iodo-5-methyl-1H- [1, 2, 3] triazole and 276mg of thiazolo (5, 4-b) pyridine (B.Stanovnik, Synthesis, 1974, 120) were dissolved in DMF3mL, and 100mg of sodium acetate and 103mg of Herrman catalyst were added thereto, and after stirring at 140 ℃ for 8 hours, the reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1) to give the title compound as a white solid (30 mg).

¹H NMR(300MHz、CDCl₃) δ: 2.69(3H, s), 7.42-7.68(5H, m), 8.26(1H, dd, J ═ 1.5 and 8.3Hz), 8.60(1H, dd, J ═ 1.5Hz, 4.6Hz)

ESI-MS found: m/z 328.2[ M + H, ESI ]

(example 108)

4- (2-fluoromethyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-fluoroethylisoquinolin-1-one

To a solution of 6-bromo-2H-isoquinolin-1-one (300 mg) in toluene (3 ml) was added phosphorus oxychloride (100. mu.l) and dimethylaniline (340. mu.l) under a nitrogen atmosphere at room temperature, and the mixture was stirred at 90 ℃ for 7 hours. After cold water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by thin layer chromatography (hexane: ethyl acetate 5: 1) to give a compound, which was dissolved in acetonitrile 2 ml. To the solution, 56. mu.l of 2, 2-dichloro-2- (fluorosulfonyl) acetic acid and 45mg of sodium hydrogencarbonate were added at room temperature, and the mixture was stirred at 40 ℃ for 36 hours. After sodium bicarbonate was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (hexane: ethyl acetate 1: 1) to give the title compound (44 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：6.52(1H，d，J＝8.0Hz)，7.28(1H，d，J＝7.6Hz)，7.63(1H，dd，J＝1.8，8.6Hz)，7.70(1H，d，J＝1.6Hz)，7.79(1H，d，J＝60.0Hz)，8.25(1H，d，J＝8.4Hz)

ESI-MS found: m/z 275.9[ M + H ] +

2) Preparation of 4- (2-fluoromethyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：2.55(3H，d，J＝2.4Hz)，6.70(1H，d，J＝8.0Hz)，7.31(1H，d，J＝7.6Hz)，7.48-7.54(1H，m)，7.85(1H，t，J＝60.4Hz)，7.96(1H，dd，J＝1.6，8.4Hz)，8.03(1H，s)，8.06-8.13(1H，m)，8.48(1H，d，J＝4.8Hz)，8.52(1H，d，J＝8.4Hz)

ESI-MS found: m/z 372.0[ M + H ] +

(example 109)

4- (2-difluoromethyl-1-oxo-3, 4-dihydroisoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

After 20mg of palladium on charcoal was added to a solution of 7mg of 4- (2-difluoromethyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole in 10ml of ethanol, hydrogen was added under pressure of 4 atm to carry out hydrogenation. After 8 hours, the reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (chloroform: methanol 10: 1) to give the title compound as a white solid, 2 mg.

¹H NMR(400MHz、CDCl₃)δ：2.52(3H，d，J＝1.2Hz)，3.16(2H，t，J＝6.6Hz)，3.78(2H，t，J＝6.4Hz)，7.48-7.54(1H，m)，7.57(1H，t，J＝61.0Hz)，7.75(1H，d，J＝8.0Hz)，7.81(1H，s)，8.08(1H，t，J＝8.4Hz)，8.22(1H，d，J＝8.8Hz)，8.47(1H，d，J＝6.0Hz)

ESI-MS found: m/z 374.1[ M + H ] +

(example 110)

4- ([1, 7] naphthyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 1, 7-naphthyridin-6-yl trifluoromethanesulfonate

264mg of 6-amino-1, 7-naphthyridine (Rosita Tan, tetrahedron letters, 1966, 1233) and 2mL of trifluoromethanesulfonic acid were dissolved in DMF4mL, and 251mg of sodium nitrite was added, and after stirring at room temperature for 90 minutes, the reaction mixture was diluted with ethyl acetate, washed with water, a saturated aqueous sodium bicarbonate solution and a saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off to leave a residue, which was purified by silica gel column chromatography (ethyl acetate: hexane: 1) to give the title compound (320 mg).

¹H NMR(300MHz、CDCl₃) δ: 7.61(1H, s), 7.71(1H, dd, J ═ 4.1 and 8.5Hz), 8.26(1H, d, J ═ 8.5Hz), 9.12(1H, d, J ═ 4.1Hz), 9.35(1H, s)

ESI-MS found: m/z 279.2[ M + H ] +

2) Preparation of 4- ([1, 7] naphthyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

95.2mg of 1, 7-naphthyridin-6-yl trifluoromethanesulfonate and 75mg of 1- (2-fluoropyridin-3-yl) -4-tri-n-butyltin-5-methyl-1H- [1, 2, 3] triazole prepared in reference example 1 were dissolved in DMF2mL, 22mg of triphenylarsine and 11.7mg of tris (dibenzylideneacetone) dipalladium (0) were added, and after stirring at 60 ℃ for 66 minutes, the reaction mixture was diluted with a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off to leave a residue, which was subjected to separation and purification by thin layer silica gel column chromatography (chloroform: methanol: 19: 1) to give the title compound as a white solid (9.7 mg).

¹H NMR(300MHz、CDCl₃)δ：2.80(3H，d，J＝1.2Hz)，7.47-7.52(1H，m)，7.61-7.65(1H，m)，8.04-8.10(1H，m)，8.27(1H，d，J＝5.9Hz)，8.47(1H，d，J＝4.9Hz)，8.62(1H，s)，9.03(1H，d，J＝4.0Hz)，9.55(1H，s)

ESI-MS found: m/z 307.0[ M + H ] +

(example 111)

4- (2-tert-Butoxycarbonyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-tert-butoxycarbonyl-1-oxo-isoindoline

In a nitrogen atmosphere, 5-bromo-1-oxo-isoindoline (1.5 g) was dissolved in tetrahydrofuran (20 ml), and after cooling to 0 ℃, 85mg of N, N-dimethylaminopyridine and di-tert-butyl dicarbonate (3.0 ml) were added and the mixture was stirred at room temperature for 30 minutes. Methanol was added to the reaction mixture, and the solvent was distilled off under reduced pressure. Water was added to the residue, which was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (300 mg).

¹H NMR(400MHz，CDCl₃)δ：1.60(9H，s)，4.74(2H，s)，7.62-7.65(2H，m)，7.76(1H，d，J＝8.0Hz)

ESI-MS found: m/z 344.2[ M + Na ] +

Under a nitrogen atmosphere, 720mg of 5-bromo-2-tert-butoxycarbonyl-1-oxo-isoindoline obtained in 1) above and 720mg of 1- (2-fluoropyridin-3-yl) -4-tri-N-butyltin-5-methyl- [1, 2, 3] triazole prepared in reference example 1 were dissolved in N, N-dimethylformamide, 178mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was heated at 115 ℃ and stirred for 4 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. Water was added to the filtrate, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound as a white solid (300 mg).

¹H NMR(400MHz、CDCl₃)δ：1.62(9H，s)，2.52(3H，d，J＝2.1Hz)，4.84(2H，s)，7.48-7.53(1H，m)，7.87-7.89(1H，m)，7.99-8.01(2H，m)，8.03(1H，m)，8.07-8.11(1H，m)，8.46-8.48(1H，m)

ESI-MS found: m/z 432.2[ M + Na ] +

(example 112)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-methylphenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (2-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 9.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.4Hz)，2.12(3H，s)，2.37(3H，s)，4.43(2H，s)，4.68-4.78(1H，m)，7.15-7.35(1H，m)，7.38-7.55(3H，m)，7.83(1H，dd，J＝1.4，7.8Hz)，7.94(1H，d，J＝8.0Hz)，8.06(1H，s)

ESI-MS found: m/z 347.2[ M + H ] +

(example 113)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (3-methylphenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (3-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 10.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.48(3H，s)，2.52(3H，s)，4.43(2H，s)，4.68-4.78(1H，m)，7.25-7.42(3H，m)，7.47(1H，t，J＝7.8Hz)，7.8(1H，d，J＝8.0Hz)，7.94(1H，d，J＝8.0Hz)，8.00(1H，s)

ESI-MS found: m/z 347.1[ M + H ] +

(example 114)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (3-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (3-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 11.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.56(3H，s)，4.43(2H，d，J＝0.4Hz)，4.65-4.75(1H，m)，7.25-7.39(3H，m)，7.55-7.62(1H，m)，7.79(1H，d，J＝8.4Hz)，7.95(1H，d，J＝7.6Hz)，7.99(1H，s)

ESI-MS found: m/z 351.1[ M +1] +

Example 115

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 12.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.52(3H，s)，4.43(2H，s)，4.65-4.75(1H，m)，7.26-7.34(2H，m)，7.50-7.58(2H，m)，7.79(1H，d，J＝8.8Hz)，7.95(1H，d，J＝8.0Hz)，8.00(1H，s)

ESI-MS found: m/z 351.1[ M + H ] +

(example 116)

4- (2-cyclobutyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-cyclobutyl-1-oxo-isoindoline

Under nitrogen, 200mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in toluene, and 418mg of cyclobutylamine hydrochloride and 0.4ml of triethylamine were added to the solution, followed by refluxing with heating for 2 hours. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (60 mg).

¹H NMR(400MHz、CDCl₃)δ：1.74-1.80(2H，m)，2.23-2.30(4H，m)，4.43(2H，s)，4.89-4.93(1H，m)，7.58(1H，d，J＝8.0Hz)，7.62(1H，s)，7.68(1H，d，J＝8.0Hz)

ESI-MS found: m/z 266.2[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-cyclobutyl-1-oxo-isoindolin-5-yl) -5-methyl-1H- [1, 2, 3] triazole

21mg of 5-bromo-2-chlorobutyl-1-oxo-isoindoline obtained in 1) above and 30mg of 1- (2-chloropyridin-3-yl) -4-tri-n-butyltin-5-methyl-1H- [1, 2, 3] triazole prepared in reference example 1 were dissolved in toluene in a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound as a white solid (16 mg).

¹H NMR(400MHz、CDCl₃)δ：1.78-1.83(2H，m)，2.29-2.35(4H，m)，2.50(3H，d，J＝2.1Hz)，4.55(2H，s)，4.96-5.00(1H，m)，7.49-7.52(1H，m)，7.80-7.82(1H，m)，7.93-7.95(1H，m)，8.00(1H，m)，8.07-8.11(1H，m)8.46-8.47(1H，m)

ESI-MS found: m/z 364.3[ M + H ] +

(example 117)

4- (2-ethoxycarbonyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the same method as example 49, a method based thereon, or a combination thereof with a usual method, 6-bromo-2-ethoxycarbonyl-imidazo [1, 2-a ] pyridine and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 1, the title compound was obtained as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.46(3H，t，J＝7.1Hz)，2.50(3H，d，J＝2.2Hz)，4.49(2H，q，J＝7.1Hz)，7.50-7.54(1H，m)，7.65-7.69(1H，m)，7.82(1H，d，J＝9.4Hz)，8.05-8.12(1H，m)，8.29(1H，s)，8.48(1H，d，J＝4.9Hz)，8.02(1H，s)

ESI-MS found: m/z 367.3[ M + H ] +

(example 118)

4- (2-cyclopentyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-cyclopentyl-1-oxo-isoindoline

The reaction was carried out in the same manner as in example 116-1) except for using cyclopentylamine instead of the cyclobutylamine hydrochloride used in example 116-1) to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.58-1.83(6H，m)，1.90-2.04(2H，m)，4.34(2H，s)，4.70-4.78(1H，m)，7.58(1H，d，J＝8.0Hz)，7.59(1H，s)，7.69(1H，d，J＝8.0Hz)

ESI-MS found: m/z 282.2[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-cyclopentyl-1-oxo-isoindolin-5-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained by the method of example 116-2) using the compound obtained in 1) above and the compound of reference example 1, 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole.

¹H NMR(400MHz、CDCl₃)δ：1.70-2.04(6H，m)，2.50(3H，m)，4.45(2H，s)，4.82-4.79(1H，m)，7.49-7.52(1H，m)，7.80-7.82(1H，m)，7.94-7.98(2H，m)，8.07-8.11(1H，m)，8.46-8.47(1H，m)

ESI-MS found: m/z 378.3[ M + H ] +

(example 119)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

125mg of the halide 5-bromo-2-isopropyl-1-oxo-isoindoline obtained in example 36 and 280mg of the tin compound 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole of reference example 13 were dissolved in 3ml of toluene in a nitrogen atmosphere, 115mg of tetrakis (triphenylphosphine) palladium was added, and after degassing, the mixture was stirred at 115 degrees under heating for 13 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (130 mg).

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.45(3H，d，J＝1.6Hz)，4.43(2H，s)，4.65-4.75(1H，m)，7.05-7.18(2H，m)，7.55-7.61(1H，m)，7.80(1H，d，J＝8.0Hz)，7.95(1H，d，J＝8.0Hz)，8.00(1H，s)

ESI-MS found: m/z 369.1[ M + H ] +

(example 120)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 4.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.47(3H，d，J＝2.0Hz)，4.43(2H，s)，4.65-4.75(1H，m)，7.32-7.42(2H，m)，7.55-7.63(2H，m)，7.82(1H，dd，J＝1.6，8.0Hz)，7.95(1H，d，J＝7.6Hz)，8.02(1H，d，J＝0.8Hz)

ESI-MS found: m/z 352.2[ M + H ] +

(example 121)

1- (2-fluoropyridin-3-yl) -4- (2- (1-hydroxy-1-methyl-ethyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

18.3mg of 4- (2-ethoxycarbonyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 117 was dissolved in 1.0ml of tetrahydrofuran, and after cooling to 0 ℃, 500. mu.l of a 0.93M tetrahydrofuran solution of methylmagnesium bromide was added dropwise. After stirring overnight at room temperature, a saturated sodium bicarbonate solution was added. The product was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by thin layer basic silica gel chromatography (ethyl acetate) to give the title compound as a white solid (1.02 mg).

¹H NMR(400MHz、CDCl₃)δ：1.71(6H，s)，2.48(3H，d，J＝2.0Hz)，2.79(1H，brs)，7.48-7.61(3H，m)，7.69(1H，d，J＝9.3Hz)，8.05-8.11(1H，m)，8.46-8.49(1H，m)，8.57(1H，dd，J＝1.0，1.7Hz)

APCI-MS found: m/z 353.0[ M + H ] +

(example 122)

1- (2-Fluoropyridin-3-yl) -4- (2-hydroxymethyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-Fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

36.6mg of 4- (2-ethoxycarbonyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 117 was dissolved in 1.0ml of tetrahydrofuran, and after cooling to 0 degrees, 10mg of lithium aluminum hydride was added. After stirring at room temperature for 30 minutes, sodium sulfate 10 hydrate was added and stirred for 2 hours. The resulting suspension was diluted with ethyl acetate and chloroform, and the insoluble matter was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer silica gel chromatography (several drops of ethyl acetate and methanol) to give the title compound as a white solid (24.6 mg).

¹H NMR(400MHz、CDCl₃)δ：2.49(3H，d，J＝2.0Hz)，4.90(2H，s)，7.48-7.53(1H，m)，7.59(1H，dd，J＝1.5，9.3Hz)，7.65-7.71(2H，m)，8.06-8.11(1H，m)，8.46-8.49(1H，m)，8.59(1H，s)

ESI-MS found: m/z 325.1[ M + H ] +

(example 123)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (4-methylphenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (4-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 14.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.48(3H，s)，2.51(3H，s)，4.42(2H，s)，4.67-4.77(1H，m)，7.39(4H，s)，7.79(1H，d，J＝8.0Hz)，7.94(1H，d，J＝7.6Hz)，8.00(1H，d，J＝0.8Hz)

ESI-MS found: m/z 347.2[ M + H ] +

(example 124)

1- (2-Fluoropyridin-3-yl) -4- (2-methoxymethyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-Fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

20.0mg of 1- (2-fluoropyridin-3-yl) -4- (2-hydroxymethyl-imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 122 was dissolved in 1.0ml of dimethylformamide, and after cooling to 0 ℃, 24mg of 60% sodium hydride and 50. mu.l of methyl iodide were added. After stirring at room temperature for 1 hour, a saturated sodium bicarbonate solution was added. The product was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by thin layer basic silica gel chromatography (ethyl acetate) to give the title compound as a white solid (2.91 mg).

¹H NMR(400MHz、CDCl₃)δ：2.49(3H，d，J＝2.0Hz)，3.52(3H，s)，4.67(2H，s)，7.48-7.53(1H，m)，7.56(1H，dd，J＝1.7，9.2Hz)，7.65-7.71(2H，m)，8.06-8.11(1H，m)，8.46-8.48(1H，m)，8.58-8.60(1H，m)

APCI-MS found: m/z 339.0[ M + H ] +

(example 125)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-trifluoromethyl-phenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (2-trifluoromethyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 15.

¹H NMR(400MHz、CDCl₃) δ: 1.33(6H, d, J ═ 6.8 measured Hz), 2.36(3H, s), 4.43(2H, s), 4.65-4.75(1H, m), 7.47(1H, d, J ═ 7.6Hz), 7.75-7.85(3H, m), 7.94(2H, d, J ═ 8.0Hz), 8.05(1H, s)

ESI-MS found: m/z 401.1[ M + H ] +

(example 126)

4- (2-isopropyl-1-oxo-3, 4-dihydroisoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

After 30mg of palladium on charcoal was added to 10ml of an ethanol solution containing 10mg of 4- (2-isopropyl-1-oxo-isoquinolin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole, hydrogen was added under pressure of 4 atm to carry out hydrogenation. After 8 hours, the reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (chloroform: methanol 10: 1) to give the title compound as a white solid (7 mg).

¹H NMR(400MHz、CDCl₃)δ：1.23(6H，d，J＝6.8Hz)，2.49(3H，d，J＝2.0Hz)，3.04(2H，t，J＝6.4Hz)，3.49(2H，t，J＝6.4Hz)，5.09-5.16(1H，m)，7.26-7.52(1H，m)，7.68(1H，dd，J＝1.6，8.0Hz)，7.74(1H，d，J＝0.4Hz)，8.08(1H，td，J＝1.6，8.0Hz)，8.20(1H，d，J＝8.0Hz)，8.44-8.48(1H，m)

ESI-MS found: m/z 366.1[ M + H ] +

(example 127)

4- (2-methyl-1-oxo-isoquinolin-5-yl) -1-phenyl-5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 94 and the tin reagent 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 5.

¹H NMR(400MHz、CDCl₃)δ：2.57(3H，s)，3.64(3H，s)，6.58(1H，d，J＝6.8Hz)，7.12(1H，d，J＝7.6Hz)，7.50-7.63(5H，m)，7.88(1H，dd，J＝2.0，8.4Hz)，8.02(1H，d，J＝2.0Hz)，8.54(1H，d，J＝8.4Hz)

ESI-MS found: m/z 317.1[ M + H ] +

(example 128)

4- (2-cyclobutylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-cyclobutylmethyl-1-oxo-isoindoline

The reaction was carried out in the same manner as in example 116-1) except for using 2-cyclobutylmethyl amine instead of the cyclobutyl amine hydrochloride used in example 116-1) to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.79-1.84(2H，m)，1.89-1.95(2H，m)，2.06-2.11(2H，m)，2.65-2.69(1H，m)，3.63(1H，d，J＝7.6Hz)，4.32(2H，s)，4.70-4.78(1H，m)，7.57-7.60(2H，m)，7.69-7.71(1H，m)

ESI-MS found: m/z 282.2[ M + H ] +

2) Preparation of 4- (2-cyclobutylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.83-1.99(4H，m)，2.08-2.13(2H，m)，2.50(3H，d，J＝1.9Hz)，2.68-2.76(1H，m)，3.09(2H，d，J＝7.6Hz)，4.44(2H，s)，7.49-7.52(1H，m)，7.80-7.82(1H，m)，7.94(1H，s)，7.96(1H，m)，8.06-8.11(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 378.1[ M + H ] +

(example 129)

4- [2- (3-benzyloxy-cyclobutylmethyl) -1-oxo-isoindolin-5-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 3-benzyloxy-cyclobutyl azidomethane

To a solution of 375mg of 3-benzyloxy-cyclobutanemethanol in 4ml of tetrahydrofuran at room temperature were added 840. mu.l of triethylamine followed by 232. mu.l of methanesulfonyl chloride. After stirring at room temperature for 30 minutes, the mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. After the resulting residue was dissolved in 4ml of dimethylformamide, 145mg of sodium azide was added thereto, and the mixture was stirred at 80 ℃ overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate: 85: 15) to give the title compound (365 mg).

¹H NMR(300MHz、CDCl₃)δ：1.70-2.60(5H，m)，3.25-3.35(2H，m)，3.90-4.20(1H，m)，4.40-4.42(2H，m)，7.25-7.38(5H，m)

2) Preparation of 5-bromo-2- (3-benzyloxy-cyclobutylmethyl) -1-oxo-isoindoline

After 3-benzyloxy-cyclobutylazidomethane 365mg was dissolved in methanol 10ml, 10% palladium on charcoal 80mg was added and stirred for 1 hour under a hydrogen atmosphere. The reaction solution was filtered through celite, and the resulting liquid was concentrated under reduced pressure. The resulting residue was dissolved in 5ml of toluene, and 378mg of methyl 4-bromo-2-bromo-methylbenzoate and 1ml of triethylamine were added thereto, followed by refluxing with heating and stirring overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate: hexane: 80: 20) to give the title compound (352 mg) as a white solid.

¹H NMR(300MHz、CDCl₃)δ：1.75-2.70(4H，m)，3.62-3.70(2H，m)，3.87-4.30(1H，m)，4.30-4.36(2H，m)，4.40-4.42(2H，m)7.28-7.74(8H，m)

ESI-MS found: m/z 310.1[ M + H ] +

3) Preparation of 4- [2- (3-benzyloxy-cyclobutylmethyl) -1-oxo-isoindolin-5-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained according to the procedure of example 5 using the compound obtained in the above 2) and the compound of reference example 1, 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole.

¹H NMR(400MHz、CDCl₃)δ：1.79-1.92(1H，m)，2.12-2.25(2H，m)，2.41-2.50(3H，m)，2.62-2.75(1H，m)，3.66-3.77(2H，m)，3.90-4.00(1/2H，m)，4.25-4.35(1/2H，m)，4.40-4.49(4H，m)，7.29-7.60(4H，m)，7.62-7.71(2H，m)，7.79-7.85(1H，m)，7.93-7.99(2H，m)，8.05-8.04(1H，m)，8.45-8.49(1H，m)

ESI-MS found: m/z 484.3[ M + H ] +

Example 130

4- (2- (1-methyl-cyclopropylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (1-methyl-cyclopropylmethyl) -1-oxo-isoindoline

In a nitrogen atmosphere, 50mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in methanol, and 1-methyl-cyclopropylmethylamine and 0.1ml of triethylamine were added thereto, followed by heating and refluxing overnight. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (28 mg).

¹H NMR(400MHz、CDCl₃)δ：0.43-0.44(2H，m)，0.50-0.53(2H，m)，1.02(3H，s)，3.46(2H，s)，4.44(2H，s)，4.89-4.93(1H，m)，7.59-7.62(2H，m)，7.72(1H，d，J＝8.0Hz)

ESI-MS found: m/z 282.1[ M + H ] +

2) Preparation of 4- (2- (1-methyl-cyclopropylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

28mg of 5-bromo-2- (1-methyl-cyclopropylmethyl) -1-oxo-isoindoline obtained in 1) above and 50mg of 1- (2-chloropyridin-3-yl) -4-tri-n-butyltin-5-methyl-1H- [1, 2, 3] triazole prepared in reference example 1 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound (24 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.44-0.46(2H，m)，0.55(2H，m)，1.07(3H，s)，2.51(3H，d，J＝2.15)，3.52(2H，s)，4.55(2H，s)，7.49-7.52(1H，m)，7.82-7.84(1H，m)，7.96-7.98(2H，m)，8.07-8.12(1H，m)，8.46-8.47(1H，m)

ESI-MS found: m/z 378.2[ M + H ] +

(example 131)

4- (2- (2-hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) 5-bromo-2- (2-trans)^*Preparation of (E) -tetrahydro-2H-2-pyranyloxy-cyclopropyl) -1-oxo-isoindoline

In a nitrogen atmosphere, 30mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in methanol, and 2-tetrahydro-2H-2-pyranyloxy-cyclopropylamine and 0.1ml of triethylamine were added to the solution, followed by heating and refluxing for 2 hours. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give 31mg of the compound which was referred to as trans-isomer for convenience as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.19-1.82(8H，m)，2.87-3.11(1H，m)，3.60-4.00(3H，m)，4.24-4.33(2H，m)，4.85-5.09(1H，m)，7.56-7.58(2H，m)，7.67(1H，d，J＝8.0Hz)

ESI-MS found: m/z 353.9[ M + H ] +

2)4- (2- (2-trans)^*-tetrahydro-2H-2-pyranoyloxy-cyclopropyl) -1-oxo-isoindol-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Preparation of triazoles

Dissolving 5-bromo-2- (2-trans) obtained in the above 1) in toluene in a nitrogen atmosphere^*-tetrahydro-2H-2-pyranyloxy-cyclopropyl) -1-oxo-isoindoline 31mg and 1- (2-fluoropyridin-3-yl) -4-tri-n-butyltin-5-methyl-1H- [1, 2, 3] prepared in reference example 1]40mg of triazole, 11mg of tetrakis (triphenylphosphine) palladium was added thereto, and the mixture was refluxed for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound (28 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.24-1.84(8H，m)，2.93-3.18(1H，m)，3.63-3.70(1H，m)，3.78-3.88(2H，m)，3.95-4.00(1H，m)，4.35-4.44(2H，m)，4.88-5.13(1H，m)，7.49-7.52(1H，m)，7.81(1H，d，J＝7.6Hz)，7.91-7.93(2H，m)，8.06-8.11(1H，m)，8.45-8.47(1H，m)

ESI-MS found: m/z 450.3[ M + H ] +

1)4-(2-(1R^*，2R^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole and 4- (2- (1S)^*，2S^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Preparation of triazoles

Dissolving the compound 4- (2- (2-trans) obtained in the above 2) in methanol^*-tetrahydro-2H-2-pyranoyloxy-cyclopropyl) -1-oxo-isoindol-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]15mg of triazole was added to the solution, and then 1mg of p-toluenesulfonic acid monohydrate was added to the solution, followed by stirring at room temperature for 1 hour. The reaction mixture was neutralized with a saturated sodium hydrogencarbonate solution, water was added thereto, extraction was performed with ethyl acetate, and the ethyl acetate layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give a residue, which was then separated and purified by silica gel column chromatography (ethanol: hexane: 1: 2), and then optically resolved by an optically active column (CHIRALPAK OD-H column manufactured by ダイセル Co.; hexane: ethanol: 2: 3), and 1.30mg of the obtained precut compound (referred to as the title compound) (for convenience, 1.30mg of the title compound)1R ^* ，2R ^*) (iii) 0.60mg of the compound of the obtained after-cut fraction was referred to as the title compound: ( 1S ^* ，2S ^*) Body, both white solids.

4-(2-(1R^*，2R^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

¹H NMR(400MHz、CDCl₃)δ：1.12-1.54(2H，m)，2.50(3H，d，J＝2.0Hz)，2.91-2.93(1H，m)，3.77-3.79(1H，m)，4.39(2H，dd，J＝12.4，29.2Hz)，7.85-7.87(1H，m)，7.98-8.00(3H，m)，8.07-8.11(1H，m)，8.46-8.47(1H，m)

ESI-MS found: m/z 366.3[ M + H ] +

4-(2-(1S^*，2S^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

ESI-MS found: m/z 366.3[ M + H ] +

(example 132)

Preparation of 4- [2- (3-hydroxy-cyclobutylmethyl) -1-oxo-isoindolin-5-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

155mg of 4- [2- (3-benzyloxy-1-cyclobutylmethyl) -1-oxo-isoindolin-5-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 129 was dissolved in 10ml of methanol, and 80mg of 10% palladium on charcoal was added thereto, and the mixture was stirred overnight under a hydrogen atmosphere. The reaction solution was filtered through celite, and the resulting liquid was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate: methanol 99: 1) to obtain a white solid, which was a mixture of cis and trans forms of the title compound (105 mg). The resulting mixture (70 mg) was optically resolved on an optically active column (CHIRALPAKAD-H column manufactured by ダイセル, hexane: ethanol: 400: 600) to obtain a cis form of the title compound as a front fraction and a trans form of the title compound as a back fraction.

Cis-forms

¹H NMR(300MHz、CDCl₃)δ：1.74-1.82(2H，m)，1.95(1H，d，J＝6.6Hz)，2.04-2.21(1H，m)，2.46(3H，d，J＝1.7Hz)，2.50-2.57(2H，m)，3.70(2H，d，J＝7.3Hz)，4.15-4.23(1H，m)，4.46(2H，s)，7.30-7.42(2H，m)，7.56-7.62(2H，m)，7.82(1H，d，J＝8.1Hz)，7.94(1H，d，J＝8.1Hz)，8.00(1H，s)

ESI-MS found: m/z 394.3[ M + H ] +

Trans-form body

¹H NMR(300MHz、CDCl₃)δ：1.83(1H，d，J＝5.4Hz)，2.04-2.15(2H，m)，2.22-2.29(2H，m)，2.46(3H，d，J＝1.7Hz)，2.65-2.75(1H，m)，3.72(2H，d，J＝8.0Hz)，4.44(2H，s)，4.50-4.63(1H，m)，7.30-7.42(2H，m)，7.56-7.62(2H，m)，7.82(1H，d，J＝7.6Hz)，7.95(1H，d，J＝7.6Hz)，7.99(1H，s)

ESI-MS found: m/z 394.3[ M + H ] +

(example 133)

4- (2- (2-methyl-cyclopropylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-methyl-cyclopropylmethyl) -1-oxo-isoindoline

The reaction was carried out in the same manner as in example 116-1) except for using 2-methylcyclopropylmethylamine instead of the cyclobutylamine hydrochloride used in example 116-1) to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：0.31-0.35(1H，m)0.46-0.50(1H，m)，0.70-0.76(2H，m)，1.05-1.06(3H，m)，3.93-3.44(1H，m)，3.49-3.54(1H，m)，4.44(2H，s)，7.58-7.62(2H，m)，7.70(1H，d，J＝8.4Hz)

ESI-MS found: m/z 282.1[ M + H ] +

2) Preparation of 4- (2- (2-methyl-cyclopropylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：0.34-0.37(1H，m)，0.49-0.53(1H，m)，0.76-0.77(2H，m)，1.08(3H，d，J＝5.8Hz)，2.51(3H，d，J＝2.1Hz)，3.44-3.49(1H，m)，3.56-3.61(1H，m)，4.55(2H，s)，7.49-7.52(1H，m)，7.81-7.83(1H，m)，7.95-7.99(3H，m)，8.07-8.11(1H，m(，8.46-8.47(1H，m)

ESI-MS found: m/z 378.3[ M + H ] +

(example 134)

4- [2- (3-oxo-cyclobutylmethyl) -1-oxo-isoindolin-5-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

20mg of 4- [2- (3-hydroxy-cyclobutylmethyl) -1-oxo-isoindolin-5-yl ] -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 132 was dissolved in 1ml of dimethylformamide, and 100. mu.l of triethylamine and 40mg of sulfur trioxide pyridine complex were added thereto successively at room temperature, followed by stirring for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by preparative thin layer silica gel chromatography (chloroform: methanol 20: 1) to give the title compound as a white solid (12 mg).

¹H NMR(300MHz、CDCl₃)δ：2.51(3H，d，J＝2.1Hz)，2.80-2.93(1H，m)，2.95-3.07(2H，m)，3.15-3.28(2H，m)，3.90(2H，d，J＝7.5Hz)，4.54(2H，s)，7.48-7.54(1H，m)，7.84(1H，dd，J＝1.2，8.1Hz)，7.97(1H，d，J＝8.1Hz)，8.00(1H，s)，8.06-8.12(1H，m)，8.45-8.48(1H，m)

ESI-MS found: m/z 392.3[ M + H ] +

Example 135

4- (2- (2-morpholin-4-ylethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-morpholin-4-ylethyl) -1-oxo-isoindoline

The reaction was carried out in the same manner as in example 116-1) except for using N- (2-aminomethylmorpholine) instead of the cyclobutylamine hydrochloride used in example 116-1) to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：2.49-2.51(4H，m)，2.61-2.65(2H，m)，3.67-3.69(4H，m)，3.71-3.74(2H，m)，4.49(2H，s)，7.58-7.60(1H，m)，7.61(1H，s)，7.70(1H，d，J＝8.0Hz)

ESI-MS found: m/z 327.2[ M + H ] +

2) Preparation of 4- (2- (2-morpholin-4-ylethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：2.51(3H，d，J＝1.9Hz)，2.54(br，4H)，2.68(2H，t，J＝6.2Hz)，3.70(4H，t，J＝4.6Hz)，3.77-3.80(2H，m)，4.59(2H，s)，7.49-7.52(1H，m)，7.81-7.83(1H，m)，7.95-7.98(2H，m)，8.07-8.11(1H，m)，8.46-8.48(1H，m)

ESI-MS found: m/z 423.3[ M + H ] +

(example 136)

4-2- (ethylcarbonyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2- (N-methoxy-N-methyl-carbamoyl) -imidazo [1, 2-a ] pyridine

850mg of 6-bromo-2-hydroxycarbonyl-imidazo [1, 2-a ] pyridine, 519mg of N-methoxy-N-methyl-amine hydrochloride, and 1.12g of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride were dissolved in 10ml of pyridine, and the mixture was stirred at room temperature for 2 days. To the resulting solution was added water, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (362 mg).

¹H NMR(300MHz、CDCl₃)δ：3.53(3H，s)，3.80(3H，s)，7.28(1H，d，J＝9.5Hz)，7.56(1H，d，J＝9.5Hz)8.10(1H，s)，8.30(1H，s)

2) Preparation of 6-bromo-2-ethylcarbonyl-imidazo [1, 2-a ] pyridine

100mg of the 6-bromo-2- (N-methoxy-N-methyl-carbamoyl) -imidazo [1, 2-a ] pyridine obtained above was dissolved in 2.0ml of tetrahydrofuran, cooled to-78 ℃, and 1.0ml of 1M ethyl magnesium chloride was added dropwise. After warming to 0 ℃, water was added and the product was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to obtain 60.2mg of the title compound.

¹H NMR(300MHz、CDCl₃)δ：1.24(3H，t，J＝7.0Hz)，3.19(2H，q，J＝7.0Hz)，7.30(1H，d，J＝9.5Hz)，7.56(1H，d，J＝9.5Hz)8.08(1H，s)，8.30(1H，s)

3) Preparation of 4-2- (ethylcarbonyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The halide obtained in the above 2), the tin reagent obtained in reference example 7, and tetrakis (triphenylphosphine) palladium were used to obtain the title compound as a white solid by the same method as in example 49, a method based thereon, or a combination thereof with a conventional method.

¹H NMR(400MHz、CDCl₃)δ：1.28(3H，t，J＝7.3Hz)，2.51(3H，d，J＝2.0Hz)，3.33(2H，q，J＝7.3Hz)，7.50-7.54(1H，m)，7.67-7.71(1H，m)，7.78-7.81(1H，m)，8.06-8.12(1H，m)，8.22(1H，d，J＝0.7Hz)，8.47-8.50(1H，m)，8.61-8.62(1H，m)

APCI-MS found: m/z 351.0[ M + H ] +

(example 137)

4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline

In a nitrogen atmosphere, 100mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in toluene, and 0.1ml of 2, 2-difluoroethylamine and 0.14ml of triethylamine were added to the solution, followed by heating and refluxing overnight. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (45 mg).

¹H NMR(400MHz、CDCl₃)δ：3.91-4.00(2H，m)，4.52(2H，s)，5.84-6.14(1H，m)，7.61-7.63(1H，m)，7.71(1H，s)，7.72-7.73(1H，m)

ES-MS found: m/z 277.9[ M + H ] +

2) Preparation of 4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 45mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in the above-mentioned 1) and 30mg of 1- (2-chloropyridin-3-yl) -4-tri-n-butyltin-5-methyl-1H- [1, 2, 3] triazole prepared in reference example 1 were dissolved in toluene, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound as a white solid (20 mg).

¹H NMR(400MHz、CDCl₃)δ：2.51(3H，d，J＝2.0Hz)，3.97-4.05(2H，m)，4.63(2H，s)，5.89-6.17(1H，m)，7.49-7.52(1H，m)，7.85-7.87(1H，m)，7.98-8.00(2H，m)，8.06-8.11(1H，)，8.46-8.48(1H，m)

ESI-MS found: m/z 374.2[ M + H ] +

Example 138

1- (2-fluoropyridin-3-yl) -4- (2-isopropylcarbonyl-imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-isopropylcarbonyl-imidazo [1, 2-a ] pyridine

269mg of 6-bromo-2-ethoxycarbonyl-imidazo [1, 2-a ] pyridine obtained in example 117) was dissolved in 10ml of tetrahydrofuran, cooled to-78 ℃, and 0.5ml of 2M isopropylmagnesium chloride was added dropwise. After warming to-40 ℃, water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to obtain the title compound (58.5 mg).

¹H NMR(300MHz、CDCl₃)δ：1.26(6H，d，J＝6.7Hz)，3.82(1H，sept，J＝6.7Hz)，7.30(1H，d，J＝9.5Hz)，7.58(1H，d，J＝9.5Hz)8.10(1H，s)，8.30(1H，s)

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-isopropylcarbonyl-imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using 6-bromo-2-isopropylcarbonyl-imidazo [1, 2-a ] pyridine obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 7, the title compound was obtained as a white solid by the same method as in example 49, a method based thereon, or a combination thereof with a conventional method.

¹H NMR(400MHz、CDCl₃)δ：1.29(6H，d，J＝7.0Hz)，2.51(3H，d，J＝2.0Hz)，3.87(1H，sept，J＝7.0Hz)，7.50-7.54(1H，m)，7.68(1H，dd，J＝1.7，9.5Hz)，7.80(1H，d，J＝9.5Hz)，8.07-8.12(1H，m)，8.23(1H，d，J＝0.7Hz)，8.47-8.50(1H，m)，8.61-8.62(1H，m)

APCI-MS found: m/z 365.0[ M + H ] +

Example 139

4- (2- (trans-3-hydroxy-cyclobutylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole and 4- (2- (cis-3-hydroxy-cyclobutylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

In the same manner as in example 4 except that the tin reagents of examples 129 and 132 were changed to the tin reagents of reference example 4, a mixture of the cis-form and trans-form of the title compound was obtained as a white solid. The resulting mixture was resolved on an optically active column (CHIRALPAK OJ-H column manufactured by ダイセル, hexane: ethanol 400: 600) to obtain a trans form of the title compound as a fore-cut fraction and a cis form of the title compound as a back-cut fraction.

4- (2- (trans-3-hydroxy-cyclobutylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.83(1H，d，J＝5.4Hz)，2.04-2.15(2H，m)，2.22-2.29(2H，m)，2.46(3H，d，J＝1.7Hz)，2.65-2.75(1H，m)，3.72(2H，d，J＝8.0Hz)，4.44(2H，s)，4.50-4.63(1H，m)，7.30-7.42(2H，m)，7.56-7.62(2H，m)，7.82(1H，d，J＝7.6Hz)，7.95(1H，d，J＝7.6Hz)，7.99(1H，s)

ESI-MS found: m/z 393.3[ M + H ] +

4- (2- (cis-3-hydroxy-cyclobutylmethyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.74-1.82(2H，m)，1.95(1H，d，J＝6.6Hz)，2.04-2.21(1H，m)，2.46(3H，d，J＝1.7Hz)，2.50-2.57(2H，m)，3.70(2H，d，J＝7.3Hz)，4.15-4.23(1H，m)，4.46(2H，s)，7.30-7.42(2H，m)，7.56-7.62(2H，m)，7.82(1H，d，J＝8.1Hz)，7.94(1H，d，J＝8.1Hz)，8.00(1H，s)

ESI-MS found: m/z 393.3[ M + H ] +

(example 140)

4- (2-acetyl-imidazo [1, 2-a ] pyridin-6-yl) 1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using 2-acetyl-6-bromo-imidazo [1, 2-a ] pyridine and the tin reagent obtained in reference example 1 and tetrakis (triphenylphosphine) palladium, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：2.51(3H，d，J＝2.2Hz)，2.75(3H，s)，7.50-7.54(1H，m)，7.69(1H，dd，J＝0.7，9.5Hz)，7.78-7.82(1H，m)，8.07-8.12(1H，m)，8.22(1H，d，J＝0.7Hz)，8.47-8.49(1H，m)，8.62(1H，dd，J＝1.2，1.7Hz)

ESI-MS found: m/z 337.3[ M + H ] +

(embodiment 141)

1- (2-fluoropyridin-3-yl) -4- (2- (1-methoxy-ethyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2- (1-methoxyethyl) -imidazo [1, 2-a ] pyridine

In 2ml of methanol, 60mg of 6-bromo-2-methylcarbonyl-imidazo [1, 2-a ] pyridine was dissolved, and 38mg of sodium borohydride was added thereto at 0 ℃. After stirring at room temperature for 5 minutes, saturated brine was added. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 2.0ml of dimethylformamide, and 30mg of 60% sodium hydride and 47. mu.l of methyl iodide were added thereto, and the mixture was warmed to room temperature and stirred for 1 hour. After water was added to the obtained solution, the product was extracted with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to obtain 52mg of the title compound.

¹H NMR(400MHz、CDCl₃)δ：1.58(3H，d，J＝6.6Hz)，4.58(2H，q，J＝6.6Hz)，7.21(1H，dd，J＝1.0，9.5Hz)，7.48(1H，d，J＝9.5Hz)7.51(1H，s)，8.22-8.25(1H，m)

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2- (1-methoxy-ethyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

The halide obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 1 were used to obtain the title compound as a white solid by the same method as in example 49, a method based thereon, or a combination thereof with a conventional method.

¹H NMR(400MHz、CDCl₃)δ：1.62(3H，d，J＝6.6Hz)，2.48(3H，d，J＝2.2Hz)，3.43(3H，s)，4.62(1H，q，J＝6.6Hz)，7.46-7.53(1H，m)，7.55(1H，dd，J＝1.7，9.5Hz)，7.63(1H，s)7.69(1H，d，J＝9.4Hz)，8.06-8.11(1H，m)，8.46-8.48(1H，m)，8.57-8.58(1H，m)

ESI-MS found: m/z 353.3[ M + H ] +

(example 142)

4- (2- (2-hydroxycyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1)4-(2-(1R^*，2R^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3]Triazole and 4- (2- (1S)^*，2S^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3]Preparation of triazoles

The same procedures as in example 131 were carried out using the tin reagent of reference example 4 instead of the tin reagent of reference example 1 used in example 131 to obtain a racemate of the title compound, and then the optical resolution was carried out using an optically active column (CHIRALPAK OJ-H column manufactured by ダイセル Co.; hexane: ethanol: 1: 3), and the obtained precut compound was referred to as "title compound 1R ^* ，2R ^*) (iii) the compound of the obtained after-fraction is referred to as the title compound1S ^* ，2S ^*) Body, both white solids.

¹H NMR(400MHz、CDCl₃)δ：1.10-1.20(1H，m)，1.22-1.32(1H，m)，7.45(3H，d，J＝1.8Hz)，2.91-3.00(1H，m)，3.54(1H，s)，3.77-3.86(1H，m)，4.35(1H，d，J＝16.0Hz)，4.44(1H，d，J＝16.0Hz)，7.30-7.42(2H，m)，7.52-7.63(2H，m)，7.79-7.86(1H，m)，7.92(1H，d，J＝7.9Hz)，7.98(1H，s)

ESI-MS found: m/z 365.1[ M + H ] +

2)4-(2-(1S^*，2R^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3]Triazole and 4- (2- (1R)^*，2S^*) -hydroxy-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3]Preparation of triazoles

The same procedures as in example 131 were carried out except for using the tin reagent of reference example 4 instead of the cis-isomer compound obtained as a by-product in 1) of example 131 and the tin reagent of reference example 4 to obtain a racemate of the title compound, and then purifying the racemate with an optically active column (CHIRALPAK AD-H column manufactured by ダイセル; hexane: ethanol 1: 3) and the resulting prefractionated compound is referred to as (1S) of the title compound for simplicity^*，2R^*) The resulting compound of the latter fraction was referred to as (1R) of the title compound^*，2S^*) Body, both white solids.

¹H NMR(400MHz、CDCl₃)δ：0.85-0.96(1H，m)，1.03-1.12(1H，m)，2.47(3H，d，J＝1.8Hz)，2.67-2.77(1H，m)，3.82-3.94(1H，m)，4.55(2H，s)，4.64(1H，s)，7.30-7.42(2H，m)，7.52-7.65(2H，m)，7.30-7.34(1H，m)，7.92(1H，d，J＝8.2Hz)，9.02(1H，s)

ESI-MS found: m/z 365.1[ M + H ] +

(example 143)

1- (2-fluoropyridin-3-yl) -4- (2-ethyl-imidazo [1, 2-a ] pyrimidin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 2-ethyl-6-iodo-imidazo [1, 2-a ] pyrimidine

755mg of 1-bromo-2-butanone was dissolved in 15ml of ethanol, 1.0g of 2-amino-5-iodopyrimidine was added thereto, and the mixture was stirred under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were successively added. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound as a white solid (110 mg).

1H NMR(300MHz，CDCl3)δ：1.38(3H，t，J＝7.0Hz)，2.88(2H，q，J＝7.0Hz)，7.25(1H，s)，8.52(1H，d，J＝2.4Hz)，8.58(1H，d，J＝2.4Hz)

ESI-MS found: m/z 274.0[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-ethyl-imidazo [1, 2-a ] pyrimidin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained above and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 1, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.40(3H，t，J＝7.5Hz)，2.51(3H，d，J＝2.0Hz)，2.92(2H，q，J＝7.5Hz)，7.27(1H，s)，7.48-7.56(1H，m)，8.01-8.12(1H，m)，8.45-8.52(1H，m)，8.80-8.90(2H，m)

ESI-MS found: m/z 324.2[ M + H ] +

(example 144)

4- (2- (1-methyl-cyclopropylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 30mg of 5-bromo-2- (1-methyl-cyclopropylmethyl) -1-oxo-isoindoline obtained in example 130-1) and 20mg of 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 4 were dissolved in toluene, and 8mg of tetrakis (triphenylphosphine) palladium was added and heated under reflux for 2 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound (6 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.43-0.46(2H，m)，0.54-0.56(2H，m)，1.07(3H，s)，2.47(3H，d，J＝1.6Hz)，3.51(2H，s)，4.54(2H，s)，7.33-7.54(2H，m)，7.56-7.61(2H，m)，7.82-7.84(1H，m)，7.95-7.97(1H，m)，8.01(1H，s)

ESI-MS found: m/z 377.2[ M + H ] +

(example 145)

1- (2-fluoropyridin 3-yl) -4- (2-ethyl-imidazo [1, 2-a ] pyrazin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-ethyl-imidazo [1, 2-a ] pyrazine

513mg of 1-bromo-2-butanone is dissolved in 10ml of ethanol, 500mg of 2-amino-5-bromopyrazine is added, and the mixture is stirred overnight under heating and refluxing. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were successively added. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to obtain 244mg of a crude purified product of the title compound.

ESI-MS found M/z 276.0, 228.0[ M + H ] +

2) Preparation of 1- (2-fluoropyridin-3-yl) -4- (2-ethyl-imidazo [1, 2-a ] pyrazin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 1, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a conventional method.

¹H NMR(400MHz、CDCl₃)δ：1.41(3H，t，J＝7.6Hz)，2.70(3H，d，J＝1.7Hz)，2.92(2H，q，J＝7.6Hz)，7.46-7.52(1H，m)，7.57(1H，d，J＝0.5Hz)，8.01-8.06(1H，m)，8.22-8.28(1H，m)，8.95(1H，d，J＝1.4Hz)，9.03-9.06(1H，m)

ESI-MS found: m/z 324.1[ M + H ] +

(example 146)

4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 80mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 50mg of 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 4 were dissolved in toluene, and 15mg of tetrakis (triphenylphosphine) palladium was added and heated under reflux overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound as a white solid (16 mg).

¹H NMR(400MHz、CDCl₃)δ：2.47(3H，d，J＝1.7Hz)，3.96-4.05(2H，m)，4.62(2H，s)，5.89-3.16(1H，m)，7.33-7.41(2H，m)，7.56-7.60(2H，m)，7.86-7.88(1H，m)，7.96-8.01(2H，m)

ESI-MS found: m/z 373.1[ M + H ] +

(example 147)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (4-chloro-2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 49 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 16, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.88-0.98(4H，m)，2.45(3H，d，J＝1.7Hz)，2.94-3.01(1H，m)，4.41(2H，s)，7.37-7.42(2H，m)，7.51-7.56(1H，m)，7.79(1H，dd，J＝1.3，7.9Hz)，7.92-7.96(2H，m)

ESI-MS found: m/z 383.1[ M + H ] +

Example 148

4- (2- (1-hydroxy-cyclopropylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (1-hydroxy-cyclopropylmethyl) -1-oxo-isoindoline

The reaction was carried out in the same manner as in example 116-1) except for using 1-hydroxy-cyclopropylmethylamine instead of the cyclobutylamine hydrochloride used in example 116-1) to obtain the title compound.

¹H NMR(400MHz、CDCl₃)δ：0.67-0.70(2H，m)，0.88-0.91(2H，m)，3.70(2H，s)，3.79(1H，s)，4.54(2H，s)，7.55-7.59(2H，m)，7.63-7.65(1H，m)，

ESI-MS found: m/z 284.1[ M + H ] +

2) Preparation of 4- (2- (1-hydroxy-cyclopropylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained by the method of example 116-2) using the compound obtained in 1) above and the compound of reference example 4, 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole.

¹H NMR(400MHz、CDCl₃)δ：0.71-0.74(2H，m)，0.91-0.94(2H，m)，2.47(3H，d，J＝1.75Hz)，3.69(1H，s)，3.78(2H，s)，4.65(2H，s)，7.33-7.41(2H，m)，7.56-7.61(2H，m)，7.82-7.84(1H，m)，7.93-7.95(1H，m)，8.00(1H，m)

ESI-MS found: m/z 379.2[ M + H ] +

Example 149

4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

28mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 60mg of 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 13 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound as a white solid (20 mg).

¹H NMR(400MHz、CDCl₃)δ：2.46(3H，d，J＝1.76Hz)，3.96-4.05(2H，m)，4.62(2H，s)，5.89-6.16(1H，m)，7.09-7.15(2H，m)，7.55-7.61(1H，m)，7.84-7.86(1H，m)，7.96-8.00(2H，m)

ESI-MS found: m/z 391.1[ M + H ] +

Example 150

4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (4-chloro-2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

28mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 60mg of 1- (4-chloro-2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 16 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound 21mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.47(3H，d，J＝1.7Hz)，4.01(2H，dt，J＝4.1，14.6Hz)，4.62(2H，s)，6.02(1H，tt，J＝51.4，41Hz)，7.39-7.41(2H，m)，7.52-7.56(1H，m)，7.84-7.86(1H，m)，7.96-7.99(2H，m)

ESI-MS found: m/z 407.1[ M + H ] +

(example 151)

4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

28mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 60mg of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 12 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound (22 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.52(3H，m)，3.96-4.05(2H，m)，4.62(2H，s)，5.88-6.17(1H，m)，7.26-7.31(2H，m)，7.49-7.53(2H，m)，7.83-7.85(1H，m)，7.96-7.99(2H，m)

ESI-MS found: m/z 373.1[ M + H ] +

(example 152)

4- (2- (trans-3-methoxy-cyclobutylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole and

4- (2- (cis-3-methoxy-cyclobutylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 3-methoxy-cyclobutylmethanol

500mg of 3-methoxycyclobutanecarboxylic acid was dissolved in 10ml of tetrahydrofuran. Under ice-cooling, 292mg of lithium aluminum hydride was slowly added thereto, and stirred for further 2 hours. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate: hexane: 40: 60) to give the title compound (230 mg).

¹H NMR(300MHz、CDCl₃)δ：1.60-2.45(5H，m)，3.22-3.24(3H，m)，3.59-3.66(2H，m)，3.73-4.00(1H，m)

2) Preparation of 3-methoxy-cyclobutylformamide

To a tetrahydrofuran solution of 220mg of 1) 3-methoxy-cyclobutylmethanol obtained in the above 1) was added 530. mu.l of triethylamine and 220. mu.l of methanesulfonyl chloride successively under ice cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling the solvent under reduced pressure was dissolved in 4ml of dimethylformamide, 245mg of sodium azide was added, and the mixture was stirred at 80 ℃ for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was separated and purified by silica gel column chromatography (ethyl acetate: hexane: 10: 90) to give the title compound (195 mg).

¹H NMR(300MHz、CDCl₃)δ：1.61-2.60(5H，m)，3.22(3H，s)，3.27-3.35(2H，m)，3.72-4.01(1H，m)

3) Preparation of 5-bromo- (2- (3-methoxy-cyclobutylmethyl) -1-oxo-isoindoline

190mg of 3-methoxy-cyclobutyl azidomethane obtained in the above 2) was dissolved in 8ml of methanol. After adding 10% palladium on charcoal in catalytic amount, the mixture was stirred at room temperature for 1.5 hours under hydrogen atmosphere. The reaction solution was filtered through celite, and the resulting liquid was concentrated under reduced pressure. The resulting residue was dissolved in 3ml of toluene, and 420mg of methyl 4-bromo-2-bromomethylbenzoate and 1ml of triethylamine were added thereto, followed by refluxing with heating and stirring overnight. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate: hexane: 80: 20) to give the title compound as a white solid (98 mg).

¹H NMR(300MHz、CDCl₃)δ：1.67-2.67(5H，m)，3.21(3H，s)，3.42-4.12(3H，m)，4.33-4.38(2H，m)，7.43-7.78(3H，m)

4)4- (2- (trans-3-methoxy-cyclobutylmethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole and

Using 5-bromo- (2- (3-methoxy-cyclobutylmethyl) -1-oxo-isoindoline obtained in 3) above and the compound of reference example 4, 1- (2-fluorophenyl-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole, the procedure of example 5 was followed to give a mixture of cis and trans forms of the title compound. The resulting mixture was optically resolved on an optically active column (CHIRALPAKAD-H column manufactured by ダイセル, hexane: ethanol 400: 600) to obtain a trans form of the title compound as a fore-cut fraction and a cis form of the title compound as a after-cut fraction.

¹H NMR(300MHz、CDCl₃) δ: 2.10-2.18(4H, m), 2.46(3H, d, J ═ 1.8Hz), 3.24(3H, s), 3.74(2H, d, J ═ 8.1Hz), 4.11(1H, quintuple, J ═ 6.3Hz), 4.44(2H, s), 7.35-7.42(2H, m), 7.55-7.61(2H, m), 7.82(1H, dd, J ═ 1.5, 7.8Hz), 7.95(1H, d, J ═ 7.8Hz), 8.00(1H, s)

ESI-MS found: m/z 407.2[ M + H ] +

¹H NMR(300MHz、CDCl₃)δ：1.70-1.82(2H，m)，2.15-2.28(1H，m)2.42-2.51(2H, m), 2.46(3H, d, J ═ 1.8Hz), 3.24(3H, s), 3.69(2H, d, J ═ 7.2Hz), 3.78(1H, quintuple, J ═ 6.6Hz), 4.46(2H, s), 7.32-7.41(2H, m), 7.56-7.62(2H, m), 7.82(1H, dd, J ═ 1.5, 8.1Hz), 7.94(1H, d, J ═ 8.1Hz), 7.99(1H, s)

ESI-MS found: m/z 407.2[ M + H ] +

(example 153)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-chlorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Under a nitrogen atmosphere, 50mg of 5-bromo-2-isopropyl-1-oxo-isoindoline obtained in example 112-1) and 100mg of 1- (2-chlorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 25 were dissolved in toluene, and 22mg of tetrakis (triphenylphosphine) palladium was added and heated under reflux overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound (18 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.83Hz)，2.41(3H，s)，4.42(2H，s)，4.68-4.75(1H，m)，7.50-7.51(2H，m)，7.54-7.58(1H，m)，7.64-7.66(1H，m)，7.81-7.84(1H，m)，7.93-7.95(1H，m)，8.05(1H，s)

ESI-MS found: m/z 367.2[ M + H ] +

(example 154)

4- (2-n-propyl-1-oxo-isoindolin-5-yl) -1- (2-chlorophenyl) -5-methyl-1H- [1, 2, 3] triazole

25mg of 5-bromo-2-propyl-1-oxo-isoindoline obtained in example 85-1) and 56mg of 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 11 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound 9mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.97-1.01(3H，m)，1.71-1.76(2H，m)，2.47(3H，d，J＝1.7Hz)，3.60-3.64(2H，m)，4.46(2H，s)，7.35-7.41(2H，m)，7.58(2H，m)，7.80-7.82(1H，m)，7.94-7.96(1H，m)，8.01(1H，m)

ESI-MS found: m/z 351.2[ M + H ] +

Example 155

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 49 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.87-0.99(4H，m)，2.51(3H，s)，2.95-3.05(1H，m)，4.41(2H，s)，7.27-7.32(2H，m)，7.49-7.53(2H，m)，7.76-7.79(1H，m)，7.93(1H，d，J＝8.1Hz)，7.95(1H，s)

ESI-MS found: m/z 349.2[ M + H ] +

(example 156)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2, 4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 49 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 13, the title compound was obtained as a white solid using the same method as example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.88-0.98(4H，m)，2.45(3H，d，J＝1.7Hz)，2.95-3.05(1H，m)，4.41(2H，s)，7.08-7.17(2H，m)，7.54-7.61(1H，m)，7.79(1H，d，J＝8.1Hz)，7.93(1H，d，J＝8.1Hz)，7.96(1H，s)

ESI-MS found: m/z 367.1[ M + H ] +

(example 157)

4- (2-propyl-1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

25mg of 5-bromo-2-propyl-1-oxo-isoindoline obtained in example 85-1) and 56mg of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 12 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound as a white solid (10 mg).

¹H NMR(400MHz、CDCl₃)δ：0.99(3H，t，J＝7.4Hz)，1.68-1.78(2H，m)，2.51(3H，m)，3.62(2H，t，J＝7.4Hz)，4.46(2H，s)，7.26-7.30(2H，m)，7.50-7.53(2H，m)，7.77-7.79(1H，m)，7.93-7.98(2H，m)

ESI-MS found: m/z 351.2[ M + H ] +

(example 158)

4- (2-propyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

25mg of 5-bromo-2-propyl-1-oxo-isoindoline obtained in example 85-1) and 56mg of 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 13 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound (13 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：0.99(3H，d，J＝7.4Hz)，1.69-1.78(2H，m)，2.45(3H，d，J＝1.7Hz)，3.62(2H，t，J＝7.4Hz)，4.46(2H，s)，7.09-7.16(2H，m)，7.55-7.61(1H，m)，7.79-7.81(1H，m)，7.93-7.96(1H，m)，7.99(1H，m)

ESI-MS found: m/z 369.2[ M + H ] +

(example 159)

4- (2-ethyl-1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

150mg of 5-bromo-2-ethyl-1-oxo-isoindoline obtained in example 26-1) and 240mg of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 12 were dissolved in toluene under a nitrogen atmosphere, 72mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound (76 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.31(3H，t，J＝7.2Hz)，2.52(3H，s)，3.69-3.74(2H，m)，4.47(2H，s)，7.27-7.31(2H，m)，7.50-7.53(2H，m)，7.77-7.79(1H，M)，7.93-7.95(1H，M)，7.99(1H，M)

ESI-MS found: m/z 337.1[ M + H ] +

(example 160)

4- (2-ethyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

150mg of 5-bromo-2-ethyl-1-oxo-isoindoline obtained in example 26-1) and 252mg of 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 13 were dissolved in toluene under a nitrogen atmosphere, 72mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound as a white solid (70 mg).

¹H NMR(400MHz、CDCl₃)δ：1.31(3H，t，J＝7.2Hz)，2.46(3H，d，J＝1.7Hz)，3.72(2H，q，J＝7.2Hz)，4.47(2H，s)，7.09-7.16(2H，m)，7.55-7.61(1H，m)，7.79-7.81(1H，m)，7.93-7.95(1H，m)，8.00(1H，m)

ESI-MS found: m/z 355.1[ M + H ] +

(example 161)

4- (2-Ethyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 72 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 4, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.31(3H，t，J＝7.1Hz)，2.47(3H，d，J＝1.7Hz)，3.72(2H，q，J＝7.1Hz)，4.48(2H，s)，7.33-7.42(2H，m)，7.51-7.62(2H，m)，7.82(1H，d，J＝7.6Hz)，7.95(1H，d，J＝7.6Hz)，8.01(1H，s)

ESI-MS found: m/z 337.1[ M + H ] +

(example 162)

4- (2- (2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

27mg of 5-bromo-2- (2-methyl-propyl) -1-oxo-isoindoline obtained in example 89-1) and 56mg of 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 4 were dissolved in toluene under a nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound 21mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：9.99(6H，d，J＝6.6Hz)，2.04-2.13(1H，m)，2.47(3H，d，J＝1.9Hz)，3.46(2H，d，J＝7.6Hz)，4.47(2H，s)，7.3-7.412(2H，m)，7.56-7.61(2H，m)，7.81-7.83(1H，m)，7.94-7.96(1H，m)，8.00(1H，m)

ESI-MS found: m/z 365.2[ M + H ] +

(example 163)

4- (2- (1-methyl-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (1-methyl-cyclopropyl) -1-oxo-isoindoline

300mg of 1-methyl-cyclopropylamine was dissolved in 10ml of 10% methanol hydrochloride, and the solution was stirred at room temperature for 10 minutes and then concentrated under reduced pressure. The resulting residue was dissolved in 5ml of toluene, 540mg of methyl 4-bromo-2-bromo-methylbenzoate and 5ml of triethylamine were added, and the mixture was stirred overnight under reflux with heating. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (ethyl acetate: hexane: 80: 20) to give the title compound as a white solid (98 mg).

¹H NMR(300MHz、CDCl₃)δ：0.78-0.84(2H，m)，1.00-1.06(2H，m)，1.42(3H，s)，4.35(2H，s)，7.55-7.69(3H，m)

2) Preparation of 4- (2- (1-methyl-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained according to the procedure of example 5 using 5-bromo-2- (1-methyl-cyclopropyl) -1-oxo-isoindoline obtained in 1) above and 1- (2-fluorophenyl-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole, a compound of reference example 4.

¹H NMR(300MHz、CDCl₃)δ：0.82-0.88(2H，m)，1.05-1.11(2H，m)，1.47(3H，s)，2.46(2H，d，J＝1.8Hz)，4.46(2H，s)，7.32-7.42(2H，m)，7.55-7.63(2H，m)，7.81(1H，dd，J＝1.2，8.1Hz)，7.92(1H，d，J＝8.1Hz)，7.98(1H，s)

ESI-MS found: m/z 363.2[ M + H ] +

(example 164)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 36 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 6, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.58(3H，s)，4.43(2H，s)，4.72(1H，spt，J＝6.8Hz)，7.57-7.61(1H，m)，7.78-7.82(1H，m)，7.93-7.99(3H，m)，8.81-8.86(2H，m)

ESI-MS found: m/z 334.2[ M + H ] +

(example 165)

4- (2-propyl-1-oxo-isoindolin-5-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 85 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 6, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.99(3H，t，J＝7.3Hz)，1.73(2H，sept，J＝7.3Hz)，2.58(3H，s)，3.63(2H，t，J＝7.3Hz)，4.47(2H，s)，7.52-7.600(1H，m)，7.79(1H，d，J＝7.8Hz)，7.92-7.99(3H，m)，8.81-8.85(2H，m)

APCI-MS found: m/z 334.2[ M + H ] +

(example 166)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (4-fluoro-2-methyl-phenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (4-fluoro-2-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 17.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.11(3H，s)，2.36(3H，s)，4.43(2H，s)，4.68-4.75(1H，m)，7.06-7.16(2H，m)，7.26-7.31(1H，m)，7.80-7.96(2H，m)，8.04(1H，s)

ESI-MS found: m/z 365.2[ M + H ] +

(example 167)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2, 6-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (2, 6-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 18.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.45(3H，s)，4.43(2H，s)，4.68-4.75(1H，m)，7.20(2H，dt，J＝1.6，8.8Hz)，7.55-7.62(1H，m)，7.79-7.97(2H，m)，8.03(1H，s)

ESI-MS found: m/z 369.2[ M + H ] +

(example 168)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoro-4-methyl-phenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (2-fluoro-4-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 19.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.44(3H，d，J＝2.0Hz)，2.49(3H，s)，4.42(2H，s)，4.67-4.75(1H，m)，7.14-7.19(2H，m)，7.44(1H，t，J＝8.0Hz)，7.79-7.95(2H，m)，8.01(1H，s)

ESI-MS found: m/z 365.3[ M + H ] +

(example 169)

4- (2-methoxy-1-oxo-indan-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-methoxy-1-indanone

To a solution of 100mg of 5-bromo-1-indanone in 15ml of acetonitrile was added 232mg of [ hydroxy (p-nitrobenzenesulfonyloxy) iodo ] benzene at room temperature, and the mixture was refluxed for 3 hours. The reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 20ml of methanol and refluxed overnight. The reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure, the resulting solution was dissolved in ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 95: 5) to give the title compound (59 mg) as a white solid.

2) Preparation of 4- (2-methoxy-1-oxo-indan-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using 5-bromo-2-methoxy-1-indanone obtained in the above-mentioned 1) and 1- (2-fluorophenyl-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which is a compound of reference example 4, the title compound was obtained according to the procedure of example 1.

¹H NMR(300MHz、CDCl₃)δ：2.48(3H，d，J＝1.8Hz)，3.09(1H，dd，J＝4.5，16.8Hz)，3.60(1H，dd，J＝7.5，16.8Hz)，3.67(3H，s)，4.25(1H，dd，J＝4.5，7.5Hz)，7.32-7.41(2H，m)，7.56-7.61(2H，m)，7.80-7.89(2H，m)，7.96(1H，s)

ESI-MS found: m/z 338.2[ M + H ] +

Example 170

4- (2-ethoxy-1-indanone-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2-ethoxy-1-indanone

To a solution of 130mg of 5-bromo-1-indanone in 20ml of acetonitrile was added 310mg of [ hydroxy (p-nitrobenzenesulfonyloxy) iodo ] benzene at room temperature, and the mixture was refluxed for 3 hours. The reaction mixture was returned to room temperature, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 20ml of ethanol and refluxed overnight. The reaction mixture was returned to room temperature, the solvent was evaporated under reduced pressure, the resulting solution was dissolved in ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was purified by silica gel column chromatography (hexane: ethyl acetate 95: 5) to give the title compound as a white solid (84 mg).

¹H NMR(300MHz、CDCl₃)δ：1.28(3H，t，J＝7.5Hz)，2.96-3.04(1H，m)，3.42-3.52(1H，m)，3.68-3.78(1H，m)，3.94-4.04(1H，m)，4.22-4.27(1H，m)，7.50-7.68(3H，m)

2) Preparation of 4- (2-ethoxy-1-indanone-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using 5-bromo-2-ethoxy-1-indanone obtained in the above-mentioned 1) and 1- (2-fluorophenyl-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole which is a compound of reference example 4, the title compound was obtained according to the procedure of example 1.

¹H NMR(300MHz、CDCl₃)δ：1.32(3H，t，J＝7.2Hz)，2.47(3H，d，J＝1.8Hz)，3.10(1H，dd，J＝4.5，17.1Hz)，3.59(1H，dd，J＝7.5，17.1Hz)，3.72-3.83(1H，m)，3.96-4.07(1H，m)，4.34(1H，dd，J＝4.5，7.5Hz)，7.31-7.42(2H，m)，7.55-7.61(2H，m)，7.79-7.89(2H，m)，7.95(1H，s)

ESI-MS found: m/z 352.2[ M + H ] +

(example 171)

4- (2-methoxy-2-methyl-1-indanone-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

4-((2S^*-3-methoxy- (2R)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluorophenyl-3-yl) -5-methyl-1H- [1, 2, 3]Triazole and

4-((2R^*-3-methoxy- (2S)^*) -methyl-1-oxoindan-5-yl) -1- (2-fluorophenyl-3-yl) -5-methyl-1H- [1, 2, 3]Triazole compounds

Using 5-bromo-2-methoxy-2-methyl-1-indanone obtained in 53-2) and 1- (2-fluorophenyl-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] of the compound of reference example 4]Triazole was obtained as the racemate of the title compound according to the procedure of example 1. The resulting mixture was optically resolved on an optically active column (CHIRALPAK AD-H column manufactured by ダイセル, 500: 500 (hexane: ethanol)), and the obtained precut compound was referred to as (2S of the title compound) for the sake of convenience^*，2R^*) The resulting compound of the latter fraction was referred to as (2R) of the title compound^*，2S^*) Body, both white solids.

¹H NMR(300MHz、CDCl₃)δ：1.49(3H，s)，2.48(3H，d，J＝1.8Hz)，3.15(1H，d，J＝17.1Hz)，3.33(3H，s)，3.45(1H，d，J＝17.1Hz)，7.32-7.43(2H，m)，7.56-7.63(2H，m)，7.80-7.84(1H，m)，7.89(1H，d，J＝7.8Hz)，7.96(1H，s)

ESI-MS found: m/z 352.2[ M + H ] +

(example 172)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-ethylphenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (2-ethylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 20.

¹H NMR(400MHz、CDCl₃)δ：1.13(3H，t，J＝7.6Hz)，1.33(6H，d，J＝6.8Hz)，2.37(3H，s)，2.40(2H，q，J＝7.4，15.0Hz)，4.42(2H，s)，4.67-4.77(1H，m)，7.36-7.57(3H，m)，7.83(1H，d，J＝8.8Hz)，7.94(1H，d，J＝7.6Hz)，8.07(1H，d，J＝0.8Hz)

ESI-MS found: m/z 361.3[ M + H ] +

(example 173)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-isopropylphenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (2-isopropylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 21.

¹H NMR(400MHz、CDCl₃)δ：1.19(6H，d，J＝6.8Hz)，1.33(6H，d，J＝6.8Hz)，2.37(3H，s)，2.49-2.56(1H，m)，4.43(2H，s)，4.68-4.76(1H，m)，7.21-7.26(1H，m)，7.38(1H，dt，J＝2.0，7.4Hz)，7.53-7.80(2H，m)，7.84(1H，d，J＝6.4Hz)，7.91-7.97(1H，m)，8.07(1H，s)

ESI-MS found: m/z 375.3[ M + H ] +

(example 174)

4- (2-isopropyl-1, 3-dioxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

37mg of the compound obtained in example 119, 41mg of sodium acetate and 3 drops of bromine were dissolved in 2.0ml of acetic acid, and the mixture was stirred at room temperature for 20 minutes. After adding saturated sodium bicarbonate and ethyl acetate, the organic layer was separated and dried over anhydrous sodium sulfate. The residue obtained by distillation of the solvent under reduced pressure was purified by thin layer silica gel column chromatography (hexane: ethyl acetate 50: 50) to give the title compound (19.5 mg) as a white solid.

¹H NMR(300MHz、CDCl₃)δ：1.52(6H，d，J＝6.9Hz)，2.48(3H，d，J＝1.8Hz)，4.57(1H，sept，J＝7.0Hz)，7.09-7.19(2H，m)，7.51-7.62(1H，m)，7.93(1H，d，J＝7.8Hz)，8.16(1H，d，J＝1.5Hz)，8.24(1H，dd，J＝1.5，7.8Hz)

ESI-MS found: m/z 383.1[ M + H ] +

(example 175)

4- (2-isopropyl-3-ethoxy-1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

As a by-product of example 174, the title compound was obtained in 9.2 mg.

¹H NMR(300MHz、CDCl₃)δ：1.13(3H，t，J＝7.0Hz)，1.42(3H，d，J＝6.9Hz)，1.45(3H，d，J＝6.9Hz)，2.45(3H，d，J＝1.7Hz)，3.01-3.12(1H，m)，3.27-3.40(1H，m)，4.45(1H，sept，J＝6.9Hz)，7.08-7.19(2H，m)，7.51-7.61(1H，m)，7.83-7.91(2H，m)，8.01(1H，s)

ESI-MS found: m/z 435.1[ M + Na ]

(example 176)

4- (2-cyclopropyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 48 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 6, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.96-1.04(4H，m)，2.01-2.05(1H，m)，2.55(3H，s)，7.45-7.49(2H，m)，7.52-7.63(2H，m)，7.91-7.95(1H，m)，8.51-8.52(1H，m)，8.81-8.84(2H，m)

ESI-MS found: m/z 317.2[ M + H ] +

(example 177)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindoline

In a nitrogen atmosphere, 3.4g of methyl 4-bromo-2-bromo-methylbenzoate was dissolved in toluene, and 4.85ml of 2-hydroxy-2-methyl-propylamine and triethylamine were added thereto, followed by heating and refluxing overnight. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound (3.73 g) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.29(6H，s)，2.76(1H，s)，3.59(2H，s)，4.59(2H，s)，7.60-7.62(2H，m)，7.72(1H，d，J＝8.4Hz)

ES-MS found: m/z 286.1[ M + H ] +

2) Preparation of 4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

106mg of 5-bromo-2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindoline obtained in 1) above and 100mg of 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 4 were dissolved in toluene under a nitrogen atmosphere, 43mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound 73mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.47(3H，d，J＝1.7Hz)，3.13(1H，s)，3.65(2H，s)，4.68(2H，s)，7.33-7.41(2H，m)，7.56-7.61(2H，m)，7.83-7.85(1H，m)，7.95-7.97(1H，m)，8.00(1H，br)

ESI-MS found: m/z 381.2[ M + H ] +

(example 178)

4- (2- (1-methyl-cyclopropylmethyl) 1-oxo-isoindolin-5-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 130 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 6, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.43-0.51(2H，m)，0.54-0.87(2H，m)，1.07(3H，s)，2.58(3H，s)，3.52(2H，s)，4.56(2H，s)，7.52-7.61(1H，m)，7.81(1H，dd，J＝1.6，7.7Hz)，7.93-7.99(3H，m)，8.81-8.86(2H，m)

ESI-MS found: m/z 360.2[ M + H ] +

(example 179)

4- (2-methyl-1-oxo-isoindolin-6-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 94 and the tin reagent 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 13.

¹H NMR(400MHz、CDCl₃)δ：2.49(3H，d，J＝1.6Hz)，3.63(3H，s)，6.57(1H，d，J＝7.2Hz)，7.10-7.71(4H，m)，7.88(1H，dd，J＝2.0，8.4Hz)，8.01(1H，d，J＝1.2Hz)，8.54(1H，d，J＝8.4Hz)

ESI-MS found: m/z 353.1[ M + H ] +

(example 180)

4- (2-ethyl-imidazo [1, 2-a ] pyridin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 95 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 6, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.38(3H，t，J＝7.6Hz)，2.55(3H，s)，2.86(2H，q，J＝7.6Hz)，7.44(1H，s)，7.49(1H，dd，J＝2.0，9.4Hz)，7.52-7.61(1H，m)，7.63-7.66(1H，d，J＝9.4Hz)，7.92-7.95(1H，m)，8.54(1H，d，J＝1.7Hz)，8.54-8，85(2H，m)

ESI-MS found: m/z 305.2[ M + H ] +

(example 181)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

85mg of 5-bromo-2- (2-hydroxy-methyl-propyl) -1-oxo-isoindoline obtained in example 177-1) and 100mg of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 12 were dissolved in toluene under a nitrogen atmosphere, 35mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (31 mg).

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.52(3H，s)，3.08(1H，s)，3.65(2H，s)，4.68(2H，s)，7.27-7.31(2H，m)，7.50-7.53(2H，m)，7.80-7.82(1H，m)，7.95-7.98(2H，m)

ESI-MS found: m/z 381.2[ M + H ] +

(example 182)

1- (2-fluorophenyl) -4- (6-propyl-6, 7-dihydro-5H-pyrrolo [3, 4b ] pyridin-5-one-2-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 2- (benzyloxy) -6-propyl-5H-pyrrolo [3, 4-b ] pyridine-5, 7(6H) -dione

In 10ml of toluene was dissolved 510mg of 2- (benzyloxy) furo [3, 4-b ] pyridine-5, 7-dione, and 354mg of propylamine and 835. mu.l of triethylamine were added thereto, followed by stirring under reflux overnight. After cooling to room temperature, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 50: 50) to give the title compound as a white solid (56 mg).

1H NMR(300MHz，CDCl3)δ：0.96(3H，t，J＝7.3Hz)，1.63-1.79(2H，m)3.68(2H，t，J＝7.3Hz)，5.07(2H，s)，7.03(1H，d，J＝8.3Hz)，7.30-7.52(5H，m)，7.98(1H，d，J＝8.3Hz)

ESI-MS found: m/z 297.2[ M + H ] +

2) Preparation of 2- (benzyloxy) -6-propyl-6, 7-dihydro-5H-pyrrolo [3, 4-b ] pyridin-5-one

23mg of the compound obtained in 1) above was dissolved in 1.0ml of acetic acid, 20mg of zinc was added, and the mixture was stirred at 80 ℃ for 1.5 hours. After the resulting mixture was cooled to room temperature, water and a 3N aqueous solution of sodium hydroxide were added to the mixture, and the product was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 2.0ml of chloroform, 127. mu.l of triethylborane was added thereto, and after cooling to 0 ℃ 30. mu.l of trifluoroacetic acid was added dropwise. The mixture was stirred at room temperature overnight, the solvent was distilled off under reduced pressure, ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution were added to the resulting residue, and the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by basic thin layer silica gel chromatography (hexane: ethyl acetate 50: 50) to give the title compound as a white solid (14.2 mg).

1H NMR(300MHz，CDCl3)δ：0.97(3H，t，J＝7.3Hz)，1.60-1.80(2H，m)3.58(2H，t，J＝7.3Hz)，4.32(2H，s)，5.44(2H，s)，6.84(1H，d，J＝8.3Hz)，7.25-7.49(5H，m)，7.96(1H，d，J＝8.3Hz)

ESI-MS found: m/z 283.2[ M + H ] +

3) Preparation of 5-oxo-6-propyl-6, 7-dihydro-5H-pyrrolo [3, 4b ] pyridin-2-yl trifluoromethanesulfonate

12mg of the compound obtained in the above 2) was dissolved in 2.5ml of methanol, 10mg of 10% palladium on charcoal was added, and the mixture was stirred for 6 hours under a hydrogen atmosphere. The catalyst was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in 1ml of methylene chloride, cooled to 0 ℃ and then added with 50. mu.l of pyridine and 15. mu.l of trifluoromethanesulfonic anhydride. After stirring at room temperature for 2 hours, water was added, the product was extracted with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude purified product of the title compound.

4) Preparation of 1- (2-fluorophenyl) -4- (6-propyl-6, 7-dihydro-5H-pyrrolo [3, 4b ] pyridin-5-one-2-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 3), and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 4, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.00(3H，t，J＝7.4HZ)，1.71-1.77(2H，m)，2.68(3H，d，J＝1.7Hz)，3.65(2H，t，J＝7.3Hz)，4.47(2H，s)，7.32-7.41(2H，m)，7.52-7.62(2H，m)，8.20(1H，d，J＝8.1Hz)，8.38(1H，d，J＝8.1Hz)

ESI-MS found: m/z 352.2[ M + H ] +

(example 183)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

85mg of 5-bromo-2- (2-hydroxy-methyl-propyl) -1-oxo-isoindoline obtained in example 177-1) and 100mg of 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 13 were dissolved in toluene under a nitrogen atmosphere, 35mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (20 mg).

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.46(3H，d，J＝1.76Hz)，3.08(1H，s)，3.65(2H，s)，4.68(2H，s)，7.10-7.12(2H，m)，7.52-7.59(2H，m)，7.82-7.84(1H，m)，7.95-7.99(2H，m)

ESI-MS found: m/z 399.2[ M + H ] +

(example 184)

4- (2-methyl-1-oxo-isoquinolin-6-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 94 and the tin reagent 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 13.

¹H NMR(400MHz、CDCl₃)δ：2.50(3H，d，J＝2.0Hz)，3.64(3H，s)，6.58(1H，d，J＝7.6Hz)，7.12(1H，d，J＝7.6Hz)，7.32-7.42(2H，m)，7.55-7.62(2H，m)，7.90(1H，dd，J＝2.0，8.4Hz)，8.03(1H，d，J＝1.6Hz)，8.69(1H，d，J＝8.0Hz)

ESI-MS found: m/z 335.1[ M + H ] +

(example 185)

4- (2-isopropyl-1-oxo-isoquinolin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 101 and the same alkyltin compound 1- (pyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 6.

¹H NMR(400MHz、CDCl₃)δ：1.23(6H，d，J＝6.8Hz)，2.56(3H，m)，3.04(2H，t，J＝6.6Hz)，3.49(2H，t，J＝6.4Hz)，5.09-5.15(1H，m)，7.55-7.60(1H，m)，7.66(1H，dd，J＝1.6，8.4Hz)，7.74(1H，d，J＝0.8Hz)，7.91-7.95(1H，m)，8.19(1H，d，J＝8.4Hz)，8.79-8.85(2H，m)

ESI-MS found: m/z 348.2[ M + H ] +

(example 186)

4- (2-isopropyl-1-oxo-3, 4-dihydroisoquinolin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

After 50mg of palladium on charcoal was added to 10ml of a solution of 4- (2-isopropyl-1-oxo-isoquinolin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole in 25mg of ethanol, hydrogen was added under pressure of 4 atm to carry out hydrogenation. After 8 hours, the reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (chloroform: methanol: 10: 1) to give the title compound as a white solid (23 mg).

¹H NMR(400MHz、CDCl₃)δ：1.42(6H，d，J＝6.8Hz)，2.60(3H，s)，5.38-5.48(1H，m)，6.64(1H，d，J＝7.2Hz)，7.21(1H，d，J＝7.6Hz)，7.56-7.61(1H，m)，7.86(1H，dd，J＝1.6，8.4Hz)，7.92-7.97(1H，m)，7.99(1H，d，J＝2.0Hz)，8.56(1H，d，8.4Hz)，8.80-8.87(2H，m)

ESI-MS found: m/z 346.2[ M + H ] +

(example 187)

4- (2- (2-hydroxy-1-methyl-ethyl) -1-oxo-isoindolin-5-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

10mg of 5-bromo-2- (2-hydroxy-1-methyl-ethyl) -1-oxo-isoindoline obtained in example 76-1) and 20mg of the compound prepared in reference example 4 were dissolved in toluene under a nitrogen atmosphere, and 35mg of tetrakis (triphenylphosphine) palladium was added to the solution, and the mixture was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound (7 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.37(3H，d，J＝2.9Hz)，2.45(3H，d，J＝1.7Hz)，3.77-3.81(1H，m)，3.89-3.93(1H，m)，4.44-4.50(1H，m)，4.45-4.60(2H，m)，7.32-7.41(2H，m)，7.55-7.61(2H，m)，7.79-7.81(1H，m)，7.90-7.92(1H，m)，7.98-7.99(1H，m)

ESI-MS found: m/z 367.2[ M + H ] +

(example 188)

4- (2- (2, 2-difluoro-ethyl) -1-oxo-isoindolin-5-yl) -1- (2, 6-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

100mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 175mg of 1- (2, 6-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 18 were dissolved in toluene under a nitrogen atmosphere, 41mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound as a white solid (95 mg).

¹H NMR(400MHz、CDCl₃)δ：2.45(3H，s)，3.97-4.05(2H，m)，4.62(2H，s)，5.89-6.18(1H，m)，7.18-7.22(2H，m)，7.55-7.62(1H，m)，7.86-7.87(1H，m)，7.97-7.99(1H，m)，8.02(1H，m)

ESI-MS found: m/z 391.1[ M + H ] +

(example 189)

4- (2- (2, 2-difluoro-ethyl) -1-oxo-isoindolin-5-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

100mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 162mg of 1- (pyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 6 were dissolved in toluene under a nitrogen atmosphere, 41mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound (15 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.58(3H，s)，3.97-4.05(2H，m)，4.63(2H，s)，5.89-6.17(1H，m)，7.57-7.60(1H，m)，7.84-7.86(1H，m)，7.92-7.95(1H，m)，7.98-7.99(1H，m)，8.81-8.84(2H，m)

ESI-MS found: m/z 356.2[ M + H ] +

(example 190)

4- (2- (2-fluoroethyl) -imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of ethyl (6-bromoimidazo [1, 2-a ] pyridin-2-yl) acetate

4.90mg of ethyl 4-chloro-3-oxobutyrate was dissolved in 50ml of ethanol, 5.19g of 2-amino-5-bromopyridine was added thereto, and the mixture was stirred under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and aqueous sodium hydrogencarbonate solution were added successively. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate 60: 40) to give the title compound 9.49g as a white solid.

1H NMR(300MHz，CDCl3)δ：1.29(3H，t，J＝7.6Hz)，3.86(2H，s)，4.16(2H，q，J＝7.6Hz)，7.18-7.25(1H，m)，7.45(1H，d，J＝8.0Hz)，7.58(1H、s)，8.21-8.24(1H，m)

2) Preparation of 2- (6-bromoimidazo [1, 2-a ] pyridin-2-yl) ethanol

4.25g of the ester obtained in 1) was dissolved in 50ml of tetrahydrofuran, and after cooling to 0 ℃, 570mg of lithium aluminum hydride was added. After stirring at room temperature for 30 minutes, sodium sulfate 10 hydrate was added and further stirred for 2 hours. The resulting solution was diluted with chloroform, and after insoluble matter was filtered, the solution was concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (chloroform: methanol: 7: 1) to obtain 1.23g of a crude purified product of the title compound.

3) Preparation of 6-bromomy- (2-fluoroethyl) imidazo [1, 2-a ] pyridine

139mg of the alcohol obtained in 2) was dissolved in 2.0ml of tetrahydrofuran, and after cooling to-78 ℃, 225. mu.l of diethylaminosulfur trifluoride was added. After warming to room temperature, stirring was carried out for 5 minutes, and then a saturated aqueous sodium bicarbonate solution was added to extract the product with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give the title compound (10.2 mg).

1H NMR(300MHz，CDCl3)δ：3.20(2H，td，J＝6.0，26.1Hz)，4.82(2H，td，J＝6.0，94.3Hz)，7.22(1H，d，J＝8.0Hz)，7.51-7.57(2H，m)，8.22(1H，s)

4) Preparation of 4- (2- (2-fluoroethyl) -imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 3), and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 1, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：2.44(3H，d，J＝2.0Hz)，3.24(2H，td，J＝6.2，24.9Hz)，4.85(2H，td，J＝6.2，47.1Hz)，7.30-7.42(2H，m)，7.52-7.67(5H，m)，8.55-8.57(1H，m)

ESI-MS found: m/z 340.3[ M + H ] +

(example 191)

1- (2-fluorophenyl) -4- (2- (2-methoxyethyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2-methoxyethyl-imidazo [1, 2-a ] pyridine

110mg of the alcohol obtained in 2) of example 190 was dissolved in 2.0ml of dimethylformamide, 56mg of 60% sodium hydride was added under ice cooling, the temperature was raised to room temperature, the mixture was cooled again to 0 ℃ and 56. mu.l of methyl iodide was added. After stirring overnight at room temperature, water was added and the product was extracted with ethyl acetate. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give the title compound (24 mg).

1H NMR(300MHz，CDCl3)δ：3.06(2H，t，J＝6.3Hz)，3.40(3H、s)，3.77(2H，t，J＝6.3Hz)，7.15-7.20(1H，m)，7.40-7.46(2H，m)，8.20(1H，s)

2) Preparation of 1- (2-fluorophenyl) -4- (2- (2-methoxyethyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 1, the title compound was obtained as a white solid using the same method as example 49, a method based thereon, or a combination thereof with a conventional method.

¹H NMR(400MHz、CDCl₃)δ：2.43(3H，d，J＝2.0Hz)，3.10(2H，t，J＝6.6Hz)，3.41(3H，s)，3.82(2H，t，J＝6.6Hz)，7.32-7.44(2H，m)，7.52-7.66(5H，m)，8.53-8.55(1H，m)

ESI-MS found: m/z 352.3[ M + H ] +

(example 192)

4- (2- (2, 2-difluoro-ethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluoro-2-methyl-phenyl) -5-methyl-1H- [1, 2, 3] triazole

100mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 173mg of 1- (4-fluoro-2-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 17 were dissolved in toluene under a nitrogen atmosphere, 41mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound as a white solid (80 mg).

¹H NMR(400MHz、CDCl₃)δ：2.10(3H，s)，2.37(3H，s)，4.01(2H，dt，J＝4.3Hz，14.6Hz)，4.62(2H，s)，6.03(1H，tt，J＝4.3Hz，55.7Hz)，7.07-7.16(2H，m)，7.27-7.30(1H，m)，7.85-7.88(1H，m)，7.96-7.98(1H，m)，8.03-8.04(1H，m)

ESI-MS found: m/z 387.2[ M + H ] +

(example 193)

4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (thiophen-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 36 and the tin reagent 1- (thien-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 22.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，d，J＝6.8Hz)，2.58(3H，s)，4.42(2H，s)，4.56-4.75(1H，m)，7.36(1H，dd，J＝0.8，5.2Hz)，7.51-7.56(2H，m)，7.78(1H，d，J＝7.6Hz)，7.94(1H，d，J＝8.4Hz)，7.98(1H，s)

ESI-MS found: m/z 339.2[ M + H ] +

(example 194)

4- (2-Acetylmethyl) -imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 1- (6-bromoimidazo [1, 2-a ] pyridin-2-yl) acetone

425mg of the ester obtained in 1) of example 190 was dissolved in 10ml of tetrahydrofuran, and after cooling to-20 ℃, 8.1ml of 0.93M methylmagnesium bromide was added. After stirring at-10 ℃ for 30 minutes, water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give the title compound (84 mg).

1H NMR(300MHz，CDCl3)δ：2.29(3H，s)，3.91(2H，s)，7.19-7.29(1H，m)，7.45(1H，d，J＝8.7Hz)，7.52(1H，s)，8.44(1H，s)

2) Preparation of 4- (2-acetylmethyl) -imidazo [1, 2-a ] pyridin-6-yl) -1- (2-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the compound obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 4, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a conventional method.

¹H NMR(400MHz、CDCl₃) δ: 2.31(3H, s), 2.44(3H, d, J ═ 1.7Hz), 3.97(2H, s), 7.30-7.42(2H, m), 7.56-7.68(5H, m), 8.55-8.57(1H, m) ESI-MS found: m/z 350.2[ M + H ]]+

(example 195)

4- (2- (2-fluoroethyl) -imidazo [1, 2-a ] pyridin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 190 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 6, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃) δ: 2.55(3H, s), 3.24(2H, dd, J ═ 6.1, 25.1Hz), 4.84(2H, dd, J ═ 6.1, 47.1Hz), 7.52-7.60(3H, m), 7.66(1H, d, J ═ 9.3Hz), 7.92-7.96(1H, m), 8.54(1H, d, J ═ 1.2Hz), 8.81-8.85(2H, m) ESI-MS found: m/z 323.2[ M + H ]]+

(example 196)

4- (2- (2-fluoro-1-fluoromethyl-ethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-fluoro-1-fluoromethyl-ethyl) -1-oxo-isoindoline

In a nitrogen atmosphere, 100mg of methyl 4-bromo-2-bromomethylbenzoate was dissolved in toluene, and 120mg of 2-fluoro-1-fluoromethyl-ethylamine hydrochloride and 0.20ml of triethylamine were added thereto, followed by heating and refluxing overnight. The reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 1: 2) to give the title compound as a white solid (5 mg).

¹H NMR(400MHz、CDCl₃)δ：4.70-4.75(2H，m)，4.80-4.87(3H，m)，7.61-7.62(1H，m)，7.64(1H，s)，7.73-7.75(1H，m)

ES-MS found: m/z 292.0[ M + H ] +

2) Preparation of 4- (2- (2-fluoro-1-fluoromethyl-ethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

10mg of 5-bromo-2- (2-fluoro-1-fluoromethyl-ethyl) -1-oxo-isoindoline obtained in 1) above and 30mg of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 12 were dissolved in toluene under nitrogen atmosphere, 11mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane ═ 2: 1) to give the title compound as a white solid (2 mg).

¹H NMR(400MHz、CDCl₃)δ：2.52(3H，s)，4.65(2H，s)，4.73-4.93(5H，m)，7.27-731(2H，m)，7.50-7.53(2H，m)，7.83-7.85(1H，m)，7.973-7.99(2H，m)

ESI-MS found: m/z 387.2[ M + H ] +

(example 197)

4- (2- (2-fluoroethyl) -imidazo [1, 2-a ] pyridin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 190 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：2.49(3H，s)，3.18-3.29(2H，m)，4.84(2H，dt，J＝47.0，6.1Hz)，7.27-7.33(2H，m)，7.49-7.57(4H，m)，7.65(1H，d，J＝9.3Hz)，8.53-8.55(1H，m)

ESI-MS found: m/z 340.2[ M + H ] +

(example 198)

4- (2- (1-methyl-cyclopropyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained according to the procedure for example 5 using 5-bromo-2- (1-methyl-cyclopropyl) -1-oxo-isoindoline obtained in example 163-1) and the compound 1- (4-fluorophenyl-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole obtained in reference example 12.

¹H NMR(400MHz、CDCl₃)δ：0.81-0.86(2H，m)，1.05-1.10(2H，m)，1.47(3H，s)，2.51(3H，s)，4.46(2H，s)，7.26-7.32(2H，m)，7.49-7.54(2H，m)，7.77(1H，d，J＝8.1Hz)，7.92(1H，d，J＝8.1Hz)，7.96(1H，s)

ESI-MS found: m/z 363.2[ M + H ] +

(example 199)

1- (2, 4-difluorophenyl) 4- (2- (2-fluoroethyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 190 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 13, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：2.43(3H，d，J＝1.7Hz)，3.19-3.27(2H，m)，4.84(2H，dt，J＝46.9，6.2Hz)，7.09-7.17(2H，m)，7.54-7.68(4H，m)，8.55(1H，dd，J＝0.9，1.7Hz)

ESI-MS found: m/z 358.2[ M + H ] +

(example 200)

4- (2-ethoxycarbonylmethyl-1 oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of ethyl (5-bromo-1-oxo-1, 3-dihydro-2H-isoindolin-2-yl) acetate

The reaction was carried out in the same manner as in example 49-1 except for using glycine ethyl ester instead of cyclopropylamine used in example 49-1 to obtain the title compound.

1H NMR(300MHz，CDCl3)δ：1.29(3H，t，J＝7.6Hz)，4.22(2H，q，J＝7.6Hz)，4.38(2H、s)，4.51(2H、s)7.54-7.67(2H，m)，7.74(1H，d，J＝8.0Hz)

2) Preparation of 4- (2-ethoxycarbonylmethyl-1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.31(3H，t，J＝7.1Hz)，2.52(3H，s)，4.24(2H，q，J＝7.1Hz)，4.44(2H，s)，4.62(2H，s)，7.26-7.32(2H，m)，7.50-7.54(2H，m)，7.81(1H，d，J＝7.6Hz)，7.97-8.00(2H，m)

ESI-MS found: m/z 395.2[ M + H ] +

(embodiment 201)

1- (2-fluorophenyl) 4- (2- (2-hydroxy-2-methyl-propyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 1- (6-bromoimidazo [1, 2-a ] pyridin-2-yl) -2-methylpropan-2-ol

5.66g of the compound obtained in 1) of example 190 was dissolved in 50ml of diethyl ether, cooled to 0 ℃ and 30ml of 3.0M methylmagnesium iodide was added. After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain 1.17g of the title compound as a white solid.

1H NMR(300MHz，CDCl3)δ：1.24(6H，s)，2.89(2H，s)，4.54(1H、s)，7.20-7.25(1H、m)，7.37(1H，s)7.41-7.46(1H，m)，8.22-8.23(1H，m)

2) Preparation of 1- (2-fluorophenyl) 4- (2- (2-hydroxy-2-methyl-propyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 4, the title compound was obtained as a white solid using the same method as example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.27(6H，s)，2.44(3H，d，J＝1.7Hz)，2.93(2H，s)，7.33-7.42(2H，m)，7.49(1H，s)，7.52-7.67(4H，m)，8.58-8.60(1H，m)

ESI-MS found: m/z 366.3[ M + H ] +

(embodiment 202)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1-phenyl-5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 177 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 5, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.17(3H，s)，3.50(2H，s)，3.65(2H，s)，7.52-7.63(5H，m)，7.83(1H，d，J＝8.0Hz)，7.96(1H，d，J＝8.0Hz)，8.00(1H，s)

ESI-MS found: m/z 363.3[ M + H ] +

Example 203

4- (2-Acetylmethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-oxopropyl) isoindolin-1-one

4.78g of the compound obtained in 1) of example 200 was dissolved in 100ml of diethyl ether, cooled to 0 ℃ and 24ml of 3.0M methylmagnesium iodide was added. After stirring at room temperature for 1 hour, water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to give the title compound (232 mg).

1H NMR(400MHz，CDCl3)δ：2.24(3H，s)，4.44(2H，s)，4.47(2H、s)，7.60-7.65(2H，m)，7.71-7.75(1H，m)

2) Preparation of 4- (2-acetylmethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：2.26(3H，s)，2.52(3H，s)，4.49(2H，s)，4.57(2H，s)，7.26-7.32(2H，m)，7.50-7.54(2H，m)，7.82(1H，dd，J＝1.5，8.0Hz)，7.97(1H，d，J＝8.0Hz)，7.98(1H，d，J＝1.5Hz)

ESI-MS found: m/z 365.2[ M + H ] +

(example 204)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2- (2-hydroxy-2-methyl-propyl) -isoquinolin-1-one

Under a nitrogen atmosphere, 23mg of 60% sodium hydride was added to a solution of 62mg of 6-bromo-2H-isoquinolin-1-one in 2ml of dimethylformamide at 0 ℃ and stirred for 30 minutes, then 0.055ml of 3-bromo-2-methyl-propane was added at 0 ℃ and stirred for 2 hours at room temperature. After cold water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was separated and purified by thin layer chromatography (hexane: ethyl acetate 3: 1). The resulting compound was dissolved in concentrated hydrochloric acid, stirred at 100 ℃ for 3 hours, cooled to room temperature, made alkaline with 50% aqueous sodium hydroxide solution, and stirred at room temperature for 3 hours. After cold water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (hexane: ethyl acetate 3: 1) to give the title compound as a white solid (20 mg).

¹H NMR(400MHz、CDCl₃)δ：1.29(6H，s)，3.56(1H，s)，4.07(2H，s)，6.43(1H，d，J＝7.6Hz)，7.17(1H，d，J＝7.2Hz)，7.58(1H，dd，J＝1.8，8.6Hz)，7.70(1H，d，J＝1.6Hz)，8.27(1H，d，J＝8.4Hz)

ESI-MS found: m/z 238.1[ M + H ] +

2) Preparation of 4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

100mg of the halide 6-bromo-2- (2-hydroxy-2-methyl-propyl) -isoquinolin-1-one obtained in 1) above and 200mg of the alkyltin compound 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole, which was the same as in reference example 12, were dissolved in 3ml of toluene under a nitrogen atmosphere, 100mg of tetrakis (triphenylphosphine) palladium was added, and after degassing, the mixture was stirred at 115 ℃ for 10 hours under heating. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: hexane: 1: 2) and washed with pentane to give 95mg of the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.55(3H，s)，3.88(1H，s)，4.12(2H，s)，6.62(1H，d，J＝7.6Hz)，7.17(1H，d，J＝7.6Hz)，7.25-7.33(2H，m)，7.49-7.55(2H，m)，7.89(1H，dd，J＝1.6，8.4Hz)，8.03(1H，d，J＝1.6Hz)，8.53(1H，d，J＝8.4Hz)

ESI-MS found: m/z 393.2[ M + H ] +

(example 205)

4- (2- (2-methyl-2-acetoxy-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-methyl-2-acetoxy-propyl) -1-oxo-isoindoline

In a nitrogen atmosphere, 50mg of 5-bromo-2- (2-hydroxy-methyl-propyl) -1-oxo-isoindoline obtained in example 177-1) was dissolved in tetrahydrofuran, and 21mg of acetic anhydride and 20ml of sodium hydride were added to the solution, and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound (44 mg) as a white solid.

¹H NMR(400MHz，CDCl3)δ：1.52(6H，s)，2.05(3H，s)，3.84(2H，s)，4.49(2H，s)，7.60-7.63(2H，m)，7.71-7.73(1H，m)

ES-MS found: m/z 326.1[ M + H ] +

2) Preparation of 4- (2- (2-methyl-2-acetoxy-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Under nitrogen, 44mg of 5-bromo-2- (2-fluoro-1-fluoromethyl-ethyl) -1-oxo-isoindoline obtained in 1) above and 76mg of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 12 were dissolved in toluene, and 16mg of tetrakis (triphenylphosphine) palladium was added to the solution, and the mixture was refluxed for 6 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by TLC (thin layer silica gel column chromatography) (ethyl acetate: hexane: 2: 1) to give the title compound as a white solid (20 mg).

¹H NMR(400MHz、CDCl₃)δ：1.56(6H，d，J＝9.2Hz)，2.07(3H，s)，2.52(3H，s)，3.89(2H，s)，4.60(.2H，s)，7.27-7.31(2H，m)，7.50-7.53(2H，m)，7.79-7.82(1H，m)，7.96-8.00(2H，m)

ESI-MS found: m/z 423.3[ M + H ] +

(example 206)

1- (2, 4-difluorophenyl) 4- (2- (2-hydroxy-2-methyl-propyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 201 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 13, the title compound was obtained as a white solid using the same method as example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.27(6H，s)，2.44(3H，d，J＝1.7Hz)，2.93(2H，s)，7.10-7.16(2H，m)，7.49(1H，s)，7.52-7.66(3H，m)，8.58(1H，s)

ESI-MS found: m/z 384.3[ M + H ] +

(example 207)

Preparation of 1- (4-fluorophenyl) 4- (2- (2-hydroxy-2-methyl-propyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 201 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.27(6H，s)，2.50(3H，s)，2.93(2H，s)，7.25-7.32(2H，m)，7.49-7.55(4H，m)，7.65(1H，d，J＝9.3Hz)，8.57(1H，s)

ESI-MS found: m/z 366.2[ M + H ] +

(example 208)

4- (2, 2-difluoro-ethyl-1-oxo-isoindolin-5-yl) -1-phenyl-5-methyl-1H- [1, 2, 3] triazole

100mg of 5-bromo-2- (2, 2-difluoroethyl) -1-oxo-isoindoline obtained in example 137-1) and 162mg of 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 5 were dissolved in toluene under a nitrogen atmosphere, 41mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 2: 1) to give the title compound as a white solid (55 mg).

¹H NMR(400MHz、CDCl₃)δ：2.54(3H，s)，3.96-4.05(2H，m)，4.62(2H，s)，5.88-6.17(1H，m)，7.51-7.63(5H)，7.84-7.86(1H)，7.96-8.00(2H，m)

ESI-MS found: m/z 355.2[ M + H ] +

(example 209)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 204 and the same alkyltin compound 1- (pyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 6.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，s)，2.61(3H，s)，3.82(1H，s)，4.12(2H，s)，6.63(1H，d，J＝7.6Hz)，7.19(1H，d，J＝7.2Hz)，7.57-7.61(1H，m)，7.90(1H，dd，J＝0.8，8.4Hz)，7.95(1H，ddd，J＝0.8，2.4，8.0Hz)，8.54(1H，d，J＝9.4Hz)，8.81-8.86(2H，m)

ESI-MS found: m/z 376.2{ M + H } +

(example 210)

1- (2, 4-difluorophenyl) -4- (2- (2-fluoro-2-methyl-propyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2- (2-fluoro-2-methylpropyl) imidazo [1, 2-a ] pyridine

135mg of the compound obtained in 1) of example 201 was dissolved in 5.0ml of methylene chloride, cooled to-78 ℃ and 198. mu.l of diethylaminosulfur trifluoride was added. After warming to room temperature, saturated aqueous sodium bicarbonate was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to give the title compound (96.1 mg).

1H NMR(400MHz，CDCl3)δ：1.43(6H，d，J＝21.5Hz)，3.11(2H，d，J＝20.5Hz)，7.15-7.22(1H，m)，7.42-7.48(2H，m)，8.21-8.23(1H，m)

ESI-MS found: m/z 271.1, 273.1[ M + H ] +

2) Preparation of 1- (2, 4-difluorophenyl) -4- (2- (2-fluoro-2-methyl-propyl) -imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 1) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 13, the title compound was obtained as a white solid using the same method as example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.47(6H，d，J＝21.5Hz)，2.43(3H，d，J＝1.9Hz)，3.16(2H，d，J＝20.5Hz)，7.09-7.15(2H，m)，7.53-7.61(3H，m)，7.66(1H，d，J＝9.2Hz)，8.55(1H，d，J＝1.4Hz)

ESI-MS found: m/z 386.2[ M + H ] +

(example 211)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluoro-2-methyl-phenyl) -5-methyl-1H- [1, 2, 3] triazole

100mg of 5-bromo-2- (2-hydroxy-methyl-propyl) -1-oxo-isoindoline obtained in example 177-1) and 170mg of 1- (4-fluoro-2-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 17 were dissolved in toluene under a nitrogen atmosphere, 40mg of tetrakis (triphenylphosphine) palladium was added, and the mixture was refluxed overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound 61mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.10(3H，s)，2.37(3H，s)，3.10(1H，s)，3.65(2H，s)，4.63(2H，s)，7.10-7.15(2H，m)，7.26-7.30(1H，m)，7.83-7.85(1H，m)，7.95-7.97(1H，m)，8.03(1H，m)

ESI-MS found: m/z 395.2[ M + H ] +

(example 212)

4- (2- (2-fluoro-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

100mg of 4- (2- (2-hydroxy-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole obtained in example 181-1) was dissolved in 1, 2-dichloromethane under a nitrogen atmosphere, cooled to-78 ℃, and then 0.1ml of diethylaminosulfur trifluoride was added thereto and stirred for 10 minutes. Water was added thereto, the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated aqueous sodium hydrogencarbonate solution and a saturated brine and was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1) to give the title compound as a white solid (30 mg).

¹H NMR(400MHz、CDCl₃)δ：1.42(6H，d，J＝21.4Hz)，2.52(3H，s)，3.78(2H，d，J＝23.6Hz)，4.64(2H，s)，7.26-7.32(2H，m)，7.49-7.54(2H，m)，7.82-7.84(1H，m)，7.96-7.97(2H，m)

ESI-MS found: m/z 383.2[ M + H ] +

(example 213)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 204 and the same alkyltin compound 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 13.

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.49(3H，d，J＝1.6Hz)，3.88(1H，s)，4.12(2H，s)，6.62(1H，d，J＝7.2)，7.08-7.20(2H，m)，7.55-7.63(1H，m)，7.91(1H，dd，J＝2.0，8.4Hz)，8.05(1H，d，J＝1.6Hz)，8.53(1H，d，J＝8.4Hz)

ESI-MS found: m/z 411.3[ M + H ] +

(example 214)

4- (2- (2, 2-difluoroethyl) -1-oxo-isoquinolin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 6-bromo-2- (2, 2-difluoroethyl) -isoquinolin-1-one

To a solution of 49mg of 6-bromo-2H-isoquinolin-1-one in 2ml of dimethylformamide was added 44mg of 60% sodium hydride at room temperature under a nitrogen atmosphere, and after stirring for 30 minutes, 169mg of 2, 2-difluoroiodoethane was added and the mixture was stirred at room temperature for 6 hours. After cold water was added to the reaction mixture, the mixture was extracted with chloroform, and the chloroform layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (chloroform: methanol 10: 1) to give the title compound 41mg as a white solid.

2) Preparation of 4- (2- (2, 2-difluoroethyl) -1-oxo-isoquinolin-6-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

The coupling reaction of the compound obtained in 1) above and an alkyltin compound 1- (pyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole similar to that in reference example 6 was carried out in the same manner as in example 3 to obtain the title compound as a white solid.

¹H NMR(400MHz、CDCl₃)δ：2.61(3H，s)，4.34(2H，td，J＝4.4，13.6Hz)，6.18(1H，tt，J＝4.4，56.0Hz)，6.63(1H，d，J＝7.2Hz)，7.12(1H，d，J＝7，2Hz)，7.59(1H，dd，J＝4.8，8.0Hz)，7.89-7.97(2H，m)，8.02(1H，d，J＝1.6Hz)，8.52(1H，d，J＝8.4Hz)，8.81-8.87(2H，m)

ESI-MS found: m/z 368.2[ M + H ] +

(example 215)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 100mg of 5-bromo-2- (2-hydroxy-methyl-propyl) -1-oxo-isoindoline obtained in example 177-1) and 150mg of 1- (pyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 6 were dissolved in toluene, and 40mg of tetrakis (triphenylphosphine) palladium was added and heated under reflux overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate: hexane: 1: 2) to give the title compound as a white solid (4 mg).

¹H NMR(400MHz、CDCl₃)δ：2.58(3H，s)，3.65(2H，s)，4.69(2H，s)，7.50-7.60(1H，m)，7.82(1H，d，J＝8.4Hz)，7.92-7.98(2H，m)，7.81-8.84(2H，m)

ESI-MS found: m/z 364.2[ M + H ] +

(example 216)

4- (2- (2-amino-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (2, 4-difluoro-phenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 2- (2-amino-2-methylpropyl) -5-bromoisoindolin-1-one

The reaction was carried out in the same manner as in example 49-1 using 1, 2-diamino-2-methylpropane instead of cyclopropylamine used in example 49-1 to give the title compound.

1H NMR(300MHz，CDCl3)δ：1.17(6H，s)，3.48(2H，s)，4.62(2H，s)，7.59-7.62(2H，m)，7.72(1H，d，J＝8.0Hz)

2) Preparation of 4- (2- (2-amino-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (2, 4-difluoro-phenyl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.56(6H，s)，2.46(3H，d，J＝1.5Hz)，3.54(2H，s)，4.71(2H，s)，7.09-7.23(2H，m)，7.56-7.61(1H，m)，7.83(1H，d，J＝7.8Hz)，7.95-7.98(2H，m)

ESI-MS found: m/z 398.2[ M + H ] +

(example 217)

4- (2- (2-hydroxy-2-methyl-propyl) -3-methyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluoro-phenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (2-hydroxy-2-methyl-propyl) -3-methyl-1-oxo-isoindoline

100mg of 5-bromo-2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindoline obtained in example 177-1) was dissolved in tetrahydrofuran under nitrogen, and 40mg of sodium hydride and 0.4ml of methyl iodide were added to the solution, followed by refluxing with heating for 2 hours. After the reaction mixture was cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer silica gel column chromatography (ethyl acetate) to give the title compound (7 mg) as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.23(3H，s)，1.30(3H，s)，1.48(3H，d，J＝6.8Hz)，3.23(1H，d，J＝14.8Hz)，3.88(1H，d，J＝14.4Hz)，4.79-4.80(1H，m)，7.58-7.62(2H，m)，7.70-7.72(1H，m)

2) Preparation of 4- (2- (2-hydroxy-2-methyl-propyl) -3-methyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluoro-phenyl) -5-methyl-1H- [1, 2, 3] triazole

In a nitrogen atmosphere, 7mg of 5-bromo-2- (2-fluoro-2-methyl-propyl) -3-methyl-1-oxo-isoindoline obtained in the above-mentioned 1) and 10mg of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole prepared in reference example 12 were dissolved in toluene, and 2mg of tetrakis (triphenylphosphine) palladium was added to the solution, followed by refluxing with heating overnight. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration with celite. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane ═ 1: 2) to give the title compound 5mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.30(1H，d，J＝9.5Hz)，1.55(3H，d，J＝6.8Hz)，2.52(3H，s)，3.31(1H，d，J＝14.6Hz)，3.90(1H，d，J＝14.6Hz)，4.85-4.87(1H，m)，7.26-7.31(2H，m)，7.50-7.53(2H，m)，7.76-7.78(1H，m)，7.93-7.95(1H，m)7.99(1H，br)

ESI-MS found: m/z 395.2[ M + H ] +

(example 218)

4- (2- (2-methanesulfonylamino-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (2, 4-difluoro-phenyl) -5-methyl-1H- [1, 2, 3] triazole

10mg of the compound obtained in example 217 was dissolved in 2ml of chloroform, and 20. mu.l of methanesulfonyl chloride and 20. mu.l of triethylamine were added thereto, and after 30 minutes at room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate) to give the title compound as a white solid (12.3 mg).

¹H NMR(400MHz、CDCl₃)δ：1.51(6H，s)，2.46(3H，d，J＝1.5Hz)，3.06(3H，s)，3.75(2H，s)，4.74(2H，s)，5.48(1H，s)，7.09-7.16(2H，m)，7.56-7.61(1H，m)，7.88(1H，d，J＝8.2Hz)，7.95-7.97(2H，m)

ESI-MS found: m/z 476.1[ M + H ] +

(example 219)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl) -1-phenyl-5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 3 using the halide obtained in example 204 and the same alkyltin compound 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole as in reference example 5.

¹H NMR(400MHz、CDCl₃)δ：1.32(6H，s)，2.57(3H，s)，3.92(1H，s)，4.12(2H，s)，6.62(1H，d，J＝8.0Hz)，7.17(1H，d，J＝8.0Hz)，7.51-7.69(5H，m)，7.90(1H，dd，J＝4.0，8.0Hz)，8.04(1H，s)，8.52(1H，d，J＝8.0Hz)

ESI-MS found: m/z 375.3[ M + H ] +

(example 220)

4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-3, 4-dihydroisoquinolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

After adding 50mg of palladium on charcoal to 10ml of a solution of 30mg of 4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole in ethanol, hydrogen was added under pressure of 4 atm for hydrogenation. After 8 hours, the reaction mixture was filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was purified by thin layer chromatography (chloroform: methanol 10: 1) to give the title compound 19mg as a white solid.

¹H NMR(400MHz、CDCl₃)δ：1.33(6H，s)，2.51(3H，s)，3，12(2H，t，J＝6.6Hz)，3.62(2H，s)，3.76(2H，t，J＝.6.6Hz)，4.06(1H，brs)，7.26-7.32(2H，m)，7.48-7.54(2H，m)，7.67(1H，dd，J＝1.4，8.2Hz)，7.79(1H，s)，8.16(1H，d，J＝8.0Hz)

ESI-MS found: m/z 395.3[ M + H ] +

(example 221)

4- (2- (2, 2-difluoroethyl) - (2, 4-difluorophenyl) -imidazo [1, 2-a ] pyridin-6-yl) -1-5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 2- (6-bromoimidazo [1, 2-a ] pyridin-2-yl) -N-methoxy-N-methylacetamide

2.0g of the ester obtained in 1) of example 190 was dissolved in 5ml of ethanol, and 5ml of a 3N aqueous sodium hydroxide solution was added thereto and the mixture was stirred overnight. The resulting mixture was neutralized with 6N aqueous hydrochloric acid, and the solvent was distilled off under reduced pressure. Chloroform-methanol was added to the residue, insoluble matter was filtered, and the filtrate was concentrated under reduced pressure to obtain 1.26g of a mixture of carboxylic acids. The resulting carboxylic acid 810mg was dissolved in pyridine 10ml, and N, O-dimethylhydroxylamine hydrochloride 466mg and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride 1010mg were added thereto, followed by stirring at room temperature for 3 hours. To the resulting solution was added water, and the product was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate) to give the title compound (630 mg).

1H NMR(400MHz，CDCl3)δ：3.24(3H，s)，3.75(3H，s)4.01(2H，s)，7.17-7.22(1H，m)，7.44(1H，d，J＝8.4Hz)，7.61(1H，s)，8.20-8.22(1H，m)

2) Preparation of 6-bromoimidazo-2- (2, 2-difluoroethyl) imidazo [1, 2-a ] pyridine

630mg of the compound obtained in the above 1) was dissolved in 15ml of tetrahydrofuran, cooled to-5 ℃ and 80mg of lithium aluminum hydride was added. After stirring at room temperature for 1 hour, dilute hydrochloric acid was added and the mixture was washed with ethyl acetate. Saturated sodium bicarbonate was added to the aqueous layer to make the mixture basic, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 530mg of a mixture of aldehydes. 530mg of the obtained aldehyde was dissolved in 20ml of methylene chloride, cooled to-15 ℃, and then 880. mu.l of diethylaminosulfur trifluoride aqueous solution was added thereto and stirred for 30 minutes. After a saturated aqueous sodium hydrogencarbonate solution was added to the resulting solution, the product was extracted with ethyl acetate. The organic layer was dried over saturated anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (hexane: ethyl acetate) and thin layer silica gel chromatography (hexane: ethyl acetate 2: 1) successively to obtain the title compound (17.1 mg).

1H NMR(400MHz，CDCl3)δ：3.35(2H，dt，J＝4.7，16.9Hz)，6.16(1H，tt，J＝4.7，56.4Hz)，7.22-7.28(1H，m)，7.43(1H，d，J＝8.0Hz)，7.48(1H，s)，8.23-8.24(1H，m)

3) Preparation of 4- (2- (2, 2-difluoroethyl) - (2, 4-difluorophenyl) -imidazo [1, 2-a ] pyridin-6-yl) -1-5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 2) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 13, the title compound was obtained as a white solid using the same method as example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：2.44(3H，d，J＝1.4Hz)，3.40(2H，dt，J＝4.7，16.9Hz)，6.22(1H，tt，J＝4.7，56.4Hz)，7.10-7.17(2H，m)，7.55-7.61(3H，m)，7.67(1H，d，J＝9.3Hz)，8.56-8.58(1H，m)

ESI-MS found: m/z 376.1[ M + H ] +

(example 222)

4- (2- (3-fluoro-propyl) -1-oxo-isoindolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 5-bromo-2- (3-hydroxypropyl) isoindolin-1-one

The reaction was carried out in the same manner as in example 49-1 except for using 3-aminopropanol instead of cyclopropylamine used in example 49-1 to obtain the title compound.

1H NMR(400MHz，CDCl3)δ：1.80-1.88(2H，m)，3.44-3.46(1H，m)，3.55-3.61(2H，m)，3.77(2H，t，J＝7.0Hz)，4.39(2H，s)，7.60-7.64(2H，m)，7.71(1H，d，J＝8.0Hz)

2) Preparation of 3- (5-bromo-1-oxo-1, 3-dihydro-2H-isoindol-2-yl) propyl methanesulfonate

270mg of the compound obtained in 1) was dissolved in 5ml of chloroform, and after cooling to 0 ℃, 93. mu.l of methanesulfonyl chloride and 167. mu.l of triethylamine were added thereto, and the mixture was stirred at room temperature overnight. To the resulting solution was added saturated aqueous sodium bicarbonate solution, and the product was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 75: 35) to obtain the title compound (310 mg).

1H NMR(400MHz，CDCl3)δ：2.12-2.20(2H，m)，3.03(3H，s)，3.75(2H，t，J＝7.0Hz)，4.30(2H，t，J＝7.0Hz)，4.41(2H，s)，7.60-7.64(2H，m)，7.70(1H，d，J＝8.0Hz)

3) Preparation of 5-bromo-2- (3-fluoropropyl) -isoindolin-1-one

The compound obtained in 2) was dissolved in 4ml of acetonitrile, 350mg of tetrabutylammonium fluoride 3 hydrate was added, and the mixture was stirred at 80 ℃ for 1 hour. After cooling to room temperature, water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain the title compound (27.7 mg).

1H NMR(300MHz，CDCl3)δ：2.02-2.19(2H，m)，3.75(2H，t，J＝7.0Hz)，4.31(2H，s)，4.41(2H，s)，4.42-4.65(2H，m)7.53-7.63(2H，m)，7.71(1H，d，J＝8.0Hz)

4) Preparation of 4- (2- (3-fluoro-propyl) -1-oxo-isoindolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 3), and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：2.03-2.19(2H，m)，2.52(3H.s)，3.80(2H，t，J＝7.1Hz)，4.49-4.64(4H，m)，7.26-7.31(2H，m)，7.50-7.53(2H，m)，7.80(1H，d，J＝7.7Hz)，7.95(1H，d，J＝7.7Hz)，7.99(1H，s)

ESI-MS found: m/z 369.2[ M + H ] +

(example 223)

4- (2- (2-methanesulfonylamino-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of 2- (2-amino-2-methylpropyl) -5- [1(2, 4-difluorophenyl) -5-methyl-1H-1, 2, 3-triazol-4-yl ] isoindolin-1-one

Using the halide obtained in 1) of example 218 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 13, the title compound was obtained as a white solid using the same method as in example 217, a method based thereon, or a combination thereof with a usual method.

2) Preparation of 4- (2- (2-methanesulfonylamino-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

57mg of the compound obtained in 1) was dissolved in 2ml of chloroform, and 23. mu.l of methanesulfonyl chloride and 42. mu.l of triethylamine were added thereto, and after 30 minutes at room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel thin layer chromatography (ethyl acetate) to give the title compound as a white solid (62 mg).

¹H NMR(400MHz、CDCl₃)δ：1.55(6H，s)，2.52(3H，s)，3.06(3H，s)，3.75(2H，s)，4.74(2H，s)，5.44(1H，s)，7.26-7.31(2H，m)，7.50-7.54(2H，m)，7.87(1H，d，J＝8.8Hz)，7.95-7.97(2H，m)

ESI-MS found: m/z 458.2[ M + H ] +

(example 224)

1- (2, 4-difluorophenyl) -5-methyl-4- (2- (2-hydroxy-2-methyl-propyl) -quinolin-6-yl) -1H- [1, 2, 3] triazole

1) Preparation of 1- (6-bromoquinolin-2-yl) -2-methylpropan-2-ol

2.22g of 6-bromoquinazidine was added to 20ml of diethyl ether, and after cooling to-78 ℃, 3.76ml of 2.66M n-butyllithium was added dropwise. The resulting suspension was stirred for 5 minutes, and 2ml of anhydrous acetone was added thereto, followed by stirring for 10 minutes, and then water was added thereto. The product was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate 2: 1) to obtain 1.14g of the title compound.

1H NMR(400MHz，CDCl3)δ：1.28(6H，s)，3.09(2H，s)，5.81(1H，s)，7.28(1H，d，J＝8.3Hz)，7.77(1H，dd，J＝2.4，8.6Hz)，7.90(1H，d，J＝8.6Hz)，7.97(1H，d，J＝2.4Hz)，8.03(1H，d，J＝8.3Hz)

2) Preparation of 1- (2, 4-difluorophenyl) -5-methyl-4- (2- (2-hydroxy-2-methyl-propyl) -quinolin-6-yl) -1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.31(6H，s)，2.51(3H，d，J＝1.5Hz)，3.13(2H，s)，6.05(1H，brs)，7.10-7.17(2H，m)，7.31(1H，d，J＝8.3Hz)，7.57-7.63(1H，m)，8.12-8.17(2H，m)，8.19(1H，d，J＝8.3Hz)，8.24(1H，s)

ESI-MS found: m/z 395.3[ M + H ] +

(example 225)

4- (2- (3-hydroxy-3-methyl-butyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of methyl 3- (5-bromo-1-oxo-1, 3-dihydro-2H-isoindol-2-yl) propionate

A reaction was carried out in the same manner as in example 49-1 except for using β -aniline instead of cyclopropylamine used in example 49-1 to obtain the title compound.

1H NMR(400MHz，CDCl3)δ：2.75(2H，t，J＝6.4Hz)，3.69(3H，s)，3.89(2H，t，J＝6.4Hz)，4.46(2H，s)，7.56-7.61(2H，m)，7.71(1H，d，J＝8.8Hz)

2) Preparation of 5-bromo-2- (3-hydroxy-3-methylbutyl) isoindolin-1-one

312mg of the compound obtained in 1) above was dissolved in 2ml of diethyl ether, and after cooling to 0 ℃ 3.0M methyl magnesium iodide 1.33ml was added. After stirring at room temperature for 1 hour, water was added and the product was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 1) to obtain the title compound (83.3 mg).

1H NMR(400MHz，CDCl3)δ：1.28(6H，s)，1.83(2H，t，J＝7.3Hz)，3.76(2H，t，J＝7.3Hz)，4.40(2H，s)，7.58-7.62(2H，m)，7.70(1H，d，J＝8.3Hz)

3) Preparation of 4- (2- (3-hydroxy-3-methyl-butyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in the above 2) and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.31(6H，s)，1.86(2H，t，J＝7.6Hz)，2.26(1H，brs)，2.52(3H，s)，3.81(2H，t，J＝7.6Hz)，4.51(2H，s)，7.26-7.32(2H，m)，7.49-7.53(2H，m)，7.78(1H，d，J＝7.8Hz)，7.93(1H，d，J＝7.8Hz)，7.99(1H，s)

ESI-MS found: m/z 395.2[ M + H ] +

(example 226)

4- (2- (2, 2-difluoroethyl) -imidazo [1, 2-a ] pyridin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 221 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：2.50(3H，s)，3.39(2H，tt，J＝4.6，16.9Hz)，6.20(1H，tt，J＝4.6，56.6Hz)，7.24-7.32(2H，m)，7.49-7.60(4H，m)，7.67(1H，d，J＝9.3Hz)，8.55(1H，s)

ESI-MS found: m/z 358.2[ M + H ] +

(example 227)

1- (4-fluorophenyl) -5-methyl-4- (2- (2-hydroxy-2-methyl-propyl) -quinolin-6-yl) -1H- [1, 2, 3] triazole

Using the halide obtained in example 224 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 12, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.31(6H，s)，2.57(3H，s)，3.13(2H，s)，6.05(1H，brs)，7.25-7.33(3H，m)，7.50-7.57(2H，m)，8.13-8.24(4H，m)

ESI-MS found: m/z 377.2[ M + H ] +

(example 228)

4- (1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole

The title compound was obtained in the same manner as in example 81 except for using the tin reagent of reference example 13 in place of the tin reagent used in example 81.

¹H NMR(400MHz、CDCl₃)δ：2.47(3H，d，＝1.5Hz)，4.55(2H，s)，6.29(1H，brs)，7.08-7.17(2H，m)，7.55-7.62(1H，m)，7.85(1H，d，J＝7.3Hz)，7.99(1H，d，J＝7.3Hz)，8.02(1H，s)

ESI-MS found: m/z 327.1[ M + H ] +

(example 229)

4- (2-propyl-1-oxo-isoindolin-5-yl) -1- (2-amino-pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

To 72mg of the compound obtained in example 85, 2ml of isopropyl alcohol and 2ml of 25% aqueous ammonia were added, and the mixture was stirred at 120 ℃ for 2 days. The solvent was evaporated under reduced pressure, and the resulting residue was purified by thin layer silica gel chromatography to give the title compound as a white solid (15.7 mg).

¹H NMR(400MHz、CDCl₃)δ：0.99(3H，t，J＝7.6Hz)，1.70-1.78(2H，m)，2.46(3H，s)，3.63(2H，t，J＝7.3Hz)，4.47(2H，s)，4.78(2H，brs)，6.81-6.91(1H，m)，7.46-7.50(1H，m)，7.81(1H，d，J＝8.1Hz)，7.96(1H，d，J＝8.1Hz)，7.99(1H，s)，8.27-8.30(1H，m)

ESI-MS found: m/z 349.2[ M + H ] +

(example 230)

1- (4-fluorophenyl) -4- (2- (3-hydroxy-3-methyl-butyl) imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

1) Preparation of ethyl 3- (6-bromoimidazo [1, 2-a ] pyridin-2-yl) propionate

Ethyl 5-chloro-3-oxopentanoate (4.28 g) was dissolved in ethanol (40 ml), and 2.94g of 2-amino-5-bromopyridine was added to the solution, followed by stirring under reflux overnight. After cooling to room temperature, the solvent was distilled off under reduced pressure, and ethyl acetate and a saturated aqueous sodium bicarbonate solution were successively added. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by preparative thin layer silica gel chromatography (hexane: ethyl acetate 50: 50) to give 990mg of the crude purified product of the title compound. .

2) Preparation of 4- (6-bromoimidazo [1, 2-a ] pyridin-2-yl) 2-methylbutan-2-ol

225mg of the ester obtained in 1) was dissolved in 4ml of diethyl ether, and after cooling to 0 ℃ was added 1.27ml of a 3M diethyl ether solution of methyl magnesium iodide. After stirring at room temperature for 30 minutes, water was added, and extraction was performed with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane: ethyl acetate 1: 4) to give the title compound (195 mg).

1H NMR(400MHz，CDCl3)δ：1.32(6H，s)，1.95(2H，t，J＝7.3Hz)，2.92(2H，t，J＝7.3Hz)，7.16-7.21(1H，m)，7.33(1H，s)，7.41(1H，d，J＝7.8Hz)，8.18-8.20(1H、m)

3) Preparation of 1- (4-fluorophenyl) -4- (2- (3-hydroxy-3-methyl-butyl) imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

¹H NMR(400MHz、CDCl₃)δ：1.26(6H，s)，1.99(2H，t，J＝7.6Hz)，2.49(3H，s)，2.96(2H，t，J＝7.6Hz)，7.23-7.32(2H，m)，7.45-7.54(4H，m)，7.61(1H，d，J＝9.2Hz)，8.54(1H，d，J＝1.0Hz)

ESI-MS found: m/z 380.2[ M + H ] +

(example 231)

4- (2-propyl-1-oxo-isoindolin-5-yl) -1- (2-nitro-pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 85 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 23, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.00(3H，t，J＝7.4Hz)，1.71-1.78(2H，m)，2.49(3H，s)，3.63(2H，t，J＝7.4Hz)，4.48(2H，s)，7.80(1H，d，J＝7.8Hz)，7.89-8.01(3H，m)，8.10(1H，dd，j＝1.5，7.8Hz)，8.83(1H，dd，J＝2.1，4.7Hz)

ESI-MS found: m/z 379.2[ M + H ] +

(example 232)

1- (2, 4-difluorophenyl) -4- (2- (3-hydroxy-3-methyl-butyl) imidazo [1, 2-a ] pyridin-6-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 230 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 13, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：1.31(6H，s)，1.99(2H，t，J＝7.3Hz)，2.43(3H，d，J＝1.4Hz)，2.96(2H，t，J＝7.6Hz)，7.09-7.16(2H，m)7.45(1H，s)，7.50-7.63(3H，m)，8.55(1H，d，J＝1.0Hz)

ESI-MS found: m/z 398.2[ M + H ] +

(example 233)

4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-bromo-pyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole

Using the halide obtained in example 85 and the tin reagent and tetrakis (triphenylphosphine) palladium obtained in reference example 24, the title compound was obtained as a white solid using the same method as in example 49, a method based thereon, or a combination thereof with a usual method.

¹H NMR(400MHz、CDCl₃)δ：0.89-0.99(4H，m)，2.46(3H，s)，2.94-3.02(1H，m)，4.41(2H，s)，7.55-7.79(1H，m)，7.80-7.86(2H，m)，7.94(1H，d，J＝7.8Hz)，8.00(1H，s)，8.64(1H，dd，J＝2.0，4.9Hz)

ESI-MS found: m/z 412.0[ M + H ] +

(reference example 1)

1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 3-azido-2-fluoropyridine

After a solution of 5.3ml of diisopropylamine in 100ml of tetrahydrofuran was cooled to-78 ℃ under a nitrogen atmosphere, 24ml of a 1.58M n-butyllithium/hexane solution was added dropwise to the solution. The reaction mixture was heated to 0 ℃ and stirred for 5 minutes, then cooled again to-78 ℃ and a solution of 3.7g of 2-fluoropyridine in 10ml of tetrahydrofuran was added. Stirring at-78 deg.c for 10 min, adding 10ml tetrahydrofuran solution of n-dodecyl azido phenylsulfone 8.9g, stirring, heating the reaction liquid to-60 deg.c, and adding water to terminate the reaction. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain 3.02g of the title compound as a tan crude purified product.

2) Preparation of 1- (2-fluoropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

10g of tributyl (1-propynyl) tin was added to a 10ml toluene solution of 3.02g of the compound obtained in the above 1), and the mixture was stirred at 120 ℃ for 3 hours. The resulting solution was cooled to room temperature, and then purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain 6.40g of the title compound as a yellow oil.

1H NMR(400MHz，CDCl3)δ：0.90(9H，t，J＝7.4Hz)，1.19-1.29(12H，m)，1.35-1.66(6H，m)2.28(3H，d，J＝1.6Hz)7.41-7.46(1H，m)，7.97-8.02(1H，m)，8.37-8.39(1H，m)

ESI-MS found: m/z 469.3[ M + H ] +

(reference example 2)

1- (2-fluoropyridin-3-yl) -4-tributylstannyl-1H- [1, 2, 3] triazole

To a solution of 280mg of the compound 3-azido-2-fluoropyridine obtained in reference example 1-1 in 3.0ml of toluene was added 958mg of tributyl (1-ethynyl) tin, and the reaction mixture was stirred overnight at 80 ℃ and for 2 hours at 100 ℃. The resulting solution was cooled to room temperature, and then purified by silica gel column chromatography (hexane: ethyl acetate 80: 20) to obtain 380mg of the title compound as a colorless oil.

1H NMR(300MHz，CDCl3)δ：0.90(9H，t，J＝7.3Hz)，1.03-1.43(12H，m)，1.44-1.73(6H，m)7.38-7.45(1H，m)，8.08(1H，d，J＝3.3Hz)，8.22-8.30(1H，m)，8.46-8.57(1H，m)

APCI-MS found: m/z 454.9[ M + H ] +

(reference example 3)

1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 5-azido-2-fluoropyridine

A40 ml solution of 3.5g of 5-bromo-2-fluoropyridine in diethyl ether was cooled to-78 ℃ under a nitrogen atmosphere, and 8.3ml of 2.6M n-butyllithium was added dropwise to the solution. After the reaction mixture was stirred at-78 ℃ for 10 minutes, 20ml of diethyl ether (5.1 g) of 2, 4, 6-triisopropylazidophenylsulfone was added thereto, and the mixture was stirred, and after the temperature of the reaction mixture was raised to-65 ℃, water was added thereto to terminate the reaction. The product was extracted with diethyl ether, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain 1.80g of the title compound as a tan crude purified product.

2) Preparation of 1- (2-fluoropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a solution of 1.80g of the compound obtained in the above 1) in 15ml of toluene was added 4.33g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. The resulting solution was cooled to room temperature, and then purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain 3.90g of the title compound as a yellow oil.

¹H NMR(400MHz，CDCl3)δ：0.91(9H，t，J＝7.6Hz)，1.15-1.24(6H，m)，1.30-1.42(6H，m)1.53-1.65(6H，m)，2.36(3H，t，J＝2.0Hz)7.20(1H，dd，J＝3.2，8.8Hz)，7.95-8.00(1H，m)，8.37(1H，dd，J＝0.8，2.8Hz)

ESI-MS found: m/z 469.6[ M + H ] +

(reference example 4)

1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2-fluorobenzene

A solution of 510mg of sodium nitrite dissolved in 2ml of water was added dropwise to a solution of 1.0g of 2-fluorophenylhydrazine hydrochloride in 5ml of concentrated hydrochloric acid and 6ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 400mg of the crude title compound as a brown oil.

2) Preparation of 1- (2-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a solution of 400mg of the compound obtained in 1) in 5ml of toluene was added 2.9g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ for 4.5 hours. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give 680mg of the title compound as a yellow oil.

1H NMR(300MHz，CDCl3)δ：0.90(9H，t，J＝7.5Hz)，1.19-1.29(12H，m)，1.35-1.66(6H，m)2.32(3H，s)，7.19-7.24(2H，m)，7.42-7.49(2H，m)

APCI-MS found: m/z 468.5[ M + H ] +

(reference example 5)

1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of azidobenzene

A solution of 4.1g of sodium nitrite dissolved in 5ml of water was added dropwise to a solution of 5ml of phenylhydrazine in 50ml of concentrated hydrochloric acid and 15ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate, washed with water and then saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 3.2g of the crude title compound as a brown oil.

2) Preparation of 1-phenyl-5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 1ml of a toluene solution of 120mg of the compound obtained in 1) was added 1.7g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ for 12 hours. After cooling the resulting solution to room temperature, the reaction solution was purified directly by silica gel column chromatography (hexane: ethyl acetate 90: 10) to obtain 246mg of the title compound as a yellow oil.

1H NMR(300MHz，CDCl3)δ：0.90(9H，t，J＝7.5Hz)，1.15-1.42(12H，m)，1.54-1.66(6H，m)2.32(3H，s)，7.42-7.59(5H，m)

ESI-MS found: m/z 450.1[ M + H ] +

(reference example 6)

1- (3-pyridyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 3-azidopyridine

A solution of sodium azide (1.5 g) dissolved in water (5 ml) was added dropwise to a 10% hydrochloric acid (15 ml) solution of 3-aminopyridine (2.0 g) under ice cooling. After stirring for 20 minutes under ice cooling, a solution of sodium nitrite 1.8g dissolved in 5ml of water was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with chloroform, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.5g of the crude title compound as a brown oil.

2) Preparation of 1- (3-pyridyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a 10ml toluene solution of 800mg of the compound obtained in 1) was added 1.2g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ for 6 hours. After the resulting solution was cooled to room temperature, the solvent was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane: diethyl ether: 90: 10) to obtain 610mg of the title compound as a yellow oil.

¹H NMR(400MHz，CDCl3)δ：0.91(9H，t，J＝7.5Hz)，1、20-1.41(12H，m)，1.56-1.62(6H，m)2.38(3H，s)，7.49-7.53(1H，m)，7.86-7.89(1H，m)，8.74-8.74(1H，m)，8.74-8.78(1H，m)

ESI-MS found: m/z 451.1[ M + H ] +

(reference example 7)

1- (2-chloropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 3-azido-2-chloropyridine

Under a nitrogen atmosphere, 7.0ml of a tetrahydrofuran solution of 1.4ml of diisopropylamine was cooled to-78 ℃ and 6.3ml of a 1.58M n-butyllithium/hexane solution was added dropwise to the solution. The reaction mixture was heated to 0 ℃ and stirred for 5 minutes, then cooled again to-78 ℃ and a solution of 1.13g of 2-chloropyridine in 5.0ml of tetrahydrofuran was added. After the reaction mixture was stirred at-78 ℃ for 10 minutes, 7.0ml of tetrahydrofuran solution containing 1.62g of 2, 4, 6-triisopropylazidophenylsulfone was added thereto, and the mixture was stirred, and after the temperature of the reaction mixture was raised to-60 ℃, water was added thereto to terminate the reaction. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 80: 20) to obtain 1.02g of the title compound as a tan crude purified product.

2) Preparation of 1- (2-chloropyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a solution of 685mg of the compound obtained in the above 1) in 4.0ml of toluene was added 1.65g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. The resulting solution was cooled to room temperature, and then purified by silica gel column chromatography (hexane: ethyl acetate 80: 20) to obtain 1.10g of the title compound as a yellow oil.

1H NMR(400MHz，CDCl3)δ：0.90(9H，t，J＝8.0Hz)，1.16-1.40(12H，m)，1.50-1.67(6H，m)2.23(3H，s)7.45-7.50(1H，m)，7.79-7.83(1H，m)，8.70-8.60(1H，m)

(reference example 8)

1- (2-fluoropyridin-6-yl) -4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 6-azido-2-fluorobenzene

A solution of 325mg of sodium nitrite dissolved in 3ml of water was added dropwise to a solution of 10ml of concentrated hydrochloric acid (500 mg of 6-fluorophenylhydrazine hydrochloride) and 6ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2.5 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 424mg of the crude title compound as a brown oil.

2) Preparation of 1- (2-fluoropyridin-6-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 2ml of a toluene solution of 424mg of the compound obtained in 1) was added 1.32g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ for 4 hours. The resulting solution was cooled to room temperature, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: 90: 10) to give 910mg of the title compound as a yellow oil.

1H NMR(300MHz，CDCl3)δ：0.90(9H，t，J＝7.3Hz)，1.16-1.40(12H，m)，1.43-1.70(6H，m)2.67(3H，s)，6.92-6.99(1H，m)，7.95-8.02(2H，m)

(reference example 9)

1- (2-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2-methylbenzene

A solution of 1.7g of sodium nitrite dissolved in 10ml of water was added dropwise to a solution of 20ml of concentrated hydrochloric acid (3.5 g of 2-methylphenylhydrazine hydrochloride) and 35ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2g of the crude title compound as a brown oil.

2) Preparation of 1- (2-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 1g of the compound obtained in 1) was added 1.9ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound (2.0 g) as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.2Hz)，1.15-1.65(18H，m)，2.00(3H，s)，2.13(3H，t，1.8Hz)，7.20-7.24(1H，m)，7.32-7.43(3H，m)

ESI-MS found: m/z 468.0[ M + H ] +

(reference example 10)

1- (3-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-3-methylbenzene

A solution of 2.6g of sodium nitrite dissolved in 5ml of water was added dropwise to a solution of 16ml of concentrated hydrochloric acid (2.5 g of 3-methylphenylhydrazine hydrochloride) and 25ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.2g of the crude title compound as a brown oil.

2) Preparation of 1- (3-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 780mg of the compound obtained in 1) was added 1.6ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound 620mg as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.4Hz)，1.16-1.64(18H，m)，2.32(3H，t，2.0Hz)，2.43(3H，s)，7.21-7.29(3H，m)，7.37-7.42(1H，m)

ESI-MS found: m/z 468.0[ M + H ] +

(reference example 11)

1- (3-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-3-fluorobenzene

A solution of 2.5g of sodium nitrite dissolved in 30ml of water was added dropwise to a solution of 4.8g of concentrated hydrochloric acid (30 ml) and diethyl ether (50 ml) of 3-fluorophenylhydrazine hydrochloride under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2g of the crude title compound as a brown oil.

2) Preparation of 1- (3-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 2g of the compound obtained in 1) was added 3.8ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound (2.7 g) as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.4Hz)，1.16-1.65(18H，m)，2.35(3H，t，2.0Hz)，7.16-7.34(3H，m)，7.47-7.54(1H，m)

ESI-MS found: m/z 467.9[ M + H ] +

(reference example 12)

1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-4-fluorobenzene

A solution of sodium nitrite (2.5 g) dissolved in water (30 ml) was added dropwise to a solution of 4.8g of 4-fluorophenylhydrazine hydrochloride (30 ml) in concentrated hydrochloric acid (30 ml) and diethyl ether (50 ml) under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.9g of the crude title compound as a brown oil.

2) Preparation of 1- (4-fluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 1.9g of the compound obtained in 1) was added 3.6ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound (2.3 g) as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.4Hz)，1.15-1.65(18H，m)，2.32(3H，t，2.0Hz)，7.21(2H，dd，J＝8.2，9.0Hz)，7.44(2H，dd，J＝4.6，9.0Hz)

ESI-MS found: m/z 467.9[ M + H ] +

(reference example 13)

1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2, 4-difluorobenzene

A solution of 2.2g of sodium nitrite dissolved in 5ml of water was added dropwise to a solution of 2g of 2, 4-difluorophenylhydrazine hydrochloride in 13ml of concentrated hydrochloric acid and 25ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.7g of the crude title compound as a brown oil.

2) Preparation of 1- (2, 4-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 1.7g of the compound obtained in 1) was added 3.4ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give 3.1g of the title compound as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.4Hz)，1.17-1.65(18H，m)，2.23-2.25(3H，m)，7.01-7.09(2H，m)，7.46-7.53(1H，m)

ESI-MS found: m/z 490.0[ M + H ] +

(reference example 14)

1- (4-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-4-methylbenzene

A solution of sodium nitrite (2.5 g) dissolved in water (30 ml) was added dropwise to a solution of 4-methylphenylhydrazine hydrochloride (4.8 g) in concentrated hydrochloric acid (30 ml) and diethyl ether (50 ml) under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.1g of the crude title compound as a brown oil.

2) Preparation of 1- (4-methylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 620mg of the compound obtained in 1) was added 1.3ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound 690mg as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.2Hz)，1.15-1.65(18H，m)，2.31(3H，t，1.8Hz)，2.43(3H，s)，7.32(4H，d，J＝2.4Hz)

ESI-MS found: m/z 468.0[ M + H ] +

(reference example 15)

1- (2-trifluoromethyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2-trifluoromethyl-benzene

A solution of 1.9g of sodium nitrite dissolved in 8ml of water was added dropwise to a solution of 7.5ml of concentrated hydrochloric acid (1.8 g of 2-trifluoromethyl-aniline), 10ml of water and 35ml of ethanol under ice cooling. After stirring for 30 minutes under ice cooling, a solution prepared by dissolving 2.0g of sodium azide in 8ml of water was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was neutralized with sodium bicarbonate, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.5g of the crude title compound as a brown oil.

2) Preparation of 1- (2-trifluoromethyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 0.7g of the compound obtained in 1) was added 1.5ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give 0.9g of the title compound as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.2Hz)，1.16-1.64(18H，m)，2.13(3H，t，J＝2.0Hz)，7.37(1H，d，J＝7.6Hz)，7.66-7.76(2H，m)，7.84-7.89(1H，m)

ESI-MS found: m/z 517.9[ M + H ] +

(reference example 16)

1- (4-chloro-2-fluorobenzen-6-yl) -4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 6-azido-4-chloro-2-fluorobenzene

10ml of ethanol, 4ml of water and 4ml of concentrated hydrochloric acid were added to 728mg of 4-chloro-2-fluoroaniline under ice cooling, and after cooling to 0 ℃, a solution in which 380mg of sodium nitrite was dissolved in 4ml of water was added. After stirring at room temperature for 1 hour, it was cooled again to 0 ℃ and a solution of 390mg of sodium azide dissolved in 4ml of water was added. After stirring overnight at room temperature, the product was extracted with ether, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give the crude title compound.

2) Preparation of 1- (4-chloro-2-fluoropyridin-6-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 4ml of a toluene solution of the compound obtained in 1) was added 1.65g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ for 4 hours. The resulting solution was cooled to room temperature. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate: 80: 20) to give 1.29g of the title compound as a yellow oil.

1H NMR(300MHz，CDCl3)δ：0.90(9H，t，J＝7.3Hz)，1.08-1.42(12H，m)，1.43-1.72(6H，m)2.24(3H，d，J＝1.7Hz)，7.29-7.49(3H，m)

(reference example 17)

1- (4-fluoro-2-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-4-fluoro-2-methyl-benzene

A solution of 2.9g of sodium nitrite dissolved in 11ml of water was added to a solution of 9.3ml of concentrated hydrochloric acid (2.5 g of 4-fluoro-2-methyl-aniline), 14ml of water and 50ml of ethanol under ice cooling. After stirring for 30 minutes under ice cooling, a solution of 3.0g of sodium azide dissolved in 11ml of water was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was neutralized with sodium bicarbonate, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.3g of the crude title compound as a brown oil.

2) Preparation of 1- (4-fluoro-2-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a 10ml toluene solution of 1.5g of the compound obtained in 1) was added 3.0ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound (2.1 g) as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.86(9H，t，J＝7.2Hz)，1.13-1.62(18H，m)，1.96(3H，s)，2.10(3H，t，J＝1.8Hz)，6.95-7.07(2H，m)，7.18(1H，dd，J＝5.2，8.8Hz)

ESI-MS found: m/z 482.3[ M + H ] +

(reference example 18)

1- (2, 6-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2, 6-difluorobenzene

A solution of 2.9g of sodium nitrite dissolved in 11ml of water was added dropwise to a solution of 9.3ml of concentrated hydrochloric acid (2.5 g of 2, 6-difluoroaniline), 14ml of water and 50ml of ethanol under ice cooling. After stirring for 30 minutes under ice cooling, a solution of 3.0g of sodium azide dissolved in 11ml of water was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was neutralized with sodium bicarbonate, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.1g of the crude title compound as a brown oil.

2) Preparation of 1- (2, 6-difluorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a 10ml toluene solution of 1.6g of the compound obtained in 1) was added 3.0ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound (2.8 g) as a yellow oil.

ESI-MS found: m/z 486.2[ M + H ] +

(reference example 19)

1- (2-fluoro-4-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2-fluoro-4-methyl-benzene

A solution of 2.9g of sodium nitrite dissolved in 11ml of water was added dropwise to a solution of 9.3ml of concentrated hydrochloric acid (2.5 g of 2-fluoro-4-methyl-aniline), 14ml of water and 50ml of ethanol under ice cooling. After stirring for 30 minutes under ice cooling, a solution of 3.0g of sodium azide dissolved in 11ml of water was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was neutralized with sodium bicarbonate, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.6g of the crude title compound as a brown oil.

2) Preparation of 1- (2-fluoro-4-methyl-phenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a 10ml solution of 1.0g of the compound obtained in 1) in toluene was added 2.0ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give 1.8g of the title compound as a yellow oil.

ESI-MS found: m/z 482.3[ M + H ] +

(reference example 20)

1- (2-ethylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2-ethylbenzene

A solution of 1.7g of sodium nitrite dissolved in 20ml of water was added dropwise to a solution of 3.5g of 2-ethylphenylhydrazine hydrochloride in 20ml of concentrated hydrochloric acid and 35ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 2.2g of the crude title compound as a brown oil.

2) Preparation of 1- (2-ethylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 1.0g of the compound obtained in 1) was added 1.9ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give the title compound (2.0 g) as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.2Hz)，1.05(3H，t，J＝7.6Hz)，1.17-1.65(18H，m)，2.14(3H，t，2.0Hz)，2.31(2H，q，J＝7.7Hz)，7.19(1H，dd，J＝1.0，7.8Hz)，7.33(1H，dd，J＝1.6，7.6Hz)，7.39-7.49(2H，m)

ESI-MS found: m/z 478.3[ M + H ] +

(reference example 21)

1- (2-isopropylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2-isopropylbenzene

A solution of 2.9g of sodium nitrite dissolved in 11ml of water was added dropwise to a solution of 9.3ml of concentrated hydrochloric acid (2.6 g of 2-isopropylaniline), 14ml of water and 50ml of ethanol under ice cooling. After stirring for 30 minutes under ice cooling, a solution of 3.0g of sodium azide dissolved in 11ml of water was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was neutralized with sodium bicarbonate, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.7g of the crude title compound as a brown oil.

2) Preparation of 1- (2-isopropylphenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 1.0g of the compound obtained in 1) was added 1.7ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give 1.1g of the title compound as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.90(9H，t，J＝7.4Hz)，1.13(6H，d，J＝7.2Hz)，1.17-1.65(18H，m)，2.12(3H，t，1.8Hz)，2.37-2.45(1H，m)，7.14-7.19(1H，m)，7.29-7.34(1H，m)，7.47-7.51(2H，m)

ESI-MS found: m/z 492.3[ M + H ] +

Reference example 22

1- (thien-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 3-azidothiophene

A solution of 11ml of water in which 2.9g of sodium nitrite was dissolved was added dropwise to a solution of 1.8g of 3-aminothiophene in 9.3ml of concentrated hydrochloric acid, 14ml of water and 50ml of ethanol under ice cooling. After stirring for 30 minutes under ice cooling, a solution of 3.0g of sodium azide dissolved in 11ml of water was added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was neutralized with sodium bicarbonate, extracted with chloroform, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.3g of the crude title compound as a brown oil.

2) Preparation of 1- (thien-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To 5ml of a toluene solution of 1.0g of the compound obtained in 1) was added 1.5ml of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 90: 10) to give 1.0g of the title compound as a yellow oil.

ESI-MS found: m/z 456.2[ M + H ] +

(reference example 23)

1- (2-nitropyridin-5-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

To a 6ml solution of 1.29g of 5-azido-2-nitropyridine in toluene was added 5.89g of tributyl (1-propynyl) tin, and the mixture was stirred at 120 ℃ overnight. The resulting solution was cooled to room temperature, and then purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain the title compound 962mg as a yellow oil.

1H NMR(400MHz，CDCl3)δ：0.91(9H，t，J＝8.0Hz)，1.12-1.28(6H，m)，1.29-1.40(6H，m)1.51-1.65(6H，m)，2.26(3H，s)7.81-7.86(1H，m)，7.99-8.03(1H，m)，8.72-8.76(1H，m)

Reference example 24

1- (2-bromopyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 3-azido-2-bromopyridine

Under a nitrogen atmosphere, a 10ml solution of 0.53ml of tetrahydrofuran of diisopropylamine was cooled to-78 ℃ and 2.3ml of a 1.58M n-butyllithium/hexane solution was added dropwise to the solution. The reaction mixture was heated to 0 ℃ and stirred for 5 minutes, then cooled again to-78 ℃ and 1.0ml of 2-bromopyridine 569mg of tetrahydrofuran was added. After the reaction solution was stirred at-78 ℃ for 10 minutes, 1.05g of tetrahydrofuran solution (1.0 ml) was added thereto, and the reaction solution was stirred, and after the temperature of the reaction solution was raised to-60 ℃, water was added to terminate the reaction. The product was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane: ethyl acetate: 90: 10) to obtain a dark brown crude purified product of the title compound.

2) Preparation of 1- (2-bromopyridin-3-yl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

Tributyl (1-propynyl) tin 987mg was added to a toluene 2.0ml solution of the compound obtained in the above 1), and the mixture was stirred at 120 ℃ for 3 hours. The resulting solution was cooled to room temperature, and then purified by silica gel column chromatography (hexane: ethyl acetate 75: 25) to obtain 190mg of the title compound as a yellow oil.

1H NMR(400MHz，CDCl3)δ：0.90(9H，t，J＝8.0Hz)，1.12-1.40(12H，m)，1.48-1.68(6H，m)2.22(3H，s)7.46-7.51(1H，m)，7.73-7.77(1H，m)，8.55-8.58(1H，m)

(reference example 25)

1- (2-chlorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

1) Preparation of 1-azido-2-chlorobenzene

A solution of 8.28g of sodium nitrite dissolved in 50ml of water was added dropwise to a solution of 17.9g of 2-chlorophenylhydrazine hydrochloride in 100ml of concentrated hydrochloric acid and 150ml of diethyl ether under ice cooling. The reaction mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 16g of the crude title compound as a brown oil.

2) Preparation of 1- (2-chlorophenyl) -5-methyl-4-tributylstannyl-1H- [1, 2, 3] triazole

12g of tributyl (1-propynyl) tin was added to a solution of 16g of the compound obtained in 1) in 20ml of toluene, and the mixture was stirred at 120 ℃ for 6 hours. After cooling the resulting solution to room temperature, a saturated aqueous potassium fluoride solution was added to the reaction mixture, which was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate 9: 1) to give 10g of the title compound as a yellow oil.

¹H NMR(400MHz、CDCl₃)δ：0.86(9H，m)，1.11-1.22(6H，m)，1.31-1.40(6H，m)，1.51-1.66(6H，m)，2.18(3H，s)，7.41-7.51(3H，m)，7.58(1H，d，J＝8.0Hz)

ESI-MS found: m/z 484.1[ M + H ] +

Pharmacological test examples in which the compound according to the present invention was used as a test compound are shown below.

Pharmacological test example 1 mGluR1 inhibitory Effect Using the compounds of the present invention, mGluR1 inhibitory effect was measured.

(cell culture)

A mGluR1a stable expression strain was obtained by transfecting cDNA of human metabotropic glutamate receptor 1a (mGluR1a) into CHO cells using LIPOFECTAMINE (GibcoBRL Co., Ltd.). CHO cells expressing mGluR1a were cultured in DMEM medium containing 10% dialyzed fetal calf serum, 1% proline, 100 units/ml penicillin, 0.1mg/ml streptomycin sulfate, 2mM glutamine.

(intracellular calcium concentration measurement)

On the day before the measurement, mGluR1 a-expressing CHO cells were plated in a 96-well plate (ViewPlate, Packard Co.) at a density of 50000 cells per well, and 4. mu.M Fluo-3 was added thereto in CO₂Culturing in an incubator for 1 hour. Then, the cells were washed 4 times with HBSS solution containing 20mM HEPES and 2.5mM Probenecid, and then the intracellular calcium concentration was measured using a fluorescent microplate reader (FLIPR, manufactured by Mollerular Device Co.). The test compound and glutamic acid were prepared in HBSS solution containing 20mM HEPES and 2.5mM Probenecid. Test compounds were added 5 minutes before agonist stimulation, using 10 μ M glutamate.

As a result, with respect to mGluR1, the compounds related to the present invention described in table 1 below did not show agonist properties at 10 μ M or less. The increase in calcium by 10. mu.M glutamic acid was inhibited in a dose-dependent manner.

(Table 1)

	IC50(nM)
	IC50(nM)	Example 34	2.3
Example 36	6.5	Example 34	2.3
Example 36	6.5	Example 49	3.2
Example 85	4.4	Example 49	3.2
Example 85	4.4	Example 87	4.3
Example 119	4.3	Example 87	4.3
Example 119	4.3	Example 151	2.5
Example 181	18	Example 151	2.5
Example 181	18	Example 204	3.4
Example 227	2.4	Example 204	3.4

As animal models in which conventional antipsychotic drugs including haloperidol and risperidone have been shown to act, a model in which spontaneous motility is increased and a model in which prepulse inhibition is decreased by administration of methamphetamine are known. In both test systems, the effect of agents with mGluR1 antagonism was investigated.

(pharmacological test example 2 inhibitory Effect of the Compound on the increase in spontaneous motility of mice caused by methamphetamine)

The amount of activity was measured using male ICR (CD-1) mice (20 to 40g) using an activity measuring device (Neuroscience) which senses the movement of an animal using an infrared sensor. The compound or an appropriate solvent was administered to mice, and after 30 minutes, physiological saline or 2mg/kg methamphetamine was administered, and the activity level was measured between 60 minutes after administration. The difference between the amount of exercise of the methamphetamine-administered group and the amount of exercise of the solvent-administered group during the measurement period was defined as 100%, and the amount of exercise of the test compound group was expressed as% inhibition. By subcutaneous administration of methamphetamine, the amount of activity increased significantly between 60 minutes after administration. By orally administering the compound having mGluR1 antagonistic effect (3mg/kg) according to the present invention before administration of methamphetamine for 30 minutes, the amount of activity induced by methamphetamine was significantly inhibited. The results are shown in Table 2.

From these results, it is understood that the compound of the present invention or a pharmaceutically acceptable salt thereof exhibits a significant antagonistic action against the spontaneous hyperactivity induced by methamphetamine.

(Table 2)

EXAMPLES Compounds	Amount of exercise (suppression%)
EXAMPLES Compounds	Amount of exercise (suppression%)	Example 34	＞50％
Example 36	＞50％	Example 34	＞50％
Example 36	＞50％	Example 49	＞50％
Example 85	＞50％	Example 49	＞50％
Example 85	＞50％	Example 87	＞50％
Example 119	＞50％	Example 87	＞50％
Example 119	＞50％	Example 151	＞50％
Example 181	＞50％	Example 151	＞50％
Example 181	＞50％	Example 204	＞50％
Example 227	＞50％	Example 204	＞50％

(pharmacological test example 3: inhibitory Effect of the Compound on the reduction of inhibition of prepulse inhibition by methamphetamine)

Assays for the specific detection of prepulse inhibition of antipsychotic action have also been investigated. The startle reflex at the time of stimulus administration was measured by combining the startle reflex for the acoustic stimulus of 120dB (pulse stimulus) and the acoustic stimuli of 63, 66 and 72dB (pre-pulse) prior to the pulse stimulus in the presence of a background sound of 60dB using a startle reflex measuring device (manufactured by San Diego instruments) that senses the physical activity of rats. The compound of the present invention or an appropriate solvent is administered to rats, and after 30 minutes, physiological saline or 3mg/kg methamphetamine is administered to the rats to measure the startle reflex. The startle reflex at the time of pulse stimulation and at the time of the presence of a prepulse were set to A, B in this order, and the value of prepulse inhibition (hereinafter referred to as PPI) was calculated by the following calculation formula.

The PPI calculation method comprises the following steps: PPI (%) < 100 × (A-B)/A

The startle reflex to the pulse stimulation is reduced to about 50% in the presence of 72dB of preceding pre-pulse (pre-pulse suppression). The startle reflex after pre-treatment with methamphetamine was only reduced by about 20% without a reduction in pre-pulse suppression. In the model, the compound (1-10 mg/kg) having mGluR1 antagonistic action is orally administered 30 minutes before the administration of methamphetamine, and the reduction of prepulse caused by methamphetamine tends to be recovered. The compounds showed significant inhibitory effect on reduction of PPI by methamphetamine, the results of which are shown in table 3.

From these results, it is clear that the compound of the present invention restores the methamphetamine-induced PPI disorder.

(Table 3)

EXAMPLES Compounds	Inhibitory effect on PPI disorder
EXAMPLES Compounds	Inhibitory effect on PPI disorder	Example 34	Is effective
Example 36	Is effective	Example 34	Is effective
Example 36	Is effective	Example 49	Is effective
Example 85	Is effective	Example 49	Is effective
Example 85	Is effective	Example 87	Is effective
Example 119	Is effective	Example 87	Is effective
Example 119	Is effective	Example 151	Is effective
Example 181	Is effective	Example 151	Is effective
Example 181	Is effective	Example 204	Is effective
Example 227	Is effective	Example 204	Is effective

From the results of the above pharmacological test examples 2 and 3, it was confirmed that the compound having mGluR1 antagonistic activity according to the present invention has an action similar to that of a schizophrenia drug in an animal model showing an action of a schizophrenia therapeutic drug represented by haloperidol and risperidone.

Accordingly, the compounds to which the present invention relates, which have mGluR1 antagonistic action, may prove to be useful agents for the treatment and/or prevention of schizophrenia.

Industrial applicability

The invention may be achieved by novel substances having mGluR1 antagonism.

The diaryl substituted 5-membered hetero ring derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof has a potent mGluR1 inhibitory activity and is useful for the prevention or treatment of mental disorders such as spasticity, acute pain, inflammatory pain, chronic pain, cerebral infarction, cerebral injury caused by transient ischemic attack, schizophrenia and the like, anxiety, drug dependence, Parkinson's disease, gastrointestinal disorders.

Claims

1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,

in the formula, X₁Represents an oxygen atom, a nitrogen atom or CR²，

X₂Represents a nitrogen atom or a carbon atom,

X₃represents a nitrogen atom or a carbon atom,

X₄represents a nitrogen atom or a carbon atom,

R¹represents the following formula (II-1):

in the formula, -X₅-represents-S-or-A₄＝A₃-，A₁Represents a carbon atom or a nitrogen atom, A₂～A₄Is CR in its entirety⁴Or A is₂～A₄Any 1 or 2 of (A) represents a nitrogen atom, A₂～A₄The remaining 2 or 1 of (a) represent CR⁴，

In A₁When it is a carbon atom, it represents a double bond, A₁And represents a single bond when it is a nitrogen atom,

R⁴represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a mono-or di-lower alkylamino group, a hydroxyl group, a lower alkoxycarbonyl group, a carbamoyl group or a mono-or di-lower alkylcarbamoylamino group,

(1) the constituent atoms of the A ring being all carbon atoms, a saturated, partially saturated or unsaturated 5-or 6-membered ring which may be substituted by 1 or 2 oxy groups, or

(2) As constituent atoms of the A ring, a saturated, partially saturated or unsaturated 5-or 6-membered ring which may have 1 to 3 hetero atoms selected from N, S and O in the ring, other than carbon atoms, and which may be substituted with 1 or 2 oxo groups,

R³represents a group (A) or (B) which may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group which may be substituted by a halogen atom, a cyano group, a nitro group, a lower alkoxy group, a hydroxyl group and an amino group，

(A) Phenyl radical

(B) A 5-or 6-membered unsaturated or partially saturated heterocyclic group having 1 to 3 heteroatoms selected from N, S and O in the ring,

however, the compounds represented by the formula (1) do not include 4- [5- (2-naphthyl) -1H- [1, 2, 4] triazol-3-yl ] -pyridine, 3- (1, 3-benzodioxol-5-yl) -5- (2-ethylphenyl) -1H-1, 2, 4-triazole, 6- [5- (4-pyridyl) -1H-1, 2, 4 triazol-4-yl ] -quinoline, 3- [ 5-phenyl-4H- [1, 2, 4] triazol-3-yl ] naphthalen-2-ol, 3- [ 5-pyridin-4-yl-1H- [1, 2, 4] triazol-3-yl ] -naphthalen-2-ol, and, 5- (quinolin-2-yl) -2- (3-cyano-phenyl) -tetrazole, 3- [5- (3, 5-dichloropyridin-4-yl) -2-methyl-2H- [1, 2, 4] triazol-3-yl ] -quinoline, 3-naphthalen-2-yl-5-phenyl-4H- [1, 2, 4] triazole, 3-benzo [1, 3] dioxan-5-yl-1-methyl-5-o-tolyl-1H- [1, 2, 4] triazole, 5- (5-phenyl-4H- [1, 2, 4] triazol-3-yl) isobenzofuran-1, a 3-diketone of a ketone having a structure,

Substituent group α: lower alkyl, cycloalkyl whose arbitrary 1 carbon atom constituting it may be substituted by an oxygen atom, lower alkoxy, a halogen atom, mono-or di-lower alkylamino, alkanoyl, alkylsulfonyl, lower alkoxycarbonyl, carbamoyl, mono-or di-lower alkylcarbamoyl, amino and hydroxy;

the lower alkyl group may be substituted with a hydroxyl group, a halogen atom, an aryl group, a di-lower alkylamino group, a lower alkoxy group, an oxy group, a lower alkoxycarbonyl group, an alkanoyloxy group or a lower alkylsulfonylamino group, the di-lower alkyl groups may be bonded to each other, they may form an aliphatic heterocyclic ring of 5 to 7 members together with a nitrogen atom, or 1 carbon atom constituting the aliphatic heterocyclic ring may be substituted with an oxygen atom; when the lower alkyl is branched lower alkyl, the branched alkyl can be combined with each other to form a cycloalkyl or cycloalkylene with 3-6 carbon atoms; when the lower alkyl is branched lower alkyl, the branched alkyl groups can be combined with each other to form a cycloalkyl group with 3-6 carbon atoms which can be substituted by lower alkyl, hydroxy, aralkyl or lower alkoxy; when the same carbon atom constituting the a ring has 2 lower alkyl groups, the lower alkyl groups may together form a cycloalkyl group.

2. The compound of claim 1, wherein formula (I) is formula (I-1): or a pharmaceutically acceptable salt thereof,

Formula (I-2),

Formula (I-3),

Formula (I-4),

In the formula, the symbols are the same as those described above.

3. A compound or pharmaceutically acceptable salt thereof as claimed in claim 1 or 2 wherein R¹Is of the formula (II-A)

In the formula, the symbols are the same as those described above.

4. The compound according to claim 3, wherein the formula (II-B) in the formula (II-A) is phenyl, or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3 or 4, wherein the A ring has at least 1 nitrogen atom as a constituent atom of the A ring, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 3, wherein formula (II-a) is formula (II-C), or a pharmaceutically acceptable salt thereof

Or formula (II-D)

The group may have 1 to 3 substituents selected from the above substituent group a which may have an A ring,

in the formula, X₆Represents CH₂CH or CH₂-CH₂，X₇～X₁₀One of them is a nitrogen atom and the others represent carbon atoms.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein formula (II-a) is formula (II-C).

8. The compound of claim 6, or a pharmaceutically acceptable salt thereof, wherein formula (II-a) is formula (II-D).

9. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein formula (I) is formula (I-1) or formula (I-4), but does not include R ¹In the case of a substituted or unsubstituted naphthyl group.

10. The compound according to claim 1, wherein the compound represented by formula (I) is:

5-methyl-1-phenyl-4- (quinolin-6-yl) -1H- [1, 2, 3] triazole,

5-methyl-4- (1-oxo-indan-5-yl) -1-phenyl-1H- [1, 2, 3] triazole,

5-methyl-4- (2-methylbenzothiazol-5-yl) -1-phenyl-1H- [1, 2, 3] triazole,

4- (1H-indol-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

5-methyl-4- (naphthalen-2-yl) -5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -5-methyl-4-quinazolin-6-yl) -1H- [1, 2, 3] triazole,

4- (2, 2-dimethyl-1-oxo-indan-5-yl) -5-methyl-1-phenyl-1H- [1, 2, 3] triazole,

5-methyl-4- (4-oxo-4H-chromen-6-yl) -1-phenyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin 3-yl) -4-isoquinolin-7-yl-5-methyl-1H- [1, 2, 3] triazole,

1- (2-fluoropyridin-3-yl) -4-isoquinolin-3-yl-5-methyl-1H- [1, 2, 3] triazole,

([1, 8] naphthyridin-3-yl) -4-phenyl-5-methyl-1H- [1, 2, 3] triazole,

11. The compound according to claim 1, wherein the compound represented by formula (I) is 1- (2-fluoropyridin-3-yl) -5-methyl-4- (1-oxoindan-2-spiro-1' -cyclopropyl-5-yl) -1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1, wherein the compound represented by formula (I) is 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1, wherein the compound represented by formula (I) is 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluoropyridin-3-yl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, wherein the compound represented by formula (I) is 1- (2-fluoropyridin-3-yl) -5-methyl-4- (2-propyl-1-oxo-isoindolin-5-yl) -1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1, wherein the compound represented by formula (I) is 4- (2-cyclopropyl-1-oxo-isoindolin-5-yl) -1- (2-fluorophen-3-yl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1, wherein the compound represented by formula (I) is 4- (2-isopropyl-1-oxo-isoindolin-5-yl) -1- (2, 4-difluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1, wherein the compound represented by formula (I) is 4- (2- (2, 2-difluoroethyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1, wherein the compound represented by formula (I) is 4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoindolin-5-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1, wherein the compound represented by formula (I) is 4- (2- (2-hydroxy-2-methyl-propyl) -1-oxo-isoquinolin-6-yl) -1- (4-fluorophenyl) -5-methyl-1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1, wherein the compound represented by formula (I) is 1- (4-fluorophenyl) -5-methyl-4- (2- (2-hydroxy-2-methyl-propyl) -quinolin-6-yl) -1H- [1, 2, 3] triazole, or a pharmaceutically acceptable salt thereof.

An mGluR1 inhibitor comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.

22. A therapeutic and/or prophylactic agent for mental disorders such as spasticity, acute pain, inflammatory pain, chronic pain, cerebral infarction, or brain injury caused by transient ischemic attack, schizophrenia, anxiety, drug dependence, parkinson's disease, or gastrointestinal disorders, which comprises the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.